Table 2.7.

6 List of clinical trials

Type of test Conducting a Where the Purpose of the test Test design Test drug, method of Number of Healthy subjects Dosing period Progress of the
(Handling of clinical test and administration subjects or test
materials) trial report is Type of Route of administration at Name of Type of report
Plan number attached control primary patient's
registrat diagnosis
ion
(Example)
Late phase II ONO-8025-06 Submit on Dose-response studies Double-blind 0.1, 0.2, 0.5 mg/day (tablets) 401 Overactive 12 weeks Completed
trials first and placebo-controlled Randomisation Twice daily, orally bladder patients Final report
(Reference) applicatio efficacy testing between Addendum
n parallel
groups
Placebo
comparison
Phase III ONO-8025-08 Submit on Verification of Double-blind 0.2 mg/day (tablets), twice a 781 Overactive 12 weeks Completed
comparative first superiority to placebo Randomisation day bladder patients Final report
study applicatio and non-inferiority to between Oral administration
(Reference) n propiverine parallel
hydrochloride groups
- 242 -

Placebo and
Real drug
control
comparison
Increasing KRP197-T301 5.3.3.5 Safety during long-term Unblinded 0.2 mg/day continuous group 435 Overactive 0.2 mg/day Completed
doses and long- /ONO-8025-12 (Populatio administration and 2 doses (tablets) bladder patients continuous Interim report
term n Efficacy study Uncontrolled 0.1 mg twice a day, orally group: 52 weeks Final report
administration pharmacoki 0.4 mg/day
Tests netic 0.4 mg/day increased dose increased dose
(Evaluation analysis) group (tablets) group: 64 weeks
materials) 5.3.5.2 0.1 mg b.i.d. for 12 weeks, (52 weeks after
then 0.2 mg b.i.d., orally 0.4 mg/day
increase)
Long-term ONO-8025-07 Submit on Study of safety and Unblinded 0.2 mg/day (tablets), twice a 481 Overactive 52 weeks Completed
administration first efficacy during long- Uncontrolled day bladder patients Final report
study applicatio term administration Oral administration
(Reference) n

tests
2.7.6 Summary of i
 2.7.6 Summary of the individual tests

ONO-8025 Late Phase II double-blind, placebo-controlled, dose-response study in

patients with overactive bladder [ONO-8025-06].
(1) Outline of the test
Title of the ONO-8025 Late phase II double-blind placebo-controlled dose-response study in
clinical trial patients with overactive bladder
Clinical trial
ONO-8025-06
protocol number
Clinical trial
Ono Pharmaceutical Industry Co.
sponsors
Principal Toshiaki Kawaguchi, Department of Urology, Hirosaki University School of
Investigator Medicine, and others (64 persons in total)
Clinical trial sites Hirosaki University School of Medicine, Department of Urology and others (Total
64 facilities)
Trial Period 30 October 2001 (date of obtaining consent for the first case)
30 October 2002 (date of last medication in last case)
Development phase Late Phase II
Objective To investigate the efficacy and safety of three doses of ONO-8025 in patients
with overactive bladder by means of a placebo-controlled, multicentre, double-
blind, randomised controlled study; to examine the dose-response of ONO-8025
and to test the efficacy of the clinical dose in comparison with placebo.
Test design Multicentre, double-blind, placebo-controlled
Clinical Trial Patients with overactive bladder were orally administered placebo twice
Method daily after breakfast and after dinner in a single-blind fashion during the
observation phase (2 weeks) and in a double-blind fashion during the
treatment phase (12 weeks) assigned to placebo, 0.1 mg/day, 0.2 mg/day or
0.5 mg/day groups.
Number of subjects At time of planning 400 patients treated with investigational drug for
therapeutic period
At the time of analysis Number of patients treated with study drug for the
treatment phase: 401
Number of cases analysed for efficacy (number of PPS recruits): 355
Number of cases analysed for safety: 401
Target Overactive bladder patients
Selection criteria Patients with overactive bladder who fulfilled all of the following 1) to 4)
were selected.
1) Age: 20 years and over (at the time of obtaining consent)
2) Gender and inpatient/outpatient status: Not applicable
(3) Patients who fulfil all of the following criteria during the week before
the end of the observation period
(1) Frequency of urinary incontinence: 5 or more total incontinence sessions
per week
(2) Frequency of urination: average of 8 or more urinations per day
(3) Frequency of urinary urgency: average of at least one urinary urgency per
day
(4) Patients who are judged by the investigator (or sub-investigator) to be
able to accurately record the symptom diary
Exclusion criteria Patients with any of the following 1) to 14) were excluded.
1) Patients with genuine stress incontinence (GSI)
2) Patients with bladder tumours, bladder stones, cystitis and urinary tract
infections
(3) Patients who have undergone urogenital surgery within 6 months prior to
the observation period
4) Patients with indwelling catheters or intermittent urinary continence
5) Patients who have undergone electrical stimulation therapy or bladder
training within 3 months prior to the observation period and have shown a
positive response
(6) Patients who have received concomitantly banned drugs within 2 weeks prior

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 2.7.6 Summary of the individual tests

to the observation period (except for estrogen preparations)

(7) Patients with contraindications to the administration of anticholinergic
drugs (severe heart disease, glaucoma, myasthenia gravis, obstruction of
the pylorus, duodenum or intestinal tract, gastric atony, intestinal
atony).
(8) Patients with a history of serious allergy or serious adverse reactions
to drugs
9) Patients with a residual urine volume of 100 mL or more
(10) Patients with total bilirubin greater than 3.0 mg/dL or AST (GOT) and ALT
(GPT) greater than 2.5 times the institutional normal (or greater than 100
IU/L)
(11) Patients with a serum creatinine of 2.0 mg/dL or more
(12) Patients who are pregnant, lactating, or who may become pregnant, or who
wish to become pregnant during the study period.
(13) Patients who have not yet completed 4 months of treatment with all other
investigational drugs or who have previously received KRP-197 (ONO-8025)
(14) Other patients who are judged by the investigator (or sub-investigator)
to be unsuitable for the study

Test drug
Preparations Formulation Content Lot.No Expiry date
Dosage and serial ONO-8025 Film Each tablet contains
number S160370 July 2004
0.05 mg tablet Coated tablets 0.05 mg
ONO-8025 Film Each tablet contains
S160370 July 2004
0.1 mg tablet Coated tablets 0.1 mg
ONO-8025 Film Each tablet contains
S160370 July 2004
0.25 mg tablet Coated tablets 0.25 mg

Control drug Preparations Formulation Content Lot.No Expiry date

Dosage and serial ONO-8025
ONO-8025 0.05 mg tablet and S160360
number 0.05 mg tablet July 2004
Externally unidentifiable tablets S160370
placebo
ONO-8025
ONO-8025 0.1 mg tablet and S160360
0.1 mg tablet July 2004
Externally unidentifiable tablets S160370
placebo
ONO-8025
ONO-8025 0.25 mg tablet and S160360
0.25 mg tablet July 2004
Externally unidentifiable tablets S160370
placebo
Method of Three tablets were administered orally twice a day after breakfast and after
administration dinner.
Duration Observation period (2 weeks)
Therapeutic phase (12 weeks)
Combination therapy 1) Treatment prohibited before the observation period
(1) Medication prohibited within 8 weeks prior to observation period
Estrogen preparations (but allowed if the same dose has been used for at least
8 weeks prior to the observation period).

(2) Medication prohibited within 13 days prior to the observation period

(1) Drugs for frequent urination and urinary incontinence
Anticholinergics and cholinergic agonists
3) Tricyclic antidepressants
4) Anticonvulsants
5) Anti-Parkinson's drugs

2) Prohibited treatments from the observation phase to the treatment phase

(1) Contraindications
(1) Drugs for frequent urination and urinary incontinence
Anticholinergics and cholinergic agonists
3) Tricyclic antidepressants
4) Anticonvulsants
5) Anti-Parkinson's drugs

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 2.7.6 Summary of the individual tests

6) Estrogen preparations
(vii) All other drugs currently under development and of undefined efficacy.
However, estrogen preparations could be used in combination if they had
been used at the same dose for at least 8 weeks prior to the observation
period. No change in dosage and administration was made during the study
period (observation phase to treatment phase).

(2) No concomitant therapy

During the trial period (observation phase to treatment phase), concomitant
use of the therapies specified in the exclusion criteria (urogenital surgery,
indwelling catheters, intermittent urinary continence, electrical stimulation
therapy, bladder training) was prohibited.

(3) Possible concomitant medications

Other than the above-mentioned concomitantly prohibited drugs, concomitant use
was allowed. However, for Ca antagonists, alpha 1 blockers, and antihistamines,
the same drug was used during the study period (observation phase to treatment
phase), and the dosage and administration were not changed as much as possible.
Evaluation criteria Efficacy and safety assessments were carried out according to the schedule
shown in Table 2.7.6.1-1.
Effectiveness
1) Primary endpoint: Total number of urinary incontinence visits per week
(2) Secondary endpoints: average number of voidings per day, average number
of urinary urgencies per day, degree of urinary urgency,
average amount of urine voided per voiding, disappearance
rate of urinary incontinence frequency, number of days with
zero total urinary incontinence frequency per week, quality
of life score (King Health Questionnaire)

Assessment criteria Safety

(continued) In addition to the occurrence of adverse events and side effects (adverse
events for which a causal relationship to the study drug cannot be ruled out),
blood pressure and pulse rate, electrocardiogram, residual urine volume, and
general clinical examination were evaluated. The degree of thirst was judged
in three levels: mild, moderate and severe, referring to the following
criteria.

Degree Judgement criteria (for reference)

1. mild Almost unnoticeable

2. moderate tolerable with drinking water, etc.

3. altitude Ingestion of water or other substances is not

tolerable (discontinuation of the study drug)

The names of adverse events listed in the case report form were read into
major organ categories and basic terms based on MedDRA ver 5.0J (Pharmaceutical
Regulatory Terminology).
Statistical methods (1) Target population for analysis
The primary analysis population for efficacy was the PPS. A secondary FAS
analysis was also performed. The safety analysis population consisted of
patients who were not GCP non-compliant, who were eligible for the study
and who had received at least one dose of the study drug for the treatment
phase.
(2) Main analysis of efficacy
The superiority of ONO-8025 over placebo and the dose-response of the four
treatment groups, including placebo, were tested by using the maximum

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 2.7.6 Summary of the individual tests

contrast method for the percentage change from the end of the observation
period in the total number of urinary incontinences per week at the end of
the treatment period (after 12 weeks of treatment or at discontinuation).
The superiority of ONO-8025 over placebo was tested by contrast (-3 1 1),
and the choice of dose-response pattern was based on the p-values of contrast
(-3 1 1), (-5 - 1 3 3) and (-3 - 1 1 3). The multiplicity caused by the
choice of contrast was adjusted for by the Permutation method.
3) Safety analysis
Adverse events (subjective symptoms, subjective findings, and abnormal
laboratory changes) were tabulated and listed for each treatment group by
item, causal relationship, and severity. The incidence of adverse events,
the incidence of adverse events for which a causal relationship to the study
drug could not be ruled out, and the incidence of dry mouth were calculated,
and the dose-response of the four groups, including the placebo group, was
examined by the Cochran-Armitage trend test.
4) Additional analysis of efficacy
The same analysis as for the primary endpoint was performed on the percentage
change from the end of the observation period in the total number of urge
incontinence episodes per week at the end of the study (after 12 weeks of
treatment or at discontinuation).
Date of report 23 March 2004

Table 2.7.6.1-1 Observation and inspection items and timing

Wash-out
Observation period Treatment period
period
Occasion 12 weeks or
-4 weeks -2 weeks 0 4 weeks 8 weeks When to
stop
○1)
Obtaining consent circle
Patient background
Complications, circle
medical history etc.
Medication status circle circle circle circle
Symptom diary
Urinary
incontinence
frequency
Urination
frequency
circle circle circle circle
Frequency of
urgency to urinate
Amount of
urination per time
Degree of urgency to
urinate
circle circle circle circle
Quality of life circle circle
Amount of urine
remaining
circle circle circle circle
Blood pressure and
pulse rate
circle circle circle circle
Electrocardiogram
(12-lead)
circle circle circle circle
Laboratory tests circle circle circle circle
Adverse events
(1) Not required if consent was obtained prior to the start of the washout

Summary - Conclusion

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 2.7.6 Summary of the individual tests

(1) Breakdown of subjects

The total number of patients enrolled in the study was 401, of which 355 were recruited
for PPS, 391 for FAS, and 401 for safety (see Figure 2.7.6.1-1). The treatment of cases
is also shown in Table 2.7.6.1-2.

仮登録例
P群：プラセボ群
562 L群：ONO-8025 0.1 mg/日群
M群：ONO-8025 0.2 mg/日群
H群：ONO-8025 0.5 mg/日群

本登録時の不適格例
本登録例 （治療期未実施例）

P群 L群 M群 H群 161

101 99 100 101

安全性の解析対象集団 安全性の解析対象集団
採用例 不採用例

P群 L群 M群 H群 P群 L群 M群 H群

101 99 100 101 0 0 0 0

FAS採用例 FAS不採用例 PPS採用例 PPS不採用例

P群 L群 M群 H群 P群 L群 M群 H群 P群 L群 M群 H群 P群 L群 M群 H群

99 98 98 96 2 1 2 5 95 91 93 76 6 8 7 25

Figure 2.7.6.1-1 Breakdown of subjects

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 2.7.6 Summary of the individual tests

Table 2.7.6.1-2 Treatment of cases

該当 PPS FAS 安全性

問題項目 内容 該当症例の薬剤No.
例数 採否 採否 採否

観察期誤投与 観察期に治療期用治験薬が誤投与された症例 2 × × ○ 27-3，32-3

観察期終了前1週間の1週間あたりの合計尿失禁回数が5
選択基準違反 2 × × ○ 19-6，22-1
回以上を満たさない症例

膀胱腫瘍，膀胱結石，膀胱炎，尿路感染症を合併する症
2 × × ○ 40-1，70-2
例

観察期前6カ月以内に泌尿器生殖器手術を施行された症
1 × × ○ 30-2
例

観察期前2週間以内に併用禁止薬が投与された症例
除外基準違反 1 × × ○ 22-3
（ただし，エストロゲン製剤を除く）
総ビリルビンが3.0 mg/dL以上の症例またはAST
（GOT），ALT（GPT）が施設正常値の2.5倍以上（ある 1 × × ○ 14-6
いは100 IU/L以上）の症例

残尿量が100 mL以上の症例 1 × × ○ 61-2

2-2，5-1，6-3，6-4，14-6，
15-2，15-3，19-8，22-4，23-6，
24-1，27-3，32-3，32-6，34-1，
早期中止・脱落
治療期の投与期間が8週間（56日間）未満の症例 32 × ○ ○ 38-3，42-3，48-1，55-8，56-3，
（8週未満）
56-5，58-1，62-1，62-2，66-1，
70-2，70-6，71-5，74-3，76-1，
78-2，78-5
8-4，22-3，29-1，46-3，51-2，
観察期から治療期に併用禁止薬が投与された症例 7 × ○ ○
53-4，70-2

観察期から治療期に併用禁止療法が施行された症例 1 × ○ ○ 72-4
処置違反・
服薬率違反
エストロゲン製剤について，観察期から治療期に用法・
1 × ○ ○ 24-1
用量の変更が行われた症例

治療期用治験薬の服薬率が80%未満の症例 2 × ○ ○ 56-5，78-5

主要評価不完備 尿失禁回数の最終観察日が8週間（56日）未満の症例 2 × ○ ○ 72-7，74-2

(2) Efficacy results

The primary endpoint was the total number of urinary incontinences per week at the
end of the study (after 12 weeks of treatment or at discontinuation). The change (%)
(mean ± standard deviation) in the total number of urinary incontinences per week at
the end of the observation period was -42.86 ± 70.17 in the placebo group compared
with -59.81 ± 61.48 in the 0.1 mg/day group, -71.61 ± 43.95 in the 0.2 mg/day group
and -82.19 ± 28.68 in the 0.5 mg/day group. The superiority of the ONO-8025 group over
the placebo group was verified (t-test for contrast: contrast (-3 1 1 1), p<0.0001, see
Table 2.7.6.1-3). The dose-response pattern of the four groups, including the placebo
group, was monotonically increasing (contrast t-test: contrast (-3 -1 1 3), p<0.0001).
A secondary analysis of the primary endpoint showed a significant difference in the
percentage change in total urinary incontinence frequency from the end of the observation
period between the ONO-8025 and placebo groups for the 0.2 mg/day and 0.5 mg/day groups
(Dunnett test, p=0.0010 and p <0.0001). The change in total urinary incontinence
frequency relative to the end of the observation period was also superior in the ONO-
8025 group to placebo (t-test for contrast: contrast (-3 1 1 1), p=0.0234), and the
dose-response pattern was monotonically increasing, as was the rate of change (t-test

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 2.7.6 Summary of the individual tests

for contrast: contrast (-3 -1 1 3), p=0.0001). ), p=0.0033).

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 2.7.6 Summary of the individual tests

Table 2.7.6.1-3 Per week at end (after 12 weeks of treatment or at discontinuation)

Percentage change in total number of urinary incontinence visits to the end of the
observation period
Population for analysis: PPS

観察期終了時（実測値：回） 終了時（変化率：％） 最大対比法 Dunnett検定

評価項目 投与群
1）
例数 　平均　 ± 標準偏差 例数 　平均　 ± 標準偏差 対比（4群） p値 p値2）

P群 95 18.18 ± 17.65 94 -42.86 ± 70.17 (-3 1 1 1) p<0.0001 * P VS 0.1mg p=0.0906 N.S.

1週間あた
0.1 mg/日群 91 15.73 ± 10.81 91 -59.81 ± 61.48 (-5 -1 3 3) p<0.0001 * P VS 0.2mg p=0.0010 **
りの合計
尿失禁
0.2 mg/日群 93 15.76 ± 14.33 93 -71.61 ± 43.95 (-3 -1 1 3) p<0.0001 * P VS 0.5mg p<0.0001 ***
回数
0.5 mg/日群 76 17.64 ± 16.11 76 -82.19 ± 28.68

1) p-value adjusted for multiplicity by Permutation method (one-tailed test, significance level: 0.025)

2) p-value (two-tailed test, significance level: 0.05)

The secondary endpoint, the change (mean ± standard deviation) in the mean daily
frequency of urination at the end of the treatment period (after 12 weeks of treatment
or at the time of discontinuation) compared with the end of the observation period, was
-1.07 ± 1.93 in the placebo group, -1.72 ± 2.11 in the 0.1 mg/day group, -1.59 ±
1.89 in the 0.2 mg/day group, and -2.33 ± 2.20 in the 0.5 mg/day group. 5 mg/day group
- 2.33 ± 2.20, indicating a superiority of the ONO-8025 group over the placebo group
(t-test for contrast: contrast (-3 1 1 1), p = 0.0014, see Table 2.7.6.1-4). The dose-
response pattern in the four groups, including the placebo group, was monotonically
increasing (contrast t-test: contrast (-3 -1 1 3), p = 0.0003). Because the mean number
of urinary voidings per day at the end of the observation period was biased between treatment
groups, an adjusted analysis was performed using the mean number of urinary voidings per
day at the end of the observation period as a covariate (see Table 2.7.6.1-5). As a result,
the change in the mean daily frequency of urination at the end of the treatment period
(after 12 weeks of treatment or at the time of discontinuation) compared with the end of
the observation period (least squares mean ± standard error) was -1.17 ± 0.19 in the
placebo group, -1.71 ± 0.19 in the 0.1 mg/day group, -1.77 ± 0.19 in the 0.2 mg/day group,
and 0.77 ± 0.19 in the 0.2 mg/day group. 0.19, and -2.00±0.21 for the 0.5 mg/day group,
indicating superiority of the ONO-8025 group over the placebo group (t-test for contrast:
contrast (-3 1 1 1), p=0.0016, no adjustment for multiplicity). The dose-response pattern
of the four groups, including the placebo group, was low-dose saturated (contrast t-test:
contrast (-3 1 1), p=0.0016, without adjustment for multiplicity).

Table 2.7.6.1-4 Average number of urinations per day at the end of the treatment
period (after 12 weeks or at cessation)
Difference at the end of the observation period
Population for analysis: PPS

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 2.7.6 Summary of the individual tests

観察期終了時（実測値：回） 終了時（差：回） 最大対比法 Dunnett検定

評価項目 投与群
1）
例数 　平均　 ± 標準偏差 例数 　平均　 ± 標準偏差 対比（4群） p値 p値2）

P群 95 11.42 ± 2.79 94 -1.07 ± 1.93 (-3 1 1 1) p=0.0014 * P VS 0.1mg p=0.0791 N.S.

1日あたり 0.1 mg/日群 90 11.76 ± 2.56 90 -1.72 ± 2.11 (-5 -1 3 3) p=0.0014 * P VS 0.2mg p=0.1920 N.S.
の平均排
尿回数 0.2 mg/日群 93 11.18 ± 2.48 93 -1.59 ± 1.89 (-3 -1 1 3) p=0.0003 * P VS 0.5mg p=0.0002 ***

0.5 mg/日群 76 12.79 ± 3.51 76 -2.33 ± 2.20

1) p-value adjusted for multiplicity by Permutation method (one-tailed test, significance level: 0.025)
2) p-value (two-tailed test, significance level: 0.05)

Table 2.7.6.1-5 Adjustment by covariates for differences in mean number of urinations

per day
Population for analysis: PPS
1)
Prognostic factors Dose group Least ± Standard Degrees Comparison p-value
squares mean ( error of
% freedom
)

Average number of urinations per Group P -1.17 ± 0.19 348 (-3 1 1) p=0.0016 *
day (
%
)
0.1 mg/day -1.71 ± 0.19 348 (-5 -1 3 3) p=0.0019 *
group (
%
)
0.2 mg/day -1.77 ± 0.19 348 (-3 -1 1 3) p=0.0024 *
group (

%
)
0.5 mg/day -2.00 ± 0.21 348

group (
%
)

(1) p-value not accounting for multiplicity, one-tailed test, *: p<0.025, N.S.: p≥0.025

At the end of the treatment period (after 12 weeks of treatment or at the time of
discontinuation), the change (%) (mean ± standard deviation) in the mean number of
urinary urgency per day from the end of the observation period was -38.12 ± 62.58 in
the placebo group compared with -60.29 ± 43.51 in the 0.1 mg/day group, -57.37 ± 53.28
in the 0.2 mg/day group, and -62.31 ± 32.64 in the 0.5 mg/day group. ±53.28, and the

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 2.7.6 Summary of the individual tests

0.5 mg/day group -62.31±32.64, indicating superiority of the ONO-8025 group over the
placebo group (t-test for contrast: contrast (-3 1 1 1), p=0.0008, see Table 2.7.6.1-
6). The dose-response pattern of the four groups, including the placebo group, was low-
dose saturated (t-test of contrasts: contrast (-3 1 1), p=0.0008).
The change in the level of urinary urgency at the end of the treatment period (after
12 weeks of treatment or at discontinuation) compared with the end of the observation
period was not significantly different in terms of superiority to placebo or dose-
response in a comparison of the four groups including the placebo group.

Table 2.7.6.1-6 Urinary urgency per day at end (after 12 weeks of treatment or at
discontinuation)
Percentage change in the mean frequency compared to the end of the
observation period
Population for analysis: PPS

観察期終了時（実測値：回） 終了時（変化率：％） 最大対比法 Dunnett検定

評価項目 投与群
例数 　平均　 ± 標準偏差 例数 　平均　 ± 標準偏差 対比（4群） p値1） p値2）

P群 95 4.86 ± 3.72 94 -38.12 ± 62.58 (-3 1 1 1) p=0.0008 * P VS 0.1mg p=0.0079 **

1日あたり 0.1 mg/日群 91 4.77 ± 2.95 91 -60.29 ± 43.51 (-5 -1 3 3) p=0.0026 * P VS 0.2mg p=0.0246 *
の尿意切迫
感の平均
回数 0.2 mg/日群 93 4.40 ± 3.13 93 -57.37 ± 53.28 (-3 -1 1 3) p=0.0047 * P VS 0.5mg p=0.0053 **

0.5 mg/日群 76 5.83 ± 4.58 76 -62.31 ± 32.64

1) p-value adjusted for multiplicity by Permutation method (one-tailed test, significance level: 0.025)
2) p-value (two-tailed test, significance level: 0.05)

At the end of the treatment period (after 12 weeks of treatment or at the time of
discontinuation), the change (mL) (mean ± standard deviation) in the mean volume of
urination per voiding relative to the end of the observation period was 2.29 ± 42.70
in the placebo group compared with 14.06 ± 37.50 in the 0.1 mg/day group, 9.89 ± 37.64
in the 0.2 mg/day group, and 26.11 ± 43.79 in the 0.5 mg/day group. There was a
superiority of the ONO-8025 group over the placebo group (t-test for contrast: contrast
(-3 1 1 1), p=0.0048, see Table 2.7.6.1-7). The dose-response pattern of the four groups,
including the placebo group, was monotonically increasing (contrast t-test: contrast (-
3 -1 1 3), p=0.0009).

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 2.7.6 Summary of the individual tests

Table 2.7.6.1-7 Mean volume of urine voided per voiding at the end of the treatment
period (after 12 weeks or at cessation)
Difference at the end of the observation period
Population for analysis: PPS

観察期終了時（実測値：mL） 終了時（差：mL） 最大対比法 Dunnett検定

評価項目 投与群
例数 　平均　 ± 標準偏差 例数 　平均　 ± 標準偏差 対比（4群） p値1） p値2）

P群 89 156.51 ± 66.21 86 2.29 ± 42.70 (-3 1 1 1) p=0.0048 * P VS 0.1 mg p=0.1367 N.S.

0.1 mg/日群 89 137.50 ± 46.45 89 14.06 ± 37.50 (-5 -1 3 3) p=0.0051 * P VS 0.2 mg p=0.4653 N.S.
平均1回
排尿量
0.2 mg/日群 89 143.49 ± 52.06 86 9.89 ± 37.64 (-3 -1 1 3) p=0.0009 * P VS 0.5 mg p=0.0006 ***

0.5 mg/日群 75 142.15 ± 56.38 75 26.11 ± 43.79

1) p-value adjusted for multiplicity by Permutation method (one-tailed test, significance level: 0.025)

2) p-value (two-tailed test, significance level: 0.05)

At the end of the treatment period (after 12 weeks of treatment or at the time of
discontinuation), the percentage change (mean ± standard deviation) in the total number
of urge urinary incontinence per week from the end of the observation period was -18.94
± 272.76 in the placebo group, compared with -57.07 ± 72.88 in the 0.1 mg/day group,
-75.67 ± 41.11 in the 0.2 mg/day group, and -74.20 ± 93.45 in the 0.5 mg/day group.
67±41.11, and 0.5 mg/day group -74.20±93.45, indicating superiority of the ONO-8025
group over the placebo group (t-test for contrast: contrast (-3 1 1 1), p=0.0010, see
Table 2.7.6.1-8). The dose-response pattern of the four groups, including the placebo
group, was medium dose saturated (t-test of contrasts: contrast (-5 -1 3 3), p=0.0006).

Table 2.7.6.1-8 per week at the end (after 12 weeks of treatment or at

discontinuation)
Percentage change in the total number of urge incontinence
visits to the end of the observation period
解析対象集団：PPS

観察期終了時（実測値：回） 終了時（変化率：％） 最大対比法 Dunnett検定

評価項目 投与群
例数 　平均　 ± 標準偏差 例数 　平均　 ± 標準偏差 対比（4群） p値1） p値2）

P群 93 15.99 ± 16.87 92 -18.94 ± 272.76 (-3 1 1 1) p=0.0010 * P VS 0.1mg p=0.2287 N.S.

1週間あた 0.1 mg/日群 88 14.00 ± 10.73 88 -57.07 ± 72.88 (-5 -1 3 3) p=0.0006 * P VS 0.2mg p=0.0335 *
りの切迫性
尿失禁回数 0.2 mg/日群 92 14.52 ± 14.29 92 -75.67 ± 41.11 (-3 -1 1 3) p=0.0052 * P VS 0.5mg p=0.0541 N.S.

0.5 mg/日群 76 15.59 ± 16.17 76 -74.20 ± 93.45

1) p-value adjusted for multiplicity by Permutation method (one-tailed test, significance level: 0.025)
2) p-value (two-tailed test, significance level: 0.05)

Of the nine domains of the King Health Questionnaire used to assess quality of life,
there was a superiority of the ONO-8025 group over the placebo group in terms of change
at the end of one domain of subjective severity (after 12 weeks of treatment or at
discontinuation) compared with the end of the observation phase (t-test for contrast:

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 2.7.6 Summary of the individual tests

contrast (-3 1 1 1), p=0.0143, no multiple adjustment). No multiplicity adjustment).

The dose-response pattern of the four groups, including the placebo group, was low-dose
saturated (t-test for contrast: contrast (-3 1 1), p=0.0143, not adjusted for
multiplicity).
These results demonstrated the superiority of ONO-8025 over placebo in the primary
endpoint of percent change in total number of urinary incontinence per week. The dose-
response pattern of the four groups, including the placebo group, was monotonically
increasing, with increasing improvement with dose. Furthermore, the 0.2 mg/day and 0.5
mg/day groups of ONO-8025 showed significant improvement over placebo.
As well as urinary incontinence, the superiority of ONO-8025 over placebo and the
dose-response of the four groups including the placebo group were observed in terms of
frequency of urination (frequency of urination) and reduction in frequency of urinary
urgency, which are the main clinical symptoms of overactive bladder. It was confirmed
that ONO-8025 is effective in the treatment of urinary incontinence, frequency and
urinary urgency in overactive bladder.

(3) Safety results

The total number of patients included in the safety analysis was 401 (101 in the
placebo group, 99 in the 0.1 mg/day group, 100 in the 0.2 mg/day group and 101 in the
0.5 mg/day group).
The list of adverse events by severity, the list of adverse events by severity and
the list of adverse events by causality are shown in Tables 2.7.6.1-13 to 2.7.6.1-15.
The incidence of adverse events was 55.4%, 65.7%, 66.0%, and 84.2% in the placebo, 0.1
mg/day, 0.2 mg/day, and 0.5 mg/day groups, respectively, indicating a dose-response in
the four groups, including the placebo group (Cochran-Armitage trend test, p<0.0001,
and p<0.001). See Table 2.7.6.1-9).

Table 2.7.6.1-9 Adverse event incidence

投与群 有 無 合計 Cochran-Armitage傾向検定1)

P群 56 ( 55.4) 45 ( 44.6) 101 p<0.0001 *

0.1 mg/日群 65 ( 65.7) 34 ( 34.3) 99
0.2 mg/日群 66 ( 66.0) 34 ( 34.0) 100
0.5 mg/日群 85 ( 84.2) 16 ( 15.8) 101
1）両側検定、*：p<0.05、N.S.：p≧0.05
（ ）内はパーセントを示した。

Adverse events occurring at an incidence of 5% or greater in any of the ONO-8025

treatment groups were dry mouth, nasopharyngitis, constipation, positive urine
leukocytes, headache NOS, sore throat, abnormal eye sensation, floating dizziness,
dyspepsia and vomiting NOS. The incidence of dry mouth, the most frequent symptom, was
9.9%, 16.2%, 24.0%, and 50.5% in the placebo, 0.1 mg/day, 0.2 mg/day, and 0.5 mg/day

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 2.7.6 Summary of the individual tests

groups, respectively, indicating a dose-response in the four groups, including the

placebo group (Cochran-Armitage trend test, p p<0.0001). The incidence of moderate or
greater dry mouth requiring water intake or other treatment was 1.0%, 4.0%, 6.0%, and
18.8% in the placebo, 0.1 mg/day, 0.2 mg/day, and 0.5 mg/day groups, respectively, and
the proportion of patients with moderate or greater dry mouth increased with increasing
dose (see Tables 2.7.6.1-10 ).

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 2.7.6 Summary of the individual tests

Table 2.7.6.1-10 Occurrence of dry mouth by causality and severity

投与群 症例数 重症度1） 軽度 中等度 高度 計

関連性 無 有 無 有 無 有 　

P群 101 発現例数 2 7 0 1 0 0 10

発現率(％) 2.0 6.9 0.0 1.0 0.0 0.0 9.9

発現件数 2 7 0 1 0 0 10

0.1 mg/日群 99 発現例数 3 9 0 3 0 1 16

発現率(％) 3.0 9.1 0.0 3.0 0.0 1.0 16.2

発現件数 3 9 0 3 0 1 16

0.2 mg/日群 100 発現例数 1 17 0 5 0 1 24

発現率(％) 1.0 17.0 0.0 5.0 0.0 1.0 24.0

発現件数 2 18 0 5 0 1 26

0.5 mg/日群 101 発現例数 3 29 1 12 0 6 51

発現率(％) 3.0 28.7 1.0 11.9 0.0 5.9 50.5

発現件数 3 32 1 12 0 6 54

1）口渇の重症度判定基準
　 軽　度：ほとんど気にならない程度
　 中等度：摂水などで我慢できる程度
　 高　度：摂水などでも我慢できない程度（治験薬の投与中止）

The incidence of adverse events with an undeniable causal relationship to the study
drug was 20.8%, 30.3%, 37.0%, and 62.4% in the placebo, 0.1 mg/day, 0.2 mg/day, and 0.5
mg/day groups, respectively, indicating a dose-response in the four groups including
the placebo group (Cochran- Armitage trend test, p<0.0001, see Table 2.7.6.1-11). Adverse
events with an incidence of ≥5% that could not be ruled out were dry mouth, constipation
and abnormal eye sensations, which were considered to be anticholinergic adverse events.

Table 2.7.6.1-11 Incidence of adverse events for which a causal relationship to the
investigational product cannot be ruled out

投与群 有 無 合計 Cochran-Armitage傾向検定1)

P群 21 ( 20.8) 80 ( 79.2) 101 p<0.0001 *

0.1 mg/日群 30 ( 30.3) 69 ( 69.7) 99
0.2 mg/日群 37 ( 37.0) 63 ( 63.0) 100
0.5 mg/日群 63 ( 62.4) 38 ( 37.6) 101
1）両側検定、*：p<0.05、N.S.：p≧0.05
（ ）内はパーセントを示した。

The discontinuation rate due to adverse events (including patients who withdrew consent
because of an adverse event) was 0.0%, 5.1%, 3.0%, and 16.8% in the placebo, 0.1 mg/day,
0.2 mg/day, and 0.5 mg/day groups, respectively. The 0.5 mg/day group had more
discontinuations due to adverse events such as dry mouth, with a discontinuation rate
approximately five times higher than the 0.2 mg/day group.
There were no deaths in this study. The number of other serious adverse events was 1

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 2.7.6 Summary of the individual tests

in the placebo group (pneumonia), 4 in the 0.1 mg/day group (chest pain, intra-articular
hematoma of the left knee, trauma, left cervical tumor), 4 in the 0.2 mg/day group
(seizure, abdominal pain, cataract, gastric cancer), and 4 in the 0.5 mg/day group (2
bladder tumors, right-sided abdominal pain, gastric cancer). The most serious adverse
reaction was chest pain (suspected angina pectoris) in one patient in the 0.1 mg/day
group, which recovered quickly after medical treatment (diltiazem hydrochloride,
nicorandil, isosorbide nitrate tape). The chest pain observed at 0.1 mg/day was suspected
to be caused by atypical angina due to coronary vasoconstriction, since ONO-8025 did
not affect cardiac contractility or coronary blood flow based on basic studies in guinea
pig explanted hearts, and there was no dose-related increase in the incidence of adverse
cardiac events or ECG abnormalities in this study. As there was no dose-related increase
in the frequency of adverse cardiac events or ECG abnormalities in the study, the
association between chest pain and Clozapine is considered to be low. Other important
adverse events included severe thirst in 8 patients (1 patient in the 0.1 mg/day group,
1 patient in the 0.2 mg/day group, and 6 patients in the 0.5 mg/day group) and moderate
urinary retention requiring urinary continence in 1 patient in the 0.5 mg/day group with
benign prostatic hyperplasia, all of which were considered to be anticholinergic adverse
events. Severe thirst resolved or abated with discontinuation or completion of treatment,
except for one patient who was lost to follow-up because of withdrawal of consent.
Moderate urinary retention, observed in one patient with benign prostatic hyperplasia,
occurred 1 day after dosing and resolved on the day of onset after urinary continence.
There was no significant change in residual urine volume in the 0.1 mg/day and 0.2
mg/day groups compared with the end of the observation period, although there was a
significant increase in residual urine volume in the 0.5 mg/day group after 8 weeks of
treatment (increase of 6.37 ± 25.74 mL, Wilcoxon signed rank test, p = 0.0161 There
was no significant change in residual urine volume at any other time point, including
the end of the study. An adverse event of increased residual urine volume (moderate)
was observed in one patient in the 0.5 mg/day group.
There were scattered significant (downward) changes in systolic and diastolic blood
pressure versus end-of-observation in the ONO-8025 group, but neither systolic nor
diastolic blood pressure were clinically problematic. There were some significant
changes in pulse rate relative to the end of the observation period in the ONO-8025
group, but these were not clinically relevant. Adverse events of increased blood pressure
were observed in four patients (one patient in the placebo group and three patients in
the 0.5 mg/day group), and were judged to be moderate in one patient in the 0.5 mg/day
group and mild in all others.
There was no significant dose-response relationship in the incidence of ECG
abnormalities at any time point in the ECG study. The incidence of adverse ECG events
was 4.0% (4/101 patients), 4.0% (4/99 patients), 2.0% (2/100 patients), and 3.0% (3/101
patients) in the placebo, 0.1 mg/day, 0.2 mg/day, and 0.5 mg/day groups, respectively,
all of which were mild in severity. The incidence of adverse events related to
electrocardiographic abnormalities that could not be ruled out as causally related to
the study drug was 2.0% (2/101), 1.0% (1/99), 1.0% (1/100), and 1.0% (1/101) in the

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 2.7.6 Summary of the individual tests

placebo, 0.1 mg/day, 0.2 mg/day, and 0.5 mg/day groups, respectively. There was no
difference between the treatment groups.
In the general laboratory tests, comparison of laboratory values at the end of the
observation period and at the end of the study (after 12 weeks of treatment or at
discontinuation) revealed a scattered number of laboratory parameters that were
significantly different, but none that varied significantly (see Tables 2.7.6.1-12). Of
the adverse laboratory events, 6 (8) abnormal laboratory changes were judged to be
moderate. Of these, three (3) occurred in the ONO-8025 group: one (1) case of positive
urine leukocytes in the 0.1 mg/day group, one (1) case of positive urine leukocytes in
the 0.2 mg/day group, and one (1) case of increased blood triglycerides in the 0.5
mg/day group. The positive urine leukocytes in the 0.1 mg/day group and the increased
blood triglycerides in the 0.5 mg/day group were judged to be adverse reactions. No
patients discontinued treatment due to abnormal laboratory values.
Based on these results, ONO-8025 showed an increase with increasing dose in the
incidence of adverse events, adverse drug reactions, dry mouth, moderate or greater dry
mouth, and discontinuation of adverse drug reactions, and the incidence of all of these
events was higher in the 0.5 mg/day group compared with the 0.1 mg/day and 0.2 mg/day
groups. The recommended clinical dose was considered to be 0.2 mg/day or lower. In one
patient in the 0.5 mg/day group with benign prostatic hyperplasia, urinary retention
requiring continence was observed. This event was thought to be due to the
anticholinergic effect and therefore ONO-8025 should be administered with caution to
patients with lower urinary tract obstructive diseases such as benign prostatic
hyperplasia.

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 2.7.6 Summary of the individual tests

Table 2.7.6.1-12 Pre- and post-dose changes in clinical laboratory values

解析対象集団：安全性解析対象集団
Wilcoxon
検査項目 投与群 時期 症例数 平均 ± 標準偏差 最小値 25%点 中央値 75%点 最大値 符号付順位検定1)

白血球数 P群 開始前 101 5784.4 ± 1443.6 2900 4800.0 5800.0 6500.0 12600 －
（/mm3） 4週後 98 5756.5 ± 1464.7 3400 4900.0 5500.0 6600.0 11200 p=0.8178 N.S.
8週後 92 5777.2 ± 1545.9 2800 4700.0 5490.0 6950.0 11100 p=0.8815 N.S.
12週後 94 5880.5 ± 1700.3 3100 4600.0 5580.0 6700.0 12000 p=0.2485 N.S.
終了時 97 5891.5 ± 1704.4 3100 4600.0 5560.0 6700.0 12000 p=0.2613 N.S.
0.1 mg群 開始前 93 5893.3 ± 1218.5 3130 5100.0 5700.0 6700.0 10000 －
4週後 91 5749.6 ± 1296.8 3200 4900.0 5700.0 6500.0 9600 p=0.1628 N.S.
8週後 92 5795.4 ± 1411.7 3520 4800.0 5500.0 6435.0 10000 p=0.3358 N.S.
12週後 92 5750.9 ± 1317.9 3100 4700.0 5685.0 6550.0 9300 p=0.3372 N.S.
終了時 92 5750.9 ± 1317.9 3100 4700.0 5685.0 6550.0 9300 p=0.3372 N.S.
0.2 mg群 開始前 98 5697.7 ± 1380.8 2600 4700.0 5425.0 6800.0 10000 －
4週後 98 5542.8 ± 1357.0 2260 4700.0 5450.0 6300.0 10500 p=0.0851 N.S.
8週後 95 5567.3 ± 1505.9 3000 4400.0 5300.0 6500.0 10100 p=0.0484 *
12週後 91 5545.6 ± 1423.1 2800 4600.0 5200.0 6600.0 9600 p=0.0443 *
終了時 95 5565.8 ± 1480.0 2800 4600.0 5200.0 6600.0 10000 p=0.0587 N.S.
0.5 mg群 開始前 94 5845.1 ± 1321.2 2700 4900.0 5700.0 6700.0 9210 －
4週後 90 5665.2 ± 1263.2 3400 4800.0 5500.0 6300.0 9500 p=0.0872 N.S.
8週後 82 5558.5 ± 1305.3 3500 4600.0 5400.0 6300.0 9130 p=0.0034 *
12週後 74 5696.2 ± 1270.4 3200 4800.0 5500.0 6700.0 8300 p=0.2511 N.S.
終了時 85 5746.7 ± 1347.8 3200 4810.0 5500.0 6800.0 9130 p=0.4263 N.S.
赤血球数 P群 開始前 101 436.8 ± 46.5 333 405.0 437.0 464.0 592 －
4 3
(10 /mm ) 4週後 98 429.3 ± 44.9 320 399.0 429.5 458.0 566 p=0.0002 *
8週後 92 428.7 ± 43.0 331 399.5 427.5 452.0 534 p=0.0001 *
12週後 94 430.1 ± 47.4 329 400.0 424.5 460.0 553 p=0.0015 *
終了時 97 430.1 ± 47.3 329 400.0 425.0 460.0 553 p=0.0006 *
0.1 mg群 開始前 93 433.5 ± 36.6 355 409.0 427.0 456.0 550 －
4週後 91 427.1 ± 37.3 338 400.0 426.0 454.0 560 p=0.0007 *
8週後 92 425.5 ± 37.8 338 401.5 419.5 450.5 585 p=0.0002 *
12週後 92 425.0 ± 35.5 346 402.0 418.0 447.0 561 p=0.0001 *
終了時 92 425.0 ± 35.5 346 402.0 418.0 447.0 561 p=0.0001 *
0.2 mg群 開始前 98 423.5 ± 42.5 306 402.0 424.0 451.0 528 －
4週後 98 420.0 ± 42.9 299 393.0 421.0 446.0 506 p=0.0221 *
8週後 95 417.3 ± 43.4 297 396.0 417.0 445.0 527 p=0.0012 *
12週後 91 415.7 ± 42.5 305 393.0 419.0 446.0 515 p=0.0001 *
終了時 95 416.5 ± 42.4 305 396.0 419.0 446.0 515 p=0.0001 *
0.5 mg群 開始前 94 429.0 ± 36.1 346 404.0 437.0 451.0 528 －
4週後 90 423.2 ± 39.0 333 400.0 422.0 449.0 520 p=0.0014 *
8週後 82 419.0 ± 34.9 348 394.0 417.5 445.0 519 p=0.0001 *
12週後 74 418.4 ± 39.2 320 392.0 419.5 449.0 522 p=0.0001 *
終了時 85 419.2 ± 39.1 320 392.0 421.0 447.0 522 p=0.0001 *
ヘモグロビン P群 開始前 101 13.34 ± 1.49 8.0 12.40 13.20 14.20 18.6 －
（g/dL） 4週後 98 13.15 ± 1.50 8.1 12.20 12.95 14.00 17.2 p=0.0004 *
8週後 92 13.12 ± 1.44 7.8 12.20 13.00 13.95 16.7 p=0.0001 *
12週後 94 13.15 ± 1.50 9.4 12.10 12.95 13.90 16.9 p=0.0012 *
終了時 97 13.14 ± 1.50 9.4 12.10 13.00 13.90 16.9 p=0.0006 *
0.1 mg群 開始前 93 13.27 ± 1.10 10.3 12.70 13.30 13.90 16.1 －
4週後 91 13.08 ± 1.09 9.8 12.40 13.00 13.90 15.2 p=0.0023 *
8週後 92 13.04 ± 1.12 8.9 12.20 13.10 13.85 15.2 p=0.0005 *
12週後 92 13.06 ± 1.06 9.1 12.30 12.95 13.80 15.3 p=0.0013 *
終了時 92 13.06 ± 1.06 9.1 12.30 12.95 13.80 15.3 p=0.0013 *
0.2 mg群 開始前 98 13.13 ± 1.49 9.4 12.20 13.10 14.20 17.0 －
4週後 98 13.03 ± 1.48 9.5 12.00 12.90 13.90 16.6 p=0.0301 *
8週後 95 12.97 ± 1.45 9.3 12.10 12.90 13.90 16.7 p=0.0024 *
12週後 91 12.90 ± 1.38 9.1 12.00 12.80 13.80 15.9 p=0.0001 *
終了時 95 12.92 ± 1.40 9.1 12.00 12.80 13.80 15.9 p=0.0002 *
0.5 mg群 開始前 94 13.36 ± 1.23 9.1 12.50 13.35 14.10 16.4 －
4週後 90 13.15 ± 1.28 9.0 12.50 13.20 13.90 15.9 p=0.0002 *
8週後 82 13.03 ± 1.13 10.4 12.40 12.95 13.90 15.6 p=0.0001 *
12週後 74 13.04 ± 1.29 8.7 12.40 13.10 13.70 16.4 p=0.0001 *
終了時 85 13.08 ± 1.26 8.7 12.50 13.10 13.80 16.4 p=0.0001 *

1）：両側検定（*: p<0.05、N.S.: p≧ 0.05）

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 2.7.6 Summary of the individual tests

Table 2.7.6.1-12 Pre- and post-dose changes in clinical laboratory values (continued)
解析対象集団：安全性解析対象集団
Wilcoxon
1)
検査項目 投与群 時期 症例数 平均 ± 標準偏差 最小値 25%点 中央値 75%点 最大値 符号付順位検定

ヘマトクリット値 P群 開始前 101 40.17 ± 4.21 29.3 37.10 39.90 42.50 54.2 －
（％） 4週後 98 39.61 ± 4.00 29.0 36.60 39.40 41.90 49.8 p=0.0004 *
8週後 92 39.47 ± 3.92 28.4 36.40 39.30 41.75 48.2 p=0.0001 *
12週後 94 39.63 ± 4.16 29.3 36.70 39.05 42.50 50.7 p=0.0014 *
終了時 97 39.63 ± 4.18 29.3 36.70 39.10 42.50 50.7 p=0.0006 *
0.1 mg群 開始前 93 40.15 ± 3.23 32.1 38.10 40.40 42.10 47.7 －
4週後 91 39.57 ± 3.21 30.7 37.30 39.90 41.80 46.3 p=0.0024 *
8週後 92 39.49 ± 3.24 28.1 37.55 39.80 41.65 46.4 p=0.0018 *
12週後 92 39.40 ± 3.24 28.8 37.30 39.30 41.75 46.3 p=0.0003 *
終了時 92 39.40 ± 3.24 28.8 37.30 39.30 41.75 46.3 p=0.0003 *
0.2 mg群 開始前 98 39.62 ± 4.27 27.9 37.00 39.70 41.90 50.1 －
4週後 98 39.28 ± 4.24 28.4 36.40 38.95 41.90 50.5 p=0.0210 *
8週後 95 39.13 ± 4.23 28.2 36.30 39.20 41.50 52.8 p=0.0069 *
12週後 91 38.83 ± 3.98 28.3 36.70 38.90 41.20 48.0 p=0.0001 *
終了時 95 38.87 ± 3.98 28.3 36.70 39.00 41.40 48.0 p=0.0001 *
0.5 mg群 開始前 94 40.12 ± 3.44 29.3 38.10 40.25 42.00 50.9 －
4週後 90 39.51 ± 3.60 28.9 37.60 39.50 41.90 49.3 p=0.0004 *
8週後 82 39.31 ± 3.20 31.8 37.30 39.50 41.50 48.5 p=0.0001 *
12週後 74 39.05 ± 3.54 27.7 36.60 39.25 41.10 47.0 p=0.0001 *
終了時 85 39.17 ± 3.47 27.7 36.90 39.20 41.20 47.0 p=0.0001 *
血小板数 P群 開始前 101 23.08 ± 6.50 3.3 19.20 22.50 25.90 55.8 －
（104/mm3） 4週後 98 22.53 ± 6.06 4.3 18.90 22.20 25.50 51.2 p=0.1918 N.S.
8週後 92 22.73 ± 6.38 5.9 18.70 21.80 25.40 52.0 p=0.6222 N.S.
12週後 94 22.53 ± 6.55 4.2 18.50 21.50 25.30 50.8 p=0.0656 N.S.
終了時 97 22.48 ± 6.46 4.2 18.50 21.50 25.00 50.8 p=0.0406 *
0.1 mg群 開始前 93 23.65 ± 5.38 11.3 19.50 23.30 26.80 36.7 －
4週後 91 23.05 ± 4.67 10.3 19.40 22.90 26.60 34.4 p=0.2507 N.S.
8週後 92 23.01 ± 5.26 10.4 19.40 22.05 25.75 38.6 p=0.0287 *
12週後 92 22.93 ± 5.16 10.6 19.35 22.45 26.65 43.1 p=0.0124 *
終了時 92 22.93 ± 5.16 10.6 19.35 22.45 26.65 43.1 p=0.0124 *
0.2 mg群 開始前 98 23.09 ± 5.17 9.7 19.80 22.50 26.00 36.8 －
4週後 98 22.34 ± 5.12 9.3 18.70 22.10 26.20 38.6 p=0.0060 *
8週後 95 22.18 ± 5.00 9.1 18.60 21.80 25.70 36.5 p=0.0003 *
12週後 91 22.19 ± 4.81 9.1 18.90 22.10 25.10 34.9 p=0.0007 *
終了時 95 22.15 ± 4.73 9.1 18.90 22.10 25.00 34.9 p=0.0007 *
0.5 mg群 開始前 94 23.14 ± 5.06 11.5 20.30 22.55 26.10 38.9 －
4週後 90 22.22 ± 5.07 11.6 19.10 21.80 24.80 40.4 p=0.0006 *
8週後 82 22.33 ± 5.31 12.7 18.70 21.75 25.40 38.5 p=0.0032 *
12週後 74 22.43 ± 5.11 12.2 18.40 21.95 25.00 38.9 p=0.0150 *
終了時 85 22.35 ± 5.00 12.2 18.40 21.80 24.80 38.9 p=0.0105 *
総蛋白 P群 開始前 101 7.118 ± 0.423 6.00 6.800 7.100 7.400 8.10 －
（g/dL） 4週後 98 7.084 ± 0.401 5.90 6.800 7.100 7.400 8.30 p=0.3008 N.S.
8週後 92 7.075 ± 0.451 5.90 6.800 7.100 7.350 8.40 p=0.1005 N.S.
12週後 94 7.100 ± 0.439 5.90 6.900 7.100 7.300 8.40 p=0.3555 N.S.
終了時 97 7.090 ± 0.436 5.90 6.800 7.100 7.300 8.40 p=0.3439 N.S.
0.1 mg群 開始前 93 7.152 ± 0.567 5.70 6.800 7.200 7.400 9.40 －
4週後 92 7.093 ± 0.451 6.30 6.800 7.100 7.400 8.50 p=0.2096 N.S.
8週後 92 7.061 ± 0.437 6.10 6.700 7.100 7.300 8.60 p=0.0538 N.S.
12週後 92 7.046 ± 0.472 6.00 6.700 7.000 7.400 8.70 p=0.0023 *
終了時 92 7.046 ± 0.472 6.00 6.700 7.000 7.400 8.70 p=0.0023 *
0.2 mg群 開始前 98 7.115 ± 0.480 6.10 6.700 7.100 7.500 8.60 －
4週後 98 6.998 ± 0.435 6.00 6.700 7.000 7.300 8.30 p=0.0005 *
8週後 95 7.013 ± 0.426 6.00 6.700 7.000 7.300 8.10 p=0.0058 *
12週後 91 6.966 ± 0.428 6.10 6.700 6.900 7.200 8.40 p=0.0007 *
終了時 95 6.978 ± 0.433 6.10 6.700 7.000 7.200 8.40 p=0.0010 *
0.5 mg群 開始前 94 7.139 ± 0.415 6.20 6.900 7.200 7.400 8.00 －
4週後 90 7.000 ± 0.413 5.90 6.700 7.000 7.300 8.00 p=0.0001 *
8週後 82 6.963 ± 0.426 5.80 6.700 6.900 7.200 8.20 p=0.0001 *
12週後 74 6.981 ± 0.483 5.90 6.600 6.950 7.300 8.10 p=0.0001 *
終了時 85 6.988 ± 0.471 5.90 6.700 7.000 7.300 8.10 p=0.0001 *

1）：両側検定（*: p<0.05、N.S.: p≧ 0.05）

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 2.7.6 Summary of the individual tests

Table 2.7.6.1-12 Pre- and post-dose changes in clinical laboratory values (continued)
解析対象集団：安全性解析対象集団
Wilcoxon
1)
検査項目 投与群 時期 症例数 平均 ± 標準偏差 最小値 25%点 中央値 75%点 最大値 符号付順位検定

アルブミン P群 開始前 99 4.282 ± 0.259 3.70 4.100 4.300 4.500 5.00 －

（g/dL） 4週後 96 4.249 ± 0.263 3.50 4.100 4.300 4.400 4.90 p=0.1354 N.S.
8週後 90 4.222 ± 0.287 3.40 4.000 4.200 4.400 5.10 p=0.0215 *
12週後 92 4.226 ± 0.253 3.50 4.100 4.200 4.400 4.90 p=0.0038 *
終了時 95 4.227 ± 0.253 3.50 4.100 4.200 4.400 4.90 p=0.0045 *
0.1 mg群 開始前 92 4.302 ± 0.285 3.40 4.100 4.300 4.500 5.10 －
4週後 91 4.267 ± 0.249 3.70 4.100 4.200 4.500 4.90 p=0.0658 N.S.
8週後 91 4.242 ± 0.214 3.80 4.100 4.300 4.400 4.70 p=0.0320 *
12週後 91 4.239 ± 0.252 3.50 4.100 4.300 4.400 4.70 p=0.0077 *
終了時 91 4.239 ± 0.252 3.50 4.100 4.300 4.400 4.70 p=0.0077 *
0.2 mg群 開始前 96 4.278 ± 0.300 3.40 4.100 4.200 4.450 5.30 －
4週後 95 4.208 ± 0.295 3.30 4.000 4.200 4.400 5.10 p=0.0023 *
8週後 92 4.213 ± 0.275 3.50 4.000 4.200 4.400 5.00 p=0.0032 *
12週後 88 4.177 ± 0.275 3.40 4.000 4.200 4.350 4.90 p=0.0001 *
終了時 92 4.184 ± 0.279 3.40 4.000 4.200 4.400 4.90 p=0.0001 *
0.5 mg群 開始前 93 4.317 ± 0.250 3.70 4.200 4.300 4.500 5.00 －
4週後 89 4.228 ± 0.275 3.60 4.100 4.300 4.400 4.90 p=0.0001 *
8週後 81 4.211 ± 0.254 3.50 4.100 4.200 4.400 4.70 p=0.0001 *
12週後 72 4.228 ± 0.293 3.40 4.000 4.300 4.400 4.80 p=0.0008 *
終了時 83 4.231 ± 0.294 3.40 4.000 4.300 4.400 4.80 p=0.0012 *
総ビリルビン P群 開始前 101 0.589 ± 0.280 0.19 0.400 0.500 0.700 1.80 －
（mg/dL） 4週後 98 0.576 ± 0.257 0.20 0.400 0.500 0.700 1.80 p=0.8526 N.S.
8週後 92 0.582 ± 0.317 0.20 0.400 0.500 0.700 2.40 p=0.8382 N.S.
12週後 94 0.563 ± 0.236 0.20 0.400 0.500 0.700 1.50 p=0.5087 N.S.
終了時 97 0.566 ± 0.243 0.20 0.400 0.500 0.700 1.50 p=0.4831 N.S.
0.1 mg群 開始前 93 0.547 ± 0.239 0.20 0.400 0.500 0.650 1.70 －
4週後 92 0.586 ± 0.266 0.20 0.400 0.500 0.700 1.70 p=0.0278 *
8週後 92 0.561 ± 0.242 0.20 0.400 0.520 0.700 1.40 p=0.5412 N.S.
12週後 92 0.574 ± 0.227 0.20 0.400 0.500 0.700 1.20 p=0.1910 N.S.
終了時 92 0.574 ± 0.227 0.20 0.400 0.500 0.700 1.20 p=0.1910 N.S.
0.2 mg群 開始前 98 0.546 ± 0.230 0.20 0.400 0.500 0.700 1.20 －
4週後 98 0.558 ± 0.228 0.10 0.400 0.500 0.700 1.40 p=0.5821 N.S.
8週後 94 0.575 ± 0.239 0.17 0.400 0.540 0.700 1.30 p=0.0865 N.S.
12週後 91 0.558 ± 0.231 0.20 0.400 0.500 0.670 1.30 p=0.5038 N.S.
終了時 95 0.559 ± 0.230 0.20 0.400 0.500 0.670 1.30 p=0.5101 N.S.
0.5 mg群 開始前 94 0.519 ± 0.205 0.20 0.310 0.500 0.620 1.10 －
4週後 90 0.532 ± 0.209 0.20 0.400 0.500 0.600 1.17 p=0.5354 N.S.
8週後 82 0.539 ± 0.205 0.20 0.400 0.500 0.700 1.41 p=0.6194 N.S.
12週後 74 0.535 ± 0.197 0.20 0.400 0.500 0.600 1.30 p=0.1207 N.S.
終了時 85 0.539 ± 0.220 0.20 0.400 0.500 0.600 1.41 p=0.0963 N.S.
AST(GOT) P群 開始前 101 22.7 ± 8.5 13 18.0 21.0 25.0 81 －
（IU/L） 4週後 98 22.3 ± 7.4 12 18.0 20.5 25.0 60 p=0.4530 N.S.
8週後 92 21.6 ± 7.1 13 17.0 21.0 23.0 55 p=0.0137 *
12週後 94 23.0 ± 8.3 13 18.0 22.0 26.0 67 p=0.7061 N.S.
終了時 97 22.9 ± 8.3 13 18.0 22.0 26.0 67 p=0.8176 N.S.
0.1 mg群 開始前 93 24.1 ± 9.1 12 19.0 22.0 26.0 72 －
4週後 92 23.4 ± 10.4 8 18.0 20.0 25.5 79 p=0.0371 *
8週後 92 21.6 ± 6.5 11 17.5 20.0 24.0 51 p=0.0001 *
12週後 92 22.4 ± 6.4 9 18.0 21.5 25.0 44 p=0.0146 *
終了時 92 22.4 ± 6.4 9 18.0 21.5 25.0 44 p=0.0146 *
0.2 mg群 開始前 98 23.2 ± 7.7 12 19.0 21.5 26.0 61 －
4週後 98 22.2 ± 7.0 12 17.0 21.0 25.0 59 p=0.0025 *
8週後 95 22.2 ± 6.3 13 17.0 22.0 25.0 52 p=0.0066 *
12週後 91 22.4 ± 5.9 12 18.0 22.0 25.0 44 p=0.1481 N.S.
終了時 95 22.2 ± 5.9 12 18.0 22.0 25.0 44 p=0.0917 N.S.
0.5 mg群 開始前 94 22.5 ± 6.1 12 18.0 22.0 25.0 50 －
4週後 90 21.2 ± 6.6 11 17.0 19.0 24.0 52 p=0.0002 *
8週後 82 20.7 ± 6.1 12 16.0 19.0 24.0 49 p=0.0005 *
12週後 74 21.0 ± 6.9 11 17.0 19.0 23.0 53 p=0.0096 *
終了時 85 20.8 ± 6.6 11 16.0 19.0 23.0 53 p=0.0013 *

1）：両側検定（*: p<0.05、N.S.: p≧ 0.05）

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 2.7.6 Summary of the individual tests

Table 2.7.6.1-12 Pre- and post-dose changes in clinical laboratory values (continued)
解析対象集団：安全性解析対象集団
Wilcoxon
検査項目 投与群 時期 症例数 平均 ± 標準偏差 最小値 25%点 中央値 75%点 最大値 符号付順位検定1)

ALT(GPT) P群 開始前 101 21.4 ± 13.0 9 15.0 18.0 22.0 97 －

（IU/L） 4週後 98 21.1 ± 13.0 7 14.0 17.0 23.0 68 p=0.3193 N.S.
8週後 91 20.1 ± 10.8 5 13.0 17.0 24.0 60 p=0.3367 N.S.
12週後 94 21.7 ± 13.7 6 14.0 18.0 23.0 83 p=0.7921 N.S.
終了時 97 21.4 ± 13.6 6 14.0 18.0 23.0 83 p=0.6624 N.S.
0.1 mg群 開始前 93 21.9 ± 12.0 8 14.0 20.0 25.0 101 －
4週後 92 21.3 ± 14.4 7 14.0 17.0 21.5 103 p=0.0350 *
8週後 92 19.8 ± 10.2 6 13.0 17.0 24.0 68 p=0.0204 *
12週後 92 20.4 ± 10.8 5 14.0 18.0 23.5 74 p=0.0783 N.S.
終了時 92 20.4 ± 10.8 5 14.0 18.0 23.5 74 p=0.0783 N.S.
0.2 mg群 開始前 98 19.9 ± 11.9 8 15.0 17.5 22.0 92 －
4週後 98 18.7 ± 11.1 7 13.0 17.0 21.0 80 p=0.0025 *
8週後 95 18.4 ± 10.6 8 13.0 16.0 19.0 75 p=0.0007 *
12週後 91 18.2 ± 10.1 8 13.0 16.0 19.0 75 p=0.0033 *
終了時 95 18.2 ± 9.9 8 13.0 16.0 19.0 75 p=0.0011 *
0.5 mg群 開始前 94 19.6 ± 8.9 5 14.0 18.0 23.0 63 －
4週後 90 18.0 ± 8.1 3 13.0 17.0 21.0 52 p=0.0006 *
8週後 82 18.1 ± 9.0 6 12.0 16.5 22.0 69 p=0.0009 *
12週後 74 17.9 ± 9.4 5 12.0 15.0 23.0 60 p=0.0116 *
終了時 85 17.6 ± 8.9 5 12.0 15.0 23.0 60 p=0.0029 *
γ-GTP P群 開始前 101 27.2 ± 21.6 5 14.0 22.0 33.0 154 －
（IU/L） 4週後 98 27.3 ± 22.7 6 15.0 20.0 30.0 149 p=0.5314 N.S.
8週後 92 27.7 ± 21.9 5 14.0 21.0 33.0 140 p=0.9432 N.S.
12週後 94 27.9 ± 21.7 6 14.0 22.0 32.0 144 p=0.3175 N.S.
終了時 97 27.7 ± 21.4 6 15.0 22.0 32.0 144 p=0.2359 N.S.
0.1 mg群 開始前 93 33.1 ± 39.1 6 16.0 24.0 35.0 313 －
4週後 91 32.8 ± 52.7 6 14.0 23.0 32.0 481 p=0.1724 N.S.
8週後 91 33.5 ± 50.3 7 15.0 23.0 34.0 460 p=0.2447 N.S.
12週後 92 31.6 ± 34.0 8 15.0 23.0 35.5 271 p=0.1222 N.S.
終了時 92 31.6 ± 34.0 8 15.0 23.0 35.5 271 p=0.1222 N.S.
0.2 mg群 開始前 98 25.0 ± 20.7 5 13.0 18.0 29.0 133 －
4週後 98 25.1 ± 22.2 4 13.0 19.0 25.0 145 p=0.6655 N.S.
8週後 95 24.8 ± 22.4 5 12.0 18.0 27.0 155 p=0.3323 N.S.
12週後 90 22.9 ± 18.6 6 13.0 16.0 25.0 137 p=0.1892 N.S.
終了時 94 23.0 ± 18.2 6 13.0 17.0 25.0 137 p=0.1303 N.S.
0.5 mg群 開始前 94 32.2 ± 28.0 9 16.0 23.0 36.0 151 －
4週後 90 28.7 ± 24.3 8 15.0 21.5 33.0 164 p=0.0001 *
8週後 82 29.3 ± 24.1 9 15.0 20.5 33.0 152 p=0.0002 *
12週後 74 28.6 ± 22.5 8 15.0 20.5 32.0 135 p=0.0012 *
終了時 85 28.3 ± 21.6 8 15.0 21.0 35.0 135 p=0.0001 *
Al-P P群 開始前 101 222.3 ± 71.6 118 161.0 214.0 277.0 411 －
（IU/L） 4週後 98 220.4 ± 70.4 105 160.0 205.5 261.0 405 p=0.3889 N.S.
8週後 92 224.6 ± 74.0 101 164.5 210.5 272.0 424 p=0.7510 N.S.
12週後 94 224.8 ± 71.9 99 165.0 214.5 279.0 421 p=0.5301 N.S.
終了時 97 222.8 ± 71.6 99 164.0 210.0 276.0 421 p=0.5651 N.S.
0.1 mg群 開始前 93 222.5 ± 86.1 82 161.0 203.0 273.0 463 －
4週後 92 222.9 ± 88.8 77 160.0 205.0 268.0 595 p=0.6444 N.S.
8週後 92 224.4 ± 84.3 85 161.0 215.5 252.5 486 p=0.4335 N.S.
12週後 92 221.0 ± 80.7 86 161.0 209.0 251.0 435 p=0.9968 N.S.
終了時 92 221.0 ± 80.7 86 161.0 209.0 251.0 435 p=0.9968 N.S.
0.2 mg群 開始前 97 225.8 ± 108.5 91 148.0 200.0 273.0 670 －
4週後 97 228.1 ± 112.2 89 155.0 202.0 277.0 834 p=0.8415 N.S.
8週後 94 222.5 ± 100.6 87 152.0 210.0 274.0 681 p=0.2675 N.S.
12週後 90 221.7 ± 96.6 81 156.0 208.0 264.0 629 p=0.1317 N.S.
終了時 94 222.0 ± 96.4 81 156.0 208.0 264.0 629 p=0.2131 N.S.
0.5 mg群 開始前 94 230.8 ± 94.7 90 176.0 207.0 264.0 598 －
4週後 89 223.3 ± 89.4 90 170.0 208.0 254.0 658 p=0.1758 N.S.
8週後 82 223.9 ± 84.1 88 174.0 207.0 256.0 530 p=0.0381 *
12週後 74 221.4 ± 81.4 91 168.0 208.0 248.0 547 p=0.0004 *
終了時 85 218.2 ± 78.7 91 170.0 202.0 244.0 547 p=0.0026 *

1）：両側検定（*: p<0.05、N.S.: p≧ 0.05）

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 2.7.6 Summary of the individual tests

Table 2.7.6.1-12 Pre- and post-dose changes in clinical laboratory values (continued)
解析対象集団：安全性解析対象集団
Wilcoxon
検査項目 投与群 時期 症例数 平均 ± 標準偏差 最小値 25%点 中央値 75%点 最大値 符号付順位検定1)

LDH P群 開始前 101 274.9 ± 105.8 110 185.0 234.0 360.0 653 －
（IU/L） 4週後 98 273.7 ± 108.9 113 183.0 234.0 358.0 628 p=0.4263 N.S.
8週後 92 266.9 ± 102.4 121 181.5 223.5 353.0 482 p=0.7784 N.S.
12週後 94 273.3 ± 107.7 130 178.0 226.0 360.0 495 p=0.6304 N.S.
終了時 97 271.7 ± 107.3 121 178.0 226.0 355.0 495 p=0.4813 N.S.
0.1 mg群 開始前 92 288.6 ± 97.0 136 199.0 294.0 372.5 490 －
4週後 91 279.3 ± 106.2 132 190.0 259.0 364.0 618 p=0.1119 N.S.
8週後 91 271.1 ± 99.5 134 184.0 241.0 354.0 486 p=0.0210 *
12週後 91 271.8 ± 97.4 138 190.0 230.0 355.0 523 p=0.0245 *
終了時 91 271.8 ± 97.4 138 190.0 230.0 355.0 523 p=0.0245 *
0.2 mg群 開始前 98 280.9 ± 106.6 76 193.0 244.5 367.0 503 －
4週後 98 272.3 ± 110.2 89 184.0 232.5 350.0 591 p=0.0249 *
8週後 95 272.9 ± 109.1 80 184.0 232.0 364.0 611 p=0.0559 N.S.
12週後 91 273.4 ± 108.4 72 185.0 224.0 378.0 546 p=0.1574 N.S.
終了時 95 270.5 ± 107.1 72 185.0 220.0 378.0 546 p=0.2141 N.S.
0.5 mg群 開始前 94 289.7 ± 104.0 128 199.0 292.0 369.0 552 －
4週後 90 283.1 ± 103.4 123 189.0 290.5 368.0 517 p=0.0028 *
8週後 82 272.1 ± 99.0 131 188.0 249.5 350.0 528 p=0.0001 *
12週後 74 278.5 ± 105.4 126 186.0 266.5 357.0 539 p=0.0546 N.S.
終了時 85 274.3 ± 104.8 126 183.0 244.0 357.0 539 p=0.0057 *
クレアチニン P群 開始前 101 0.726 ± 0.206 0.40 0.580 0.700 0.800 1.33 －
（mg/dL） 4週後 98 0.744 ± 0.217 0.40 0.600 0.700 0.900 1.30 p=0.2697 N.S.
8週後 92 0.739 ± 0.220 0.40 0.580 0.700 0.800 1.50 p=0.4418 N.S.
12週後 94 0.736 ± 0.207 0.40 0.590 0.700 0.840 1.40 p=0.5824 N.S.
終了時 97 0.736 ± 0.208 0.40 0.590 0.700 0.840 1.40 p=0.7162 N.S.
0.1 mg群 開始前 93 0.715 ± 0.174 0.39 0.600 0.700 0.810 1.10 －
4週後 92 0.722 ± 0.170 0.39 0.600 0.700 0.840 1.10 p=0.2888 N.S.
8週後 92 0.725 ± 0.177 0.40 0.600 0.700 0.875 1.20 p=0.4745 N.S.
12週後 92 0.735 ± 0.175 0.39 0.600 0.700 0.890 1.20 p=0.0263 *
終了時 92 0.735 ± 0.175 0.39 0.600 0.700 0.890 1.20 p=0.0263 *
0.2 mg群 開始前 98 0.766 ± 0.200 0.47 0.600 0.700 0.900 1.47 －
4週後 98 0.780 ± 0.208 0.41 0.610 0.770 0.900 1.50 p=0.1190 N.S.
8週後 95 0.785 ± 0.220 0.40 0.620 0.760 0.900 1.91 p=0.0897 N.S.
12週後 91 0.777 ± 0.200 0.40 0.610 0.710 0.900 1.40 p=0.1584 N.S.
終了時 95 0.774 ± 0.201 0.40 0.610 0.710 0.900 1.40 p=0.2003 N.S.
0.5 mg群 開始前 94 0.788 ± 0.235 0.43 0.610 0.710 0.900 1.50 －
4週後 90 0.816 ± 0.239 0.45 0.600 0.800 0.900 1.63 p=0.0001 *
8週後 82 0.796 ± 0.237 0.42 0.600 0.800 0.910 1.59 p=0.0183 *
12週後 74 0.845 ± 0.269 0.46 0.620 0.800 0.900 1.85 p=0.0001 *
終了時 85 0.845 ± 0.274 0.45 0.620 0.800 0.900 1.85 p=0.0001 *
BUN P群 開始前 101 15.44 ± 3.76 6.0 13.50 15.00 17.40 29.0 －
（mg/dL） 4週後 98 15.82 ± 4.29 8.7 13.00 15.15 18.00 33.0 p=0.5588 N.S.
8週後 92 15.60 ± 3.70 8.0 13.00 16.00 18.00 28.0 p=0.9983 N.S.
12週後 94 16.21 ± 3.79 7.5 13.90 15.90 18.20 30.0 p=0.2464 N.S.
終了時 97 16.14 ± 3.81 7.5 13.90 16.00 18.00 30.0 p=0.1904 N.S.
0.1 mg群 開始前 93 15.93 ± 4.18 9.0 13.00 15.80 18.00 31.0 －
4週後 92 15.94 ± 4.09 7.0 13.65 15.85 17.75 29.0 p=0.8910 N.S.
8週後 92 15.64 ± 3.91 10.0 12.45 15.15 17.55 28.7 p=0.2118 N.S.
12週後 92 16.41 ± 4.51 9.0 13.10 16.00 19.00 30.1 p=0.2565 N.S.
終了時 92 16.41 ± 4.51 9.0 13.10 16.00 19.00 30.1 p=0.2565 N.S.
0.2 mg群 開始前 97 16.62 ± 4.85 8.0 13.10 15.60 19.00 33.0 －
4週後 97 16.46 ± 4.93 7.0 13.00 16.00 19.00 38.4 p=0.8418 N.S.
8週後 94 16.90 ± 5.53 8.0 13.00 15.60 19.00 41.5 p=0.9459 N.S.
12週後 90 16.39 ± 4.91 4.0 13.50 16.00 18.60 32.3 p=0.5408 N.S.
終了時 94 16.30 ± 4.86 4.0 13.00 16.00 18.60 32.3 p=0.4508 N.S.
0.5 mg群 開始前 93 16.54 ± 5.05 5.0 13.00 16.00 19.00 29.0 －
4週後 89 17.17 ± 5.85 7.0 13.00 16.00 19.50 35.9 p=0.0942 N.S.
8週後 81 16.73 ± 5.05 8.0 13.20 16.00 19.00 31.0 p=0.3979 N.S.
12週後 73 17.00 ± 5.89 8.0 12.50 16.00 19.90 37.1 p=0.6069 N.S.
終了時 84 17.05 ± 6.05 8.0 12.40 15.70 19.95 37.1 p=0.4360 N.S.

1）：両側検定（*: p<0.05、N.S.: p≧ 0.05）

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 2.7.6 Summary of the individual tests

Table 2.7.6.1-12 Pre- and post-dose changes in clinical laboratory values (continued)
解析対象集団：安全性解析対象集団
Wilcoxon
検査項目 投与群 時期 症例数 平均 ± 標準偏差 最小値 25%点 中央値 75%点 最大値 符号付順位検定1)

トリグリセライド P群 開始前 101 131.9 ± 86.2 28 77.0 111.0 164.0 585 －

（mg/dL） 4週後 98 151.2 ± 98.1 39 89.0 117.0 196.0 533 p=0.0102 *
8週後 92 135.9 ± 78.7 29 79.0 118.0 168.0 450 p=0.3234 N.S.
12週後 94 137.9 ± 73.9 39 81.0 116.0 179.0 393 p=0.0700 N.S.
終了時 97 136.5 ± 73.8 39 79.0 114.0 179.0 393 p=0.0612 N.S.
0.1 mg群 開始前 94 151.5 ± 108.7 29 79.0 123.5 200.0 746 －
4週後 92 142.8 ± 89.6 24 80.0 126.0 178.0 490 p=0.4503 N.S.
8週後 92 157.3 ± 116.1 31 83.0 121.5 202.5 653 p=0.7404 N.S.
12週後 92 153.6 ± 103.1 32 79.5 134.5 193.5 606 p=0.3181 N.S.
終了時 92 153.6 ± 103.1 32 79.5 134.5 193.5 606 p=0.3181 N.S.
0.2 mg群 開始前 98 125.5 ± 73.0 31 73.0 106.0 154.0 444 －
4週後 97 119.9 ± 65.6 37 73.0 101.0 150.0 320 p=0.4961 N.S.
8週後 95 124.2 ± 72.2 33 74.0 94.0 158.0 388 p=0.6372 N.S.
12週後 90 123.8 ± 77.6 39 67.0 101.5 153.0 473 p=0.7342 N.S.
終了時 94 122.4 ± 76.3 39 67.0 101.5 142.0 473 p=0.6533 N.S.
0.5 mg群 開始前 94 129.0 ± 68.4 34 85.0 113.5 149.0 431 －
4週後 90 130.4 ± 66.4 31 84.0 116.5 164.0 380 p=0.6290 N.S.
8週後 82 137.1 ± 73.6 35 82.0 116.0 183.0 382 p=0.3255 N.S.
12週後 74 129.0 ± 68.4 44 80.0 113.0 158.0 356 p=0.3714 N.S.
終了時 85 129.8 ± 67.6 44 80.0 113.0 159.0 356 p=0.3377 N.S.
総コレステロール P群 開始前 100 208.2 ± 37.7 132 185.5 203.5 229.0 398 －
（mg/dL） 4週後 97 205.4 ± 38.2 122 184.0 201.0 226.0 412 p=0.1821 N.S.
8週後 91 201.4 ± 31.8 112 180.0 204.0 223.0 300 p=0.0606 N.S.
12週後 93 203.6 ± 34.5 124 185.0 206.0 222.0 302 p=0.0657 N.S.
終了時 96 202.8 ± 34.3 124 184.0 204.0 221.5 302 p=0.0511 N.S.
0.1 mg群 開始前 93 215.3 ± 36.9 137 193.0 218.0 241.0 304 －
4週後 92 210.9 ± 33.6 137 187.5 214.0 234.0 314 p=0.0500 *
8週後 92 208.9 ± 36.3 134 184.5 209.5 232.0 313 p=0.0045 *
12週後 92 208.0 ± 31.9 137 188.0 204.5 226.5 290 p=0.0014 *
終了時 92 208.0 ± 31.9 137 188.0 204.5 226.5 290 p=0.0014 *
0.2 mg群 開始前 98 204.0 ± 34.5 122 181.0 201.0 225.0 309 －
4週後 97 198.8 ± 33.7 121 179.0 191.0 225.0 296 p=0.0115 *
8週後 95 199.1 ± 36.7 120 174.0 198.0 223.0 315 p=0.0099 *
12週後 90 198.6 ± 34.3 118 177.0 195.5 226.0 290 p=0.0047 *
終了時 94 198.1 ± 33.8 118 177.0 193.5 225.0 290 p=0.0017 *
0.5 mg群 開始前 93 209.0 ± 35.8 131 189.0 207.0 229.0 329 －
4週後 89 203.1 ± 34.6 114 180.0 204.0 223.0 311 p=0.0027 *
8週後 81 204.4 ± 37.0 121 180.0 203.0 223.0 349 p=0.0012 *
12週後 73 205.2 ± 35.7 126 183.0 205.0 223.0 345 p=0.0011 *
終了時 84 202.3 ± 36.1 126 179.5 203.0 222.5 345 p=0.0007 *
尿酸 P群 開始前 101 4.99 ± 1.54 1.8 3.80 4.80 5.70 9.3 －
（mg/dL） 4週後 98 5.01 ± 1.51 2.1 4.00 4.70 5.90 9.4 p=0.7056 N.S.
8週後 92 5.01 ± 1.52 1.7 3.90 4.80 6.00 9.2 p=0.4820 N.S.
12週後 94 5.21 ± 1.53 2.5 3.90 4.90 6.00 10.2 p=0.0500 N.S.
終了時 97 5.16 ± 1.55 1.7 3.90 4.80 6.00 10.2 p=0.0655 N.S.
0.1 mg群 開始前 93 4.71 ± 1.28 2.2 3.90 4.60 5.40 8.8 －
4週後 91 4.84 ± 1.36 1.8 4.00 4.70 5.60 9.4 p=0.0832 N.S.
8週後 92 4.81 ± 1.43 1.8 3.85 4.60 5.80 9.3 p=0.2286 N.S.
12週後 92 4.94 ± 1.46 1.9 4.00 4.80 5.70 9.6 p=0.0019 *
終了時 92 4.94 ± 1.46 1.9 4.00 4.80 5.70 9.6 p=0.0019 *
0.2 mg群 開始前 98 4.86 ± 1.29 2.3 3.80 4.90 5.80 7.3 －
4週後 98 4.91 ± 1.35 2.3 3.90 4.80 5.80 9.1 p=0.6771 N.S.
8週後 95 5.01 ± 1.39 2.5 4.00 5.00 5.90 9.2 p=0.2064 N.S.
12週後 91 4.96 ± 1.36 2.2 4.00 4.80 6.10 8.1 p=0.0508 N.S.
終了時 95 4.96 ± 1.36 2.2 4.00 4.80 6.10 8.1 p=0.0903 N.S.
0.5 mg群 開始前 94 4.92 ± 1.33 2.2 4.00 4.85 5.70 8.5 －
4週後 90 5.06 ± 1.31 1.8 4.30 4.75 5.90 8.6 p=0.0327 *
8週後 82 5.11 ± 1.34 2.2 4.30 4.95 5.70 8.8 p=0.0792 N.S.
12週後 73 5.16 ± 1.41 2.3 4.40 5.00 6.00 9.9 p=0.0128 *
終了時 84 5.08 ± 1.38 2.3 4.30 4.90 5.90 9.9 p=0.0892 N.S.

1）：両側検定（*: p<0.05、N.S.: p≧ 0.05）

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 2.7.6 Summary of the individual tests

Table 2.7.6.1-12 Pre- and post-dose changes in clinical laboratory values (continued)
解析対象集団：安全性解析対象集団
Wilcoxon
検査項目 投与群 時期 症例数 平均 ± 標準偏差 最小値 25%点 中央値 75%点 最大値 符号付順位検定1)

Na P群 開始前 101 141.25 ± 2.25 133.0 140.00 141.00 143.00 148.0 －

（mEq/L） 4週後 98 141.47 ± 2.10 137.0 140.00 141.00 143.00 148.0 p=0.6982 N.S.
8週後 92 141.05 ± 2.17 136.0 140.00 141.00 143.00 146.0 p=0.3273 N.S.
12週後 94 141.57 ± 1.96 137.0 140.00 141.65 143.00 147.0 p=0.2240 N.S.
終了時 97 141.56 ± 1.94 137.0 140.00 141.30 143.00 147.0 p=0.1775 N.S.
0.1 mg群 開始前 93 141.34 ± 2.19 135.1 140.00 141.00 143.00 147.0 －
4週後 91 141.09 ± 2.49 135.5 139.00 141.00 143.00 147.0 p=0.5118 N.S.
8週後 92 141.39 ± 2.38 136.0 140.00 142.00 143.00 147.0 p=0.9370 N.S.
12週後 92 141.55 ± 2.27 137.0 140.00 141.00 143.00 147.0 p=0.3579 N.S.
終了時 92 141.55 ± 2.27 137.0 140.00 141.00 143.00 147.0 p=0.3579 N.S.
0.2 mg群 開始前 98 141.08 ± 2.39 135.0 140.00 141.00 143.00 148.0 －
4週後 98 141.38 ± 2.16 137.0 140.00 141.00 143.00 148.0 p=0.1905 N.S.
8週後 95 141.54 ± 2.13 136.0 140.00 141.00 143.00 146.0 p=0.0300 *
12週後 91 141.47 ± 2.29 135.0 140.00 141.00 143.00 148.0 p=0.0737 N.S.
終了時 95 141.51 ± 2.27 135.0 140.00 141.00 143.00 148.0 p=0.0675 N.S.
0.5 mg群 開始前 94 141.31 ± 2.25 134.0 140.00 141.90 143.00 145.0 －
4週後 90 141.41 ± 2.14 135.0 140.00 141.00 143.00 147.0 p=0.6645 N.S.
8週後 82 141.54 ± 2.07 136.0 140.90 141.00 143.00 147.0 p=0.1379 N.S.
12週後 74 141.30 ± 2.42 135.4 140.00 141.00 143.00 147.0 p=0.6911 N.S.
終了時 85 141.43 ± 2.42 135.4 140.00 141.00 143.00 147.0 p=0.4335 N.S.
K P群 開始前 101 4.188 ± 0.377 3.50 4.000 4.100 4.400 5.50 －
（mEq/L） 4週後 98 4.075 ± 0.319 3.40 3.800 4.060 4.300 4.90 p=0.0037 *
8週後 92 4.088 ± 0.355 3.40 3.900 4.000 4.200 5.50 p=0.0319 *
12週後 94 4.063 ± 0.334 3.40 3.800 4.000 4.300 5.10 p=0.0011 *
終了時 97 4.065 ± 0.332 3.40 3.800 4.000 4.300 5.10 p=0.0017 *
0.1 mg群 開始前 93 4.124 ± 0.421 3.30 3.900 4.100 4.400 5.90 －
4週後 91 4.084 ± 0.311 3.36 3.900 4.100 4.300 4.90 p=0.3252 N.S.
8週後 92 4.056 ± 0.323 3.30 3.890 4.000 4.235 5.10 p=0.1468 N.S.
12週後 92 4.055 ± 0.328 3.30 3.800 4.100 4.300 4.90 p=0.1276 N.S.
終了時 92 4.055 ± 0.328 3.30 3.800 4.100 4.300 4.90 p=0.1276 N.S.
0.2 mg群 開始前 98 4.172 ± 0.375 3.40 3.900 4.100 4.400 5.50 －
4週後 98 4.121 ± 0.296 3.50 3.900 4.100 4.300 4.90 p=0.1714 N.S.
8週後 95 4.120 ± 0.313 3.30 3.900 4.100 4.300 5.20 p=0.0678 N.S.
12週後 91 4.094 ± 0.293 3.30 3.900 4.100 4.300 4.80 p=0.0090 *
終了時 95 4.081 ± 0.295 3.30 3.900 4.100 4.280 4.80 p=0.0065 *
0.5 mg群 開始前 94 4.173 ± 0.314 3.50 3.900 4.100 4.400 5.00 －
4週後 90 4.111 ± 0.310 3.30 4.000 4.100 4.300 4.80 p=0.1675 N.S.
8週後 82 4.108 ± 0.318 3.20 3.900 4.100 4.300 4.80 p=0.1827 N.S.
12週後 74 4.063 ± 0.305 3.00 3.900 4.100 4.200 4.70 p=0.0045 *
終了時 85 4.080 ± 0.311 3.00 3.900 4.100 4.200 4.90 p=0.0205 *
Cl P群 開始前 101 104.55 ± 2.75 94.0 103.00 105.00 106.00 110.0 －
（mEq/L） 4週後 98 104.86 ± 2.62 95.0 103.00 105.00 106.00 112.0 p=0.2740 N.S.
8週後 92 104.77 ± 2.34 97.0 104.00 105.00 106.00 111.0 p=0.3425 N.S.
12週後 94 104.92 ± 2.62 98.0 103.00 105.00 107.00 111.0 p=0.0594 N.S.
終了時 97 104.92 ± 2.60 98.0 103.00 105.00 107.00 111.0 p=0.0495 *
0.1 mg群 開始前 93 104.29 ± 2.54 96.1 103.00 105.00 106.00 110.0 －
4週後 91 104.49 ± 2.40 98.0 103.00 104.00 106.20 109.0 p=0.5263 N.S.
8週後 92 104.52 ± 2.66 98.0 103.00 104.00 106.00 111.0 p=0.4586 N.S.
12週後 92 104.54 ± 2.53 98.0 103.00 104.35 106.00 111.0 p=0.4215 N.S.
終了時 92 104.54 ± 2.53 98.0 103.00 104.35 106.00 111.0 p=0.4215 N.S.
0.2 mg群 開始前 98 104.63 ± 2.78 99.0 103.00 104.95 107.00 110.2 －
4週後 98 104.75 ± 2.59 99.0 103.00 104.60 106.40 111.0 p=0.4732 N.S.
8週後 95 104.93 ± 2.37 100.0 103.00 105.00 107.00 110.0 p=0.1156 N.S.
12週後 91 105.19 ± 2.71 98.0 103.00 105.00 106.70 112.0 p=0.0408 *
終了時 95 105.18 ± 2.73 98.0 103.00 105.00 106.70 112.0 p=0.0801 N.S.
0.5 mg群 開始前 94 104.55 ± 2.76 94.0 103.00 105.00 106.00 109.7 －
4週後 90 104.93 ± 2.74 98.0 103.20 105.00 106.80 113.3 p=0.1701 N.S.
8週後 82 105.22 ± 2.24 99.0 104.00 105.00 107.00 112.0 p=0.0009 *
12週後 74 104.61 ± 2.63 97.0 103.00 104.80 106.00 111.3 p=0.6368 N.S.
終了時 85 104.72 ± 2.55 97.0 103.00 105.00 106.00 111.3 p=0.4950 N.S.

1）：両側検定（*: p<0.05、N.S.: p≧ 0.05）

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 2.7.6 Summary of the individual tests

Table 2.7.6.1-12 Pre- and post-dose changes in clinical laboratory values (continued)
解析対象集団：安全性解析対象集団
Wilcoxon
1)
検査項目 投与群 時期 症例数 - ± + ++ +++ ++++ 符号付順位検定

P群 開始前 100 88 6 4 1 1 0 －
4週後 97 84 12 0 1 0 0 p=0.3569 N.S.
8週後 90 81 6 3 0 0 0 p=0.2750 N.S.
12週後 93 79 10 4 0 0 0 p=0.8160 N.S.
終了時 96 82 10 4 0 0 0 p=0.8160 N.S.
0.1 mg群 開始前 93 83 7 1 2 0 0 －
4週後 92 82 6 2 2 0 0 p=0.4629 N.S.
8週後 92 83 4 3 2 0 0 p=0.8111 N.S.
12週後 91 82 4 4 1 0 0 p=1.0000 N.S.
尿蛋白 終了時 91 82 4 4 1 0 0 p=1.0000 N.S.
0.2 mg群 開始前 98 86 7 4 0 1 0 －
4週後 97 92 2 1 1 1 0 p=0.1191 N.S.
8週後 95 85 7 2 0 1 0 p=0.3828 N.S.
12週後 91 78 7 4 1 1 0 p=0.7291 N.S.
終了時 95 81 7 5 1 1 0 p=0.5069 N.S.
0.5 mg群 開始前 92 80 6 3 2 1 0 －
4週後 88 79 3 4 2 0 0 p=0.4312 N.S.
8週後 82 68 8 3 3 0 0 p=0.8518 N.S.
12週後 73 62 7 3 1 0 0 p=0.9646 N.S.
終了時 83 70 8 4 1 0 0 p=0.9646 N.S.
P群 開始前 101 91 3 2 1 3 1 －
4週後 98 90 2 2 2 1 1 p=0.2852 N.S.
8週後 91 82 3 2 1 1 2 p=0.8125 N.S.
12週後 94 85 2 3 1 3 0 p=0.6719 N.S.
終了時 97 88 2 3 1 3 0 p=0.6719 N.S.
0.1 mg群 開始前 93 86 2 2 1 1 1 －
4週後 92 85 3 1 2 1 0 p=1.0000 N.S.
8週後 92 84 2 0 0 5 1 p=0.1484 N.S.
12週後 91 85 2 2 0 2 0 p=0.7500 N.S.
尿糖 終了時 91 85 2 2 0 2 0 p=0.7500 N.S.
0.2 mg群 開始前 98 86 1 3 2 3 3 －
4週後 98 89 4 0 0 4 1 p=0.0313 *
8週後 95 82 3 5 0 2 3 p=0.7148 N.S.
12週後 91 83 2 1 1 3 1 p=0.1016 N.S.
終了時 95 87 2 1 1 3 1 p=0.1016 N.S.
0.5 mg群 開始前 93 87 0 0 1 2 3 －
4週後 89 80 2 3 0 3 1 p=0.4688 N.S.
8週後 82 75 1 1 1 3 1 p=0.7500 N.S.
12週後 73 67 1 1 1 2 1 p=1.0000 N.S.
終了時 84 77 1 2 1 2 1 p=1.0000 N.S.
P群 開始前 101 2 97 1 1 0 0 －
4週後 98 1 94 3 0 0 0 p=1.0000 N.S.
8週後 91 0 90 1 0 0 0 p=1.0000 N.S.
12週後 94 1 89 4 0 0 0 p=0.6250 N.S.
終了時 97 1 92 4 0 0 0 p=0.6250 N.S.
0.1 mg群 開始前 93 4 88 0 1 0 0 －
4週後 92 4 87 1 0 0 0 p=1.0000 N.S.
8週後 92 3 88 1 0 0 0 p=1.0000 N.S.
12週後 91 2 89 0 0 0 0 p=1.0000 N.S.
尿ウロビリノゲン 終了時 91 2 89 0 0 0 0 p=1.0000 N.S.
0.2 mg群 開始前 97 1 92 4 0 0 0 －
4週後 97 3 94 0 0 0 0 p=0.0625 N.S.
8週後 94 2 90 2 0 0 0 p=0.4531 N.S.
12週後 90 1 88 1 0 0 0 p=0.2500 N.S.
終了時 94 1 91 2 0 0 0 p=0.6250 N.S.
0.5 mg群 開始前 92 2 88 2 0 0 0 －
4週後 88 0 87 1 0 0 0 p=1.0000 N.S.
8週後 81 1 80 0 0 0 0 p=1.0000 N.S.
12週後 73 2 70 1 0 0 0 p=1.0000 N.S.
終了時 83 2 80 1 0 0 0 p=1.0000 N.S.

1）：両側検定（*: p<0.05、N.S.: p≧ 0.05）

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 Table 2.7.6.1-13 List of adverse events by severity
投与群 0.1 mg/日 0.2 mg/日 0.5 mg/日 プラセボ
安全性解析対象集団 99 100 101 101
重症度 軽度 中等度 高度 計 軽度 中等度 高度 計 軽度 中等度 高度 計 軽度 中等度 高度 計
有害事象項目 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数
全例 46 ( 46.5) 106 15 ( 15.2) 27 4 ( 4.0) 4 65 ( 65.7) 137 52 ( 52.0) 136 12 ( 12.0) 19 2 ( 2.0) 2 66 ( 66.0) 157 52 ( 51.5) 199 26 ( 25.7) 55 7 ( 6.9) 7 85 ( 84.2) 261 42 ( 41.6) 102 14 ( 13.9) 24 56 ( 55.4) 126
心臓障害 4 ( 4.0) 4 4 ( 4.0) 4 2 ( 2.0) 2 1 ( 1.0) 1 3 ( 3.0) 3 3 ( 3.0) 5 3 ( 3.0) 5 4 ( 4.0) 6 4 ( 4.0) 6
動悸 1 ( 1.0) 1 1 ( 1.0) 1 1 ( 1.0) 1 1 ( 1.0) 1 1 ( 1.0) 1 1 ( 1.0) 1
洞性不整脈 2 ( 2.0) 2 2 ( 2.0) 2 1 ( 1.0) 1 1 ( 1.0) 1
上室性期外収縮 2 ( 2.0) 2 2 ( 2.0) 2 1 ( 1.0) 1 1 ( 1.0) 1
心室性期外収縮 1 ( 1.0) 1 1 ( 1.0) 1 1 ( 1.0) 1 1 ( 1.0) 1 1 ( 1.0) 1 1 ( 1.0) 1
不整脈 1 ( 1.0) 1 1 ( 1.0) 1
右脚ブロック 1 ( 1.0) 1 1 ( 1.0) 1
結節性調律 1 ( 1.0) 2 1 ( 1.0) 2
洞性徐脈 1 ( 1.0) 1 1 ( 1.0) 1
洞性頻脈 1 ( 1.0) 1 1 ( 1.0) 1
耳および迷路障害 1 ( 1.0) 1 1 ( 1.0) 1
ろう 1 ( 1.0) 1 1 ( 1.0) 1
眼障害 4 ( 4.0) 4 4 ( 4.0) 4 7 ( 7.0) 10 1 ( 1.0) 1 8 ( 8.0) 11 14 ( 13.9) 19 1 ( 1.0) 1 15 ( 14.9) 20 3 ( 3.0) 3 3 ( 3.0) 3
眼の異常感 2 ( 2.0) 2 2 ( 2.0) 2 2 ( 2.0) 2 2 ( 2.0) 2 5 ( 5.0) 5 5 ( 5.0) 5 1 ( 1.0) 1 1 ( 1.0) 1
霧視 1 ( 1.0) 1 1 ( 1.0) 1 4 ( 4.0) 6 4 ( 4.0) 6
眼脂 1 ( 1.0) 1 1 ( 1.0) 1 1 ( 1.0) 1 1 ( 1.0) 1 1 ( 1.0) 1 1 ( 1.0) 1
羞明 3 ( 3.0) 3 3 ( 3.0) 3
眼精疲労 1 ( 1.0) 1 1 ( 1.0) 1
眼瞼痙攣 1 ( 1.0) 1 1 ( 1.0) 1
結膜出血 1 ( 1.0) 1 1 ( 1.0) 1
結膜炎 1 ( 1.0) 1 1 ( 1.0) 1
アレルギー性結膜炎 1 ( 1.0) 1 1 ( 1.0) 1
複視 1 ( 1.0) 1 1 ( 1.0) 1
眼瞼浮腫 1 ( 1.0) 1 1 ( 1.0) 1
緑内障 1 ( 1.0) 1 1 ( 1.0) 1
流涙増加 1 ( 1.0) 1 1 ( 1.0) 1
光視症 1 ( 1.0) 1 1 ( 1.0) 1
網膜裂孔 1 ( 1.0) 1 1 ( 1.0) 1
視覚障害 1 ( 1.0) 2 1 ( 1.0) 2
眼球乾燥 1 ( 1.0) 1 1 ( 1.0) 1
眼そう痒症 1 ( 1.0) 1 1 ( 1.0) 1
胃腸障害 17 ( 17.2) 18 2 ( 2.0) 3 19 ( 19.2) 21 16 ( 16.0) 28 4 ( 4.0) 5 20 ( 20.0) 33 25 ( 24.8) 45 7 ( 6.9) 15 32 ( 31.7) 60 12 ( 11.9) 16 4 ( 4.0) 4 16 ( 15.8) 20
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便秘 2 ( 2.0) 2 1 ( 1.0) 2 3 ( 3.0) 4 11 ( 11.0) 14 1 ( 1.0) 1 12 ( 12.0) 15 9 ( 8.9) 12 1 ( 1.0) 1 10 ( 9.9) 13 3 ( 3.0) 3 1 ( 1.0) 1 4 ( 4.0) 4
悪心 2 ( 2.0) 2 2 ( 2.0) 2 1 ( 1.0) 1 1 ( 1.0) 1 2 ( 2.0) 2 4 ( 4.0) 4 4 ( 4.0) 5 8 ( 7.9) 9 1 ( 1.0) 1 1 ( 1.0) 1 2 ( 2.0) 2
下痢 4 ( 4.0) 4 4 ( 4.0) 4 2 ( 2.0) 2 2 ( 2.0) 2 1 ( 1.0) 1 1 ( 1.0) 1 3 ( 3.0) 3 3 ( 3.0) 3
上腹部痛 2 ( 2.0) 2 2 ( 2.0) 2 1 ( 1.0) 1 1 ( 1.0) 1 2 ( 2.0) 2 2 ( 2.0) 2 1 ( 1.0) 1 3 ( 3.0) 3 1 ( 1.0) 1 1 ( 1.0) 1
消化不良 2 ( 2.0) 2 2 ( 2.0) 2 5 ( 5.0) 7 1 ( 1.0) 1 6 ( 5.9) 8
胃不快感 1 ( 1.0) 1 1 ( 1.0) 1 2 ( 2.0) 2 2 ( 2.0) 2 2 ( 2.0) 5 2 ( 2.0) 3 4 ( 4.0) 8 1 ( 1.0) 1 1 ( 1.0) 1
嘔吐 1 ( 1.0) 1 1 ( 1.0) 1 1 ( 1.0) 1 1 ( 1.0) 1 3 ( 3.0) 4 2 ( 2.0) 2 5 ( 5.0) 6
腹痛 1 ( 1.0) 1 1 ( 1.0) 1 1 ( 1.0) 1 2 ( 2.0) 2 3 ( 3.0) 3 2 ( 2.0) 2 2 ( 2.0) 2
腹部膨満 1 ( 1.0) 1 1 ( 1.0) 1 1 ( 1.0) 1 1 ( 1.0) 1 1 ( 1.0) 1 1 ( 1.0) 1
軟便 1 ( 1.0) 1 1 ( 1.0) 1 2 ( 2.0) 2 2 ( 2.0) 2
歯痛 1 ( 1.0) 1 2 ( 2.0) 2 3 ( 3.0) 3
鼓腸 1 ( 1.0) 1 1 ( 1.0) 1 1 ( 1.0) 1 1 ( 1.0) 1
胃炎 1 ( 1.0) 1 1 ( 1.0) 1 1 ( 1.0) 1 1 ( 1.0) 1
歯肉腫脹 1 ( 1.0) 1 1 ( 1.0) 1 1 ( 1.0) 1 1 ( 1.0) 1
舌炎 1 ( 1.0) 1 1 ( 1.0) 1 1 ( 1.0) 1 1 ( 1.0) 1
口唇乾燥 1 ( 1.0) 1 1 ( 1.0) 1 1 ( 1.0) 1 1 ( 1.0) 1
口内炎 1 ( 1.0) 1 1 ( 1.0) 1 1 ( 1.0) 1 1 ( 1.0) 1
腹部不快感 1 ( 1.0) 1 1 ( 1.0) 1
下腹部痛 1 ( 1.0) 1 1 ( 1.0) 1
口唇炎 1 ( 1.0) 1 1 ( 1.0) 1
胃ポリープ 1 ( 1.0) 1 1 ( 1.0) 1
胃食道逆流性疾患 1 ( 1.0) 1 1 ( 1.0) 1
口腔内不快感 1 ( 1.0) 1 1 ( 1.0) 1
舌苔 1 ( 1.0) 1 1 ( 1.0) 1
胃腸不快感 1 ( 1.0) 1 1 ( 1.0) 1
全身障害および投与局所様態 14 ( 14.1) 15 4 ( 4.0) 4 2 ( 2.0) 2 20 ( 20.2) 21 22 ( 22.0) 24 5 ( 5.0) 5 1 ( 1.0) 1 28 ( 28.0) 30 33 ( 32.7) 41 13 ( 12.9) 13 6 ( 5.9) 6 52 ( 51.5) 60 12 ( 11.9) 13 2 ( 2.0) 2 14 ( 13.9) 15
口渇 12 ( 12.1) 12 3 ( 3.0) 3 1 ( 1.0) 1 16 ( 16.2) 16 18 ( 18.0) 20 5 ( 5.0) 5 1 ( 1.0) 1 24 ( 24.0) 26 32 ( 31.7) 35 13 ( 12.9) 13 6 ( 5.9) 6 51 ( 50.5) 54 9 ( 8.9) 9 1 ( 1.0) 1 10 ( 9.9) 10
末梢性浮腫 1 ( 1.0) 1 1 ( 1.0) 1 1 ( 1.0) 1 1 ( 1.0) 1 2 ( 2.0) 2 2 ( 2.0) 2
倦怠感 3 ( 3.0) 3 3 ( 3.0) 3
浮腫 1 ( 1.0) 1 1 ( 1.0) 1 1 ( 1.0) 1 1 ( 1.0) 1 1 ( 1.0) 1 1 ( 1.0) 1
1 ( 1.0) 1 1 ( 1.0) 1 1 ( 1.0) 1 1 ( 1.0) 1 1 ( 1.0) 1 1 ( 1.0) 1

2.7.6 Summary of the

発熱
胸痛 1 ( 1.0) 1 1 ( 1.0) 1 1 ( 1.0) 1 1 ( 1.0) 1
無力症 1 ( 1.0) 1 1 ( 1.0) 1
胸部不快感 1 ( 1.0) 1 1 ( 1.0) 1
異常感 1 ( 1.0) 1 1 ( 1.0) 1

individual tests
冷感 1 ( 1.0) 1 1 ( 1.0) 1
異物感 1 ( 1.0) 1 1 ( 1.0) 1
肝胆道系障害 1 ( 1.0) 1 1 ( 1.0) 1
胆石症 1 ( 1.0) 1 1 ( 1.0) 1
免疫系障害 1 ( 1.0) 1 1 ( 1.0) 1
季節性アレルギー 1 ( 1.0) 1 1 ( 1.0) 1
感染症および寄生虫症 15 ( 15.2) 18 4 ( 4.0) 4 19 ( 19.2) 22 13 ( 13.0) 17 2 ( 2.0) 3 15 ( 15.0) 20 13 ( 12.9) 18 2 ( 2.0) 2 15 ( 14.9) 20 13 ( 12.9) 16 3 ( 3.0) 5 16 ( 15.8) 21
鼻咽頭炎 11 ( 11.1) 12 2 ( 2.0) 2 13 ( 13.1) 14 9 ( 9.0) 10 1 ( 1.0) 1 10 ( 10.0) 11 9 ( 8.9) 11 1 ( 1.0) 1 10 ( 9.9) 12 12 ( 11.9) 13 2 ( 2.0) 2 14 ( 13.9) 15
膀胱炎 4 ( 4.0) 4 4 ( 4.0) 4 2 ( 2.0) 2 2 ( 2.0) 2 4 ( 4.0) 5 4 ( 4.0) 5 1 ( 1.0) 1 1 ( 1.0) 1
齲歯 1 ( 1.0) 1 1 ( 1.0) 1 2 ( 2.0) 2
鼻炎 1 ( 1.0) 1 1 ( 1.0) 1 1 ( 1.0) 1 1 ( 1.0) 1
白癬 1 ( 1.0) 1 1 ( 1.0) 1 1 ( 1.0) 1 1 ( 1.0) 1
咽喉頭炎 1 ( 1.0) 1 1 ( 1.0) 1 1 ( 1.0) 1 1 ( 1.0) 1
膀胱炎 1 ( 1.0) 1 1 ( 1.0) 1
カンジダ症 1 ( 1.0) 1 1 ( 1.0) 1
蜂巣炎 1 ( 1.0) 1 1 ( 1.0) 1
帯状疱疹 1 ( 1.0) 1 1 ( 1.0) 1
口腔カンジダ症 1 ( 1.0) 1 1 ( 1.0) 1
中耳炎 1 ( 1.0) 1 1 ( 1.0) 1
 Table 2.7.6.1-13 List of adverse events by severity (continued)
投与群 0.1 mg/日 0.2 mg/日 0.5 mg/日 プラセボ
安全性解析対象集団 99 100 101 101
重症度 軽度 中等度 高度 計 軽度 中等度 高度 計 軽度 中等度 高度 計 軽度 中等度 高度 計
有害事象項目 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数
肺炎 1 ( 1.0) 1 1 ( 1.0) 1
皮下組織膿瘍 1 ( 1.0) 1 1 ( 1.0) 1
トリコモナス症 1 ( 1.0) 1 1 ( 1.0) 1
上気道感染 1 ( 1.0) 1 1 ( 1.0) 1
尿路感染 1 ( 1.0) 1 1 ( 1.0) 1
傷害、中毒および処置合併症 3 ( 3.0) 3 1 ( 1.0) 1 1 ( 1.0) 1 5 ( 5.1) 5 1 ( 1.0) 1 1 ( 1.0) 1 2 ( 2.0) 2 1 ( 1.0) 1 1 ( 1.0) 1
足骨折 1 ( 1.0) 1 1 ( 1.0) 1 1 ( 1.0) 1 1 ( 1.0) 1
事故 1 ( 1.0) 1 1 ( 1.0) 1
胸部の圧挫傷 1 ( 1.0) 1 1 ( 1.0) 1
異物による損傷 1 ( 1.0) 1 1 ( 1.0) 1
手骨折 1 ( 1.0) 1 1 ( 1.0) 1
損傷 1 ( 1.0) 1 1 ( 1.0) 1
関節捻挫 1 ( 1.0) 1 1 ( 1.0) 1
臨床検査 14 ( 14.1) 23 1 ( 1.0) 1 15 ( 15.2) 24 18 ( 18.0) 20 1 ( 1.0) 1 19 ( 19.0) 21 17 ( 16.8) 29 3 ( 3.0) 3 20 ( 19.8) 32 16 ( 15.8) 22 3 ( 3.0) 5 19 ( 18.8) 27
尿中白血球陽性 4 ( 4.3) 4 1 ( 1.1) 1 5 ( 5.4) 5 9 ( 9.2) 9 1 ( 1.0) 1 10 ( 10.2) 10 4 ( 4.3) 5 4 ( 4.3) 5 4 ( 4.0) 4 4 ( 4.0) 4
血中トリグリセリド増加 3 ( 3.2) 3 3 ( 3.2) 3 1 ( 1.1) 1 1 ( 1.1) 1 2 ( 2.1) 2 5 ( 5.0) 5 1 ( 1.0) 1 6 ( 5.9) 6
尿中赤血球陽性 2 ( 2.2) 2 2 ( 2.2) 2 3 ( 3.3) 3 3 ( 3.3) 3 3 ( 3.0) 3 3 ( 3.0) 3
血中尿酸増加 2 ( 2.2) 2 2 ( 2.2) 2 4 ( 4.1) 4 4 ( 4.1) 4 2 ( 2.1) 2 2 ( 2.1) 2
尿中蛋白陽性 1 ( 1.1) 1 1 ( 1.1) 1 1 ( 1.0) 1 1 ( 1.0) 1 2 ( 2.2) 2 2 ( 2.2) 2 1 ( 1.0) 1 1 ( 1.0) 1
γ-グルタミルトランスフェラーゼ増加 3 ( 3.2) 3 3 ( 3.2) 3 1 ( 1.0) 1 1 ( 1.0) 1 1 ( 1.1) 1 1 ( 1.1) 1
ヘモグロビン減少 3 ( 3.2) 3 3 ( 3.2) 3 1 ( 1.0) 1 1 ( 1.0) 1
血圧上昇 2 ( 2.0) 2 1 ( 1.0) 1 3 ( 3.0) 3 1 ( 1.0) 1 1 ( 1.0) 1
血中コレステロール増加 2 ( 2.0) 2 2 ( 2.0) 2 1 ( 1.0) 1 1 ( 1.0) 1
血中尿素増加 1 ( 1.1) 1 1 ( 1.1) 1 1 ( 1.0) 1 1 ( 1.0) 1 1 ( 1.0) 1 1 ( 1.0) 1
血中アルカリホスファターゼ増加 1 ( 1.0) 1 1 ( 1.0) 1 1 ( 1.1) 1 1 ( 1.1) 1 1 ( 1.0) 1 1 ( 1.0) 1
ヘマトクリット減少 2 ( 2.1) 2 2 ( 2.1) 2 1 ( 1.0) 1 1 ( 1.0) 1
赤血球数減少 2 ( 2.1) 2 2 ( 2.1) 2 1 ( 1.0) 1 1 ( 1.0) 1
血中乳酸脱水素酵素増加 2 ( 2.0) 2 2 ( 2.0) 2
アラニン・アミノトランスフェラーゼ増加 1 ( 1.1) 1 1 ( 1.1) 1 1 ( 1.0) 1 1 ( 1.0) 1
アスパラギン酸アミノトランスフェラーゼ増加 1 ( 1.1) 1 1 ( 1.1) 1 1 ( 1.0) 1 1 ( 1.0) 1
血中ビリルビン増加 2 ( 2.2) 2 2 ( 2.2) 2
血中クレアチニン増加 2 ( 2.1) 2 2 ( 2.1) 2
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白血球数増加 2 ( 2.2) 2 2 ( 2.2) 2

血中コレステロール減少 1 ( 1.0) 1 1 ( 1.0) 1
血中カリウム 1 ( 1.1) 1 1 ( 1.1) 1
血小板数増加 1 ( 1.1) 1 1 ( 1.1) 1
血中アミラーゼ 1 ( 1.0) 1 1 ( 1.0) 1
血中クレアチンホスホキナーゼ増加 1 ( 1.0) 1 1 ( 1.0) 1
心電図異常 1 ( 1.0) 1 1 ( 1.0) 1
尿中赤血球陽性 1 ( 1.0) 1 1 ( 1.0) 1
残尿量 1 ( 1.0) 1 1 ( 1.0) 1
代謝および栄養障害 1 ( 1.0) 1 3 ( 3.0) 4 4 ( 4.0) 5
食欲不振 2 ( 2.0) 2 2 ( 2.0) 2
糖尿病 1 ( 1.0) 1 1 ( 1.0) 1
食欲減退 1 ( 1.0) 2 1 ( 1.0) 2
筋骨格系および結合組織障害 4 ( 4.0) 4 1 ( 1.0) 1 5 ( 5.1) 5 2 ( 2.0) 2 2 ( 2.0) 2 1 ( 1.0) 1 1 ( 1.0) 1 2 ( 2.0) 2 5 ( 5.0) 7 2 ( 2.0) 2 7 ( 6.9) 9
関節痛 1 ( 1.0) 1 1 ( 1.0) 1 2 ( 2.0) 2 3 ( 3.0) 3 1 ( 1.0) 1 4 ( 4.0) 4
背部痛 1 ( 1.0) 1 1 ( 1.0) 1 2 ( 2.0) 2 2 ( 2.0) 2
頚部痛 1 ( 1.0) 1 1 ( 1.0) 1 1 ( 1.0) 1 1 ( 1.0) 1
四肢痛 1 ( 1.0) 1 1 ( 1.0) 1 1 ( 1.0) 1 1 ( 1.0) 1
筋骨格硬直 1 ( 1.0) 1 1 ( 1.0) 1 1 ( 1.0) 1 1 ( 1.0) 1
関節リウマチ 1 ( 1.0) 1 1 ( 1.0) 1
腱鞘炎 1 ( 1.0) 1 1 ( 1.0) 1
四肢不快感 1 ( 1.0) 1 1 ( 1.0) 1
神経系障害 8 ( 8.1) 8 2 ( 2.0) 2 10 ( 10.1) 10 9 ( 9.0) 11 1 ( 1.0) 1 10 ( 10.0) 12 13 ( 12.9) 17 5 ( 5.0) 6 18 ( 17.8) 23 3 ( 3.0) 4 2 ( 2.0) 4 5 ( 5.0) 8
頭痛 2 ( 2.0) 2 2 ( 2.0) 2 4 ( 4.0) 4 4 ( 4.0) 4 4 ( 4.0) 4 5 ( 5.0) 5 1 ( 1.0) 1 6 ( 5.9) 6 2 ( 2.0) 2 2 ( 2.0) 3 4 ( 4.0) 5
浮動性めまい 2 ( 2.0) 2 2 ( 2.0) 2 2 ( 2.0) 3 2 ( 2.0) 3 3 ( 3.0) 3 2 ( 2.0) 2 5 ( 5.0) 5 1 ( 1.0) 1 1 ( 1.0) 1 2 ( 2.0) 2
味覚異常 2 ( 2.0) 2 2 ( 2.0) 2 4 ( 4.0) 4 2 ( 2.0) 2 6 ( 5.9) 6
傾眠 1 ( 1.0) 1 1 ( 1.0) 1 2 ( 2.0) 2 2 ( 2.0) 2 3 ( 3.0) 3 3 ( 3.0) 3 1 ( 1.0) 1 1 ( 1.0) 1
感覚減退 1 ( 1.0) 1 1 ( 1.0) 1 1 ( 1.0) 1 1 ( 1.0) 1 2 ( 2.0) 2
痙攣 1 ( 1.0) 1 1 ( 1.0) 1
体位性めまい 1 ( 1.0) 1 1 ( 1.0) 1

2.7.6 Summary of the

片頭痛 1 ( 1.0) 1 1 ( 1.0) 1
神経痛 1 ( 1.0) 1 1 ( 1.0) 1
腎および尿路障害 1 ( 1.0) 2 1 ( 1.0) 1 2 ( 2.0) 3 2 ( 2.0) 4 2 ( 2.0) 4 2 ( 2.0) 3 2 ( 2.0) 3 4 ( 4.0) 6 1 ( 1.0) 2 1 ( 1.0) 2
尿閉 1 ( 1.0) 2 1 ( 1.0) 1 2 ( 2.0) 3 2 ( 2.0) 2 2 ( 2.0) 2 2 ( 2.0) 2 2 ( 2.0) 2 1 ( 1.0) 1 1 ( 1.0) 1
排尿困難 1 ( 1.0) 1 1 ( 1.0) 1 1 ( 1.0) 2 1 ( 1.0) 1 2 ( 2.0) 3

individual tests
頻尿 1 ( 1.0) 1 1 ( 1.0) 1 1 ( 1.0) 1 1 ( 1.0) 1
血尿 1 ( 1.0) 1 1 ( 1.0) 1
生殖系および乳房障害 1 ( 1.0) 1 1 ( 1.0) 1
性器出血 1 ( 1.0) 1 1 ( 1.0) 1
呼吸器、胸郭および縦隔障害 4 ( 4.0) 4 2 ( 2.0) 10 6 ( 6.1) 14 7 ( 7.0) 10 1 ( 1.0) 1 8 ( 8.0) 11 6 ( 5.9) 10 2 ( 2.0) 3 8 ( 7.9) 13 3 ( 3.0) 6 2 ( 2.0) 2 5 ( 5.0) 8
咳嗽 2 ( 2.0) 2 2 ( 2.0) 2 2 ( 2.0) 2 2 ( 2.0) 2 3 ( 3.0) 3 1 ( 1.0) 1 4 ( 4.0) 4 2 ( 2.0) 2 2 ( 2.0) 2
咽喉頭疼痛 2 ( 2.0) 2 2 ( 2.0) 2 4 ( 4.0) 4 4 ( 4.0) 5 1 ( 1.0) 1 5 ( 5.0) 6 1 ( 1.0) 1 1 ( 1.0) 1
湿性咳嗽 2 ( 2.0) 2 2 ( 2.0) 2 1 ( 1.0) 1 1 ( 1.0) 1 1 ( 1.0) 1 1 ( 1.0) 1 2 ( 2.0) 2 1 ( 1.0) 1 1 ( 1.0) 1
鼻漏 2 ( 2.0) 3 2 ( 2.0) 3 1 ( 1.0) 1 1 ( 1.0) 1 1 ( 1.0) 1 1 ( 1.0) 1
くしゃみ 1 ( 1.0) 1 1 ( 1.0) 1 2 ( 2.0) 2 2 ( 2.0) 2
呼吸困難 1 ( 1.0) 1 1 ( 1.0) 1 1 ( 1.0) 1 1 ( 1.0) 1
上気道の炎症 1 ( 1.0) 1 1 ( 1.0) 1 2 ( 2.0) 2
喘息 1 ( 1.0) 1 1 ( 1.0) 1
鼻出血 1 ( 1.0) 1 1 ( 1.0) 1
喀血 1 ( 1.0) 1 1 ( 1.0) 1
鼻閉 1 ( 1.0) 1 1 ( 1.0) 1
咽頭不快感 1 ( 1.0) 1 1 ( 1.0) 1
アレルギー性鼻炎 1 ( 1.0) 2 1 ( 1.0) 2
 Table 2.7.6.1-13 List of adverse events by severity (continued)
投与群 0.1 mg/日 0.2 mg/日 0.5 mg/日 プラセボ
安全性解析対象集団 99 100 101 101
重症度 軽度 中等度 高度 計 軽度 中等度 高度 計 軽度 中等度 高度 計 軽度 中等度 高度 計
有害事象項目 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数 例数 （％）
皮膚および皮下組織障害 3 ( 3.0) 3 3 ( 3.0) 3 6 ( 6.0) 7 1 ( 1.0) 1 7 ( 7.0) 8 4 ( 4.0) 6 1 ( 1.0) 1 5 ( 5.0) 7 5 ( 5.0) 6 5 ( 5.0)
湿疹 2 ( 2.0) 2 1 ( 1.0) 1 3 ( 3.0) 3 1 ( 1.0) 1 1 ( 1.0) 1 1 ( 1.0) 1 1 ( 1.0)
発疹 1 ( 1.0) 1 1 ( 1.0) 1 1 ( 1.0) 1 1 ( 1.0) 1 1 ( 1.0) 1 1 ( 1.0)
そう痒症 1 ( 1.0) 1 1 ( 1.0) 1 2 ( 2.0) 2 2 ( 2.0)
接触性皮膚炎 1 ( 1.0) 1 1 ( 1.0) 1 1 ( 1.0) 2 1 ( 1.0) 2
皮膚乾燥 1 ( 1.0) 1 1 ( 1.0) 1 1 ( 1.0) 1 1 ( 1.0) 1
薬剤性皮膚炎 1 ( 1.0) 1 1 ( 1.0) 1
皮脂欠乏性湿疹 1 ( 1.0) 1 1 ( 1.0) 1
紅斑 1 ( 1.0) 1 1 ( 1.0) 1
過角化 1 ( 1.0) 1 1 ( 1.0) 1
爪の障害 1 ( 1.0) 1 1 ( 1.0) 1
蕁麻疹 1 ( 1.0) 2 1 ( 1.0)
全身性そう痒症 1 ( 1.0) 1 1 ( 1.0) 1
血管障害 1 ( 1.0) 1 1 ( 1.0) 1 1 ( 1.0) 3 1 ( 1.0) 1 2 ( 2.0) 4
血腫 1 ( 1.0) 1 1 ( 1.0) 1
静脈炎 1 ( 1.0) 1 1 ( 1.0) 1
ほてり 1 ( 1.0) 3 1 ( 1.0) 3

The incidence of each laboratory measure may differ because cases with laboratory items present during the observation period and after the start of treatment were included in the total. The number of cases for each assay may vary, as cases with abnormal changes were included regardless of whether the assay was missing
or not.
-267-

2.7.6 Summary of the

individual tests
 Table 2.7.6.1-14 List of adverse reactions by severity
投与群 0.1 mg/日 0.2 mg/日 0.5 mg/日 プラセボ
安全性解析対象集団 99 100 101 101
重症度 軽度 中等度 高度 計 軽度 中等度 高度 計 軽度 中等度 高度 計 軽度 中等度 高度 計
有害事象項目 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数
全例 19 ( 19.2) 29 9 ( 9.1) 10 2 ( 2.0) 2 30 ( 30.3) 41 30 ( 30.0) 54 6 ( 6.0) 8 1 ( 1.0) 1 37 ( 37.0) 63 36 ( 35.6) 97 21 ( 20.8) 43 6 ( 5.9) 6 63 ( 62.4) 146 17 ( 16.8) 21 4 ( 4.0) 4 21 ( 20.8) 25
心臓障害 2 ( 2.0) 2 2 ( 2.0) 2 1 ( 1.0) 1 1 ( 1.0) 1 1 ( 1.0) 2 1 ( 1.0) 2 2 ( 2.0) 3 2 ( 2.0) 3
動悸 1 ( 1.0) 1 1 ( 1.0) 1 1 ( 1.0) 1 1 ( 1.0) 1
洞性不整脈 1 ( 1.0) 1 1 ( 1.0) 1 1 ( 1.0) 1 1 ( 1.0) 1
心室性期外収縮 1 ( 1.0) 1 1 ( 1.0) 1 1 ( 1.0) 1 1 ( 1.0) 1
洞性徐脈 1 ( 1.0) 1 1 ( 1.0) 1
洞性頻脈 1 ( 1.0) 1 1 ( 1.0) 1
眼障害 1 ( 1.0) 1 1 ( 1.0) 1 2 ( 2.0) 2 1 ( 1.0) 1 3 ( 3.0) 3 12 ( 11.9) 16 1 ( 1.0) 1 13 ( 12.9) 17 1 ( 1.0) 1 1 ( 1.0) 1
眼の異常感 1 ( 1.0) 1 1 ( 1.0) 1 5 ( 5.0) 5 5 ( 5.0) 5 1 ( 1.0) 1 1 ( 1.0) 1
霧視 1 ( 1.0) 1 1 ( 1.0) 1 4 ( 4.0) 6 4 ( 4.0) 6
羞明 3 ( 3.0) 3 3 ( 3.0) 3
眼精疲労 1 ( 1.0) 1 1 ( 1.0) 1
複視 1 ( 1.0) 1 1 ( 1.0) 1
眼脂 1 ( 1.0) 1 1 ( 1.0) 1
網膜裂孔 1 ( 1.0) 1 1 ( 1.0) 1
眼球乾燥 1 ( 1.0) 1 1 ( 1.0) 1
胃腸障害 8 ( 8.1) 9 2 ( 2.0) 3 10 ( 10.1) 12 9 ( 9.0) 15 2 ( 2.0) 2 11 ( 11.0) 17 14 ( 13.9) 21 4 ( 4.0) 10 18 ( 17.8) 31 1 ( 1.0) 1 1 ( 1.0) 1 2 ( 2.0) 2
便秘 2 ( 2.0) 2 1 ( 1.0) 2 3 ( 3.0) 4 9 ( 9.0) 12 1 ( 1.0) 1 10 ( 10.0) 13 5 ( 5.0) 5 5 ( 5.0) 5 1 ( 1.0) 1 1 ( 1.0) 1 2 ( 2.0) 2
悪心 1 ( 1.0) 1 1 ( 1.0) 1 1 ( 1.0) 1 1 ( 1.0) 1 3 ( 3.0) 3 3 ( 3.0) 4 6 ( 5.9) 7
消化不良 2 ( 2.0) 2 2 ( 2.0) 2 2 ( 2.0) 3 2 ( 2.0) 3
下痢 2 ( 2.0) 2 2 ( 2.0) 2 1 ( 1.0) 1 1 ( 1.0) 1
胃不快感 1 ( 1.0) 1 1 ( 1.0) 1 1 ( 1.0) 1 1 ( 1.0) 2 2 ( 2.0) 3
嘔吐 1 ( 1.0) 1 1 ( 1.0) 1 1 ( 1.0) 2 1 ( 1.0) 1 2 ( 2.0) 3
腹部膨満 1 ( 1.0) 1 1 ( 1.0) 1 1 ( 1.0) 1 1 ( 1.0) 1
腹痛 1 ( 1.0) 1 1 ( 1.0) 1 1 ( 1.0) 1 1 ( 1.0) 1
鼓腸 1 ( 1.0) 1 1 ( 1.0) 1 1 ( 1.0) 1 1 ( 1.0) 1
口唇乾燥 1 ( 1.0) 1 1 ( 1.0) 1 1 ( 1.0) 1 1 ( 1.0) 1
上腹部痛 1 ( 1.0) 1 1 ( 1.0) 1
胃炎 1 ( 1.0) 1 1 ( 1.0) 1
軟便 1 ( 1.0) 1 1 ( 1.0) 1
舌苔 1 ( 1.0) 1 1 ( 1.0) 1
胃腸不快感 1 ( 1.0) 1 1 ( 1.0) 1
全身障害および投与局所様態 9 ( 9.1) 9 3 ( 3.0) 3 2 ( 2.0) 2 14 ( 14.1) 14 17 ( 17.0) 18 5 ( 5.0) 5 1 ( 1.0) 1 23 ( 23.0) 24 29 ( 28.7) 34 12 ( 11.9) 12 6 ( 5.9) 6 47 ( 46.5) 52 7 ( 6.9) 7 1 ( 1.0) 1 8 ( 7.9) 8
口渇 9 ( 9.1) 9 3 ( 3.0) 3 1 ( 1.0) 1 13 ( 13.1) 13 17 ( 17.0) 18 5 ( 5.0) 5 1 ( 1.0) 1 23 ( 23.0) 24 29 ( 28.7) 32 12 ( 11.9) 12 6 ( 5.9) 6 47 ( 46.5) 50 7 ( 6.9) 7 1 ( 1.0) 1 8 ( 7.9) 8
胸痛 1 ( 1.0) 1 1 ( 1.0) 1
-267-

倦怠感 1 ( 1.0) 1 1 ( 1.0) 1

末梢性浮腫 1 ( 1.0) 1 1 ( 1.0) 1
感染症および寄生虫症 2 ( 2.0) 2 2 ( 2.0) 2 1 ( 1.0) 2 1 ( 1.0) 1 2 ( 2.0) 3
膀胱炎 2 ( 2.0) 2 2 ( 2.0) 2 1 ( 1.0) 1 1 ( 1.0) 1
鼻咽頭炎 1 ( 1.0) 1 1 ( 1.0) 1
咽喉頭炎 1 ( 1.0) 1 1 ( 1.0) 1
臨床検査 3 ( 3.0) 3 1 ( 1.0) 1 4 ( 4.0) 4 7 ( 7.0) 8 7 ( 7.0) 8 6 ( 5.9) 11 3 ( 3.0) 3 9 ( 8.9) 14 5 ( 5.0) 8 2 ( 2.0) 2 7 ( 6.9) 10
血中尿酸増加 3 ( 3.1) 3 3 ( 3.1) 3 2 ( 2.1) 2 2 ( 2.1) 2
血中トリグリセリド増加 1 ( 1.1) 1 1 ( 1.1) 1 1 ( 1.1) 1 1 ( 1.1) 1 1 ( 1.0) 1 1 ( 1.0) 1 2 ( 2.0) 2
尿中白血球陽性 1 ( 1.1) 1 1 ( 1.1) 1 2 ( 2.0) 2 2 ( 2.0) 2
血中アルカリホスファターゼ増加 1 ( 1.0) 1 1 ( 1.0) 1 1 ( 1.1) 1 1 ( 1.1) 1 1 ( 1.0) 1 1 ( 1.0) 1
γ-グルタミルトランスフェラーゼ増加 2 ( 2.2) 2 2 ( 2.2) 2 1 ( 1.0) 1 1 ( 1.0) 1
血中コレステロール増加 1 ( 1.0) 1 1 ( 1.0) 1 1 ( 1.0) 1 1 ( 1.0) 1
血中クレアチニン増加 2 ( 2.1) 2 2 ( 2.1) 2
血圧上昇 1 ( 1.0) 1 1 ( 1.0) 1 2 ( 2.0) 2
尿中赤血球陽性 1 ( 1.1) 1 1 ( 1.1) 1
尿中蛋白陽性 1 ( 1.1) 1 1 ( 1.1) 1
血中コレステロール減少 1 ( 1.0) 1 1 ( 1.0) 1
血中尿素増加 1 ( 1.0) 1 1 ( 1.0) 1
血中乳酸脱水素酵素増加 1 ( 1.0) 1 1 ( 1.0) 1
アラニン・アミノトランスフェラーゼ増加 1 ( 1.0) 1 1 ( 1.0) 1
アスパラギン酸アミノトランスフェラーゼ増加 1 ( 1.0) 1 1 ( 1.0) 1
ヘマトクリット減少 1 ( 1.1) 1 1 ( 1.1) 1
ヘモグロビン減少 1 ( 1.1) 1 1 ( 1.1) 1
赤血球数減少 1 ( 1.1) 1 1 ( 1.1) 1
血中クレアチンホスホキナーゼ増加 1 ( 1.0) 1 1 ( 1.0) 1
残尿量 1 ( 1.0) 1 1 ( 1.0) 1
代謝および栄養障害 3 ( 3.0) 4 3 ( 3.0) 4
食欲不振 2 ( 2.0) 2 2 ( 2.0) 2
食欲減退 1 ( 1.0) 2 1 ( 1.0) 2
筋骨格系および結合組織障害 1 ( 1.0) 1 1 ( 1.0) 1 1 ( 1.0) 1 1 ( 1.0) 1
頚部痛 1 ( 1.0) 1 1 ( 1.0) 1

2.7.6 Summary of the

関節リウマチ 1 ( 1.0) 1 1 ( 1.0) 1
神経系障害 1 ( 1.0) 1 1 ( 1.0) 1 3 ( 3.0) 5 3 ( 3.0) 5 6 ( 5.9) 7 4 ( 4.0) 5 10 ( 9.9) 12 1 ( 1.0) 1 1 ( 1.0) 1
味覚異常 2 ( 2.0) 2 2 ( 2.0) 2 3 ( 3.0) 3 2 ( 2.0) 2 5 ( 5.0) 5
浮動性めまい 1 ( 1.0) 2 1 ( 1.0) 2 1 ( 1.0) 1 2 ( 2.0) 2 3 ( 3.0) 3
傾眠 3 ( 3.0) 3 3 ( 3.0) 3 1 ( 1.0) 1 1 ( 1.0) 1

individual tests
頭痛 1 ( 1.0) 1 1 ( 1.0) 1 1 ( 1.0) 1 1 ( 1.0) 1 1 ( 1.0) 1 1 ( 1.0) 1
腎および尿路障害 1 ( 1.0) 2 1 ( 1.0) 1 2 ( 2.0) 3 1 ( 1.0) 1 1 ( 1.0) 1 1 2 ( 2.0) 3 2 ( 2.0) 4
尿閉 1 ( 1.0) 2 1 ( 1.0) 1 2 ( 2.0) 3 1 ( 1.0) 1 1 ( 1.0) 1 2 ( 2.0) 2 2 ( 2.0) 2
排尿困難 1 1 ( 1.0) 1 1 ( 1.0) 2
呼吸器、胸郭および縦隔障害 1 ( 1.0) 1 1 ( 1.0) 1 2 ( 2.0) 2 1 ( 1.0) 2 1 ( 1.0) 2
咳嗽 1 ( 1.0) 1 1 ( 1.0) 1
咽喉頭疼痛 1 ( 1.0) 1 1 ( 1.0) 1
湿性咳嗽 1 ( 1.0) 1 1 ( 1.0) 1
鼻漏 1 ( 1.0) 1 1 ( 1.0) 1
皮膚および皮下組織障害 1 ( 1.0) 1 1 ( 1.0) 1 1 ( 1.0) 1 1 ( 1.0) 1 1 ( 1.0) 1 1 ( 1.0) 1
皮膚乾燥 1 ( 1.0) 1 1 ( 1.0) 1
紅斑 1 ( 1.0) 1 1 ( 1.0) 1
発疹 1 ( 1.0) 1 1 ( 1.0) 1
血管障害 1 ( 1.0) 3 1 ( 1.0) 1 2 ( 2.0) 4
静脈炎 1 ( 1.0) 1 1 ( 1.0) 1
ほてり 1 ( 1.0) 3 1 ( 1.0) 3

The incidence of each laboratory measure may differ because cases with laboratory items present during the observation period and after the start of treatment were included in the total. The number of cases for each assay may vary, as cases with abnormal changes were included regardless of whether the assay was missing
or not.
 Table 2.7.6.1-15 List of adverse events by causal relationship
投与群 0.1 mg/日 0.2 mg/日 0.5 mg/日 プラセボ
安全性解析対象集団 99 100 101 101
因果関係 ① ② ③ ④ 計 ① ② ③ ④ 計 ① ② ③ ④ 計 ① ② ③ ④ 計
有害事象項目 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数
全例 3 ( 3.0) 3 10 ( 10.1) 12 17 ( 17.2) 26 35 ( 35.4) 96 65 ( 65.7) 137 7 ( 7.0) 8 17 ( 17.0) 28 13 ( 13.0) 27 29 ( 29.0) 94 66 ( 66.0) 157 15 ( 14.9) 25 32 ( 31.7) 59 16 ( 15.8) 62 22 ( 21.8) 115 85 ( 84.2) 261 1 ( 1.0) 1 12 ( 11.9) 12 8 ( 7.9) 12 35 ( 34.7) 101 56 ( 55.4) 126
心臓障害 1 ( 1.0) 1 1 ( 1.0) 1 2 ( 2.0) 2 4 ( 4.0) 4 1 ( 1.0) 1 2 ( 2.0) 2 3 ( 3.0) 3 1 ( 1.0) 2 2 ( 2.0) 3 3 ( 3.0) 5 1 ( 1.0) 1 1 ( 1.0) 2 2 ( 2.0) 3 4 ( 4.0) 6
動悸 1 ( 1.0) 1 1 ( 1.0) 1 1 ( 1.0) 1 1 ( 1.0) 1 1 ( 1.0) 1 1 ( 1.0) 1
洞性不整脈 1 ( 1.0) 1 1 ( 1.0) 1 2 ( 2.0) 2 1 ( 1.0) 1 1 ( 1.0) 1
上室性期外収縮 2 ( 2.0) 2 2 ( 2.0) 2 1 ( 1.0) 1 1 ( 1.0) 1
心室性期外収縮 1 ( 1.0) 1 1 ( 1.0) 1 1 ( 1.0) 1 1 ( 1.0) 1 1 ( 1.0) 1 1 ( 1.0) 1
不整脈 1 ( 1.0) 1 1 ( 1.0) 1
右脚ブロック 1 ( 1.0) 1 1 ( 1.0) 1
結節性調律 1 ( 1.0) 2 1 ( 1.0) 2
洞性徐脈 1 ( 1.0) 1 1 ( 1.0) 1
洞性頻脈 1 ( 1.0) 1 1 ( 1.0) 1
耳および迷路障害 1 ( 1.0) 1 1 ( 1.0) 1
ろう 1 ( 1.0) 1 1 ( 1.0) 1
眼障害 1 ( 1.0) 1 3 ( 3.0) 3 4 ( 4.0) 4 3 ( 3.0) 3 5 ( 5.0) 8 8 ( 8.0) 11 8 ( 7.9) 12 5 ( 5.0) 5 2 ( 2.0) 3 15 ( 14.9) 20 1 ( 1.0) 1 2 ( 2.0) 2 3 ( 3.0) 3
眼の異常感 1 ( 1.0) 1 1 ( 1.0) 1 2 ( 2.0) 2 2 ( 2.0) 2 2 ( 2.0) 2 2 ( 2.0) 2 3 ( 3.0) 3 5 ( 5.0) 5 1 ( 1.0) 1 1 ( 1.0) 1
霧視 1 ( 1.0) 1 1 ( 1.0) 1 3 ( 3.0) 5 1 ( 1.0) 1 4 ( 4.0) 6
眼脂 1 ( 1.0) 1 1 ( 1.0) 1 1 ( 1.0) 1 1 ( 1.0) 1 1 ( 1.0) 1 1 ( 1.0) 1
羞明 2 ( 2.0) 2 1 ( 1.0) 1 3 ( 3.0) 3
眼精疲労 1 ( 1.0) 1 1 ( 1.0) 1
眼瞼痙攣 1 ( 1.0) 1 1 ( 1.0) 1
結膜出血 1 ( 1.0) 1 1 ( 1.0) 1
結膜炎 1 ( 1.0) 1 1 ( 1.0) 1
アレルギー性結膜炎 1 ( 1.0) 1 1 ( 1.0) 1
複視 1 ( 1.0) 1 1 ( 1.0) 1
眼瞼浮腫 1 ( 1.0) 1 1 ( 1.0) 1
緑内障 1 ( 1.0) 1 1 ( 1.0) 1
流涙増加 1 ( 1.0) 1 1 ( 1.0) 1
光視症 1 ( 1.0) 1 1 ( 1.0) 1
網膜裂孔 1 ( 1.0) 1 1 ( 1.0) 1
視覚障害 1 ( 1.0) 2 1 ( 1.0) 2
眼球乾燥 1 ( 1.0) 1 1 ( 1.0) 1
眼そう痒症 1 ( 1.0) 1 1 ( 1.0) 1
胃腸障害 2 ( 2.0) 3 8 ( 8.1) 9 9 ( 9.1) 9 19 ( 19.2) 21 1 ( 1.0) 1 7 ( 7.0) 10 3 ( 3.0) 6 9 ( 9.0) 16 20 ( 20.0) 33 2 ( 2.0) 6 5 ( 5.0) 6 11 ( 10.9) 19 14 ( 13.9) 29 32 ( 31.7) 60 2 ( 2.0) 2 14 ( 13.9) 18 16 ( 15.8) 20
便秘 1 ( 1.0) 2 2 ( 2.0) 2 3 ( 3.0) 4 1 ( 1.0) 1 6 ( 6.0) 9 3 ( 3.0) 3 2 ( 2.0) 2 12 ( 12.0) 15 2 ( 2.0) 2 3 ( 3.0) 3 5 ( 5.0) 8 10 ( 9.9) 13 2 ( 2.0) 2 2 ( 2.0) 2 4 ( 4.0) 4
悪心 1 ( 1.0) 1 1 ( 1.0) 1 2 ( 2.0) 2 1 ( 1.0) 1 1 ( 1.0) 1 2 ( 2.0) 2 2 ( 2.0) 3 4 ( 4.0) 4 2 ( 2.0) 2 8 ( 7.9) 9 2 ( 2.0) 2 2 ( 2.0) 2
下痢 2 ( 2.0) 2 2 ( 2.0) 2 4 ( 4.0) 4 2 ( 2.0) 2 2 ( 2.0) 2 1 ( 1.0) 1 1 ( 1.0) 1 3 ( 3.0) 3 3 ( 3.0) 3
上腹部痛 2 ( 2.0) 2 2 ( 2.0) 2 2 ( 2.0) 2 2 ( 2.0) 2 1 ( 1.0) 1 2 ( 2.0) 2 3 ( 3.0) 3 1 ( 1.0) 1 1 ( 1.0) 1
消化不良 2 ( 2.0) 2 2 ( 2.0) 2 1 ( 1.0) 2 1 ( 1.0) 1 4 ( 4.0) 5 6 ( 5.9) 8
胃不快感 1 ( 1.0) 1 1 ( 1.0) 1 2 ( 2.0) 2 2 ( 2.0) 2 1 ( 1.0) 2 1 ( 1.0) 1 2 ( 2.0) 5 4 ( 4.0) 8 1 ( 1.0) 1 1 ( 1.0) 1
嘔吐 1 ( 1.0) 1 1 ( 1.0) 1 1 ( 1.0) 1 1 ( 1.0) 1 2 ( 2.0) 3 3 ( 3.0) 3 5 ( 5.0) 6
-267-

腹痛 1 ( 1.0) 1 1 ( 1.0) 1 1 ( 1.0) 1 2 ( 2.0) 2 3 ( 3.0) 3 1 ( 1.0) 1 1 ( 1.0) 1 2 ( 2.0) 2

腹部膨満 1 ( 1.0) 1 1 ( 1.0) 1 1 ( 1.0) 1 1 ( 1.0) 1 1 ( 1.0) 1 1 ( 1.0) 1
軟便 1 ( 1.0) 1 1 ( 1.0) 1 2 ( 2.0) 2 2 ( 2.0) 2
歯痛 3 ( 3.0) 3 3 ( 3.0) 3
鼓腸 1 ( 1.0) 1 1 ( 1.0) 1 1 ( 1.0) 1 1 ( 1.0) 1
胃炎 1 ( 1.0) 1 1 ( 1.0) 1 1 ( 1.0) 1 1 ( 1.0) 1
歯肉腫脹 1 ( 1.0) 1 1 ( 1.0) 1 1 ( 1.0) 1 1 ( 1.0) 1
舌炎 1 ( 1.0) 1 1 ( 1.0) 1 1 ( 1.0) 1 1 ( 1.0) 1
口唇乾燥 1 ( 1.0) 1 1 ( 1.0) 1 1 ( 1.0) 1 1 ( 1.0) 1
口内炎 1 ( 1.0) 1 1 ( 1.0) 1 1 ( 1.0) 1 1 ( 1.0) 1
腹部不快感 1 ( 1.0) 1 1 ( 1.0) 1
下腹部痛 1 ( 1.0) 1 1 ( 1.0) 1
口唇炎 1 ( 1.0) 1 1 ( 1.0) 1
胃ポリープ 1 ( 1.0) 1 1 ( 1.0) 1
胃食道逆流性疾患 1 ( 1.0) 1 1 ( 1.0) 1
口腔内不快感 1 ( 1.0) 1 1 ( 1.0) 1
舌苔 1 ( 1.0) 1 1 ( 1.0) 1
胃腸不快感 1 ( 1.0) 1 1 ( 1.0) 1
全身障害および投与局所様態 3 ( 3.0) 3 7 ( 7.1) 7 4 ( 4.0) 4 6 ( 6.1) 7 20 ( 20.2) 21 6 ( 6.0) 7 15 ( 15.0) 15 2 ( 2.0) 2 5 ( 5.0) 6 28 ( 28.0) 30 13 ( 12.9) 14 27 ( 26.7) 29 7 ( 6.9) 9 5 ( 5.0) 8 52 ( 51.5) 60 1 ( 1.0) 1 5 ( 5.0) 5 2 ( 2.0) 2 6 ( 5.9) 7 14 ( 13.9) 15
口渇 3 ( 3.0) 3 7 ( 7.1) 7 3 ( 3.0) 3 3 ( 3.0) 3 16 ( 16.2) 16 6 ( 6.0) 7 15 ( 15.0) 15 2 ( 2.0) 2 1 ( 1.0) 2 24 ( 24.0) 26 13 ( 12.9) 14 27 ( 26.7) 29 7 ( 6.9) 7 4 ( 4.0) 4 51 ( 50.5) 54 1 ( 1.0) 1 5 ( 5.0) 5 2 ( 2.0) 2 2 ( 2.0) 2 10 ( 9.9) 10
末梢性浮腫 1 ( 1.0) 1 1 ( 1.0) 1 1 ( 1.0) 1 1 ( 1.0) 1 1 ( 1.0) 1 1 ( 1.0) 1 2 ( 2.0) 2
倦怠感 1 ( 1.0) 1 2 ( 2.0) 2 3 ( 3.0) 3
浮腫 1 ( 1.0) 1 1 ( 1.0) 1 1 ( 1.0) 1 1 ( 1.0) 1 1 ( 1.0) 1 1 ( 1.0) 1
発熱 1 ( 1.0) 1 1 ( 1.0) 1 1 ( 1.0) 1 1 ( 1.0) 1 1 ( 1.0) 1 1 ( 1.0) 1
胸痛 1 ( 1.0) 1 1 ( 1.0) 1 1 ( 1.0) 1 1 ( 1.0) 1
無力症 1 ( 1.0) 1 1 ( 1.0) 1
胸部不快感 1 ( 1.0) 1 1 ( 1.0) 1
異常感 1 ( 1.0) 1 1 ( 1.0) 1
冷感 1 ( 1.0) 1 1 ( 1.0) 1
異物感 1 ( 1.0) 1 1 ( 1.0) 1
肝胆道系障害 1 ( 1.0) 1 1 ( 1.0) 1
胆石症 1 ( 1.0) 1 1 ( 1.0) 1
免疫系障害 1 ( 1.0) 1 1 ( 1.0) 1
季節性アレルギー 1 ( 1.0) 1 1 ( 1.0) 1
感染症および寄生虫症 19 ( 19.2) 22 19 ( 19.2) 22 2 ( 2.0) 2 13 ( 13.0) 18 15 ( 15.0) 20 2 ( 2.0) 3 13 ( 12.9) 17 15 ( 14.9) 20 16 ( 15.8) 21 16 ( 15.8) 21
鼻咽頭炎 13 ( 13.1) 14 13 ( 13.1) 14 10 ( 10.0) 11 10 ( 10.0) 11 1 ( 1.0) 1 9 ( 8.9) 11 10 ( 9.9) 12 14 ( 13.9) 15 14 ( 13.9) 15

2.7.6 Summary of the

膀胱炎 4 ( 4.0) 4 4 ( 4.0) 4 2 ( 2.0) 2 2 ( 2.0) 2 1 ( 1.0) 1 3 ( 3.0) 4 4 ( 4.0) 5 1 ( 1.0) 1 1 ( 1.0) 1
齲歯 2 ( 2.0) 2 2 ( 2.0) 2
鼻炎 1 ( 1.0) 1 1 ( 1.0) 1 1 ( 1.0) 1 1 ( 1.0) 1
白癬 1 ( 1.0) 1 1 ( 1.0) 1 1 ( 1.0) 1 1 ( 1.0) 1
咽喉頭炎 1 ( 1.0) 1 1 ( 1.0) 1 1 ( 1.0) 1 1 ( 1.0) 1

individual tests
膀胱炎 1 ( 1.0) 1 1 ( 1.0) 1
カンジダ症 1 ( 1.0) 1 1 ( 1.0) 1
蜂巣炎 1 ( 1.0) 1 1 ( 1.0) 1
帯状疱疹 1 ( 1.0) 1 1 ( 1.0) 1
口腔カンジダ症 1 ( 1.0) 1 1 ( 1.0) 1
中耳炎 1 ( 1.0) 1 1 ( 1.0) 1
肺炎 1 ( 1.0) 1 1 ( 1.0) 1
皮下組織膿瘍 1 ( 1.0) 1 1 ( 1.0) 1
トリコモナス症 1 ( 1.0) 1 1 ( 1.0) 1
上気道感染 1 ( 1.0) 1 1 ( 1.0) 1
尿路感染 1 ( 1.0) 1 1 ( 1.0) 1
傷害、中毒および処置合併症 5 ( 5.1) 5 5 ( 5.1) 5 2 ( 2.0) 2 2 ( 2.0) 2 1 ( 1.0) 1 1 ( 1.0) 1
足骨折 1 ( 1.0) 1 1 ( 1.0) 1 1 ( 1.0) 1 1 ( 1.0) 1
事故 1 ( 1.0) 1 1 ( 1.0) 1
胸部の圧挫傷 1 ( 1.0) 1 1 ( 1.0) 1
異物による損傷 1 ( 1.0) 1 1 ( 1.0) 1
手骨折 1 ( 1.0) 1 1 ( 1.0) 1
損傷 1 ( 1.0) 1 1 ( 1.0) 1
関節捻挫 1 ( 1.0) 1 1 ( 1.0) 1

Causal relationship with the investigational drug: (1) clearly related, (2) probably related, (3) not related, (4) not related
 Table 2.7.6.1-15 List of adverse events by causal relationship (continued)
投与群 0.1 mg/日 0.2 mg/日 0.5 mg/日 プラセボ
安全性解析対象集団 99 100 101 101
因果関係 ① ② ③ ④ 計 ① ② ③ ④ 計 ① ② ③ ④ 計 ① ② ③ ④ 計
有害事象項目 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数
臨床検査 4 ( 4.0) 4 11 ( 11.1) 20 15 ( 15.2) 24 1 ( 1.0) 1 6 ( 6.0) 7 12 ( 12.0) 13 19 ( 19.0) 21 1 ( 1.0) 1 2 ( 2.0) 2 6 ( 5.9) 11 11 ( 10.9) 18 20 ( 19.8) 32 3 ( 3.0) 3 4 ( 4.0) 7 12 ( 11.9) 17 19 ( 18.8) 27
尿中白血球陽性 1 ( 1.1) 1 4 ( 4.3) 4 5 ( 5.4) 5 2 ( 2.0) 2 8 ( 8.2) 8 10 ( 10.2) 10 4 ( 4.3) 5 4 ( 4.3) 5 4 ( 4.0) 4 4 ( 4.0) 4
血中トリグリセリド増加 1 ( 1.1) 1 2 ( 2.1) 2 3 ( 3.2) 3 1 ( 1.1) 1 1 ( 1.1) 1 2 ( 2.1) 2 2 ( 2.0) 2 4 ( 4.0) 4 6 ( 5.9) 6
尿中赤血球陽性 2 ( 2.2) 2 2 ( 2.2) 2 1 ( 1.1) 1 2 ( 2.2) 2 3 ( 3.3) 3 3 ( 3.0) 3 3 ( 3.0) 3
血中尿酸増加 2 ( 2.2) 2 2 ( 2.2) 2 3 ( 3.1) 3 1 ( 1.0) 1 4 ( 4.1) 4 1 ( 1.1) 1 1 ( 1.1) 1 2 ( 2.1) 2
尿中蛋白陽性 1 ( 1.1) 1 1 ( 1.1) 1 1 ( 1.0) 1 1 ( 1.0) 1 1 ( 1.1) 1 1 ( 1.1) 1 2 ( 2.2) 2 1 ( 1.0) 1 1 ( 1.0) 1
γ-グルタミルトランスフェラーゼ増加 2 ( 2.2) 2 1 ( 1.1) 1 3 ( 3.2) 3 1 ( 1.0) 1 1 ( 1.0) 1 1 ( 1.1) 1 1 ( 1.1) 1
ヘモグロビン減少 1 ( 1.1) 1 2 ( 2.1) 2 3 ( 3.2) 3 1 ( 1.0) 1 1 ( 1.0) 1
血圧上昇 1 ( 1.0) 1 1 ( 1.0) 1 1 ( 1.0) 1 3 ( 3.0) 3 1 ( 1.0) 1 1 ( 1.0) 1
血中コレステロール増加 1 ( 1.0) 1 1 ( 1.0) 1 2 ( 2.0) 2 1 ( 1.0) 1 1 ( 1.0) 1
血中尿素増加 1 ( 1.1) 1 1 ( 1.1) 1 1 ( 1.0) 1 1 ( 1.0) 1 1 ( 1.0) 1 1 ( 1.0) 1
血中アルカリホスファターゼ増加 1 ( 1.0) 1 1 ( 1.0) 1 1 ( 1.1) 1 1 ( 1.1) 1 1 ( 1.0) 1 1 ( 1.0) 1
ヘマトクリット減少 1 ( 1.1) 1 1 ( 1.1) 1 2 ( 2.1) 2 1 ( 1.0) 1 1 ( 1.0) 1
赤血球数減少 1 ( 1.1) 1 1 ( 1.1) 1 2 ( 2.1) 2 1 ( 1.0) 1 1 ( 1.0) 1
血中乳酸脱水素酵素増加 1 ( 1.0) 1 1 ( 1.0) 1 2 ( 2.0) 2
アラニン・アミノトランスフェラーゼ増加 1 ( 1.1) 1 1 ( 1.1) 1 1 ( 1.0) 1 1 ( 1.0) 1
アスパラギン酸アミノトランスフェラーゼ増加 1 ( 1.1) 1 1 ( 1.1) 1 1 ( 1.0) 1 1 ( 1.0) 1
血中ビリルビン増加 2 ( 2.2) 2 2 ( 2.2) 2
血中クレアチニン増加 2 ( 2.1) 2 2 ( 2.1) 2
白血球数増加 2 ( 2.2) 2 2 ( 2.2) 2
血中コレステロール減少 1 ( 1.0) 1 1 ( 1.0) 1
血中カリウム 1 ( 1.1) 1 1 ( 1.1) 1
血小板数増加 1 ( 1.1) 1 1 ( 1.1) 1
血中アミラーゼ 1 ( 1.0) 1 1 ( 1.0) 1
血中クレアチンホスホキナーゼ増加 1 ( 1.0) 1 1 ( 1.0) 1
心電図異常 1 ( 1.0) 1 1 ( 1.0) 1
尿中赤血球陽性 1 ( 1.0) 1 1 ( 1.0) 1
残尿量 1 ( 1.0) 1 1 ( 1.0) 1
代謝および栄養障害 2 ( 2.0) 3 1 ( 1.0) 1 1 ( 1.0) 1 4 ( 4.0) 5
食欲不振 1 ( 1.0) 1 1 ( 1.0) 1 2 ( 2.0) 2
糖尿病 1 ( 1.0) 1 1 ( 1.0) 1
食欲減退 1 ( 1.0) 2 1 ( 1.0) 2
筋骨格系および結合組織障害 1 ( 1.0) 1 4 ( 4.0) 4 5 ( 5.1) 5 1 ( 1.0) 1 1 ( 1.0) 1 2 ( 2.0) 2 2 ( 2.0) 2 2 ( 2.0) 2 7 ( 6.9) 9 7 ( 6.9) 9
関節痛 2 ( 2.0) 2 2 ( 2.0) 2 4 ( 4.0) 4 4 ( 4.0) 4
背部痛 1 ( 1.0) 1 1 ( 1.0) 1 2 ( 2.0) 2 2 ( 2.0) 2
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頚部痛 1 ( 1.0) 1 1 ( 1.0) 1 1 ( 1.0) 1 1 ( 1.0) 1

四肢痛 1 ( 1.0) 1 1 ( 1.0) 1 1 ( 1.0) 1 1 ( 1.0) 1
筋骨格硬直 1 ( 1.0) 1 1 ( 1.0) 1 1 ( 1.0) 1 1 ( 1.0) 1
関節リウマチ 1 ( 1.0) 1 1 ( 1.0) 1
腱鞘炎 1 ( 1.0) 1 1 ( 1.0) 1
四肢不快感 1 ( 1.0) 1 1 ( 1.0) 1
神経系障害 1 ( 1.0) 1 9 ( 9.1) 9 10 ( 10.1) 10 1 ( 1.0) 1 2 ( 2.0) 4 7 ( 7.0) 7 10 ( 10.0) 12 1 ( 1.0) 1 6 ( 5.9) 7 3 ( 3.0) 4 8 ( 7.9) 11 18 ( 17.8) 23 1 ( 1.0) 1 4 ( 4.0) 7 5 ( 5.0) 8
頭痛 1 ( 1.0) 1 3 ( 3.0) 3 4 ( 4.0) 4 1 ( 1.0) 1 3 ( 3.0) 3 4 ( 4.0) 4 1 ( 1.0) 1 5 ( 5.0) 5 6 ( 5.9) 6 4 ( 4.0) 5 4 ( 4.0) 5
浮動性めまい 2 ( 2.0) 2 2 ( 2.0) 2 1 ( 1.0) 2 1 ( 1.0) 1 2 ( 2.0) 3 1 ( 1.0) 1 2 ( 2.0) 2 2 ( 2.0) 2 5 ( 5.0) 5 2 ( 2.0) 2 2 ( 2.0) 2
味覚異常 1 ( 1.0) 1 1 ( 1.0) 1 2 ( 2.0) 2 1 ( 1.0) 1 3 ( 3.0) 3 1 ( 1.0) 1 1 ( 1.0) 1 6 ( 5.9) 6
傾眠 1 ( 1.0) 1 1 ( 1.0) 1 2 ( 2.0) 2 2 ( 2.0) 2 2 ( 2.0) 2 1 ( 1.0) 1 3 ( 3.0) 3 1 ( 1.0) 1 1 ( 1.0) 1
感覚減退 1 ( 1.0) 1 1 ( 1.0) 1 2 ( 2.0) 2 2 ( 2.0) 2
痙攣 1 ( 1.0) 1 1 ( 1.0) 1
体位性めまい 1 ( 1.0) 1 1 ( 1.0) 1
片頭痛 1 ( 1.0) 1 1 ( 1.0) 1
神経痛 1 ( 1.0) 1 1 ( 1.0) 1
腎および尿路障害 2 ( 2.0) 3 2 ( 2.0) 3 1 ( 1.0) 1 1 ( 1.0) 3 2 ( 2.0) 4 1 ( 1.0) 1 1 ( 1.0) 3 2 ( 2.0) 2 4 ( 4.0) 6 1 ( 1.0) 2 1 ( 1.0) 2
尿閉 2 ( 2.0) 3 2 ( 2.0) 3 1 ( 1.0) 1 1 ( 1.0) 1 2 ( 2.0) 2 1 ( 1.0) 1 1 ( 1.0) 1 2 ( 2.0) 2 1 ( 1.0) 1 1 ( 1.0) 1
排尿困難 1 ( 1.0) 1 1 ( 1.0) 1 1 ( 1.0) 2 1 ( 1.0) 1 2 ( 2.0) 3
頻尿 1 ( 1.0) 1 1 ( 1.0) 1 1 ( 1.0) 1 1 ( 1.0) 1
血尿 1 ( 1.0) 1 1 ( 1.0) 1
生殖系および乳房障害 1 ( 1.0) 1 1 ( 1.0) 1
性器出血 1 ( 1.0) 1 1 ( 1.0) 1
呼吸器、胸郭および縦隔障害 2 ( 2.0) 2 4 ( 4.0) 12 6 ( 6.1) 14 8 ( 8.0) 11 8 ( 8.0) 11 1 ( 1.0) 2 7 ( 6.9) 11 8 ( 7.9) 13 5 ( 5.0) 8 5 ( 5.0) 8
咳嗽 2 ( 2.0) 2 2 ( 2.0) 2 2 ( 2.0) 2 2 ( 2.0) 2 1 ( 1.0) 1 3 ( 3.0) 3 4 ( 4.0) 4 2 ( 2.0) 2 2 ( 2.0) 2
咽喉頭疼痛 1 ( 1.0) 1 3 ( 3.0) 3 4 ( 4.0) 4 5 ( 5.0) 6 5 ( 5.0) 6 1 ( 1.0) 1 1 ( 1.0) 1
湿性咳嗽 2 ( 2.0) 2 2 ( 2.0) 2 1 ( 1.0) 1 1 ( 1.0) 1 1 ( 1.0) 1 1 ( 1.0) 1 2 ( 2.0) 2 1 ( 1.0) 1 1 ( 1.0) 1
鼻漏 1 ( 1.0) 1 1 ( 1.0) 2 2 ( 2.0) 3 1 ( 1.0) 1 1 ( 1.0) 1 1 ( 1.0) 1 1 ( 1.0) 1
くしゃみ 1 ( 1.0) 1 1 ( 1.0) 1 2 ( 2.0) 2 2 ( 2.0) 2
呼吸困難 1 ( 1.0) 1 1 ( 1.0) 1 1 ( 1.0) 1 1 ( 1.0) 1
上気道の炎症 2 ( 2.0) 2 2 ( 2.0) 2
喘息 1 ( 1.0) 1 1 ( 1.0) 1
鼻出血 1 ( 1.0) 1 1 ( 1.0) 1

2.7.6 Summary of the

喀血 1 ( 1.0) 1 1 ( 1.0) 1
鼻閉 1 ( 1.0) 1 1 ( 1.0) 1
咽頭不快感 1 ( 1.0) 1 1 ( 1.0) 1
アレルギー性鼻炎 1 ( 1.0) 2 1 ( 1.0) 2
1 ( 1.0) 1 2 ( 2.0) 2 3 ( 3.0) 3 1 ( 1.0) 1 6 ( 6.0) 7 7 ( 7.0) 8 1 ( 1.0) 1 4 ( 4.0) 6 5 ( 5.0) 7 5 ( 5.0) 6 5 ( 5.0) 6

individual tests
皮膚および皮下組織障害
湿疹 3 ( 3.0) 3 3 ( 3.0) 3 1 ( 1.0) 1 1 ( 1.0) 1 1 ( 1.0) 1 1 ( 1.0) 1
発疹 1 ( 1.0) 1 1 ( 1.0) 1 1 ( 1.0) 1 1 ( 1.0) 1 1 ( 1.0) 1 1 ( 1.0) 1
そう痒症 1 ( 1.0) 1 1 ( 1.0) 1 2 ( 2.0) 2 2 ( 2.0) 2
接触性皮膚炎 1 ( 1.0) 1 1 ( 1.0) 1 1 ( 1.0) 2 1 ( 1.0) 2
皮膚乾燥 1 ( 1.0) 1 1 ( 1.0) 1 1 ( 1.0) 1 1 ( 1.0) 1
薬剤性皮膚炎 1 ( 1.0) 1 1 ( 1.0) 1
皮脂欠乏性湿疹 1 ( 1.0) 1 1 ( 1.0) 1
紅斑 1 ( 1.0) 1 1 ( 1.0) 1
過角化 1 ( 1.0) 1 1 ( 1.0) 1
爪の障害 1 ( 1.0) 1 1 ( 1.0) 1
蕁麻疹 1 ( 1.0) 2 1 ( 1.0) 2
全身性そう痒症 1 ( 1.0) 1 1 ( 1.0) 1
血管障害 1 ( 1.0) 1 1 ( 1.0) 1 2 ( 2.0) 4 2 ( 2.0) 4
血腫 1 ( 1.0) 1 1 ( 1.0) 1
静脈炎 1 ( 1.0) 1 1 ( 1.0) 1
ほてり 1 ( 1.0) 3 1 ( 1.0) 3

Causal relationship with the investigational drug: (1) clearly related, (2) probably related, (3) not related, (4) not related
The incidence of each laboratory measure may differ because cases with laboratory items present during the observation period and after the start of treatment were included in the total. The number of cases for each assay may vary, as cases with abnormal changes were included regardless of whether
the assay was missing or not.
 2.7.6 Summary of the individual tests

(4) Conclusion
In the efficacy evaluation, the primary endpoint of change in the total number of
urinary incontinence episodes per week at the end of the study, a comparison of the four
groups including the placebo group, demonstrated the superiority of ONO-8025 over placebo.
The dose-response pattern was monotonically increasing. A secondary analysis of the
primary endpoint showed that ONO-8025 at 0.2 mg/day and 0.5 mg/day had a significant
improvement over placebo in the percentage change in total urinary incontinence frequency
from the end of the observation period. In addition, ONO-8025 was superior to placebo
in the change in total number of urinary incontinence episodes from the end of the
observation period, and the dose-response pattern was monotonically increasing, as was
the rate of change.
Among the secondary endpoints, as with urinary incontinence, there was a superiority
of the ONO-8025 group over the placebo group and a dose-response of the four groups
including the placebo group in terms of the amount and rate of decrease from the end of
the observation period in frequency and urgency of urination, which are the main clinical
symptoms of overactive bladder.
In conclusion, ONO-8025 showed superiority to placebo in reducing the main clinical
symptoms of overactive bladder: urinary incontinence, frequency and urgency of urination.
In the safety evaluation, the incidence of adverse events was highest in the 0.5
mg/day group and approximately 20% lower in the 0.1 mg/day and 0.2 mg/day groups than
in the 0.5 mg/day group.
The most frequent adverse event was dry mouth, which occurred about twice as frequently
in the 0.5 mg/day group as in the 0.2 mg/day group. The incidence of dry mouth, which
is a clinical problem requiring water intake and other measures, was also highest in
the 0.5 mg/day group, with a low incidence of less than 10% at doses of 0.2 mg/day or
less.
The incidence of adverse events (events for which a causal relationship to the study
drug cannot be ruled out) was approximately 25% higher in the 0.5 mg/day group than in
the 0.2 mg/day group, and the incidence of dry mouth was approximately twice as high in
the 0.5 mg/day group as in the 0.2 mg/day group, including approximately three times
the incidence of dry mouth of moderate severity or greater. The incidence of both adverse
events and side effects was highest in the 0.5 mg/day group, with a lower incidence in
the groups below 0.2 mg/day. In one patient in the 0.5 mg/day group with benign prostatic
hyperplasia, urinary retention requiring continence was observed. This event was thought
to be due to anticholinergic effects, and therefore ONO-8025 should be administered with
caution to patients with lower urinary tract obstructive diseases such as benign
prostatic hyperplasia.
ONO-8025 is a bladder-selective muscarinic receptor subtype M3 and M1 receptor antagonist,
which was found in basic research to be a therapeutic agent for overactive bladder with
fewer side effects caused by anticholinergic effects. It is more potent than existing
anticholinergics (for the treatment of frequency and urinary incontinence) and is
bladder-selective, which means that it is expected to reduce side effects such as thirst,
constipation and photophobia. In this clinical study, ONO-8025 improved various symptoms

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 2.7.6 Summary of the individual tests

of urinary incontinence, frequency and urgency, which are the main clinical symptoms of
overactive bladder. On the other hand, the incidence of adverse events and side effects,
as well as the incidence of moderate to severe dry mouth, a clinical problem, was lower
at doses below 0.2 mg/day. Overactive bladder is a non-fatal, chronic disease that
requires long-term medication to maintain the therapeutic effect of the clinical symptoms
of overactive bladder. For these patients, the development of clinically problematic
dry mouth is an incentive to reduce or discontinue medication and to reduce compliance
with medication, which prevents them from receiving their intended treatment. Therefore,
the clinical significance of this drug in helping to correct this clinically problematic
dry mouth was considered to be significant at doses of 0.2 mg/day or less. However,
caution should be exercised when administering the drug to patients with obstructive
diseases of the lower urinary tract, such as benign prostatic hyperplasia.
In summary, based on both the clinical efficacy and adverse event results of this
clinical trial, it is considered appropriate to select a recommended clinical dose of
0.2 mg/day for the drug.

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 2.7.6 Summary of the individual tests

2. addendum
"Discussions on the recommended clinical dosage of Clozapine and the planning of Phase
III comparative studies in light of the post-Phase II clinical trial consultation of
Clozapine conducted on 26 March 2003 (Medical Devices and Medical Devices Notification
No. 137)".

In the post-Phase II clinical trial consultation (Medical Devices and Therapeutics

Announcement No. 137), the Pharmaceuticals and Medical Devices Agency (PMDA) noted that
"At this stage, although a dose-response trend in the rate of change in the number of
urinary incontinence episodes has been observed, the 0.1 mg/day group and the 0.2 mg/day
group do not differ from the placebo group in terms of the average daily frequency of
urination and the average daily volume of urination in the PPS analysis population.
However, as the mean number of urinations per day and the mean volume of urination per
urination in the PPS analysis population were not different from those in the placebo
group, the 0.2 mg/day group cannot be judged as the recommended dose. The validity of
the reanalysis cannot be determined. We believe that the appropriateness of the
reanalysis, including the appropriateness of the ex-post analysis, needs to be fully
considered". The Medicines Agency added: "Because of the risk of urinary retention
associated with Clozapine in patients with an enlarged prostate, we believe that it
would be preferable not to include patients with benign prostatic hyperplasia. Therefore,
we hope that this study will consider demonstrating efficacy in patients in line with
clinical practice".
Based on these details, it was decided to design a phase III comparative study after
considering the appropriateness of the 0.2 mg/day group as the recommended dose,
including the adequacy of the post-hoc analysis.

The content of the data presented on the day of the analysis on the average number of
urinations per day and the appropriateness of the analysis, including the validity of
the posterior analysis:
To show the dose-response of the mean number of urinations per day in the clinical
trial consultation, the least squares means adjusted for the mean number of urinations
per day at the end of the observation period in Figure 2.7.6.2-1 are shown.

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 2.7.6 Summary of the individual tests

P 0.1 0.2 0.5

0.00

1日あたりの平均排尿回数（差）
-0.50

最小二乗平均
-1.00

-1.50
-1.17± 0.19

-2.00
最小二乗平均 -1.71± 0.19
-1.77± 0.19
± 標準誤差
-2.00± 0.21
-2.50
投与群

Figure 2.7.6.2-1 Least squares mean of average number of urinations per day

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 2.7.6 Summary of the individual tests

Our views on the appropriateness of this analysis and the adequacy of the post-hoc
analysis are presented below.
(1) Appropriateness of the analysis
As shown in Table 2.7.6.2-1, there was a bias between the treatment groups in the mean
number of urinations per day at the end of the observation period (Kruskal-Wallis test:
p=0.0067).

Table 2.7.6.2-1 Average number of urinations per day (PPS) at the end of the
observation period
Kruskal-Wallis
項目 分類 P群 0.1 mg群 0.2 mg群 0.5 mg群 検定

全例 95 91 93 76
1日あたりの 10.0未満 31 ( 32.6) 21 ( 23.3) 37 ( 39.8) 18 ( 23.7)
平均排尿回数 10.0～12.0未満 31 ( 32.6) 31 ( 34.4) 23 ( 24.7) 19 ( 25.0)
(回） 12.0～14.0未満 22 ( 23.2) 23 ( 25.6) 19 ( 20.4) 13 ( 17.1)
14.0～16.0未満 3 ( 3.2) 9 ( 10.0) 9 ( 9.7) 17 ( 22.4)
16.0以上 8 ( 8.4) 6 ( 6.7) 5 ( 5.4) 9 ( 11.8) p=0.0067 *
欠測 0 1 0 0
平均値±標準偏差 11.42±2.79 11.76±2.56 11.18±2.48 12.79±3.51
中央値 10.86 11.29 10.71 12.29
25％点～75％点 9.43～12.57 10.14～13.00 9.14～12.86 10.14～14.43
最小値～最大値 8.0～23.0 8.0～20.9 8.0～18.7 8.0～26.4

In order to correct for this bias at the end of the observation period, we decided to
check the relationship between the value at the end of the observation period and the
value at the end of the treatment period (difference) in order to carry out an adjusted
analysis using the least squares mean.
In order to find prognostic factors for the mean daily urination frequency, variable
selection was carried out using the variable increase/decrease method, with the target
variable being the mean daily urination frequency (difference) and the explanatory
variable being the background factor. The results are presented in Table 2.7.6.2-2.

Table 2.7.6.2-2 Results of variable selection using the variable increase/decrease method

step数 選択された項目 寄与率

第一段階 観察期終了時における1日あたりの平均排尿回数 0.2187
第二段階 観察期終了時における平均1回排尿量 0.2255
モデルに選択された後、取り除かれた変数はなかった。

The average number of urinations per day at the end of the observation period was
chosen as the first step. Therefore, a scatter plot is shown in Figure 2.7.6.2-2 to
confirm the relationship between the value at the end of the observation phase and the
value at the end of the treatment phase (difference) in the average number of urinations
per day.

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 2.7.6 Summary of the individual tests

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 2.7.6 Summary of the individual tests

2
r = -0.463
治療期終了時（差） 0

-2

-4

-6

-8

-10
5 10 15 20 25 30
観察期終了時

Figure 2.7.6.2-2 Average number of urinations per day at the end of the observation
period and
Relationship at the end of the treatment period
(difference)

Figure 2.7.6.2-2 shows that the difference in mean daily urination frequency at the
end of the treatment period tends to decrease (improve) as the value at the end of the
observation period increases, suggesting that there is an association between the
difference at the end of the treatment period and the value at the end of the observation
period. These findings suggest that the value at the end of the observation period is a
prognostic factor for the mean number of urinations per day, and that it is appropriate
to perform a least-squares mean analysis to adjust for the bias.

(2) Validity of ex-post analysis

In the statistical analysis plan fixed before the vote opening, it was stated that
"other exploratory analyses will be added as necessary", and exploratory analyses of
the following contents, etc. were envisaged.
1) Adjusted and stratified analysis of items with biased background (including pre-
dose values)
2) Exploratory analysis when missing values are biased towards a particular dose group
(3) Examination of the relationship between specific adverse events (such as dry mouth
in this study) and efficacy ratings
4) Exploratory stratified analysis to clarify the characteristics of drugs
Therefore, we considered that the adjusted analysis conducted in this study was an
exploratory analysis within the scope of "Other exploratory analyses to be added as

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 2.7.6 Summary of the individual tests

necessary" in the analysis plan. In addition, it is common practice to perform an

adjustment analysis for items that have a biased prognostic background (including pre-
dose observations), and we considered this analysis to be appropriate.

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 2.7.6 Summary of the individual tests

Rationale for the appropriateness of the 0.2 mg/day group as the recommended clinical
dose:.
In a late phase II study, the primary endpoint of percent change in total incontinence
per week validated the superiority of Clozapine over placebo and showed a monotonically
increasing dose-response pattern in the four groups, including the placebo group.
Furthermore, the 0.2 mg/day and 0.5 mg/day groups significantly reduced the number of
urinary incontinence episodes compared with the placebo group.
A dose-response was observed in the rate of change in the number of urinary
incontinence episodes, with doses of 0.2 mg/day or higher significantly reducing the
rate of change in the total number of urinary incontinence episodes per week (primary
endpoint), demonstrating efficacy at doses of 0.2 mg/day or higher. In addition, the
incidence of adverse events, adverse drug reactions and discontinuation of treatment
due to adverse events were all higher in the 0.5 mg/day group than in the 0.1 and 0.2
mg/day groups.
Therefore, based on the results of both clinical efficacy and adverse events/side
effects, it was judged appropriate to select the 0.2 mg/day group as the recommended
clinical dose of the drug (see Late Phase II Study Summary Report).
Furthermore, anticholinergic drugs have been reported to pose a risk of causing urinary
retention, and caution should be exercised when administering them to patients with
obstructive diseases of the lower urinary tract, such as benign prostatic hyperplasia,
which would normally lead to urinary retention, while administration to patients with
these complications and polyuria is expected to create noise when assessing drug efficacy.
Therefore, in planning the Phase III comparative study, based on the results of the
post-Phase II study consultation, we examined the results of the late Phase II study
excluding patients with benign prostatic hyperplasia and polyuria, and examined the
appropriateness of the 0.2 mg/day group as the recommended clinical dose.
Tables 2.7.6.2-3 and 2.7.6.2-4 show the results when patients with benign prostatic
hyperplasia and polyuria were excluded from the late Phase II study. There was no
difference in the performance of the primary endpoint of urinary incontinence or the
secondary endpoints of urinary urgency or volume per voiding between patients with and
without these conditions.
In contrast, the secondary endpoint of frequency of urination was statistically
significantly reduced in the 0.2 mg/day and 0.5 mg/day groups versus placebo, excluding
patients with benign prostatic hyperplasia and polyuria.
In summary, based on the results of the post-Phase II study consultation, when planning
the Phase III comparative study, if patients with benign prostatic hyperplasia and
polyuria were excluded from the late Phase II study, the 0.2 mg/day group showed a dose-
response in urinary incontinence, frequency of urination, and urinary urgency, as well
as a significant improvement compared to the placebo group. The 0.2 mg/day group showed
a dose response in urinary incontinence, frequency of voiding and urinary urgency and a
significant improvement compared with placebo.
Furthermore, the incidence of adverse drug reactions and discontinuation rates due to
adverse events in the 0.2 mg/day group compared with the 0.5 mg/day group were considered

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 2.7.6 Summary of the individual tests

acceptable in clinical practice. Based on these results of both clinical efficacy and
adverse events/side effects, the 0.2 mg/day group was judged to be an appropriate
recommended clinical dose. The superiority of the 0.2 mg/day dose over placebo in urinary
incontinence, frequency of voiding, urgency of urination, and volume of urine voided
per voiding in a phase III comparative study suggests that the recommended clinical dose
is 0.2 mg/day.
In addition, taking into account the "demonstration of efficacy in patients in line
with clinical practice" presented at the consultation after the completion of the Phase
II study, the Phase III comparative study was planned as a double-blind comparative
study with three groups: the 0.2 mg/day group, the placebo group and the propiverine
hydrochloride group, with the inclusion of patients with clinically problematic lower
urinary tract obstructive diseases such as benign prostatic hyperplasia and polyuria as
exclusion criteria. The study was designed as a double-blind comparative study with
three groups: a 0.2 mg/day group, a placebo group and a propiverine group.

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 2.7.6 Summary of the individual tests

Table 2.7.6.2-3 Comparison of cases with benign prostatic hyperplasia from the PPS
analysis population of the late phase II study and
Results in the analysed population excluding polyuric cases
評価項目 投与群 観察期終了時 治療期終了時 最大対比法 Dunnett検定
標準 標準
症例数 平均 ± 症例数 平均 ± （多重性調整あり） プラセボ VS 0.1,0.2,0.5 mg
偏差 偏差
1週間あたりの P群 69 15.12 ± 14.72 68 -40.49 ± 71.41 (-3 1 1 1) p=0.0001 * P VS 0.1 mg p=0.0545 N.S.
合計尿失禁回数 0.1 mg群 80 15.58 ± 11.04 80 -61.39 ± 59.70 (-5 -1 3 3) p=0.0001 * P VS 0.2 mg p=0.0052 **
0.2 mg群 76 14.20 ± 9.72 76 -69.14 ± 46.83 (-3 -1 1 3) p=0.0001 * P VS 0.5 mg p=0.0001 ***
0.5 mg群 63 16.86 ± 12.52 63 -82.47 ± 29.46
1日あたりの P群 69 11.13 ± 2.54 68 -0.79 ± 1.69 (-3 1 1 1) p=0.0002 * P VS 0.1 mg p=0.0046 **
平均排尿回数 0.1 mg群 80 11.81 ± 2.65 80 -1.82 ± 2.14 (-5 -1 3 3) p=0.0006 * P VS 0.2 mg p=0.0206 *
0.2 mg群 76 11.10 ± 2.42 76 -1.67 ± 1.87 (-3 -1 1 3) p=0.0006 * P VS 0.5 mg p=0.0003 ***
0.5 mg群 63 12.43 ± 3.54 63 -2.15 ± 2.07
1日あたりの P群 69 4.42 ± 3.58 68 -33.71 ± 58.30 (-3 1 1 1) p=0.0001 * P VS 0.1 mg p=0.0038 **
尿意切迫感 0.1 mg群 80 4.70 ± 2.91 80 -58.88 ± 44.99 (-5 -1 3 3) p=0.0001 * P VS 0.2 mg p=0.0007 ***
の平均回数 0.2 mg群 76 4.33 ± 3.10 76 -62.95 ± 48.74 (-3 -1 1 3) p=0.0003 * P VS 0.5 mg p=0.0007 ***
0.5 mg群 63 5.42 ± 4.04 63 -64.24 ± 31.65
平均1回排尿量 P群 69 142.43 ± 50.25 66 4.00 ± 36.30 (-3 1 1 1) p=0.0063 * P VS 0.1 mg p=0.1135 N.S.
0.1 mg群 80 133.31 ± 44.47 80 16.85 ± 37.84 (-5 -1 3 3) p=0.0105 * P VS 0.2 mg p=0.5668 N.S.
0.2 mg群 76 139.13 ± 51.45 73 11.03 ± 38.27 (-3 -1 1 3) p=0.0022 * P VS 0.5 mg p=0.0020 **
0.5 mg群 63 136.83 ± 54.52 63 27.25 ± 41.55

Table 2.7.6.2-4 Comparison of the FAS analysis population of the late phase II study
with patients with benign prostatic hyperplasia
Results in the analysed population excluding polyuric cases
評価項目 投与群 観察期終了時 治療期終了時 最大対比法 Dunnett検定
標準 標準
症例数 平均 ± 症例数 平均 ± （多重性調整あり） プラセボ VS 0.1,0.2,0.5 mg
偏差 偏差
1週間あたりの P群 70 15.12 ± 14.61 68 -40.49 ± 71.41 (-3 1 1 1) p=0.0007 * P VS 0.1 mg p=0.0813 N.S.
合計尿失禁回数 0.1 mg群 86 15.79 ± 10.86 82 -60.60 ± 59.70 (-5 -1 3 3) p=0.0003 * P VS 0.2 mg p=0.0090 **
0.2 mg群 81 14.10 ± 9.59 79 -68.45 ± 46.07 (-3 -1 1 3) p=0.0003 * P VS 0.5 mg p=0.0008 ***
0.5 mg群 77 16.37 ± 12.33 72 -75.99 ± 48.52
1日あたりの P群 70 11.14 ± 2.53 68 -0.79 ± 1.69 (-3 1 1 1) p=0.0001 * P VS 0.1 mg p=0.0029 **
平均排尿回数 0.1 mg群 86 11.76 ± 2.64 82 -1.86 ± 2.13 (-5 -1 3 3) p=0.0008 * P VS 0.2 mg p=0.0331 *
0.2 mg群 81 11.16 ± 2.38 79 -1.60 ± 1.87 (-3 -1 1 3) p=0.0006 * P VS 0.5 mg p=0.0002 ***
0.5 mg群 77 12.26 ± 3.57 72 -2.12 ± 2.09
1日あたりの P群 70 4.43 ± 3.55 68 -33.71 ± 58.30 (-3 1 1 1) p=0.0001 * P VS 0.1 mg p=0.0033 **
尿意切迫感 0.1 mg群 86 4.70 ± 2.86 82 -58.78 ± 44.69 (-5 -1 3 3) p=0.0001 * P VS 0.2 mg p=0.0011 **
の平均回数 0.2 mg群 81 4.28 ± 3.05 79 -61.34 ± 48.84 (-3 -1 1 3) p=0.0007 * P VS 0.5 mg p=0.0014 **
0.5 mg群 77 5.44 ± 3.96 72 -61.44 ± 31.32
平均1回排尿量 P群 70 141.64 ± 50.32 66 4.00 ± 36.30 (-3 1 1 1) p=0.0078 * P VS 0.1 mg p=0.0885 N.S.
0.1 mg群 86 132.82 ± 43.72 81 17.38 ± 37.90 (-5 -1 3 3) p=0.0182 * P VS 0.2 mg p=0.5837 N.S.
0.2 mg群 81 138.67 ± 50.50 76 10.71 ± 37.61 (-3 -1 1 3) p=0.0050 * P VS 0.5 mg p=0.0036 **
0.5 mg群 77 135.45 ± 57.99 72 25.12 ± 40.43

(maximum contrast method) one-tailed test *: p<0.025, p<0.001

(Dunnett test) two-tailed *: p<0.05, **: p<0.01, ***: p<0.001, N.S.: Not Significant

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 2.7.6 Summary of the individual tests

ONO-8025 Phase III multicentre, double-blind, randomised, parallel-group study of

placebo and propiverine hydrochloride in patients with overactive bladder [ONO-
8025-08].
(1) Outline of the test
Title of the ONO-8025 Phase III multicentre, double-blind, randomised, parallel-group study
clinical trial of placebo and propiverine hydrochloride in patients with overactive bladder
Clinical trial
ONO-8025-08
protocol number
Clinical trial
Ono Pharmaceutical Industry Co.
sponsors
Principal Medical Corporation Nippon Steel Muroran General Hospital, Department of
Investigator Urology, Hitoshi Tachiki and others (158 persons in total)
Clinical trial sites Nippon Steel Muroran General Hospital Urology and others (Total 158 facilities)
Trial Period 14 October 2003 (date of consent for the first case)
10 May 2004 (date of last medication in last case)
Development phase Phase III
Objective To investigate the efficacy and safety of ONO-8025 in patients with overactive
bladder in a multicentre, double-blind, randomised, parallel-group, placebo-
and propiverine hydrochloride controlled study.
The primary endpoint will be the total number of urinary incontinences per
week, and the study will test the superiority of the drug over placebo and its
non-inferiority to propiverine hydrochloride.
Test design Multicentre, double-blind, placebo- and drug-controlled
Clinical Trial Patients with overactive bladder received placebo orally twice daily after
Method breakfast and dinner for 2 weeks in a single-blind observation phase. In the
treatment phase, patients were orally administered ONO-8025, propiverine
hydrochloride or placebo twice daily after breakfast and dinner for 12 weeks
in a double-blind fashion.
Number of subjects At the time of planning 750 patients to be treated with the investigational
drug for the therapeutic period
At the time of analysis Number of patients treated with study drug for the
treatment phase: 781
Number of patients analysed for efficacy (number of patients with
FAS): 766
Number of patients analysed for efficacy (number of patients recruited
for PPS): 709
Number of cases analysed for safety: 772
Target Overactive bladder patients
Selection criteria Patients with overactive bladder who fulfilled all the criteria from 1) to 4)
below were selected.
1) Age: 20 years and over (at the time of obtaining consent)
2) Gender and inpatient/outpatient status: Not applicable
(3) Patients who fulfil all of the following criteria in the symptom diary for
the week prior to the end of the observation period
(1) A total of 5 or more urinary incontinence sessions per week
(2) The average number of times you urinate per day is 8 or more times.
(3) The average number of urinary urgencies per day is one or more.
(4) Patients who are judged by the investigator (or sub-investigator) to be
able to accurately record the symptom diary
Exclusion criteria Patients who met any of the criteria 1) to 16) below were excluded.
1) Patients with genuine stress incontinence (GSI)
2) Patients with prostate cancer, bladder tumours, bladder stones, urinary
tract infections (cystitis, prostatitis, etc.) and interstitial cystitis,
or a history of recurrent urinary tract infections (two or more within 6
months prior to the observation period)
(3) Patients who have undergone urogenital surgery within 6 months prior to
the observation period

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 2.7.6 Summary of the individual tests

4) Patients with indwelling catheters or intermittent urinary continence

5) Patients who have undergone electrical stimulation therapy or bladder
training within 3 months prior to the observation period
(6) Patients who have received propiverine hydrochloride within 4 weeks prior
to the observation period or other concomitantly prohibited medicines
except propiverine hydrochloride within 2 weeks prior to the observation
period (except for estrogen preparations)
(7) Patients with contraindications to the administration of anticholinergic
drugs (severe heart disease, glaucoma, myasthenia gravis, obstruction of
the pylorus, duodenum or intestinal tract, gastric atony, intestinal
atony).
(8) Patients with a history of serious allergy or serious adverse reactions
to drugs
9) Patients with a residual urine volume of 100 mL or more, or with clinically
problematic obstructive diseases of the lower urinary tract such as benign
prostatic hyperplasia
(10) Patients with polyuria with a daily urine output of 3000 mL or more in
the symptom diary during the observation period
(11) Patients with total bilirubin greater than 3.0 mg/dL or AST (GOT) and ALT
(GPT) greater than 2.5 times the institutional normal (or greater than 100
IU/L)

Exclusion criteria (12) Patients with a serum creatinine of 2.0 mg/dL or more
(cont'd) (13) Patients with malignancies that may affect their general condition and
survival.
(14) Patients who are pregnant, lactating, or who may become pregnant, or who
wish to become pregnant during the study period.
(15) Patients who have not yet completed 4 months of treatment with all other
investigational drugs or who have previously received ONO-8025 (KRP-197)
(16) Other patients who are judged by the investigator (or sub-investigator)
to be unsuitable for the study
Test drug Preparations Formulation Content Lot.No Expiry date
Dosage and serial ONO-8025 Film Each tablet contains
S370580 January 2006
number 0.1 mg tablet Coated tablets 0.1 mg

Control drug Preparations Formulation Content Lot.No Expiry date

Dosage and serial ONO-8025 placebo ONO-8025 0.1 mg tablet and
S370580 January 2006
number tablets Externally unidentifiable tablets
Propiverine
Film Each tablet contains
hydrochloride 20 S370580 January 2006
Coated tablets 20 mg
mg tablets
Propiverine Propiverine hydrochloride 20 mg
hydrochloride tablets and S370580 January 2006
placebo tablets Externally unidentifiable tablets
Method of A double-dummy method was used, incorporating the actual drug and a placebo
administration that was not visually identifiable.
The ONO-8025 group received one 0.1 mg tablet of ONO-8025 and one placebo
tablet of propiverine hydrochloride orally twice daily, after breakfast and
after dinner.
The propiverine hydrochloride group received two tablets of ONO-8025 placebo
and one 20 mg tablet of propiverine hydrochloride orally after breakfast, and
two tablets of ONO-8025 placebo and one placebo tablet of propiverine
hydrochloride orally after dinner.
The placebo group received one ONO-8025 placebo tablet and one propiverine
hydrochloride placebo tablet orally twice a day, after breakfast and dinner.
Duration Observation period: 2 weeks
Treatment period: 12 weeks
Combination therapy Prohibited treatments before the observation period
(1) Medication prohibited within 8 weeks prior to the observation period
Estrogen preparations (but allowed if the same dose has been used for at
least 8 weeks prior to the observation period).

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 2.7.6 Summary of the individual tests

(2) Medication prohibited within 27 days before the observation period

Propiverine hydrochloride
(3) Medication prohibited within 13 days prior to the observation period
(1) Drugs for frequent urination and urinary incontinence (excluding
propiverine hydrochloride)
(2) Anticholinergics* and cholinergic agonists
(3) Drugs with anticholinergic effects among the following classifications
1) Antidepressants
Anticonvulsants
3) Anti-Parkinson's drugs
Type I antiarrhythmic drugs
(4) Phenothiazines
(5) Monoamine oxidase inhibitors
*: The use of anticholinergic drugs for the purpose of pretreatment during
gastrointestinal examinations was allowed.

Prohibited treatments from the observation phase to the treatment phase

(1) Prohibited concomitant medications
(1) Drugs for frequent urination and urinary incontinence
(2) Anticholinergics* and cholinergic agonists
(3) Drugs with anticholinergic effects among the following classifications
1) Antidepressants
Anticonvulsants
3) Anti-Parkinson's drugs
Type I antiarrhythmic drugs
(4) Estrogen preparations**
(5) Phenothiazines
(6) Monoamine oxidase inhibitors

Combination therapy (7) All other medicines which are currently under development and whose
(continued) efficacy has not yet been established.
* The use of anticholinergic drugs for purposes such as pretreatment during
gastrointestinal examinations was allowed. However, the use of
anticholinergics during the symptom diary should be avoided.
**: Estrogen preparations were allowed in combination if they had been used
at the same dose for at least 8 weeks prior to the observation phase.
No change in dosage and administration was permitted during the study
period (observation phase to treatment phase).
2) Concomitant therapy not permitted
During the trial period (observation phase to treatment phase), concomitant
use of the therapies specified in the exclusion criteria (urogenital surgery,
indwelling catheters, intermittent urinary continence, electrical stimulation
therapy, bladder training) was prohibited.

Possible concomitant medications

Concomitant use of drugs other than the above-mentioned contraindications
was allowed. However, for alpha 1 blockers, new use was avoided during the
study period (observation phase to treatment phase), the same drug was used,
and no change in dosage and administration was made. For Ca antagonists and
antihistamines, new use was to be avoided, the same drug was to be used, and
dosage and administration were not to be changed during the study period
(observation phase to treatment phase) if possible. However, if antihistamines
were to be used as an abortifacient, their use during the symptom diary period
was to be avoided as far as possible.
Evaluation criteria Efficacy and safety assessments were carried out according to the schedule
shown in Table 2.7.6.3.3-1.
Effectiveness
1) Primary endpoint: total number of urinary incontinences per week
(2) Secondary endpoints: mean number of voidings per day, mean number of

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 2.7.6 Summary of the individual tests

urinary urgencies per day, degree of urinary urgency, mean

amount of urine voided per voiding, total number of urge
incontinence per week, quality of life (King Health
Questionnaire)
Safety
Adverse events, adverse events for which a causal relationship to the study
drug cannot be ruled out (side effects), general clinical examination, ECG
(12-lead), blood pressure and pulse rate, residual urine output

The degree of dry mouth was judged in three stages: mild, moderate and
severe, according to the following criteria.
Degree Judgement criteria (for reference)
1. mild Almost unnoticeable
2. moderate tolerable with drinking water, etc.
Ingestion of water or other substances is not
3. altitude
tolerable (discontinuation of the study drug)

The names of adverse events listed in the case report form have been
translated into major organ categories and basic terms based on MedDRA ver
7.0J (Pharmaceutical Regulatory Terminology).

Statistical methods (1) Target population for analysis

The primary analysis population for the efficacy analysis was the Full
Analysis Set (FAS) for the placebo group and the Per Protocol Set (PPS) for
the propiverine hydrochloride group. For reference, the PPS compared ONO-8025
with placebo, and the FAS compared ONO-8025 with propiverine hydrochloride.
For the secondary efficacy analyses, the FAS was the primary analysis
population. For reference, the analysis in the PPS was performed.
The analysis population for the safety endpoints was the safety analysis
population. However, safety information was reported for all patients who
received the study drug.
(2) Main analysis of efficacy
Summary statistics of the percentage change in the total number of urinary
incontinences per week from the end of the observation period to the end of
the treatment period were calculated for each treatment group and analysed as
follows
(1) Two-sided 95% confidence intervals for the difference in mean values
between the ONO-8025 and placebo groups will be calculated, and
comparisons between the ONO-8025 and placebo groups will be made by t-
test.
(2) Only if the superiority of the ONO-8025 group to the placebo group is
verified in (1), the two-sided 95% confidence interval for the difference
in mean values between the ONO-8025 group and the propiverine
hydrochloride group is calculated and tested for non-inferiority of the
ONO-8025 group to the propiverine hydrochloride group. If the upper
confidence limit of the two-sided 95% confidence interval for the
difference in the mean percentage change in total weekly urinary
incontinence between the ONO-8025 and propiverine hydrochloride groups
is less than the non-inferiority margin of 14.5%, the non-inferiority of
the ONO-8025 group to the propiverine hydrochloride group is considered
to have been verified. If the confidence limit is below the non-
inferiority margin of 14.5 If this decision is made, a test for
differences between groups will be performed to confirm the
characteristics of the drugs and to determine whether the upper confidence
limit of the two-sided 95% confidence interval is below 0%.
Statistical methods 3) Safety analysis
(continued) Adverse events (subjective symptoms, other subjective findings, and abnormal
laboratory changes) were tabulated for each treatment group by item, causal
relationship, and severity. The incidence of adverse events, adverse reactions

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 2.7.6 Summary of the individual tests

and dry mouth were compared between ONO-8025 and placebo and between ONO-8025
and propiverine hydrochloride.
Date of report 15 September 2004

Table 2.7.6.3-1 Observation and inspection items and timing

Wash out
Observation period Treatment period
period
12 weeks
Occasion
or at
-4 weeks -2 weeks 0 4 weeks 8 weeks
discontin
uation
○1)
Obtaining consent circle

Patient background
Complications, circle
medical history etc.

Medication status circle circle circle circle

Distribution of symptom
circle circle circle circle
diaries

Review and collection of

symptom diary
Urinary incontinence
frequency
Urination frequency circle circle circle circle
Frequency of urgency
to urinate
Amount of urination
per time

Degree of urgency to
circle circle circle circle
urinate

Quality of Life (King's

circle circle
Health Questionnaire)

Amount of urine circle

circle
remaining

Blood pressure and

circle circle circle
pulse rate

Electrocardiogram (12-
circle circle
lead)

General clinical
circle circle circle
examination
Adverse events
(1) Not required if consent was obtained prior to the start of the washout

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 2.7.6 Summary of the individual tests

(2) Summary - Conclusion

1) Breakdown of subjects
The total number of patients enrolled in the study was 781, with 766 patients in the
FAS (143 in the placebo group, 318 in the ONO-8025 group, and 305 in the propiverine
hydrochloride group), 709 patients in the PPS (131 in the placebo group, 300 in the ONO-
8025 group, and 278 in the propiverine hydrochloride group), and 772 patients in the
safety The number of patients recruited to the PPS was 709 (placebo group: 131; ONO-
8025 group: 300; propiverine hydrochloride group: 278) and the number of patients
included in the safety analysis was 772 (placebo group: 145; ONO-8025 group: 321;
propiverine hydrochloride group: 306) (see Figure 2.7.6.3-1). The treatment of the cases
is also shown in Table 2.7.6.3-2.

仮登録例

1166例

本登録不適格例
本登録例
（治療期未実施例）
ONO-8025 塩酸ﾌﾟﾛﾋﾟ プラセボ 385例
群 ﾍﾞﾘﾝ群 群

324例 310例 147例

安全性解析対象集団 安全性解析対象集団
採用例 不採用例
ONO-8025 塩酸ﾌﾟﾛﾋﾟ プラセボ ONO-8025 塩酸ﾌﾟﾛﾋﾟ プラセボ
群 ﾍﾞﾘﾝ群 群 群 ﾍﾞﾘﾝ群 群

321例 306例 145例 3例 4例 2例

FAS採用例 FAS不採用例 PPS採用例 PPS不採用例

ONO-8025 塩酸ﾌﾟﾛﾋﾟ プラセボ ONO-8025 塩酸ﾌﾟﾛﾋﾟ プラセボ ONO-8025 塩酸ﾌﾟﾛﾋﾟ プラセボ ONO-8025 塩酸ﾌﾟﾛﾋﾟ プラセボ
群 ﾍﾞﾘﾝ群 群 群 ﾍﾞﾘﾝ群 群 群 ﾍﾞﾘﾝ群 群 群 ﾍﾞﾘﾝ群 群

318例 305例 143例 6例 5例 4例 300例 278例 131例 24例 32例 16例

Figure 2.7.6.3-1 Breakdown of subjects

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 2.7.6 Summary of the individual tests

Table 2.7.6.3-2 Treatment of cases

該当 PPS FAS 安全性
問題項目 内容 該当症例の薬剤No.
例数 採否 採否 採否

新たな治験責任医師を選定することが困難であり， 14-1，14-2，14-3，14-4，14-5，
治験責任医師の辞職 8 × × ×
治験中止された症例 15-1，15-2，15-3

未投与 治療期用治験薬が投与されなかった症例 1 × × × 16-3

選択基準違反 観察期の症状日誌のデータが採用できない症例 1 × × ○ 158-5

前立腺癌，膀胱腫瘍，膀胱結石，尿路感染症（膀胱
炎，前立腺炎など）および間質性膀胱炎を合併する
症例，または再発性尿路感染症（観察期6カ月以内 1 × × ○ 63-2
に2回以上発症）の既往のある症例

除外基準違反 観察期前4週間以内に塩酸プロピベリンの投与を受
けた症例，または観察期前2週間以内に塩酸プロピ 2 × × ○ 40-4，146-1
ベリンを除く他の併用禁止薬の投与を受けた症例
（ただし，エストロゲン製剤を除く）

観察期の症状日誌において1日排尿量が3000 mL以上
2 × × ○ 62-5，164-3
の多尿の症例
9-3，16-3，23-5，25-2，29-1，
31-1，34-2，41-1，62-1，63-2，
70-3，73-1，86-1，89-2，107-
3，110-4，113-5，114-4，115-
中止・脱落＊ 2，118-4，133-1，133-4，143-
治療期8週間（56日間）未満の症例 41 × ○ ○
（8週未満） 2，147-2，158-5，161-1，164-
3，175-5，176-5，194-1，195-
3，204-1，210-1，223-2，232-
2，238-2，238-3，241-4，244-
1，250-4，258-4
25-2，94-4，224-3，238-3，281-
治療期の服薬率が80％未満の症例 5 × ○ ○
5

観察期前8週間以内は投薬禁止とする薬剤を使用し
1 × ○ ○ 268-1
た症例

観察期前13日間以内は投薬禁止とする薬剤を使用し
2 × ○ ○ 40-4，146-1
た症例
処置違反・
評価データ不完備 25-2，38-5，40-1，40-4，94-4，
観察期から治療期に併用禁止薬を併用した症例 13 × ○ ○ 119-4，146-1，163-3，175-4，
176-5，186-4，186-5，252-4

エストロゲン製剤について，観察期から治療期に用
3 × ○ ○ 72-5，151-1，163-5
法・用量の変更を行った症例

観察期終了時または治療期終了時のデータが評価で 9-3，29-1，83-2，108-4，113-
7 × ○ ○
きない症例 3，203-1，240-1

＊：治験責任医師の辞職による投与中止例（14-1，14-5，15-1，15-2，15-3）を除く

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 2.7.6 Summary of the individual tests

2) Efficacy results
The primary endpoint was the percentage change in the total number of urinary
incontinences per week. The primary analysis for non-inferiority of ONO-8025 over
propiverine hydrochloride was the PPS, while the other analyses, including the
superiority of ONO-8025 over placebo, were the FAS. The percent change (mean ± standard
deviation) in the total number of urinary incontinence sessions per week from the end
of the observation period was -68.24 ± 36.90 in the ONO-8025 group compared to -49.50
± 57.22 in the placebo group, confirming the superiority of the ONO-8025 group over
the placebo group (FAS, t-test: p<0.0001, see Table 2.7.6.3-3). The percent change (mean
± standard deviation) in the total number of urinary incontinences per week from the
end of the observation period was -73.08 ± 43.15 in the propiverine hydrochloride group
compared with -68.54 ± 36.58 in the ONO-8025 group, demonstrating the non-inferiority
of the ONO-8025 group to the propiverine hydrochloride group (PPS, t-test: p=0.0001,
see Table 2.7.6.3-3). PPS, t-test: p=0.0014, non-inferiority margin: 14.5%, see Table
2.7.6.3-4).

Table 2.7.6.3-3 Per week at end (after 12 weeks of treatment or at discontinuation)

Change (%) in total number of urinary incontinence visits to the
end of the observation period (FAS)
解析対象集団：FAS
観察期終了時 12週後（または中止時）
-実測値- -変化率-
平均値の差の t検定1）
投与群
例数 平均 ± 標準偏差 例数 平均 ± 標準偏差 両側95％信頼区間 　 　

ONO-8025群 318 18.56 ± 14.81 311 -68.24 ± 36.90 -27.62 ～ -9.85 p<0.0001 *

プラセボ群 143 17.55 ± 11.18 137 -49.50 ± 57.22

1）両側検定(*：p<0.05 )

Table 2.7.6.3-4 Per week at end of treatment (after 12 weeks of treatment or at

discontinuation)
Change (%) in total number of urinary incontinence visits to the
end of the observation period (PPS)
解析対象集団：PPS
観察期終了時 12週後（または中止時）
-実測値- -変化率-
平均値の差の t検定1）
投与群
例数 平均 ± 標準偏差 例数 平均 ± 標準偏差 両側95％信頼区間 　 　

ONO-8025群 300 18.59 ± 14.88 300 -68.54 ± 36.58 -1.98 ～ 11.06 非劣性2） p=0.0014 *

塩酸ﾌﾟﾛﾋﾟﾍﾞﾘﾝ群 278 17.93 ± 14.83 278 -73.08 ± 43.15 優越性 p=0.9141 N.S.

1）片側検定（*：p<0.025、N.S.：p≧0.025）
2）非劣性マージンΔ=14.5％を上乗せした検定

The difference (mean ± standard deviation) in the mean daily frequency of urination
at the end of the observation period was -1.08 ± 1.62 in the placebo group compared
with -1.52 ± 1.70 in the ONO-8025 group and -1.80 ± 1.86 in the propiverine
hydrochloride group. (t-test: p=0.0112, see Table 2.7.6.3-5).

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 2.7.6 Summary of the individual tests

Table 2.7.6.3-5 Daily dose at end (after 12 weeks of treatment or at discontinuation)

Difference in mean frequency of urination (times) from the end of
the observation period (FAS)

解析対象集団：FAS
観察期終了時 12週後（または中止時）
-実測値- -差- 比較群1） 平均値の差の t検定2）
投与群
例数 平均 ± 標準偏差 例数 平均 ± 標準偏差 　 両側95％信頼区間 　

ONO-8025群 318 11.20 ± 2.28 311 -1.52 ± 1.70 ONO vs PRO -0.01 ～ 0.56 p=0.0554 N.S.

塩酸ﾌﾟﾛﾋﾟﾍﾞﾘﾝ群 305 11.16 ± 2.59 296 -1.80 ± 1.86 ONO vs PLA -0.78 ～ -0.10 p=0.0112 *

プラセボ群 143 11.47 ± 2.50 137 -1.08 ± 1.62

1）ONO：ONO-8025群、PRO：塩酸ﾌﾟﾛﾋﾟﾍﾞﾘﾝ群、PLA：プラセボ群
2）両側検定（*：p<0.05、N.S.：p≧0.05）

The mean change (%) (mean ± standard deviation) in the mean number of urinary
urgencies per day at the end of the observation period was -35.63±53.71 in the placebo
group compared to -53.39 ± 41.35 in the ONO-8025 group and -59.68 ± 54.73 in the
propiverine hydrochloride group. The ONO-8025 group showed a significant reduction
compared to the placebo group (t-test: p=0.0002, see Table 2.7.6.3-6). Although there
was a bias in the mean number of urinary urgencies per day at the end of the observation
period between the groups (Kruskal-Wallis test: p=0.1192), the arithmetic mean and least
squares mean were similar and the effect of the value at the end of the observation
period on the rate of change was considered to be small (see Table 2.7.6.3-7 (see Table
2.7.6.3-7).
The percentage of patients with at least one improvement in urinary urgency was
significantly higher in the ONO-8025 group than in the placebo group: 80.1% in the ONO-
8025 group and 85.2% in the propiverine hydrochloride group compared with 66.9% in the
placebo group (χ2 test: p=0 .0042).

Table 2.7.6.3-6 Daily dose at end (after 12 weeks of treatment or at

discontinuation)
Change in mean frequency of urinary urgency (%) relative to the
end of the observation period (FAS)

解析対象集団：FAS
観察期終了時 12週後（または中止時）
-実測値- -変化率- 比較群1） 平均値の差の t検定2）
投与群
例数 平均 ± 標準偏差 例数 平均 ± 標準偏差 　 両側95％信頼区間 　

ONO-8025群 318 4.87 ± 2.90 311 -53.39 ± 41.35 ONO vs PRO -1.42 ～ 14.00 p=0.1096 N.S.

塩酸ﾌﾟﾛﾋﾟﾍﾞﾘﾝ群 305 4.80 ± 3.28 296 -59.68 ± 54.73 ONO vs PLA -26.92 ～ -8.59 p=0.0002 *

プラセボ群 143 5.42 ± 3.57 137 -35.63 ± 53.71

1）ONO：ONO-8025群、PRO：塩酸ﾌﾟﾛﾋﾟﾍﾞﾘﾝ群、PLA：プラセボ群
2）両側検定（*：p<0.05、N.S.：p≧0.05）

Table 2.7.6.3-7 Mean number of urinary urgency sensations per day according to the
value at the end of the observation period

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 2.7.6 Summary of the individual tests

Adjusted mean (FAS) of change (%) at end (after 12 weeks of treatment

or at discontinuation)

解析対象集団：FAS
標準 最小二乗 標準
評価項目 投与群 平均 ± ±
誤差 平均 誤差
1日あたりの ONO-8025群 -53.39 ± 2.35 -53.31 ± 2.79
尿意切迫感の平均回数の 塩酸ﾌﾟﾛﾋﾟﾍﾞﾘﾝ群 -59.68 ± 3.18 -59.48 ± 2.86
変化率（％） プラセボ群 -35.63 ± 4.59 -36.25 ± 4.22

The difference (mL) (mean ± standard deviation) in mean voided volume per urine at
the end of the observation period was 9.28 ± 32.67 in the placebo group compared to
19.35 ± 37.37 in the ONO-8025 group and 36.07 ± 40.30 in the propiverine hydrochloride
group, with a significant increase in the ONO-8025 group compared to the placebo group
(t-test: p =0.0075, see Table 2.7.6.3-8).

Table 2.7.6.3-8 Mean volume of urine voided per voiding at the end of the treatment
period (after 12 weeks or at cessation)
Difference to end of observation period (mL) (FAS)

解析対象集団：FAS
観察期終了時 12週後（または中止時）
-実測値- -差- 比較群1） 平均値の差の t検定2）
投与群
例数 平均 ± 標準偏差 例数 平均 ± 標準偏差 　 両側95％信頼区間 　

ONO-8025群 310 147.32 ± 47.21 300 19.35 ± 37.37 ONO vs PRO -23.03 ～ -10.42 p<0.0001 *

塩酸ﾌﾟﾛﾋﾟﾍﾞﾘﾝ群 294 149.79 ± 46.41 285 36.07 ± 40.30 ONO vs PLA 2.70 ～ 17.44 p=0.0075 *

プラセボ群 140 154.19 ± 53.47 133 9.28 ± 32.67

1）ONO：ONO-8025群、PRO：塩酸ﾌﾟﾛﾋﾟﾍﾞﾘﾝ群、PLA：プラセボ群
2）両側検定（*：p<0.05）

The percent change (mean ± standard deviation) in the total number of urge
incontinence sessions per week from the end of the observation period was -49.23 ±
66.92 in the placebo group compared with -69.47 ± 37.94 in the ONO-8025 group and -
75.53 ± 44.03 in the propiverine hydrochloride group. The ONO-8025 group showed a
significant reduction compared to the placebo group (t-test: p<0.0001, see Table 2.7.6.3-
9).

Table 2.7.6.3-9 Per week at end (after 12 weeks of treatment or at discontinuation)

Percentage change (%) in total urge incontinence frequency to
the end of the observation period (FAS)

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 2.7.6 Summary of the individual tests

解析対象集団：FAS
観察期終了時 12週後（または中止時）
-実測値- -変化率- 比較群1） 平均値の差の t検定2）
投与群
例数 平均 ± 標準偏差 例数 平均 ± 標準偏差 　 両側95％信頼区間 　

ONO-8025群 318 16.55 ± 13.31 311 -69.47 ± 37.94 ONO vs PRO -0.49 ～ 12.60 p=0.0696 N.S.

塩酸ﾌﾟﾛﾋﾟﾍﾞﾘﾝ群 305 15.69 ± 13.44 296 -75.53 ± 44.03 ONO vs PLA -30.04 ～ -10.44 p<0.0001 *

プラセボ群 143 15.51 ± 10.04 137 -49.23 ± 66.92

1）ONO：ONO-8025群、PRO：塩酸ﾌﾟﾛﾋﾟﾍﾞﾘﾝ群、PLA：プラセボ群
2）両側検定（*：p<0.05、N.S.：p≧0.05）

In the secondary endpoint comparison between the ONO-8025 group and the propiverine
hydrochloride group, the mean amount of urine voided per urination was significantly
higher in the propiverine hydrochloride group than in the ONO-8025 group (t-test:
p<0.0001), but the mean number of urinations per day, the mean number of urinary
urgencies per day and the degree of urinary urgency were not different between the two
groups. urgency per day did not differ between the two groups.

The differences in the King Health Questionnaire domains relative to the end of the
observation period were significantly reduced in the ONO-8025 group compared to the
placebo group in the three domains of physical limitations, personal relationships and
subjective severity (t-test: p=0.0104, p=0.0291 and p=0.0230 respectively). In
comparison with the propiverine hydrochloride group, the propiverine hydrochloride group
showed a significant reduction compared with the ONO-8025 group in the three domains of
work/household restrictions, psychological problems and subjective severity (t-test:
p=0.0154, p=0.0039 and p=0.0096, respectively).
These results demonstrated the superiority of ONO-8025 over placebo and non-
inferiority of ONO-8025 over propiverine hydrochloride in the primary endpoint of change
in the total number of urinary incontinences per week. As well as urinary incontinence,
the frequency of urination and the frequency and severity of urinary urgency, the main
clinical symptoms of overactive bladder, were also significantly reduced in the ONO-
8025 group compared with the placebo group, indicating that the drug is effective in
treating the symptoms of urinary incontinence, frequency and urinary urgency in
overactive bladder.

(3) Safety results

A list of adverse events by severity, a list of adverse effects by severity and a list
of adverse events by causality are presented in Tables 2.7.6.3-17 to 2.7.6.3-19.
The incidence of adverse events was 68.3% in the placebo group, 72.9% in the ONO-8025
group and 81.7% in the propiverine hydrochloride group. The incidence of adverse events
in the ONO-8025 group was similar to that in the placebo group and significantly lower
than that in the propiverine hydrochloride group (Fisher's direct probability test:
p=0.3200 and p=0 .0101, see Table 2.7.6.3-10). The incidence of adverse events that
could not be ruled out as being causally related to the study drug was 26.2% in the
placebo group, 40.5% in the ONO-8025 group and 51.0% in the propiverine hydrochloride

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 2.7.6 Summary of the individual tests

group, with a significantly higher incidence in the ONO-8025 group compared with the
placebo group but a significantly lower incidence in the propiverine hydrochloride group
(Fisher's direct probability test: p=0.3200 and p=0.0101, respectively; see Table
2.7.6.3-10). The adverse events with an incidence of ≥5% in the ONO-8025 group were dry
mouth, nasopharyngitis, constipation and positive urine leukocytes. The most frequent
adverse event was dry mouth, which occurred in 13.8% of patients in the placebo group,
31.5% in the ONO-8025 group and 39.9% in the propiverine hydrochloride group. The
incidence of dry mouth in the ONO-8025 group was significantly higher than in the placebo
group, but significantly lower than in the propiverine hydrochloride group. Fisher's
direct probability test: p<0.0001 and p=0.0302 respectively, see Table 2.7.6.3-12). The
incidence of clinically challenging dry mouth of moderate severity (requiring water
intake or other measures) or greater was 0.7% in the placebo group, 5.0% in the ONO-
8025 group and 9.2% in the propiverine hydrochloride group. The incidence in the ONO-
8025 group was significantly higher than in the placebo group, but significantly lower
than in the propiverine hydrochloride group (Fisher's direct probability test: p=0.0290
and p=0.0433, respectively). In addition, there were four cases of severe dry mouth
(intolerable even with water intake) in the propiverine hydrochloride group, but none
in the placebo or ONO-8025 groups (see Table 2.7.6.3-13).

Table 2.7.6.3-10 Adverse event incidence

投与群 有 無 合計 比較群1） Fisherの直接確率検定2)
ONO-8025群 234 ( 72.9 %) 87 ( 27.1 %) 321 ONO vs PRO p=0.0101 *
塩酸ﾌﾟﾛﾋﾟﾍﾞﾘﾝ群 250 ( 81.7 %) 56 ( 18.3 %) 306 ONO vs PLA p=0.3200 N.S.
プラセボ群 99 ( 68.3 %) 46 ( 31.7 %) 145
1）ONO：ONO-8025群、PRO：塩酸ﾌﾟﾛﾋﾟﾍﾞﾘﾝ群、PLA：プラセボ群
2）両側検定（*：p<0.05、N.S.：p≧0.05）
ｃ

Table 2.7.6.3-11 Incidence of adverse events for which a causal relationship to the
investigational product cannot be ruled out
投与群 有 無 合計 比較群1） Fisherの直接確率検定2)
ONO-8025群 130 ( 40.5 %) 191 ( 59.5 %) 321 ONO vs PRO p=0.0102 *
塩酸ﾌﾟﾛﾋﾟﾍﾞﾘﾝ群 156 ( 51.0 %) 150 ( 49.0 %) 306 ONO vs PLA p=0.0034 *
プラセボ群 38 ( 26.2 %) 107 ( 73.8 %) 145
1）ONO：ONO-8025群、PRO：塩酸ﾌﾟﾛﾋﾟﾍﾞﾘﾝ、PLA：プラセボ群
2）両側検定（*：p<0.05）

Table 2.7.6.3-12 Incidence of dry mouth (adverse events)

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 2.7.6 Summary of the individual tests

投与群 有 無 合計 比較群1） Fisherの直接確率検定2)

ONO-8025群 101 ( 31.5 %) 220 ( 68.5 %) 321 ONO vs PRO p=0.0302 *
塩酸ﾌﾟﾛﾋﾟﾍﾞﾘﾝ群 122 ( 39.9 %) 184 ( 60.1 %) 306 ONO vs PLA p<0.0001 *
プラセボ群 20 ( 13.8 %) 125 ( 86.2 %) 145
1）ONO：ONO-8025群、PRO：塩酸ﾌﾟﾛﾋﾟﾍﾞﾘﾝ群、PLA：プラセボ群
2）両側検定（*：p<0.05）

Table 2.7.6.3-13 Occurrence of dry mouth by causality and severity

投与群 症例数 重症度 軽度 中等度 高度 計
因果関係 無 有 無 有 無 有 　
発現例数 12 73 2 14 0 0 101
ONO-8025群 321 発現件数 12 73 2 15 0 0 102
発現率(％) 3.7 22.7 0.6 4.4 0.0 0.0 31.5
発現例数 9 85 1 23 0 4 122
塩酸ﾌﾟﾛﾋﾟﾍﾞﾘﾝ群 306 発現件数 10 85 1 24 0 4 124
発現率(％) 2.9 27.8 0.3 7.5 0.0 1.3 39.9
発現例数 6 13 0 1 0 0 20
プラセボ群 145 発現件数 6 13 0 1 0 0 20
発現率(％) 4.1 9.0 0.0 0.7 0.0 0.0 13.8

Other than thirst, the most common adverse events thought to be anticholinergic were
constipation, misty-eyed/photophobia, and dysuria. The incidence of constipation was
7.6% in the placebo group, 11.8% in the ONO-8025 group, and 13.7% in the propiverine
hydrochloride group; foggy vision and photophobia was 3.4% in the placebo group, 3.1%
in the ONO-8025 group, and 7.2% in the propiverine hydrochloride group; and dysuria was
0.7% in the placebo group, 0.9% in the ONO-8025 group, and 2.9% in the propiverine
hydrochloride group. The incidence of all events was lower in the ONO-8025 group than
in the propiverine hydrochloride group, with significantly lower incidences of blurred
vision, abnormal eye sensation and photophobia (Fisher's direct probability test:
p=0.0281). There were no severe cases, and moderate cases of constipation in 2 patients
in the placebo group, 3 patients in the ONO-8025 group, 7 patients in the propiverine
hydrochloride group, foggy vision in 1 patient in the placebo group, and dysuria in 1
patient in the propiverine hydrochloride group.
The discontinuation rate due to adverse events (including patients who withdrew consent
because of an adverse event) was 5.5% (8/145 patients) in the placebo group, 3.4% (11/321
patients) in the ONO-8025 group and 6.2% (19/306 patients) in the propiverine
hydrochloride group. The discontinuation rate due to adverse events was lower in the
ONO-8025 group than in the propiverine group. The discontinuation rate due to dry mouth
was 0.0% (0/145 patients) in the placebo group, 0.3% (1/321 patients) in the ONO-8025
group, and 2.6% (8/306 patients) in the propiverine hydrochloride group. The
discontinuation rate due to dry mouth in the ONO-8025 group was similar to that in the
placebo group and significantly lower than that in the propiverine hydrochloride group.
Fisher's direct probability test: p=0.0181).
One patient in the ONO-8025 group died during the study. The cause of death was left

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 2.7.6 Summary of the individual tests

thoracic hemorrhage due to rupture of a thoracic aortic aneurysm, which was considered
to be a complication-related event and was not causally related to the study drug. There
were nine other serious adverse events: three in the placebo group (bladder tumour,
breast cancer and bowel obstruction), five in the ONO-8025 group (two cerebral
infarctions, worsening of disc herniation, bronchopneumonia and pneumonia) and one in
the propiverine hydrochloride group (compression fracture). In the placebo group, there
was one case of intestinal obstruction. Of the 8 serious adverse events for which a
causal relationship to the study drug was ruled out, 5 (2 cerebral infarctions,
aggravated disc herniation, bladder tumour and breast cancer) were considered to be
complication-related events and 3 (bronchopneumonia, pneumonia and compression fracture)
were considered to be incidental events. Other important adverse events included severe
dry mouth in four patients in the propiverine hydrochloride group and none in the ONO-
8025 group. In addition, 8 patients in the ONO-8025 group, 18 patients in the propiverine
hydrochloride group and 7 patients in the placebo group discontinued treatment with the
investigational drug due to the occurrence of an adverse event other than a serious
adverse event (including patients who withdrew consent due to the occurrence of an
adverse event). 8 patients in the ONO-8025 group discontinued treatment due to the
occurrence of an adverse event. The adverse events and their severity in the 8 patients
in the ONO-8025 group who discontinued treatment due to adverse events included 2 cases
of gastritis (all moderate) and 1 case each of headache (moderate), constipation
(moderate), vomiting, nausea and nasopharyngitis (moderate), supraventricular
extrasystoles, palpitations and positional vertigo (mild), headache, floating dizziness,
foggy vision, dry mouth and retinal haemorrhage (mild), and cheilitis and glossitis
(mild). (all mild). Of these adverse events, constipation, supraventricular
extrasystoles, palpitations, positional dizziness, and dry mouth were those for which a
causal relationship to the study drug could not be ruled out. Constipation disappeared
with drug treatment (sodium picosulfate, senna extract, and glycerin enema), and
supraventricular extrasystoles, palpitations, positional dizziness, and dry mouth
disappeared without treatment after discontinuation of the study drug.
There were no clinically concerning changes in any of the general clinical laboratory
parameters in either dose group (see Table 2.7.6.3-16).
In the 12-lead ECG, there was no significant increase in the rate of abnormalities at
the end of the treatment period in either treatment group, and there was no difference
in the rate of abnormalities between treatment groups. The difference (ms) (mean ±
standard deviation) in QTc at the end of the treatment period compared to the end of
the observation period was -1.35 ± 19.29 in the placebo group, -1.37 ± 21.53 in the
ONO-8025 group and 7.56 ± 20.08 in the propiverine hydrochloride group, with a
significant increase in QTc in the propiverine hydrochloride group (corresponding t-
test p<0.0001, see Table 2.7.6.3-14). QTc was also significantly prolonged in the
propiverine hydrochloride group compared with the ONO-8025 group, although there was no
difference between the ONO-8025 and placebo groups (t-test: p<0.0001). Furthermore, the
distribution of the difference in QTc showed that none of the patients in the placebo
and ONO-8025 groups had a QTc prolongation of more than 60 ms from the observation

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 2.7.6 Summary of the individual tests

period, compared with 0.7% (2/288) in the propiverine hydrochloride group, and 7.4%
(10/136) of patients in the placebo group had a QTc prolongation of 30 ms to less than
60 ms. The proportion of patients with QTc prolongation in the propiverine hydrochloride
group was almost double that in the placebo and ONO-8025 groups (see Table 2.7.6.3-15).

Table 2.7.6.3-14 QTc

群内比較 群間比較
時期 項目 投与群 症例数 平均 ± 標準 上段：ONO-8025群 vs 塩酸ﾌﾟﾛﾋﾟﾍﾞﾘﾝ群
偏差 対応のある 下段：ONO-8025群 vs 　　プラセボ群
t検定1） 平均値の差の t検定1）
両側95％信頼区間 　
観察期 絶対値 ONO-8025群 320 402.51 ± 26.76 p=0.0486 *
終了時 塩酸ﾌﾟﾛﾋﾟﾍﾞﾘﾝ群 306 398.57 ± 22.90 p=0.6014 N.S.
プラセボ群 145 401.12 ± 26.37
治療期 絶対値 ONO-8025群 298 401.01 ± 25.55 p=0.0124 *
12週後 塩酸ﾌﾟﾛﾋﾟﾍﾞﾘﾝ群 275 406.17 ± 23.44 p=0.5418 N.S.
プラセボ群 130 399.43 ± 22.37
差 ONO-8025群 298 -1.05 ± 21.68 p=0.4024 N.S. -11.80 ～ -4.90 p<0.0001 *
塩酸ﾌﾟﾛﾋﾟﾍﾞﾘﾝ群 275 7.29 ± 20.25 p<0.0001 * -3.90 ～ 4.79 p=0.8409 N.S.
プラセボ群 130 -1.50 ± 19.48 p=0.3823 N.S.
治療期 絶対値 ONO-8025群 310 401.04 ± 25.72 p=0.0056 *
終了時 塩酸ﾌﾟﾛﾋﾟﾍﾞﾘﾝ群 288 406.66 ± 23.50 p=0.5825 N.S.
プラセボ群 136 399.64 ± 22.30
差 ONO-8025群 310 -1.37 ± 21.53 p=0.2649 N.S. -12.28 ～ -5.57 p<0.0001 *
塩酸ﾌﾟﾛﾋﾟﾍﾞﾘﾝ群 288 7.56 ± 20.08 p<0.0001 * -4.23 ～ 4.21 p=0.9948 N.S.
プラセボ群 136 -1.35 ± 19.29 p=0.4152 N.S.
1）：両側検定（* ： p<0.05、N.S.：p≧0.05）

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Table 2.7.6.3-15 Distribution of the difference in QTc from the observation

period
観察期からの変化量
時期 投与群 症例数 30ms未満 30ms以上 60ms以上
60ms未満
治療期 ONO-8025群 298 276 （ 92.6） 22 （ 7.4） 0（ 0.0）
12週後 塩酸ﾌﾟﾛﾋﾟﾍﾞﾘﾝ群 275 235 （ 85.5） 38 （ 13.8） 2（ 0.7）
プラセボ群 130 120 （ 92.3） 10 （ 7.7） 0（ 0.0）
治療期 ONO-8025群 310 288 （ 92.9） 22 （ 7.1） 0（ 0.0）
終了時 塩酸ﾌﾟﾛﾋﾟﾍﾞﾘﾝ群 288 246 （ 85.4） 40 （ 13.9） 2（ 0.7）
プラセボ群 136 126 （ 92.6） 10 （ 7.4） 0（ 0.0）

（）内は％を示す

There were no clinically relevant changes in blood pressure in either treatment group.
There was no significant change in pulse rate at the end of the treatment period
compared with the end of the observation period in the placebo and ONO-8025 groups, but
there was a significant increase in the propiverine hydrochloride group (corresponding
t-test: p<0.0001). The difference in pulse rate (beats per minute) at the end of the
treatment period compared with the end of the observation period (mean ± standard
deviation) was -1.0 ± 9.6 for placebo, -0.8 ± 9.6 for ONO-8025 and 4.4 ± 9.2 for
propiverine hydrochloride.
There was no significant change in residual urine volume at the end of the observation
period in either treatment group. Adverse events of increased residual urine volume
occurred in 1.4% (2/145 patients) in the placebo group, 0.6% (2/321 patients) in the
ONO-8025 group and 1.6% (5/306 patients) in the propiverine hydrochloride group.
The incidence of adverse events, adverse drug reactions, and dry mouth was
significantly lower in the ONO-8025 group than in the propiverine hydrochloride group,
and the incidence of dry mouth (moderate or severe) and discontinuation of treatment
due to dry mouth were also significantly lower. In addition, it was shown that the drug
did not have QT prolongation effect as seen in propiverine hydrochloride, indicating
that it is a safe drug for the treatment of overactive bladder.

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 2.7.6 Summary of the individual tests

Table 2.7.6.3-16 Pre- and post-dose changes in clinical laboratory values

解析対象集団：安全性解析対象集団
標準
検査項目 投与群 時期 症例数 平均 ± 最小値 25％点 中央値 75％点 最大値 対応のあるt検定1）
偏差
白血球数 ONO群 観察期 320 5757.8 ± 1518.8 2300 4700.0 5600.0 6600.0 12000
（/mm3） 治療期4週後 314 5608.3 ± 1464.6 1900 4600.0 5450.0 6400.0 11200 p=0.0157 *
治療期12週後 299 5531.4 ± 1510.9 2600 4530.0 5400.0 6300.0 13400 p=0.0009 *
治療期終了時 311 5552.2 ± 1490.6 2600 4600.0 5500.0 6300.0 13400 p=0.0014 *
プロピベリン群 観察期 306 5791.3 ± 1616.8 2200 4600.0 5600.0 6700.0 14700
治療期4週後 296 5752.7 ± 1657.7 1800 4700.0 5500.0 6600.0 14500 p=0.3885 N.S.
治療期12週後 278 5729.3 ± 1727.0 2500 4600.0 5500.0 6600.0 17600 p=0.2391 N.S.
治療期終了時 293 5724.0 ± 1703.9 2500 4700.0 5500.0 6600.0 17600 p=0.2510 N.S.
プラセボ群 観察期 142 5891.0 ± 1505.1 3400 4800.0 5700.0 6900.0 11100
治療期4週後 136 5611.5 ± 1500.3 2900 4450.0 5400.0 6500.0 11600 p=0.0079 *
治療期12週後 130 5585.0 ± 1614.4 2980 4600.0 5300.0 6200.0 12000 p=0.0162 *
治療期終了時 137 5628.1 ± 1637.3 2980 4600.0 5300.0 6200.0 12000 p=0.0153 *
赤血球数 ONO群 観察期 320 430.7 ± 36.8 305 408.0 427.0 456.0 537
(104/mm3) 治療期4週後 314 428.8 ± 37.1 315 404.0 425.5 454.0 550 p=0.1894 N.S.
治療期12週後 299 423.8 ± 34.7 293 401.0 421.0 447.0 547 p<0.0001 *
治療期終了時 311 424.0 ± 34.9 293 401.0 421.0 447.0 547 p<0.0001 *
プロピベリン群 観察期 306 428.4 ± 33.9 344 404.0 429.0 450.0 531
治療期4週後 296 430.3 ± 33.4 353 406.0 428.5 454.0 540 p=0.1697 N.S.
治療期12週後 278 424.8 ± 33.8 336 401.0 422.5 448.0 529 p<0.0001 *
治療期終了時 293 424.8 ± 33.6 336 401.0 423.0 449.0 529 p<0.0001 *
プラセボ群 観察期 142 431.2 ± 34.4 323 409.0 430.0 453.0 526
治療期4週後 136 431.4 ± 35.1 325 404.5 432.5 454.0 527 p=0.9963 N.S.
治療期12週後 130 423.9 ± 35.4 295 399.0 422.5 448.0 513 p<0.0001 *
治療期終了時 137 424.2 ± 35.2 295 399.0 423.0 448.0 513 p<0.0001 *
ヘモグロビン ONO群 観察期 320 13.19 ± 1.29 8.0 12.50 13.20 14.00 16.3
（g/dL） 治療期4週後 314 13.17 ± 1.27 8.2 12.50 13.10 13.90 17.0 p=0.7541 N.S.
治療期12週後 299 13.24 ± 1.25 7.8 12.60 13.20 14.00 17.0 p=0.0869 N.S.
治療期終了時 311 13.23 ± 1.27 7.8 12.50 13.20 14.00 17.0 p=0.1851 N.S.
プロピベリン群 観察期 306 13.20 ± 1.11 8.2 12.40 13.30 13.90 16.3
治療期4週後 296 13.26 ± 1.10 8.5 12.50 13.20 14.00 16.4 p=0.0591 N.S.
治療期12週後 278 13.33 ± 1.16 8.6 12.60 13.30 14.00 16.9 p=0.0013 *
治療期終了時 293 13.34 ± 1.15 8.6 12.60 13.30 14.00 16.9 p=0.0008 *
プラセボ群 観察期 142 13.13 ± 1.14 7.5 12.50 13.10 13.70 16.9
治療期4週後 136 13.18 ± 1.15 7.4 12.65 13.20 13.70 17.1 p=0.3114 N.S.
治療期12週後 130 13.19 ± 1.24 6.9 12.50 13.10 14.00 16.5 p=0.3711 N.S.
治療期終了時 137 13.18 ± 1.22 6.9 12.50 13.10 14.00 16.5 p=0.3742 N.S.
ヘマトクリット値 ONO群 観察期 320 40.38 ± 3.59 28.9 38.20 40.40 42.80 49.0
（％） 治療期4週後 314 40.06 ± 3.45 28.0 38.00 40.15 42.10 49.2 p=0.0085 *
治療期12週後 299 39.50 ± 3.33 26.6 37.60 39.50 41.60 49.4 p<0.0001 *
治療期終了時 311 39.50 ± 3.35 26.6 37.60 39.60 41.60 49.4 p<0.0001 *
プロピベリン群 観察期 306 40.41 ± 3.03 28.6 38.40 40.50 42.20 50.5
治療期4週後 296 40.44 ± 3.14 29.1 38.30 40.45 42.35 54.5 p=0.7626 N.S.
治療期12週後 278 39.84 ± 3.19 29.4 37.90 39.85 41.60 50.5 p<0.0001 *
治療期終了時 293 39.86 ± 3.16 29.4 37.90 39.90 41.60 50.5 p<0.0001 *
プラセボ群 観察期 142 40.40 ± 3.21 24.7 38.50 40.30 41.90 50.6
治療期4週後 136 40.23 ± 3.17 24.4 38.20 40.20 42.15 49.0 p=0.4236 N.S.
治療期12週後 130 39.53 ± 3.31 22.2 37.60 39.80 41.40 49.7 p<0.0001 *
治療期終了時 137 39.53 ± 3.26 22.2 37.60 39.70 41.40 49.7 p<0.0001 *
血小板数 ONO群 観察期 320 23.54 ± 5.66 9.2 19.55 22.95 26.75 46.4
（104/mm3） 治療期4週後 313 23.38 ± 5.67 12.7 19.70 22.60 26.60 45.2 p=0.3012 N.S.
治療期12週後 299 23.23 ± 5.81 10.5 19.50 22.80 26.50 48.6 p=0.2635 N.S.
治療期終了時 311 23.23 ± 5.76 10.5 19.60 22.80 26.50 48.6 p=0.1671 N.S.
プロピベリン群 観察期 306 23.30 ± 6.50 11.8 19.70 22.45 26.50 95.1
治療期4週後 296 23.20 ± 6.19 11.8 19.10 22.55 27.10 74.0 p=0.2539 N.S.
治療期12週後 278 23.62 ± 5.87 12.7 20.10 22.85 26.70 72.2 p=0.6842 N.S.
治療期終了時 293 23.50 ± 5.84 12.5 19.90 22.80 26.70 72.2 p=0.6215 N.S.
プラセボ群 観察期 141 24.29 ± 5.67 12.4 20.80 23.70 27.30 43.6
治療期4週後 135 23.89 ± 5.87 10.5 20.10 23.10 26.50 42.4 p=0.1605 N.S.
治療期12週後 129 23.58 ± 5.45 10.3 20.60 23.00 26.30 39.3 p=0.1502 N.S.
治療期終了時 136 23.98 ± 5.76 10.3 20.60 23.25 26.60 41.6 p=0.2386 N.S.

1）：両側検定（*: p<0.05、N.S.: p≧ 0.05）

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 2.7.6 Summary of the individual tests

Table 2.7.6.3-16 Pre- and post-dose changes in clinical laboratory values (continued)
解析対象集団：安全性解析対象集団
標準
検査項目 投与群 時期 症例数 平均 ± 最小値 25％点 中央値 75％点 最大値 対応のあるt検定1）
偏差
総蛋白 ONO群 観察期 320 7.369 ± 0.432 6.20 7.100 7.300 7.650 8.90
（g/dL） 治療期4週後 315 7.287 ± 0.417 6.20 7.000 7.300 7.500 8.60 p<0.0001 *
治療期12週後 299 7.262 ± 0.431 6.10 7.000 7.300 7.600 8.40 p<0.0001 *
治療期終了時 311 7.267 ± 0.424 6.10 7.000 7.300 7.600 8.40 p<0.0001 *
プロピベリン群 観察期 306 7.344 ± 0.426 5.20 7.100 7.300 7.600 8.80
治療期4週後 297 7.316 ± 0.426 5.90 7.000 7.300 7.600 8.70 p=0.1477 N.S.
治療期12週後 278 7.271 ± 0.389 5.90 7.000 7.300 7.500 8.60 p<0.0001 *
治療期終了時 293 7.275 ± 0.393 5.90 7.000 7.300 7.500 8.60 p<0.0001 *
プラセボ群 観察期 142 7.338 ± 0.458 6.10 7.000 7.300 7.600 9.40
治療期4週後 136 7.291 ± 0.431 6.40 7.000 7.300 7.500 8.90 p=0.4835 N.S.
治療期12週後 130 7.207 ± 0.448 5.90 6.900 7.200 7.600 8.30 p=0.0002 *
治療期終了時 137 7.215 ± 0.449 5.90 6.900 7.200 7.600 8.30 p=0.0003 *
アルブミン ONO群 観察期 320 4.409 ± 0.255 3.70 4.200 4.400 4.600 5.10
（g/dL） 治療期4週後 315 4.349 ± 0.259 3.40 4.200 4.300 4.500 5.00 p<0.0001 *
治療期12週後 299 4.314 ± 0.254 3.40 4.200 4.300 4.500 5.10 p<0.0001 *
治療期終了時 311 4.319 ± 0.252 3.40 4.200 4.300 4.500 5.10 p<0.0001 *
プロピベリン群 観察期 306 4.376 ± 0.288 3.00 4.200 4.400 4.600 5.10
治療期4週後 297 4.368 ± 0.263 3.50 4.200 4.400 4.500 5.00 p=0.4249 N.S.
治療期12週後 278 4.342 ± 0.251 3.50 4.200 4.315 4.500 5.00 p=0.0007 *
治療期終了時 293 4.342 ± 0.251 3.50 4.200 4.300 4.500 5.00 p=0.0012 *
プラセボ群 観察期 142 4.402 ± 0.313 3.10 4.200 4.400 4.600 5.40
治療期4週後 136 4.360 ± 0.302 3.10 4.200 4.400 4.500 5.50 p=0.1272 N.S.
治療期12週後 130 4.328 ± 0.321 3.00 4.200 4.400 4.500 5.10 p=0.0007 *
治療期終了時 137 4.330 ± 0.317 3.00 4.200 4.400 4.500 5.10 p=0.0005 *
総ビリルビン ONO群 観察期 320 0.484 ± 0.193 0.10 0.300 0.500 0.600 1.40
（mg/dL） 治療期4週後 315 0.471 ± 0.192 0.10 0.300 0.400 0.600 1.60 p=0.0837 N.S.
治療期12週後 299 0.505 ± 0.200 0.20 0.400 0.500 0.600 1.60 p=0.0150 *
治療期終了時 311 0.504 ± 0.199 0.20 0.400 0.500 0.600 1.60 p=0.0202 *
プロピベリン群 観察期 306 0.487 ± 0.197 0.10 0.400 0.400 0.600 1.50
治療期4週後 297 0.463 ± 0.173 0.10 0.300 0.400 0.600 1.30 p=0.0029 *
治療期12週後 278 0.491 ± 0.169 0.20 0.400 0.500 0.600 1.10 p=0.8844 N.S.
治療期終了時 293 0.493 ± 0.171 0.20 0.400 0.500 0.600 1.10 p=0.9113 N.S.
プラセボ群 観察期 142 0.441 ± 0.193 0.20 0.300 0.400 0.500 1.20
治療期4週後 136 0.457 ± 0.193 0.10 0.300 0.400 0.600 1.10 p=0.2171 N.S.
治療期12週後 130 0.491 ± 0.177 0.20 0.400 0.500 0.600 1.10 p=0.0020 *
治療期終了時 137 0.483 ± 0.178 0.10 0.400 0.500 0.600 1.10 p=0.0036 *
ＡＳＴ（ＧＯＴ） ONO群 観察期 320 23.5 ± 8.5 9 18.0 22.0 26.0 76
（IU/L） 治療期4週後 315 22.6 ± 10.1 11 18.0 21.0 25.0 144 p=0.0423 *
治療期12週後 299 21.6 ± 8.4 10 17.0 20.0 23.0 96 p<0.0001 *
治療期終了時 311 21.7 ± 8.5 10 17.0 20.0 23.0 96 p<0.0001 *
プロピベリン群 観察期 306 23.4 ± 8.3 9 18.0 22.0 26.0 72
治療期4週後 296 21.4 ± 7.6 9 17.0 20.0 23.0 73 p<0.0001 *
治療期12週後 278 21.2 ± 8.0 10 17.0 19.5 23.0 75 p<0.0001 *
治療期終了時 293 21.2 ± 7.9 10 17.0 20.0 23.0 75 p<0.0001 *
プラセボ群 観察期 142 23.3 ± 8.4 12 18.0 22.0 26.0 81
治療期4週後 136 22.1 ± 5.9 13 18.0 21.0 25.0 45 p=0.0840 N.S.
治療期12週後 130 20.9 ± 6.1 12 17.0 20.0 23.0 48 p=0.0007 *
治療期終了時 137 21.1 ± 6.0 12 17.0 20.0 24.0 48 p=0.0006 *
ＡＬＴ（ＧＰＴ） ONO群 観察期 320 21.4 ± 12.0 6 14.0 18.0 24.5 94
（IU/L） 治療期4週後 315 20.4 ± 14.9 4 13.0 17.0 23.0 186 p=0.1072 N.S.
治療期12週後 299 19.5 ± 11.6 6 13.0 16.0 22.0 105 p=0.0012 *
治療期終了時 311 19.7 ± 12.2 6 13.0 16.0 23.0 105 p=0.0003 *
プロピベリン群 観察期 306 20.8 ± 12.0 7 14.0 18.0 24.0 92
治療期4週後 297 18.0 ± 9.4 4 12.0 16.0 21.0 87 p<0.0001 *
治療期12週後 278 18.3 ± 10.1 4 12.0 15.0 21.0 74 p<0.0001 *
治療期終了時 293 18.4 ± 10.0 4 12.0 15.0 22.0 74 p<0.0001 *
プラセボ群 観察期 142 20.0 ± 12.1 6 13.0 17.0 22.0 87
治療期4週後 136 18.2 ± 8.2 7 13.0 16.0 22.0 56 p=0.0476 *
治療期12週後 130 16.8 ± 6.7 7 13.0 15.0 19.0 48 p=0.0002 *
治療期終了時 137 17.0 ± 6.7 7 13.0 16.0 19.0 48 p=0.0002 *

1）：両側検定（*: p<0.05、N.S.: p≧ 0.05）

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 2.7.6 Summary of the individual tests

Table 2.7.6.3-16 Pre- and post-dose changes in clinical laboratory values (continued)
解析対象集団：安全性解析対象集団
標準
検査項目 投与群 時期 症例数 平均 ± 最小値 25％点 中央値 75％点 最大値 対応のあるt検定1）
偏差
γ－ＧＴＰ ONO群 観察期 320 29.3 ± 25.7 6 15.0 21.0 33.5 192
（IU/L） 治療期4週後 315 27.9 ± 25.4 3 14.0 19.0 31.0 179 p=0.0147 *
治療期12週後 299 26.6 ± 24.3 6 14.0 19.0 29.0 190 p=0.0027 *
治療期終了時 311 27.1 ± 26.0 6 14.0 19.0 29.0 190 p=0.0019 *
プロピベリン群 観察期 306 29.9 ± 31.9 8 15.0 21.0 31.0 304
治療期4週後 297 27.1 ± 22.2 7 15.0 20.0 30.0 168 p=0.0045 *
治療期12週後 278 26.0 ± 22.8 7 14.0 19.0 29.0 207 p=0.0001 *
治療期終了時 293 26.2 ± 22.5 7 14.0 19.0 30.0 207 p=0.0001 *
プラセボ群 観察期 142 30.9 ± 63.7 9 15.0 19.0 28.0 751
治療期4週後 136 27.1 ± 38.1 8 14.0 18.0 27.0 422 p=0.1173 N.S.
治療期12週後 130 25.6 ± 39.1 9 14.0 17.0 26.0 430 p=0.0379 *
治療期終了時 137 26.2 ± 38.4 9 14.0 17.0 26.0 430 p=0.0522 N.S.
Ａｌ－Ｐ ONO群 観察期 320 236.6 ± 75.0 88 182.0 225.0 291.0 531
（IU/L） 治療期4週後 315 236.7 ± 77.0 71 178.0 227.0 288.0 545 p=0.7992 N.S.
治療期12週後 299 233.8 ± 75.5 90 176.0 223.0 278.0 478 p=0.2403 N.S.
治療期終了時 311 233.8 ± 75.1 90 176.0 223.0 278.0 478 p=0.1862 N.S.
プロピベリン群 観察期 306 234.4 ± 70.8 85 185.0 225.0 279.0 438
治療期4週後 296 236.3 ± 70.0 84 184.5 231.0 288.0 534 p=0.3313 N.S.
治療期12週後 278 233.6 ± 69.8 86 182.0 227.0 273.0 489 p=0.7550 N.S.
治療期終了時 293 233.6 ± 69.3 86 182.0 227.0 273.0 489 p=0.6754 N.S.
プラセボ群 観察期 142 237.0 ± 78.5 100 175.0 234.5 291.0 516
治療期4週後 136 234.4 ± 73.9 98 178.5 220.0 285.0 441 p=0.3613 N.S.
治療期12週後 130 234.4 ± 69.8 106 180.0 226.0 286.0 419 p=0.4075 N.S.
治療期終了時 137 235.7 ± 70.1 106 180.0 226.0 286.0 419 p=0.4881 N.S.
ＬＤＨ ONO群 観察期 315 195.6 ± 45.0 119 164.0 191.0 217.0 447
（IU/L） 治療期4週後 309 189.6 ± 42.4 94 161.0 188.0 209.0 438 p<0.0001 *
治療期12週後 295 186.6 ± 42.9 99 157.0 182.0 208.0 443 p<0.0001 *
治療期終了時 306 187.3 ± 42.8 99 158.0 182.0 208.0 443 p<0.0001 *
プロピベリン群 観察期 301 191.7 ± 43.9 88 166.0 190.0 211.0 451
治療期4週後 290 183.3 ± 39.8 86 158.0 179.0 200.0 422 p<0.0001 *
治療期12週後 274 184.2 ± 45.9 90 156.0 178.0 203.0 546 p<0.0001 *
治療期終了時 288 184.4 ± 45.3 90 156.5 179.0 204.0 546 p<0.0001 *
プラセボ群 観察期 141 188.1 ± 38.0 93 164.0 180.0 209.0 368
治療期4週後 135 184.8 ± 34.5 124 159.0 179.0 209.0 326 p=0.2640 N.S.
治療期12週後 129 179.4 ± 35.2 81 157.0 175.0 202.0 303 p=0.0017 *
治療期終了時 136 180.0 ± 35.5 81 157.0 175.0 202.0 303 p=0.0022 *
クレアチニン ONO群 観察期 320 0.652 ± 0.148 0.34 0.550 0.620 0.730 1.58
（mg/dL） 治療期4週後 315 0.635 ± 0.138 0.36 0.550 0.610 0.700 1.47 p<0.0001 *
治療期12週後 299 0.646 ± 0.150 0.38 0.550 0.610 0.710 1.66 p=0.0683 N.S.
治療期終了時 311 0.646 ± 0.147 0.38 0.550 0.610 0.710 1.66 p=0.0435 *
プロピベリン群 観察期 306 0.657 ± 0.143 0.41 0.570 0.630 0.710 1.30
治療期4週後 297 0.645 ± 0.145 0.32 0.550 0.620 0.710 1.44 p=0.0175 *
治療期12週後 278 0.641 ± 0.139 0.38 0.560 0.610 0.700 1.33 p=0.0021 *
治療期終了時 293 0.645 ± 0.140 0.38 0.560 0.620 0.700 1.33 p=0.0025 *
プラセボ群 観察期 142 0.642 ± 0.139 0.41 0.550 0.620 0.700 1.16
治療期4週後 136 0.631 ± 0.141 0.38 0.530 0.610 0.695 1.16 p=0.0362 *
治療期12週後 130 0.639 ± 0.135 0.37 0.550 0.610 0.700 1.10 p=0.1415 N.S.
治療期終了時 137 0.636 ± 0.135 0.37 0.550 0.610 0.700 1.10 p=0.2136 N.S.
ＢＵＮ ONO群 観察期 320 15.01 ± 4.04 5.5 12.00 14.80 17.45 32.2
（mg/dL） 治療期4週後 315 14.64 ± 3.81 6.0 12.00 14.30 17.00 27.2 p=0.0262 *
治療期12週後 299 14.97 ± 4.04 6.0 12.10 14.70 17.70 29.0 p=0.4338 N.S.
治療期終了時 311 14.88 ± 4.01 6.0 11.90 14.70 17.60 29.0 p=0.2794 N.S.
プロピベリン群 観察期 306 15.15 ± 3.73 6.9 12.60 15.00 17.20 30.0
治療期4週後 297 14.77 ± 3.48 6.9 12.00 14.60 17.20 26.6 p=0.1095 N.S.
治療期12週後 278 14.62 ± 3.57 6.8 12.00 14.20 16.40 25.0 p=0.0530 N.S.
治療期終了時 293 14.65 ± 3.58 6.8 12.10 14.40 16.50 25.0 p=0.0401 *
プラセボ群 観察期 142 14.93 ± 4.08 5.9 11.80 14.75 17.10 28.3
治療期4週後 136 14.60 ± 3.87 6.8 11.95 13.85 17.00 26.4 p=0.2556 N.S.
治療期12週後 130 14.91 ± 4.09 6.3 12.10 14.30 17.70 29.6 p=0.8368 N.S.
治療期終了時 137 14.84 ± 4.06 6.3 12.10 14.30 17.70 29.6 p=0.8641 N.S.

1）：両側検定（*: p<0.05、N.S.: p≧ 0.05）

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 2.7.6 Summary of the individual tests

Table 2.7.6.3-16 Pre- and post-dose changes in clinical laboratory values (continued)
解析対象集団：安全性解析対象集団
標準
検査項目 投与群 時期 症例数 平均 ± 最小値 25％点 中央値 75％点 最大値 対応のあるt検定1）
偏差
トリグリセライド ONO群 観察期 320 126.8 ± 76.7 24 75.0 103.0 154.0 464
（mg/dL） 治療期4週後 314 132.1 ± 76.1 31 81.0 114.5 161.0 496 p=0.2098 N.S.
治療期12週後 299 130.9 ± 79.4 32 76.0 108.0 164.0 592 p=0.3958 N.S.
治療期終了時 311 131.1 ± 79.0 32 76.0 108.0 163.0 592 p=0.4397 N.S.
プロピベリン群 観察期 306 132.0 ± 76.0 26 75.0 118.0 167.0 486
治療期4週後 297 133.4 ± 96.6 28 78.0 109.0 155.0 910 p=0.6785 N.S.
治療期12週後 278 131.0 ± 80.1 28 79.0 111.0 162.0 624 p=0.9049 N.S.
治療期終了時 293 131.7 ± 80.9 28 77.0 111.0 163.0 624 p=0.8420 N.S.
プラセボ群 観察期 142 129.3 ± 68.9 29 78.0 109.5 178.0 438
治療期4週後 136 133.5 ± 81.9 32 80.5 107.0 174.0 521 p=0.4037 N.S.
治療期12週後 130 123.9 ± 71.7 30 77.0 105.5 151.0 447 p=0.5730 N.S.
治療期終了時 137 126.7 ± 73.1 30 79.0 108.0 152.0 447 p=0.7174 N.S.
総コレステロール ONO群 観察期 320 214.4 ± 37.5 93 186.0 214.0 233.5 346
（mg/dL） 治療期4週後 315 210.7 ± 37.1 98 188.0 208.0 233.0 343 p=0.0029 *
治療期12週後 299 208.1 ± 36.7 106 187.0 203.0 232.0 339 p<0.0001 *
治療期終了時 311 208.1 ± 36.8 106 187.0 204.0 231.0 339 p<0.0001 *
プロピベリン群 観察期 306 212.6 ± 37.1 126 188.0 211.0 236.0 385
治療期4週後 297 210.2 ± 38.2 119 184.0 210.0 233.0 403 p=0.0208 *
治療期12週後 278 205.6 ± 40.2 121 180.0 207.0 227.0 434 p<0.0001 *
治療期終了時 293 206.5 ± 40.1 121 180.0 207.0 228.0 434 p<0.0001 *
プラセボ群 観察期 142 217.0 ± 33.8 150 195.0 214.5 239.0 346
治療期4週後 136 210.2 ± 34.6 125 187.5 208.0 232.0 335 p=0.0045 *
治療期12週後 130 207.6 ± 33.5 129 185.0 203.0 233.0 306 p<0.0001 *
治療期終了時 137 208.8 ± 34.6 129 185.0 203.0 233.0 311 p<0.0001 *
尿酸 ONO群 観察期 320 4.64 ± 1.15 1.7 3.80 4.50 5.40 9.0
（mg/dL） 治療期4週後 315 4.60 ± 1.19 2.0 3.80 4.50 5.30 8.9 p=0.1761 N.S.
治療期12週後 299 4.62 ± 1.20 1.9 3.80 4.50 5.40 8.2 p=0.7672 N.S.
治療期終了時 311 4.64 ± 1.19 1.9 3.80 4.50 5.40 8.2 p=0.9567 N.S.
プロピベリン群 観察期 306 4.68 ± 1.08 2.4 3.90 4.60 5.20 10.7
治療期4週後 297 4.73 ± 1.11 2.5 3.90 4.60 5.40 9.8 p=0.1464 N.S.
治療期12週後 278 4.70 ± 1.07 2.5 3.90 4.60 5.40 8.5 p=0.6595 N.S.
治療期終了時 293 4.70 ± 1.07 2.5 3.90 4.60 5.40 8.5 p=0.7184 N.S.
プラセボ群 観察期 142 4.50 ± 1.11 2.0 3.80 4.40 5.10 7.8
治療期4週後 136 4.39 ± 1.06 1.7 3.70 4.20 5.00 8.6 p=0.0463 *
治療期12週後 130 4.46 ± 1.04 1.8 3.80 4.30 5.20 7.1 p=0.5330 N.S.
治療期終了時 137 4.44 ± 1.03 1.8 3.80 4.30 5.20 7.1 p=0.4143 N.S.
Ｎa ONO群 観察期 320 141.20 ± 1.88 133.0 140.00 141.00 142.00 149.0
（mEq/L） 治療期4週後 315 140.95 ± 1.95 134.0 140.00 141.00 142.00 148.0 p=0.0244 *
治療期12週後 299 141.13 ± 1.99 135.0 140.00 141.00 142.00 150.0 p=0.6151 N.S.
治療期終了時 311 141.13 ± 1.98 135.0 140.00 141.00 142.00 150.0 p=0.6203 N.S.
プロピベリン群 観察期 306 141.25 ± 1.99 134.0 140.00 141.00 142.00 148.0
治療期4週後 297 141.15 ± 2.02 135.0 140.00 141.00 143.00 146.0 p=0.5320 N.S.
治療期12週後 278 141.23 ± 2.20 134.0 140.00 141.00 143.00 147.0 p=0.8908 N.S.
治療期終了時 293 141.21 ± 2.21 134.0 140.00 141.00 143.00 147.0 p=0.9576 N.S.
プラセボ群 観察期 142 141.05 ± 1.86 135.0 140.00 141.00 142.00 147.0
治療期4週後 136 141.08 ± 2.05 135.0 140.00 141.00 142.00 148.0 p=0.8976 N.S.
治療期12週後 130 141.43 ± 2.04 137.0 140.00 141.00 143.00 148.0 p=0.0496 *
治療期終了時 137 141.42 ± 2.00 137.0 140.00 141.00 143.00 148.0 p=0.0404 *
Ｋ ONO群 観察期 320 4.177 ± 0.340 3.40 3.900 4.100 4.400 5.40
（mEq/L） 治療期4週後 315 4.196 ± 0.362 3.20 4.000 4.200 4.400 5.90 p=0.3349 N.S.
治療期12週後 299 4.134 ± 0.343 3.00 3.900 4.100 4.300 5.60 p=0.0490 *
治療期終了時 311 4.142 ± 0.346 3.00 3.900 4.100 4.300 5.60 p=0.0711 N.S.
プロピベリン群 観察期 306 4.205 ± 0.369 3.20 4.000 4.200 4.400 5.50
治療期4週後 296 4.181 ± 0.364 3.20 3.900 4.200 4.400 5.80 p=0.3253 N.S.
治療期12週後 278 4.095 ± 0.373 3.20 3.900 4.100 4.300 5.80 p<0.0001 *
治療期終了時 293 4.092 ± 0.367 3.20 3.900 4.100 4.300 5.80 p<0.0001 *
プラセボ群 観察期 142 4.167 ± 0.377 3.40 3.900 4.100 4.400 5.40
治療期4週後 136 4.193 ± 0.383 3.50 3.900 4.100 4.400 5.60 p=0.3697 N.S.
治療期12週後 130 4.075 ± 0.323 3.20 3.900 4.000 4.300 5.00 p=0.0030 *
治療期終了時 137 4.079 ± 0.321 3.20 3.900 4.000 4.300 5.00 p=0.0057 *

1）：両側検定（*: p<0.05、N.S.: p≧ 0.05）

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 2.7.6 Summary of the individual tests

Table 2.7.6.3-16 Pre- and post-dose changes in clinical laboratory values (continued)
解析対象集団：安全性解析対象集団
標準
検査項目 投与群 時期 症例数 平均 ± 最小値 25％点 中央値 75％点 最大値 対応のあるt検定1）
偏差
Ｃl ONO群 観察期 320 103.68 ± 2.43 94.0 102.00 104.00 105.00 113.0
（mEq/L） 治療期4週後 315 104.07 ± 2.62 96.0 102.00 104.00 106.00 113.0 p=0.0149 *
治療期12週後 299 103.52 ± 2.56 94.0 102.00 104.00 105.00 112.0 p=0.3334 N.S.
治療期終了時 311 103.52 ± 2.56 94.0 102.00 104.00 105.00 112.0 p=0.4060 N.S.
プロピベリン群 観察期 306 103.72 ± 2.53 95.0 102.00 104.00 105.00 113.0
治療期4週後 297 103.90 ± 2.52 95.0 102.00 104.00 106.00 112.0 p=0.1780 N.S.
治療期12週後 278 103.44 ± 2.55 95.0 102.00 103.00 105.00 111.0 p=0.1255 N.S.
治療期終了時 293 103.46 ± 2.62 95.0 102.00 103.00 105.00 111.0 p=0.1803 N.S.
プラセボ群 観察期 142 103.69 ± 2.25 99.0 102.00 104.00 105.00 110.0
治療期4週後 136 103.90 ± 2.65 97.0 102.00 104.00 106.00 111.0 p=0.5433 N.S.
治療期12週後 130 103.75 ± 2.42 93.0 102.00 104.00 105.00 109.0 p=0.9745 N.S.
治療期終了時 137 103.77 ± 2.38 93.0 102.00 104.00 105.00 109.0 p=0.8750 N.S.

1）：両側検定（*: p<0.05、N.S.: p≧ 0.05）

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 2.7.6 Summary of the individual tests

Table 2.7.6.3-16 Pre- and post-dose changes in clinical laboratory values (continued)
解析対象集団：安全性解析対象集団
Wilcoxon
検査項目 投与群 時期 症例数 - ± + ++ +++ ++++
符号付順位検定1）
蛋白 ONO群 観察期 320 291 17 7 4 0 1
治療期4週後 314 277 22 9 4 2 0 p=0.1963 N.S.
治療期12週後 299 270 19 5 3 2 0 p=0.5897 N.S.
治療期終了時 311 281 19 5 4 2 0 p=0.7184 N.S.
プロピベリン群 観察期 306 284 10 9 3 0 0
治療期4週後 296 265 18 10 3 0 0 p=0.1990 N.S.
治療期12週後 278 249 19 8 2 0 0 p=0.4934 N.S.
治療期終了時 293 261 21 9 2 0 0 p=0.4872 N.S.
プラセボ群 観察期 142 131 6 3 1 1 0
治療期4週後 136 124 5 4 2 1 0 p=0.3493 N.S.
治療期12週後 130 122 4 1 2 1 0 p=0.8726 N.S.
治療期終了時 137 129 4 1 2 1 0 p=0.9646 N.S.
糖 ONO群 観察期 320 299 3 5 3 8 2
治療期4週後 314 288 5 7 7 6 1 p=0.5080 N.S.
治療期12週後 299 278 6 6 5 3 1 p=0.5228 N.S.
治療期終了時 311 289 6 6 6 3 1 p=0.4818 N.S.
プロピベリン群 観察期 306 286 4 4 7 3 2
治療期4週後 296 280 3 4 5 0 4 p=0.5395 N.S.
治療期12週後 278 264 4 5 1 1 3 p=0.3316 N.S.
治療期終了時 293 276 5 6 2 1 3 p=0.2032 N.S.
プラセボ群 観察期 142 135 0 1 0 5 1
治療期4週後 136 127 2 4 0 2 1 p=0.6406 N.S.
治療期12週後 130 122 1 1 1 4 1 p=1.0000 N.S.
治療期終了時 137 129 1 1 1 4 1 p=1.0000 N.S.
ウロビリノゲン ONO群 観察期 312 22 286 4 0 0 0
治療期4週後 306 21 279 6 0 0 0 p=0.6536 N.S.
治療期12週後 291 21 266 4 0 0 0 p=0.8438 N.S.
治療期終了時 303 22 276 5 0 0 0 p=1.0000 N.S.
プロピベリン群 観察期 295 18 270 7 0 0 0
治療期4週後 285 19 258 8 0 0 0 p=0.9648 N.S.
治療期12週後 268 15 247 6 0 0 0 p=1.0000 N.S.
治療期終了時 282 17 259 6 0 0 0 p=1.0000 N.S.
プラセボ群 観察期 137 9 127 1 0 0 0
治療期4週後 131 10 118 2 1 0 0 p=1.0000 N.S.
治療期12週後 125 10 113 2 0 0 0 p=1.0000 N.S.
治療期終了時 132 10 120 2 0 0 0 p=1.0000 N.S.

1）：両側検定（*: p<0.05、N.S.: p≧ 0.05）

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 Table 2.7.6.3-17 List of adverse events by severity
投与群 0.2 mg/日 プロピベリン プラセボ
安全性解析対象集団 321 306 145
重症度 軽度 中等度 高度 計 軽度 中等度 高度 計 軽度 中等度 高度 計
有害事象項目 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数
全例 186 ( 57.9) 468 47 ( 14.6) 61 1 ( 0.3) 1 234 ( 72.9) 530 187 ( 61.1) 503 59 ( 19.3) 84 4 ( 1.3) 4 250 ( 81.7) 591 81 ( 55.9) 190 18 ( 12.4) 19 99 ( 68.3) 209
心臓障害 1 ( 0.3) 2 1 ( 0.3) 2 5 ( 1.6) 5 1 ( 0.3) 1 6 ( 2.0) 6 1 ( 0.7) 3 1 ( 0.7) 3
動悸 1 ( 0.3) 1 1 ( 0.3) 1 4 ( 1.3) 4 4 ( 1.3) 4 1 ( 0.7) 3 1 ( 0.7) 3
狭心症 1 ( 0.3) 1 1 ( 0.3) 1
上室性期外収縮 1 ( 0.3) 1 1 ( 0.3) 1
心室性期外収縮 1 ( 0.3) 1 1 ( 0.3) 1
耳および迷路障害 2 ( 0.7) 2 1 ( 0.3) 1 3 ( 1.0) 3
耳管閉塞 1 ( 0.3) 1 1 ( 0.3) 1
回転性眩暈 1 ( 0.3) 1 1 ( 0.3) 1
耳そう痒症 1 ( 0.3) 1 1 ( 0.3) 1
眼障害 17 ( 5.3) 18 2 ( 0.6) 2 19 ( 5.9) 20 27 ( 8.8) 37 2 ( 0.7) 2 29 ( 9.5) 39 12 ( 8.3) 14 1 ( 0.7) 1 13 ( 9.0) 15
霧視 5 ( 1.6) 5 5 ( 1.6) 5 12 ( 3.9) 12 12 ( 3.9) 12 2 ( 1.4) 2 1 ( 0.7) 1 3 ( 2.1) 3
眼の異常感 4 ( 1.2) 4 4 ( 1.2) 4 7 ( 2.3) 8 7 ( 2.3) 8 1 ( 0.7) 1 1 ( 0.7) 1
羞明 1 ( 0.3) 1 1 ( 0.3) 1 4 ( 1.3) 4 4 ( 1.3) 4 1 ( 0.7) 1 1 ( 0.7) 1
眼球乾燥 1 ( 0.3) 1 1 ( 0.3) 1 2 ( 0.6) 2 2 ( 0.7) 2 2 ( 0.7) 2 1 ( 0.7) 1 1 ( 0.7) 1
結膜炎 1 ( 0.3) 1 1 ( 0.3) 1 2 ( 1.4) 2 2 ( 1.4) 2
眼痛 2 ( 0.7) 2 2 ( 0.7) 2 1 ( 0.7) 1 1 ( 0.7) 1
眼精疲労 2 ( 0.7) 2 2 ( 0.7) 2
白内障 1 ( 0.3) 1 1 ( 0.3) 1 1 ( 0.3) 1 1 ( 0.3) 1
視力低下 1 ( 0.3) 1 1 ( 0.3) 1 1 ( 0.7) 1 1 ( 0.7) 1
硝子体浮遊物 1 ( 0.3) 1 1 ( 0.3) 1 1 ( 0.7) 1 1 ( 0.7) 1
眼そう痒症 2 ( 0.6) 2 2 ( 0.6) 2
眼瞼痙攣 1 ( 0.3) 1 1 ( 0.3) 1
霰粒腫 1 ( 0.3) 1 1 ( 0.3) 1
結膜出血 1 ( 0.3) 2 1 ( 0.3) 2
眼瞼紅斑 1 ( 0.7) 1 1 ( 0.7) 1
眼脂 1 ( 0.3) 1 1 ( 0.3) 1
眼出血 1 ( 0.3) 1 1 ( 0.3) 1
眼瞼浮腫 1 ( 0.3) 1 1 ( 0.3) 1
角膜炎 1 ( 0.3) 1 1 ( 0.3) 1
流涙増加 1 ( 0.7) 1 1 ( 0.7) 1
光視症 1 ( 0.7) 1 1 ( 0.7) 1
老視 1 ( 0.3) 1 1 ( 0.3) 1
網膜出血 1 ( 0.3) 1 1 ( 0.3) 1
2-
30
-

硝子体剥離 1 ( 0.7) 1 1 ( 0.7) 1

胃腸障害 66 ( 20.6) 92 7 ( 2.2) 10 73 ( 22.7) 102 71 ( 23.2) 91 12 ( 3.9) 13 83 ( 27.1) 104 16 ( 11.0) 22 5 ( 3.4) 5 21 ( 14.5) 27
便秘 35 ( 10.9) 38 3 ( 0.9) 3 38 ( 11.8) 41 35 ( 11.4) 37 7 ( 2.3) 7 42 ( 13.7) 44 9 ( 6.2) 9 2 ( 1.4) 2 11 ( 7.6) 11
胃不快感 9 ( 2.8) 10 9 ( 2.8) 10 9 ( 2.9) 10 1 ( 0.3) 1 10 ( 3.3) 11
下痢 8 ( 2.5) 9 1 ( 0.3) 1 9 ( 2.8) 10 2 ( 0.7) 2 1 ( 0.3) 1 3 ( 1.0) 3 3 ( 2.1) 4 3 ( 2.1) 4
嘔吐 4 ( 1.2) 4 2 ( 0.6) 2 6 ( 1.9) 6 4 ( 1.3) 6 1 ( 0.3) 1 5 ( 1.6) 7
上腹部痛 5 ( 1.6) 5 5 ( 1.6) 5 3 ( 1.0) 3 1 ( 0.3) 1 4 ( 1.3) 4
胃炎 2 ( 0.6) 2 2 ( 0.6) 3 4 ( 1.2) 5 3 ( 1.0) 3 3 ( 1.0) 3 1 ( 0.7) 1 1 ( 0.7) 1
腹部膨満 2 ( 0.6) 2 2 ( 0.6) 2 4 ( 1.3) 4 4 ( 1.3) 4 1 ( 0.7) 1 1 ( 0.7) 1
悪心 2 ( 0.6) 2 1 ( 0.3) 1 3 ( 0.9) 3 2 ( 0.7) 3 1 ( 0.3) 1 3 ( 1.0) 4
口内炎 1 ( 0.3) 1 1 ( 0.3) 1 3 ( 1.0) 3 3 ( 1.0) 3 2 ( 1.4) 3 2 ( 1.4) 3
腹痛 1 ( 0.3) 1 1 ( 0.3) 1 2 ( 0.7) 2 2 ( 0.7) 2 1 ( 0.7) 1 1 ( 0.7) 1
下腹部痛 2 ( 0.6) 2 2 ( 0.6) 2 1 ( 0.3) 1 1 ( 0.3) 1 1 ( 0.7) 1 1 ( 0.7) 1

2.7.6 Summary of individual tests

消化不良 4 ( 1.3) 4 4 ( 1.3) 4
歯肉炎 3 ( 1.0) 3 3 ( 1.0) 3 1 ( 0.7) 1 1 ( 0.7) 1
歯痛 2 ( 0.6) 2 2 ( 0.6) 2 2 ( 1.4) 2 2 ( 1.4) 2
軟便 3 ( 1.0) 3 3 ( 1.0) 3
口唇障害 2 ( 0.6) 2 2 ( 0.6) 2 1 ( 0.3) 1 1 ( 0.3) 1
舌炎 2 ( 0.6) 2 2 ( 0.6) 2
口唇乾燥 2 ( 0.6) 3 2 ( 0.6) 3
口腔内不快感 1 ( 0.3) 1 1 ( 0.3) 1 1 ( 0.3) 1 1 ( 0.3) 1
腹部不快感 1 ( 0.3) 1 1 ( 0.3) 1
アフタ性口内炎 1 ( 0.3) 1 1 ( 0.3) 1
口唇炎 1 ( 0.3) 1 1 ( 0.3) 1
変色便 1 ( 0.3) 1 1 ( 0.3) 1
鼓腸 1 ( 0.7) 1 1 ( 0.7) 1
胃潰瘍 1 ( 0.3) 1 1 ( 0.3) 1
びらん性胃炎 1 ( 0.3) 1 1 ( 0.3) 1
歯肉腫脹 1 ( 0.3) 1 1 ( 0.3) 1
痔核 1 ( 0.3) 1 1 ( 0.3) 1
腸管閉塞 1 ( 0.7) 1 1 ( 0.7) 1
舌苔 1 ( 0.3) 1 1 ( 0.3) 1
口唇のひび割れ 1 ( 0.3) 1 1 ( 0.3) 1
肛門出血 1 ( 0.3) 1 1 ( 0.3) 1
胃腸不快感 1 ( 0.3) 1 1 ( 0.3) 1
全身障害および投与局所様態 93 ( 29.0) 95 16 ( 5.0) 18 109 ( 34.0) 113 99 ( 32.4) 106 24 ( 7.8) 25 4 ( 1.3) 4 127 ( 41.5) 135 19 ( 13.1) 20 1 ( 0.7) 1 20 ( 13.8) 21
口渇 85 ( 26.5) 85 16 ( 5.0) 17 101 ( 31.5) 102 94 ( 30.7) 95 24 ( 7.8) 25 4 ( 1.3) 4 122 ( 39.9) 124 19 ( 13.1) 19 1 ( 0.7) 1 20 ( 13.8) 20
発熱 2 ( 0.6) 2 2 ( 0.6) 2 3 ( 1.0) 3 3 ( 1.0) 3 1 ( 0.7) 1 1 ( 0.7) 1
倦怠感 1 ( 0.3) 1 1 ( 0.3) 1 2 ( 0.6) 2 2 ( 0.7) 2 2 ( 0.7) 2
胸部不快感 2 ( 0.6) 2 2 ( 0.6) 2 1 ( 0.3) 1 1 ( 0.3) 1
末梢性浮腫 3 ( 0.9) 3 3 ( 0.9) 3
疼痛 2 ( 0.6) 2 2 ( 0.6) 2 1 ( 0.3) 1 1 ( 0.3) 1
疲労 2 ( 0.7) 2 2 ( 0.7) 2
胸痛 1 ( 0.3) 1 1 ( 0.3) 1
異常感 1 ( 0.3) 1 1 ( 0.3) 1
 Table 2.7.6.3-17 List of adverse events by severity (continued)
投与群 0.2 mg/日 プロピベリン プラセボ
安全性解析対象集団 321 306 145
重症度 軽度 中等度 高度 計 軽度 中等度 高度 計 軽度 中等度 高度 計
有害事象項目 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数
肝胆道系障害 1 ( 0.7) 1 1 ( 0.7) 1
胆嚢炎 1 ( 0.7) 1 1 ( 0.7) 1
免疫系障害 2 ( 0.6) 2 2 ( 0.6) 2 2 ( 0.7) 2 2 ( 0.7) 2
季節性アレルギー 2 ( 0.6) 2 2 ( 0.6) 2 2 ( 0.7) 2 2 ( 0.7) 2
感染症および寄生虫症 71 ( 22.1) 84 9 ( 2.8) 11 80 ( 24.9) 95 69 ( 22.5) 85 8 ( 2.6) 10 77 ( 25.2) 95 34 ( 23.4) 39 6 ( 4.1) 6 40 ( 27.6) 45
鼻咽頭炎 57 ( 17.8) 66 2 ( 0.6) 2 59 ( 18.4) 68 56 ( 18.3) 63 5 ( 1.6) 5 61 ( 19.9) 68 32 ( 22.1) 35 2 ( 1.4) 2 34 ( 23.4) 37
膀胱炎 3 ( 0.9) 3 3 ( 0.9) 4 6 ( 1.9) 7 6 ( 2.0) 6 6 ( 2.0) 6 1 ( 0.7) 1 1 ( 0.7) 1
単純ヘルペス 1 ( 0.3) 1 1 ( 0.3) 1 3 ( 1.0) 3 3 ( 1.0) 3 1 ( 0.7) 1 1 ( 0.7) 1
ウイルス性腸炎 2 ( 0.6) 2 1 ( 0.3) 1 3 ( 0.9) 3 1 ( 0.3) 1 1 ( 0.3) 1 1 ( 0.7) 1 1 ( 0.7) 1
胃腸炎 1 ( 0.3) 1 1 ( 0.3) 1 2 ( 0.6) 2 1 ( 0.3) 1 1 ( 0.3) 1 1 ( 0.7) 1 1 ( 0.7) 1
インフルエンザ 1 ( 0.3) 1 1 ( 0.3) 1 1 ( 0.3) 1 1 ( 0.3) 2 2 ( 0.7) 3 1 ( 0.7) 1 1 ( 0.7) 1
咽喉頭炎 2 ( 0.6) 2 2 ( 0.6) 2 1 ( 0.3) 1 1 ( 0.3) 1 1 ( 0.7) 1 1 ( 0.7) 1
帯状疱疹 1 ( 0.3) 1 1 ( 0.3) 1 1 ( 0.3) 1 1 ( 0.3) 1 2 ( 0.7) 2
気管支炎 1 ( 0.3) 1 1 ( 0.3) 1 1 ( 0.3) 1 1 ( 0.3) 1
中耳炎 2 ( 0.6) 2 2 ( 0.6) 2
鼻炎 1 ( 0.3) 1 1 ( 0.3) 1 1 ( 0.3) 1 1 ( 0.3) 1
副鼻腔炎 1 ( 0.3) 1 1 ( 0.3) 1 1 ( 0.7) 1 1 ( 0.7) 1
尿路感染 1 ( 0.3) 1 1 ( 0.3) 1 1 ( 0.3) 1 1 ( 0.3) 1
気管支肺炎 1 ( 0.3) 1 1 ( 0.3) 1
カンジダ症 1 ( 0.3) 1 1 ( 0.3) 1
真菌感染 1 ( 0.7) 1 1 ( 0.7) 1
ヘルペスウイルス感染 1 ( 0.3) 1 1 ( 0.3) 1
麦粒腫 1 ( 0.3) 1 1 ( 0.3) 1
喉頭炎 1 ( 0.3) 1 1 ( 0.3) 1
爪囲炎 1 ( 0.3) 1 1 ( 0.3) 1
肺炎 1 ( 0.3) 1 1 ( 0.3) 1
足部白癬 1 ( 0.3) 1 1 ( 0.3) 1
外陰部炎 1 ( 0.3) 1 1 ( 0.3) 1
感染性小腸結腸炎 1 ( 0.3) 1 1 ( 0.3) 1
化膿 1 ( 0.3) 1 1 ( 0.3) 1
傷害、中毒および処置合併症 3 ( 0.9) 3 3 ( 0.9) 3 6 ( 1.9) 6 3 ( 1.0) 4 6 ( 2.0) 8 9 ( 2.9) 12 3 ( 2.1) 3 1 ( 0.7) 1 4 ( 2.8) 4
関節捻挫 1 ( 0.3) 1 1 ( 0.3) 1 2 ( 0.6) 2 1 ( 0.3) 2 1 ( 0.3) 1 2 ( 0.7) 3
背部損傷 1 ( 0.3) 1 1 ( 0.3) 1
鎖骨骨折 1 ( 0.3) 1 1 ( 0.3) 1
2-
30
-

圧迫骨折 1 ( 0.3) 1 1 ( 0.3) 1

腓骨骨折 1 ( 0.3) 1 1 ( 0.3) 1
骨折 1 ( 0.3) 1 1 ( 0.3) 1
手骨折 1 ( 0.3) 1 1 ( 0.3) 1
嵌入爪 1 ( 0.7) 1 1 ( 0.7) 1
関節脱臼 1 ( 0.7) 1 1 ( 0.7) 1
裂傷 1 ( 0.3) 1 1 ( 0.3) 1
橈骨骨折 1 ( 0.3) 1 1 ( 0.3) 1
肋骨骨折 1 ( 0.7) 1 1 ( 0.7) 1
手首関節骨折 1 ( 0.7) 1 1 ( 0.7) 1
擦過傷 1 ( 0.3) 1 1 ( 0.3) 1
創傷 1 ( 0.3) 1 1 ( 0.3) 1
半月板障害 1 ( 0.3) 1 1 ( 0.3) 1

2.7.6 Summary of individual tests

冠動脈再狭窄 1 ( 0.3) 1 1 ( 0.3) 1
靱帯損傷 1 ( 0.3) 1 1 ( 0.3) 1
臨床検査 63 ( 19.6) 94 5 ( 1.6) 5 68 ( 21.2) 99 68 ( 22.2) 95 7 ( 2.3) 7 75 ( 24.5) 102 37 ( 25.5) 50 3 ( 2.1) 4 40 ( 27.6) 54
尿中白血球陽性 18 ( 5.6) 20 1 ( 0.3) 1 19 ( 5.9) 21 21 ( 6.9) 21 2 ( 0.7) 2 23 ( 7.5) 23 9 ( 6.3) 9 1 ( 0.7) 1 10 ( 7.0) 10
血中トリグリセリド増加 11 ( 3.4) 11 2 ( 0.6) 2 13 ( 4.1) 13 7 ( 2.3) 7 1 ( 0.3) 1 8 ( 2.6) 8 7 ( 4.9) 7 7 ( 4.9) 7
尿中赤血球陽性 8 ( 2.5) 8 8 ( 2.5) 8 11 ( 3.6) 11 11 ( 3.6) 11 4 ( 2.8) 4 4 ( 2.8) 4
γ-グルタミルトランスフェラーゼ増加 11 ( 3.4) 11 11 ( 3.4) 11 6 ( 2.0) 6 1 ( 0.3) 1 7 ( 2.3) 7 3 ( 2.1) 3 3 ( 2.1) 3
尿中ブドウ糖陽性 8 ( 2.5) 8 8 ( 2.5) 8 1 ( 0.3) 1 1 ( 0.3) 1 2 ( 1.4) 2 1 ( 0.7) 1 3 ( 2.1) 3
血中コレステロール増加 1 ( 0.3) 1 1 ( 0.3) 1 5 ( 1.6) 5 5 ( 1.6) 5 4 ( 2.8) 4 4 ( 2.8) 4
アラニン・アミノトランスフェラーゼ増加 6 ( 1.9) 6 6 ( 1.9) 6 2 ( 0.7) 2 2 ( 0.7) 2 1 ( 0.7) 1 1 ( 0.7) 1
白血球数減少 2 ( 0.6) 2 1 ( 0.3) 1 3 ( 0.9) 3 5 ( 1.6) 5 5 ( 1.6) 5 1 ( 0.7) 1 1 ( 0.7) 1
血中アルカリホスファターゼ増加 3 ( 0.9) 3 3 ( 0.9) 3 5 ( 1.6) 5 5 ( 1.6) 5 1 ( 0.7) 1 1 ( 0.7) 1
血圧上昇 3 ( 0.9) 3 3 ( 0.9) 3 3 ( 1.0) 3 1 ( 0.3) 1 4 ( 1.3) 4 1 ( 0.7) 1 1 ( 0.7) 2 2 ( 1.4) 3
残尿量 1 ( 0.3) 1 1 ( 0.3) 1 2 ( 0.6) 2 4 ( 1.3) 4 1 ( 0.3) 1 5 ( 1.6) 5 2 ( 1.4) 2 2 ( 1.4) 2
白血球数増加 1 ( 0.3) 1 1 ( 0.3) 1 4 ( 1.3) 4 4 ( 1.3) 4 3 ( 2.1) 3 3 ( 2.1) 3
アスパラギン酸アミノトランスフェラーゼ増加 4 ( 1.3) 4 4 ( 1.3) 4 2 ( 0.7) 2 2 ( 0.7) 2 1 ( 0.7) 1 1 ( 0.7) 1
尿中蛋白陽性 1 ( 0.3) 1 1 ( 0.3) 1 2 ( 0.7) 2 1 ( 0.3) 1 3 ( 1.0) 3 3 ( 2.1) 3 3 ( 2.1) 3
血中カリウム増加 1 ( 0.3) 1 1 ( 0.3) 1 4 ( 1.3) 4 4 ( 1.3) 4
血中尿酸増加 1 ( 0.3) 1 1 ( 0.3) 1 3 ( 1.0) 3 3 ( 1.0) 3 1 ( 0.7) 1 1 ( 0.7) 1
血中尿素増加 2 ( 0.7) 2 2 ( 0.7) 2 2 ( 1.4) 2 2 ( 1.4) 2
総蛋白減少 1 ( 0.3) 1 1 ( 0.3) 1 1 ( 0.3) 1 1 ( 0.3) 1 1 ( 0.7) 1 1 ( 0.7) 1
尿潜血陽性 2 ( 0.7) 2 2 ( 0.7) 2 1 ( 0.7) 1 1 ( 0.7) 1
血中乳酸脱水素酵素増加 1 ( 0.3) 1 1 ( 0.3) 1 1 ( 0.3) 1 1 ( 0.3) 1
血中カリウム減少 2 ( 0.6) 2 2 ( 0.6) 2
ヘマトクリット減少 1 ( 0.3) 1 1 ( 0.3) 1 1 ( 0.3) 1 1 ( 0.3) 1
ヘモグロビン減少 1 ( 0.3) 1 1 ( 0.3) 1 1 ( 0.3) 1 1 ( 0.3) 1
赤血球数減少 1 ( 0.3) 1 1 ( 0.3) 1 1 ( 0.3) 1 1 ( 0.3) 1
血圧低下 1 ( 0.3) 1 1 ( 0.3) 1 1 ( 0.7) 1 1 ( 0.7) 1
尿沈渣陽性 1 ( 0.3) 1 1 ( 0.3) 1 1 ( 0.7) 1 1 ( 0.7) 1
血小板数減少 1 ( 0.3) 1 1 ( 0.3) 1
血中アルブミン減少 1 ( 0.3) 1 1 ( 0.3) 1
尿中ウロビリン陽性 1 ( 0.7) 1 1 ( 0.7) 1
 Table 2.7.6.3-17 List of adverse events by severity (continued)
投与群 0.2 mg/日 プロピベリン プラセボ
安全性解析対象集団 321 306 145
重症度 軽度 中等度 高度 計 軽度 中等度 高度 計 軽度 中等度 高度 計
有害事象項目 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数
血中クレアチンホスホキナーゼ増加 1 ( 0.3) 1 1 ( 0.3) 1
心電図Ｔ波逆転 1 ( 0.3) 1 1 ( 0.3) 1
代謝および栄養障害 3 ( 1.0) 3 2 ( 0.7) 2 5 ( 1.6) 5
食欲減退 1 ( 0.3) 1 1 ( 0.3) 1 2 ( 0.7) 2
低カリウム血症 1 ( 0.3) 1 1 ( 0.3) 1
食欲不振 1 ( 0.3) 1 1 ( 0.3) 1
痛風 1 ( 0.3) 1 1 ( 0.3) 1
筋骨格系および結合組織障害 8 ( 2.5) 12 5 ( 1.6) 5 13 ( 4.0) 17 7 ( 2.3) 7 2 ( 0.7) 2 9 ( 2.9) 9 6 ( 4.1) 6 6 ( 4.1) 6
背部痛 1 ( 0.3) 1 3 ( 0.9) 3 4 ( 1.2) 4 3 ( 1.0) 3 1 ( 0.3) 1 4 ( 1.3) 4 2 ( 1.4) 2 2 ( 1.4) 2
関節痛 2 ( 0.6) 2 2 ( 0.6) 2 2 ( 0.7) 2 2 ( 0.7) 2 2 ( 1.4) 2 2 ( 1.4) 2
筋骨格硬直 4 ( 1.2) 4 4 ( 1.2) 4
関節炎 1 ( 0.3) 1 1 ( 0.3) 1 1 ( 0.7) 1 1 ( 0.7) 1
頚部痛 1 ( 0.3) 1 1 ( 0.3) 1 2 ( 0.7) 2
関節腫脹 1 ( 0.3) 1 1 ( 0.3) 1
筋痙攣 1 ( 0.7) 1 1 ( 0.7) 1
筋痛 1 ( 0.3) 2 1 ( 0.3) 2
四肢痛 1 ( 0.3) 1 1 ( 0.3) 1
関節周囲炎 1 ( 0.3) 1 1 ( 0.3) 1
脊椎症 1 ( 0.3) 1 1 ( 0.3) 1
椎間板突出 1 ( 0.3) 1 1 ( 0.3) 1
良性、悪性および詳細不明の新生物（嚢胞およびポリープを含む） 1 ( 0.3) 1 1 ( 0.3) 1 1 ( 0.7) 1 1 ( 0.7) 1
皮膚乳頭腫 1 ( 0.7) 1 1 ( 0.7) 1
卵巣新生物 1 ( 0.3) 1 1 ( 0.3) 1
神経系障害 14 ( 4.4) 17 4 ( 1.2) 4 18 ( 5.6) 21 16 ( 5.2) 17 3 ( 1.0) 3 19 ( 6.2) 20 7 ( 4.8) 9 7 ( 4.8) 9
頭痛 8 ( 2.5) 10 3 ( 0.9) 3 11 ( 3.4) 13 7 ( 2.3) 8 1 ( 0.3) 1 8 ( 2.6) 9 3 ( 2.1) 3 3 ( 2.1) 3
浮動性めまい 1 ( 0.3) 1 1 ( 0.3) 1 3 ( 1.0) 3 3 ( 1.0) 3 2 ( 1.4) 2 2 ( 1.4) 2
傾眠 1 ( 0.3) 1 1 ( 0.3) 1 2 ( 0.7) 2 1 ( 0.3) 1 3 ( 1.0) 3
脳梗塞 1 ( 0.3) 1 1 ( 0.3) 1 2 ( 0.6) 2
味覚異常 1 ( 0.3) 1 1 ( 0.3) 1 1 ( 0.3) 1 1 ( 0.3) 1
感覚減退 2 ( 0.7) 2 2 ( 0.7) 2
健忘 1 ( 0.3) 1 1 ( 0.3) 1
頚腕症候群 1 ( 0.7) 1 1 ( 0.7) 1
体位性めまい 1 ( 0.3) 1 1 ( 0.3) 1
意識消失 1 ( 0.7) 1 1 ( 0.7) 1
2-
30
-

末梢性ニューロパシー 1 ( 0.7) 1 1 ( 0.7) 1

坐骨神経痛 1 ( 0.3) 1 1 ( 0.3) 1
失神 1 ( 0.3) 1 1 ( 0.3) 1
視野欠損 1 ( 0.7) 1 1 ( 0.7) 1
肋間神経痛 1 ( 0.3) 1 1 ( 0.3) 1
精神障害 1 ( 0.3) 2 2 ( 0.6) 2 3 ( 0.9) 4 5 ( 1.6) 6 5 ( 1.6) 6
不眠症 1 ( 0.3) 1 1 ( 0.3) 1 2 ( 0.6) 2 4 ( 1.3) 4 4 ( 1.3) 4
抑うつ気分 1 ( 0.3) 1 1 ( 0.3) 1
リビドー減退 1 ( 0.3) 1 1 ( 0.3) 1
心身症 1 ( 0.3) 1 1 ( 0.3) 1
無為 1 ( 0.3) 1 1 ( 0.3) 1
腎および尿路障害 6 ( 1.9) 7 1 ( 0.3) 1 7 ( 2.2) 8 6 ( 2.0) 6 1 ( 0.3) 1 7 ( 2.3) 7 2 ( 1.4) 3 2 ( 1.4) 3
排尿困難 3 ( 0.9) 3 3 ( 0.9) 3 5 ( 1.6) 5 1 ( 0.3) 1 6 ( 2.0) 6 1 ( 0.7) 1 1 ( 0.7) 1

2.7.6 Summary of individual tests

緊張性膀胱 1 ( 0.3) 1 1 ( 0.3) 1 1 ( 0.7) 1 1 ( 0.7) 1
膿尿 1 ( 0.3) 1 1 ( 0.3) 1 1 ( 0.3) 1 1 ( 0.3) 1
血尿 1 ( 0.3) 1 1 ( 0.3) 1
排尿異常 1 ( 0.7) 1 1 ( 0.7) 1
尿失禁 1 ( 0.3) 1 1 ( 0.3) 1
尿閉 1 ( 0.3) 1 1 ( 0.3) 1
生殖系および乳房障害 4 ( 1.3) 5 4 ( 1.3) 5
性器出血 2 ( 0.7) 3 2 ( 0.7) 3
閉経期症状 1 ( 0.3) 1 1 ( 0.3) 1
性器分泌物 1 ( 0.3) 1 1 ( 0.3) 1
呼吸器、胸郭および縦隔障害 21 ( 6.5) 23 1 ( 0.3) 1 22 ( 6.9) 24 14 ( 4.6) 17 1 ( 0.3) 1 15 ( 4.9) 18 8 ( 5.5) 9 8 ( 5.5) 9
上気道の炎症 9 ( 2.8) 10 9 ( 2.8) 10 4 ( 1.3) 4 4 ( 1.3) 4 3 ( 2.1) 3 3 ( 2.1) 3
咽喉頭疼痛 4 ( 1.2) 4 4 ( 1.2) 4 3 ( 1.0) 3 3 ( 1.0) 3 1 ( 0.7) 1 1 ( 0.7) 1
咳嗽 1 ( 0.3) 1 1 ( 0.3) 1 3 ( 1.0) 3 1 ( 0.3) 1 4 ( 1.3) 4 1 ( 0.7) 1 1 ( 0.7) 1
鼻漏 2 ( 0.6) 2 2 ( 0.6) 2 3 ( 1.0) 3 3 ( 1.0) 3
鼻出血 1 ( 0.3) 1 1 ( 0.3) 1 2 ( 1.4) 2 2 ( 1.4) 2
咽喉乾燥 1 ( 0.3) 1 1 ( 0.3) 1 1 ( 0.7) 1 1 ( 0.7) 1
咽頭不快感 2 ( 0.7) 2 2 ( 0.7) 2
喘息 1 ( 0.3) 1 1 ( 0.3) 1
呼吸困難 1 ( 0.3) 1 1 ( 0.3) 1
鼻閉 1 ( 0.3) 1 1 ( 0.3) 1
鼻乾燥 1 ( 0.7) 1 1 ( 0.7) 1
胸腔内出血 1 ( 0.3) 1 1 ( 0.3) 1
湿性咳嗽 1 ( 0.3) 1 1 ( 0.3) 1
アレルギー性鼻炎 1 ( 0.3) 1 1 ( 0.3) 1
くしゃみ 1 ( 0.3) 1 1 ( 0.3) 1
皮膚および皮下組織障害 15 ( 4.7) 15 15 ( 4.7) 15 14 ( 4.6) 14 3 ( 1.0) 7 17 ( 5.6) 21 10 ( 6.9) 10 1 ( 0.7) 1 11 ( 7.6) 11
湿疹 3 ( 0.9) 3 3 ( 0.9) 3 3 ( 1.0) 3 3 ( 1.0) 3 2 ( 1.4) 2 1 ( 0.7) 1 3 ( 2.1) 3
皮下出血 3 ( 0.9) 3 3 ( 0.9) 3 2 ( 0.7) 2 1 ( 0.3) 3 3 ( 1.0) 5 2 ( 1.4) 2 2 ( 1.4) 2
そう痒症 2 ( 0.6) 2 2 ( 0.6) 2 2 ( 0.7) 2 1 ( 0.3) 1 3 ( 1.0) 3
発疹 1 ( 0.3) 1 1 ( 0.3) 1 1 ( 0.3) 1 1 ( 0.3) 1 1 ( 0.7) 1 1 ( 0.7) 1
皮膚嚢腫 1 ( 0.3) 1 1 ( 0.3) 1 1 ( 0.3) 1 1 ( 0.3) 1
 Table 2.7.6.3-17 List of adverse events by severity (continued)
投与群 0.2 mg/日 プロピベリン プラセボ
安全性解析対象集団 321 306 145
重症度 軽度 中等度 高度 計 軽度 中等度 高度 計 軽度 中等度 高度 計
有害事象項目 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数
皮膚炎 1 ( 0.3) 1 1 ( 0.3) 1 1 ( 0.7) 1 1 ( 0.7) 1
皮脂欠乏性湿疹 1 ( 0.3) 1 1 ( 0.3) 1 1 ( 0.3) 1 1 ( 0.3) 1
紅斑 1 ( 0.3) 1 1 ( 0.3) 1 1 ( 0.7) 1 1 ( 0.7) 1
蕁麻疹 1 ( 0.3) 1 1 ( 0.3) 1 1 ( 0.7) 1 1 ( 0.7) 1
擦過傷 1 ( 0.3) 1 1 ( 0.3) 2 2 ( 0.7) 3
全身性そう痒症 1 ( 0.3) 1 1 ( 0.3) 1 1 ( 0.7) 1 1 ( 0.7) 1
ざ瘡 1 ( 0.7) 1 1 ( 0.7) 1
薬剤性皮膚炎 1 ( 0.3) 1 1 ( 0.3) 1
顔面浮腫 1 ( 0.3) 1 1 ( 0.3) 1
過角化 1 ( 0.3) 1 1 ( 0.3) 1
皮膚線条 1 ( 0.3) 1 1 ( 0.3) 1
外科および内科処置 1 ( 0.3) 1 1 ( 0.3) 1
歯修復 1 ( 0.3) 1 1 ( 0.3) 1
血管障害 1 ( 0.3) 1 1 ( 0.3) 1 1 ( 0.3) 1 1 ( 0.3) 1
低血圧 1 ( 0.3) 1 1 ( 0.3) 1
ほてり 1 ( 0.3) 1 1 ( 0.3) 1

The incidence of each laboratory measure may differ because cases with laboratory items present during the observation period and after the start of treatment were included in the total. The number of cases for each assay may vary, as cases with abnormal changes were included regardless of whether the assay was missing
or not.
2-
30
-

2.7.6 Summary of individual tests

 Table 2.7.6.3-18 List of adverse reactions by severity
投与群 0.2 mg/日 プロピベリン プラセボ
安全性解析対象集団 321 306 145
重症度 軽度 中等度 高度 計 軽度 中等度 高度 計 軽度 中等度 高度 計
有害事象項目 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数
全例 108 ( 33.6) 154 22 ( 6.9) 25 130 ( 40.5) 179 114 ( 37.3) 197 38 ( 12.4) 44 4 ( 1.3) 4 156 ( 51.0) 245 33 ( 22.8) 43 5 ( 3.4) 5 38 ( 26.2) 48
心臓障害 1 ( 0.3) 2 1 ( 0.3) 2 2 ( 0.7) 2 2 ( 0.7) 2
動悸 1 ( 0.3) 1 1 ( 0.3) 1 1 ( 0.3) 1 1 ( 0.3) 1
上室性期外収縮 1 ( 0.3) 1 1 ( 0.3) 1
心室性期外収縮 1 ( 0.3) 1 1 ( 0.3) 1
耳および迷路障害 1 ( 0.3) 1 1 ( 0.3) 1
耳そう痒症 1 ( 0.3) 1 1 ( 0.3) 1
眼障害 5 ( 1.6) 5 5 ( 1.6) 5 14 ( 4.6) 18 2 ( 0.7) 2 16 ( 5.2) 20 3 ( 2.1) 3 3 ( 2.1) 3
霧視 2 ( 0.6) 2 2 ( 0.6) 2 5 ( 1.6) 5 5 ( 1.6) 5 1 ( 0.7) 1 1 ( 0.7) 1
眼の異常感 1 ( 0.3) 1 1 ( 0.3) 1 5 ( 1.6) 6 5 ( 1.6) 6
羞明 1 ( 0.3) 1 1 ( 0.3) 1 3 ( 1.0) 3 3 ( 1.0) 3 1 ( 0.7) 1 1 ( 0.7) 1
眼精疲労 2 ( 0.7) 2 2 ( 0.7) 2
硝子体浮遊物 1 ( 0.3) 1 1 ( 0.3) 1 1 ( 0.7) 1 1 ( 0.7) 1
眼球乾燥 2 ( 0.7) 2 2 ( 0.7) 2
結膜炎 1 ( 0.3) 1 1 ( 0.3) 1
眼瞼浮腫 1 ( 0.3) 1 1 ( 0.3) 1
胃腸障害 33 ( 10.3) 43 3 ( 0.9) 3 36 ( 11.2) 46 35 ( 11.4) 41 7 ( 2.3) 8 42 ( 13.7) 49 8 ( 5.5) 9 2 ( 1.4) 2 10 ( 6.9) 11
便秘 27 ( 8.4) 30 3 ( 0.9) 3 30 ( 9.3) 33 29 ( 9.5) 31 6 ( 2.0) 6 35 ( 11.4) 37 6 ( 4.1) 6 1 ( 0.7) 1 7 ( 4.8) 7
胃不快感 5 ( 1.6) 5 5 ( 1.6) 5 3 ( 1.0) 4 3 ( 1.0) 4
悪心 1 ( 0.3) 1 1 ( 0.3) 1 1 ( 0.3) 1 1 ( 0.3) 1 2 ( 0.7) 2
腹部膨満 1 ( 0.3) 1 1 ( 0.3) 1 1 ( 0.7) 1 1 ( 0.7) 1
口腔内不快感 1 ( 0.3) 1 1 ( 0.3) 1 1 ( 0.3) 1 1 ( 0.3) 1
口内炎 1 ( 0.3) 1 1 ( 0.3) 1 1 ( 0.7) 2 1 ( 0.7) 2
口唇障害 1 ( 0.3) 1 1 ( 0.3) 1 1 ( 0.3) 1 1 ( 0.3) 1
腹痛 1 ( 0.3) 1 1 ( 0.3) 1
上腹部痛 1 ( 0.3) 1 1 ( 0.3) 1
下痢 1 ( 0.3) 1 1 ( 0.3) 1
消化不良 1 ( 0.3) 1 1 ( 0.3) 1
胃炎 1 ( 0.3) 1 1 ( 0.3) 1
びらん性胃炎 1 ( 0.3) 1 1 ( 0.3) 1
2-
30
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腸管閉塞 1 ( 0.7) 1 1 ( 0.7) 1

口唇乾燥 1 ( 0.3) 1 1 ( 0.3) 1
全身障害および投与局所様態 73 ( 22.7) 73 14 ( 4.4) 16 87 ( 27.1) 89 86 ( 28.1) 86 23 ( 7.5) 24 4 ( 1.3) 4 113 ( 36.9) 114 13 ( 9.0) 13 1 ( 0.7) 1 14 ( 9.7) 14
口渇 73 ( 22.7) 73 14 ( 4.4) 15 87 ( 27.1) 88 85 ( 27.8) 85 23 ( 7.5) 24 4 ( 1.3) 4 112 ( 36.6) 113 13 ( 9.0) 13 1 ( 0.7) 1 14 ( 9.7) 14
倦怠感 1 ( 0.3) 1 1 ( 0.3) 1 1 ( 0.3) 1 1 ( 0.3) 1
感染症および寄生虫症 1 ( 0.3) 1 1 ( 0.3) 2 2 ( 0.6) 3 1 1 ( 0.3) 1 1 ( 0.3) 2 1 ( 0.7) 1 1 ( 0.7) 1
膀胱炎 1 ( 0.3) 2 1 ( 0.3) 2 1 ( 0.3) 1 1 ( 0.3) 1 1 ( 0.7) 1 1 ( 0.7) 1
カンジダ症 1 ( 0.3) 1 1 ( 0.3) 1
鼻炎 1 ( 0.3) 1 1 ( 0.3) 1
臨床検査 17 ( 5.3) 21 3 ( 0.9) 3 20 ( 6.2) 24 24 ( 7.8) 31 4 ( 1.3) 4 28 ( 9.2) 35 14 ( 9.7) 15 14 ( 9.7) 15
血中トリグリセリド増加 5 ( 1.6) 5 2 ( 0.6) 2 7 ( 2.2) 7 3 ( 1.0) 3 1 ( 0.3) 1 4 ( 1.3) 4 2 ( 1.4) 2 2 ( 1.4) 2
γ-グルタミルトランスフェラーゼ増加 4 ( 1.3) 4 4 ( 1.3) 4 2 ( 0.7) 2 2 ( 0.7) 2 2 ( 1.4) 2 2 ( 1.4) 2

2.7.6 Summary of individual tests

残尿量 1 ( 0.3) 1 1 ( 0.3) 1 2 ( 0.6) 2 2 ( 0.7) 2 1 ( 0.3) 1 3 ( 1.0) 3 2 ( 1.4) 2 2 ( 1.4) 2
尿中白血球陽性 1 ( 0.3) 1 1 ( 0.3) 1 2 ( 0.7) 2 2 ( 0.7) 2 4 ( 1.3) 4 1 ( 0.7) 1 1 ( 0.7) 1
白血球数減少 1 ( 0.3) 1 1 ( 0.3) 1 4 ( 1.3) 4 4 ( 1.3) 4 1 ( 0.7) 1 1 ( 0.7) 1
血中コレステロール増加 1 ( 0.3) 1 1 ( 0.3) 1 2 ( 0.7) 2 2 ( 0.7) 2 1 ( 0.7) 1 1 ( 0.7) 1
アラニン・アミノトランスフェラーゼ増加 2 ( 0.6) 2 2 ( 0.6) 2 1 ( 0.3) 1 1 ( 0.3) 1
血中尿酸増加 2 ( 0.7) 2 2 ( 0.7) 2 1 ( 0.7) 1 1 ( 0.7) 1
総蛋白減少 1 ( 0.3) 1 1 ( 0.3) 1 1 ( 0.3) 1 1 ( 0.3) 1 1 ( 0.7) 1 1 ( 0.7) 1
血中アルカリホスファターゼ増加 3 ( 1.0) 3 3 ( 1.0) 3
血中カリウム増加 1 ( 0.3) 1 1 ( 0.3) 1 1 ( 0.3) 1 1 ( 0.3) 1
血中尿素増加 2 ( 1.4) 2 2 ( 1.4) 2
白血球数増加 1 ( 0.3) 1 1 ( 0.3) 1 1 ( 0.7) 1 1 ( 0.7) 1
血中乳酸脱水素酵素増加 1 ( 0.3) 1 1 ( 0.3) 1
血小板数減少 1 ( 0.3) 1 1 ( 0.3) 1
アスパラギン酸アミノトランスフェラーゼ増加 1 ( 0.3) 1 1 ( 0.3) 1
血中アルブミン減少 1 ( 0.3) 1 1 ( 0.3) 1
血中カリウム減少 1 ( 0.3) 1 1 ( 0.3) 1
尿中ブドウ糖陽性 1 ( 0.3) 1 1 ( 0.3) 1
ヘマトクリット減少 1 ( 0.3) 1 1 ( 0.3) 1
ヘモグロビン減少 1 ( 0.3) 1 1 ( 0.3) 1
赤血球数減少 1 ( 0.3) 1 1 ( 0.3) 1
尿中蛋白陽性 1 ( 0.3) 1 1 ( 0.3) 1
血圧低下 1 ( 0.7) 1 1 ( 0.7) 1
尿潜血陽性 1 ( 0.3) 1 1 ( 0.3) 1
代謝および栄養障害 2 ( 0.7) 2 2 ( 0.7) 2 4 ( 1.3) 4
食欲減退 1 ( 0.3) 1 1 ( 0.3) 1 2 ( 0.7) 2
食欲不振 1 ( 0.3) 1 1 ( 0.3) 1
痛風 1 ( 0.3) 1 1 ( 0.3) 1
筋骨格系および結合組織障害 1 ( 0.3) 1 1 ( 0.3) 1 1 ( 0.3) 1 1 ( 0.3) 1
頚部痛 1 ( 0.3) 1 1 ( 0.3) 1
筋骨格硬直 1 ( 0.3) 1 1 ( 0.3) 1
神経系障害 3 ( 0.9) 3 3 ( 0.9) 3 3 ( 1.0) 3 1 ( 0.3) 1 4 ( 1.3) 4 1 ( 0.7) 1 1 ( 0.7) 1
感覚減退 2 ( 0.7) 2 2 ( 0.7) 2
傾眠 1 ( 0.3) 1 1 ( 0.3) 1 2 ( 0.7) 2
体位性めまい 1 ( 0.3) 1 1 ( 0.3) 1
味覚異常 1 ( 0.3) 1 1 ( 0.3) 1
 Table 2.7.6.3-18 List of adverse reactions by severity (continued)
投与群 0.2 mg/日 プロピベリン プラセボ
安全性解析対象集団 321 306 145
重症度 軽度 中等度 高度 計 軽度 中等度 高度 計 軽度 中等度 高度 計
有害事象項目 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数
頭痛 1 ( 0.3) 1 1 ( 0.3) 1
視野欠損 1 ( 0.7) 1 1 ( 0.7) 1
精神障害 1 ( 0.3) 1 1 ( 0.3) 1 1 ( 0.3) 2 1 ( 0.3) 2
リビドー減退 1 ( 0.3) 1 1 ( 0.3) 1
心身症 1 ( 0.3) 1 1 ( 0.3) 1
無為 1 ( 0.3) 1 1 ( 0.3) 1
腎および尿路障害 3 ( 0.9) 4 3 ( 0.9) 4 6 ( 2.0) 6 1 ( 0.3) 1 7 ( 2.3) 7
排尿困難 3 ( 0.9) 3 3 ( 0.9) 3 5 ( 1.6) 5 1 ( 0.3) 1 6 ( 2.0) 6
膿尿 1 ( 0.3) 1 1 ( 0.3) 1
尿閉 1 ( 0.3) 1 1 ( 0.3) 1
呼吸器、胸郭および縦隔障害 1 ( 0.3) 1 1 ( 0.3) 1 1 ( 0.3) 1 1 ( 0.3) 1 1 ( 0.7) 1 1 ( 0.7) 1
咽喉乾燥 1 ( 0.3) 1 1 ( 0.3) 1 1 ( 0.7) 1 1 ( 0.7) 1
咽喉頭疼痛 1 ( 0.3) 1 1 ( 0.3) 1
皮膚および皮下組織障害 3 ( 1.0) 3 3 ( 1.0) 3 1 ( 0.7) 1 1 ( 0.7) 1 2 ( 1.4) 2
湿疹 1 ( 0.3) 1 1 ( 0.3) 1 1 ( 0.7) 1 1 ( 0.7) 1
ざ瘡 1 ( 0.7) 1 1 ( 0.7) 1
顔面浮腫 1 ( 0.3) 1 1 ( 0.3) 1
全身性そう痒症 1 ( 0.3) 1 1 ( 0.3) 1

The incidence of each laboratory measure may differ because cases with laboratory items present during the observation period and after the start of treatment were included in the total. The number of cases for each assay may vary, as cases with abnormal changes were included regardless of whether the assay was missing
or not.
2-
30
-

2.7.6 Summary of individual tests

 Table 2.7.6.3-19 List of adverse events by causal relationship
投与群 0.2 mg/日 プロピベリン プラセボ
安全性解析対象集団 321 306 145
因果関係 ① ② ③ ④ 計 ① ② ③ ④ 計 ① ② ③ ④ 計
有害事象項目 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数
全例 14 ( 4.4) 16 65 ( 20.2) 75 51 ( 15.9) 88 104 ( 32.4) 351 234 ( 72.9) 530 24 ( 7.8) 31 84 ( 27.5) 114 48 ( 15.7) 100 94 ( 30.7) 346 250 ( 81.7) 591 1 ( 0.7) 1 15 ( 10.3) 20 22 ( 15.2) 27 61 ( 42.1) 161 99 ( 68.3) 209
心臓障害 1 ( 0.3) 2 1 ( 0.3) 2 2 ( 0.7) 2 4 ( 1.3) 4 6 ( 2.0) 6 1 ( 0.7) 3 1 ( 0.7) 3
動悸 1 ( 0.3) 1 1 ( 0.3) 1 1 ( 0.3) 1 3 ( 1.0) 3 4 ( 1.3) 4 1 ( 0.7) 3 1 ( 0.7) 3
狭心症 1 ( 0.3) 1 1 ( 0.3) 1
上室性期外収縮 1 ( 0.3) 1 1 ( 0.3) 1
心室性期外収縮 1 ( 0.3) 1 1 ( 0.3) 1
耳および迷路障害 1 ( 0.3) 1 2 ( 0.7) 2 3 ( 1.0) 3
耳管閉塞 1 ( 0.3) 1 1 ( 0.3) 1
回転性眩暈 1 ( 0.3) 1 1 ( 0.3) 1
耳そう痒症 1 ( 0.3) 1 1 ( 0.3) 1
眼障害 3 ( 0.9) 3 2 ( 0.6) 2 14 ( 4.4) 15 19 ( 5.9) 20 3 ( 1.0) 3 8 ( 2.6) 8 5 ( 1.6) 9 13 ( 4.2) 19 29 ( 9.5) 39 1 ( 0.7) 1 2 ( 1.4) 2 10 ( 6.9) 12 13 ( 9.0) 15
霧視 1 ( 0.3) 1 1 ( 0.3) 1 3 ( 0.9) 3 5 ( 1.6) 5 2 ( 0.7) 2 3 ( 1.0) 3 7 ( 2.3) 7 12 ( 3.9) 12 1 ( 0.7) 1 2 ( 1.4) 2 3 ( 2.1) 3
眼の異常感 1 ( 0.3) 1 3 ( 0.9) 3 4 ( 1.2) 4 3 ( 1.0) 3 1 ( 0.3) 1 1 ( 0.3) 2 2 ( 0.7) 2 7 ( 2.3) 8 1 ( 0.7) 1 1 ( 0.7) 1
羞明 1 ( 0.3) 1 1 ( 0.3) 1 2 ( 0.7) 2 1 ( 0.3) 1 1 ( 0.3) 1 4 ( 1.3) 4 1 ( 0.7) 1 1 ( 0.7) 1
眼球乾燥 2 ( 0.6) 2 2 ( 0.6) 2 2 ( 0.7) 2 2 ( 0.7) 2 1 ( 0.7) 1 1 ( 0.7) 1
結膜炎 1 ( 0.3) 1 1 ( 0.3) 1 2 ( 1.4) 2 2 ( 1.4) 2
眼痛 2 ( 0.7) 2 2 ( 0.7) 2 1 ( 0.7) 1 1 ( 0.7) 1
眼精疲労 1 ( 0.3) 1 1 ( 0.3) 1 2 ( 0.7) 2
白内障 1 ( 0.3) 1 1 ( 0.3) 1 1 ( 0.3) 1 1 ( 0.3) 1
視力低下 1 ( 0.3) 1 1 ( 0.3) 1 1 ( 0.7) 1 1 ( 0.7) 1
硝子体浮遊物 1 ( 0.3) 1 1 ( 0.3) 1 1 ( 0.7) 1 1 ( 0.7) 1
眼そう痒症 2 ( 0.6) 2 2 ( 0.6) 2
眼瞼痙攣 1 ( 0.3) 1 1 ( 0.3) 1
霰粒腫 1 ( 0.3) 1 1 ( 0.3) 1
結膜出血 1 ( 0.3) 2 1 ( 0.3) 2
眼瞼紅斑 1 ( 0.7) 1 1 ( 0.7) 1
眼脂 1 ( 0.3) 1 1 ( 0.3) 1
眼出血 1 ( 0.3) 1 1 ( 0.3) 1
眼瞼浮腫 1 ( 0.3) 1 1 ( 0.3) 1
角膜炎 1 ( 0.3) 1 1 ( 0.3) 1
流涙増加 1 ( 0.7) 1 1 ( 0.7) 1
光視症 1 ( 0.7) 1 1 ( 0.7) 1
1 ( 0.3) 1 1 ( 0.3) 1
2-
30
-

老視
網膜出血 1 ( 0.3) 1 1 ( 0.3) 1
硝子体剥離 1 ( 0.7) 1 1 ( 0.7) 1
胃腸障害 2 ( 0.6) 2 17 ( 5.3) 20 17 ( 5.3) 24 37 ( 11.5) 56 73 ( 22.7) 102 3 ( 1.0) 4 19 ( 6.2) 19 20 ( 6.5) 26 41 ( 13.4) 55 83 ( 27.1) 104 3 ( 2.1) 3 7 ( 4.8) 8 11 ( 7.6) 16 21 ( 14.5) 27
便秘 2 ( 0.6) 2 14 ( 4.4) 15 14 ( 4.4) 16 8 ( 2.5) 8 38 ( 11.8) 41 3 ( 1.0) 3 18 ( 5.9) 18 14 ( 4.6) 16 7 ( 2.3) 7 42 ( 13.7) 44 3 ( 2.1) 3 4 ( 2.8) 4 4 ( 2.8) 4 11 ( 7.6) 11
胃不快感 3 ( 0.9) 3 2 ( 0.6) 2 4 ( 1.2) 5 9 ( 2.8) 10 3 ( 1.0) 4 7 ( 2.3) 7 10 ( 3.3) 11
下痢 1 ( 0.3) 1 8 ( 2.5) 9 9 ( 2.8) 10 3 ( 1.0) 3 3 ( 1.0) 3 3 ( 2.1) 4 3 ( 2.1) 4
嘔吐 6 ( 1.9) 6 6 ( 1.9) 6 5 ( 1.6) 7 5 ( 1.6) 7
上腹部痛 5 ( 1.6) 5 5 ( 1.6) 5 1 ( 0.3) 1 3 ( 1.0) 3 4 ( 1.3) 4
胃炎 4 ( 1.2) 5 4 ( 1.2) 5 1 ( 0.3) 1 2 ( 0.7) 2 3 ( 1.0) 3 1 ( 0.7) 1 1 ( 0.7) 1
腹部膨満 1 ( 0.3) 1 1 ( 0.3) 1 2 ( 0.6) 2 4 ( 1.3) 4 4 ( 1.3) 4 1 ( 0.7) 1 1 ( 0.7) 1
悪心 1 ( 0.3) 1 2 ( 0.6) 2 3 ( 0.9) 3 1 ( 0.3) 1 1 ( 0.3) 1 1 ( 0.3) 2 3 ( 1.0) 4
口内炎 1 ( 0.3) 1 1 ( 0.3) 1 1 ( 0.3) 1 2 ( 0.7) 2 3 ( 1.0) 3 1 ( 0.7) 2 1 ( 0.7) 1 2 ( 1.4) 3

2.7.6 Summary of individual tests

腹痛 1 ( 0.3) 1 1 ( 0.3) 1 2 ( 0.7) 2 2 ( 0.7) 2 1 ( 0.7) 1 1 ( 0.7) 1
下腹部痛 2 ( 0.6) 2 2 ( 0.6) 2 1 ( 0.3) 1 1 ( 0.3) 1 1 ( 0.7) 1 1 ( 0.7) 1
消化不良 1 ( 0.3) 1 3 ( 1.0) 3 4 ( 1.3) 4
歯肉炎 3 ( 1.0) 3 3 ( 1.0) 3 1 ( 0.7) 1 1 ( 0.7) 1
歯痛 2 ( 0.6) 2 2 ( 0.6) 2 2 ( 1.4) 2 2 ( 1.4) 2
軟便 3 ( 1.0) 3 3 ( 1.0) 3
口唇障害 1 ( 0.3) 1 1 ( 0.3) 1 2 ( 0.6) 2 1 ( 0.3) 1 1 ( 0.3) 1
舌炎 2 ( 0.6) 2 2 ( 0.6) 2
口唇乾燥 1 ( 0.3) 1 1 ( 0.3) 2 2 ( 0.6) 3
口腔内不快感 1 ( 0.3) 1 1 ( 0.3) 1 1 ( 0.3) 1 1 ( 0.3) 1
腹部不快感 1 ( 0.3) 1 1 ( 0.3) 1
アフタ性口内炎 1 ( 0.3) 1 1 ( 0.3) 1
口唇炎 1 ( 0.3) 1 1 ( 0.3) 1
変色便 1 ( 0.3) 1 1 ( 0.3) 1
鼓腸 1 ( 0.7) 1 1 ( 0.7) 1
胃潰瘍 1 ( 0.3) 1 1 ( 0.3) 1
びらん性胃炎 1 ( 0.3) 1 1 ( 0.3) 1
歯肉腫脹 1 ( 0.3) 1 1 ( 0.3) 1
痔核 1 ( 0.3) 1 1 ( 0.3) 1
腸管閉塞 1 ( 0.7) 1 1 ( 0.7) 1
舌苔 1 ( 0.3) 1 1 ( 0.3) 1
口唇のひび割れ 1 ( 0.3) 1 1 ( 0.3) 1
肛門出血 1 ( 0.3) 1 1 ( 0.3) 1
胃腸不快感 1 ( 0.3) 1 1 ( 0.3) 1
全身障害および投与局所様態 12 ( 3.7) 13 48 ( 15.0) 48 27 ( 8.4) 28 22 ( 6.9) 24 109 ( 34.0) 113 22 ( 7.2) 23 71 ( 23.2) 71 20 ( 6.5) 20 14 ( 4.6) 21 127 ( 41.5) 135 1 ( 0.7) 1 10 ( 6.9) 10 3 ( 2.1) 3 6 ( 4.1) 7 20 ( 13.8) 21
口渇 12 ( 3.7) 13 48 ( 15.0) 48 27 ( 8.4) 27 14 ( 4.4) 14 101 ( 31.5) 102 22 ( 7.2) 23 70 ( 22.9) 70 20 ( 6.5) 20 10 ( 3.3) 11 122 ( 39.9) 124 1 ( 0.7) 1 10 ( 6.9) 10 3 ( 2.1) 3 6 ( 4.1) 6 20 ( 13.8) 20
発熱 2 ( 0.6) 2 2 ( 0.6) 2 3 ( 1.0) 3 3 ( 1.0) 3 1 ( 0.7) 1 1 ( 0.7) 1
倦怠感 1 ( 0.3) 1 1 ( 0.3) 1 2 ( 0.6) 2 1 ( 0.3) 1 1 ( 0.3) 1 2 ( 0.7) 2
胸部不快感 2 ( 0.6) 2 2 ( 0.6) 2 1 ( 0.3) 1 1 ( 0.3) 1
末梢性浮腫 3 ( 0.9) 3 3 ( 0.9) 3
疼痛 2 ( 0.6) 2 2 ( 0.6) 2 1 ( 0.3) 1 1 ( 0.3) 1
Causal relationship with the investigational drug: (1) clearly related, (2) probably related, (3) not related, (4) not related
 Table 2.7.6.3-19 List of adverse events by causal relationship (continued)
投与群 0.2 mg/日 プロピベリン プラセボ
安全性解析対象集団 321 306 145
因果関係 ① ② ③ ④ 計 ① ② ③ ④ 計 ① ② ③ ④ 計
有害事象項目 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数
疲労 2 ( 0.7) 2 2 ( 0.7) 2
胸痛 1 ( 0.3) 1 1 ( 0.3) 1
異常感 1 ( 0.3) 1 1 ( 0.3) 1
肝胆道系障害 1 ( 0.7) 1 1 ( 0.7) 1
胆嚢炎 1 ( 0.7) 1 1 ( 0.7) 1
免疫系障害 2 ( 0.6) 2 2 ( 0.6) 2 2 ( 0.7) 2 2 ( 0.7) 2
季節性アレルギー 2 ( 0.6) 2 2 ( 0.6) 2 2 ( 0.7) 2 2 ( 0.7) 2
感染症および寄生虫症 2 ( 0.6) 3 78 ( 24.3) 92 80 ( 24.9) 95 1 ( 0.3) 2 76 ( 24.8) 93 77 ( 25.2) 95 1 ( 0.7) 1 39 ( 26.9) 44 40 ( 27.6) 45
鼻咽頭炎 59 ( 18.4) 68 59 ( 18.4) 68 61 ( 19.9) 68 61 ( 19.9) 68 34 ( 23.4) 37 34 ( 23.4) 37
膀胱炎 1 ( 0.3) 2 5 ( 1.6) 5 6 ( 1.9) 7 1 ( 0.3) 1 5 ( 1.6) 5 6 ( 2.0) 6 1 ( 0.7) 1 1 ( 0.7) 1
単純ヘルペス 1 ( 0.3) 1 1 ( 0.3) 1 3 ( 1.0) 3 3 ( 1.0) 3 1 ( 0.7) 1 1 ( 0.7) 1
ウイルス性腸炎 3 ( 0.9) 3 3 ( 0.9) 3 1 ( 0.3) 1 1 ( 0.3) 1 1 ( 0.7) 1 1 ( 0.7) 1
胃腸炎 2 ( 0.6) 2 2 ( 0.6) 2 1 ( 0.3) 1 1 ( 0.3) 1 1 ( 0.7) 1 1 ( 0.7) 1
インフルエンザ 1 ( 0.3) 1 1 ( 0.3) 1 2 ( 0.7) 3 2 ( 0.7) 3 1 ( 0.7) 1 1 ( 0.7) 1
咽喉頭炎 2 ( 0.6) 2 2 ( 0.6) 2 1 ( 0.3) 1 1 ( 0.3) 1 1 ( 0.7) 1 1 ( 0.7) 1
帯状疱疹 1 ( 0.3) 1 1 ( 0.3) 1 2 ( 0.7) 2 2 ( 0.7) 2
気管支炎 1 ( 0.3) 1 1 ( 0.3) 1 1 ( 0.3) 1 1 ( 0.3) 1
中耳炎 2 ( 0.6) 2 2 ( 0.6) 2
鼻炎 1 ( 0.3) 1 1 ( 0.3) 1 1 ( 0.3) 1 1 ( 0.3) 1
副鼻腔炎 1 ( 0.3) 1 1 ( 0.3) 1 1 ( 0.7) 1 1 ( 0.7) 1
尿路感染 1 ( 0.3) 1 1 ( 0.3) 1 1 ( 0.3) 1 1 ( 0.3) 1
気管支肺炎 1 ( 0.3) 1 1 ( 0.3) 1
カンジダ症 1 ( 0.3) 1 1 ( 0.3) 1
真菌感染 1 ( 0.7) 1 1 ( 0.7) 1
ヘルペスウイルス感染 1 ( 0.3) 1 1 ( 0.3) 1
麦粒腫 1 ( 0.3) 1 1 ( 0.3) 1
喉頭炎 1 ( 0.3) 1 1 ( 0.3) 1
爪囲炎 1 ( 0.3) 1 1 ( 0.3) 1
肺炎 1 ( 0.3) 1 1 ( 0.3) 1
足部白癬 1 ( 0.3) 1 1 ( 0.3) 1
外陰部炎 1 ( 0.3) 1 1 ( 0.3) 1
感染性小腸結腸炎 1 ( 0.3) 1 1 ( 0.3) 1
化膿 1 ( 0.3) 1 1 ( 0.3) 1
2-
30
-

傷害、中毒および処置合併症 6 ( 1.9) 6 6 ( 1.9) 6 9 ( 2.9) 12 9 ( 2.9) 12 4 ( 2.8) 4 4 ( 2.8) 4

関節捻挫 2 ( 0.6) 2 2 ( 0.6) 2 2 ( 0.7) 3 2 ( 0.7) 3
背部損傷 1 ( 0.3) 1 1 ( 0.3) 1
鎖骨骨折 1 ( 0.3) 1 1 ( 0.3) 1
圧迫骨折 1 ( 0.3) 1 1 ( 0.3) 1
腓骨骨折 1 ( 0.3) 1 1 ( 0.3) 1
骨折 1 ( 0.3) 1 1 ( 0.3) 1
手骨折 1 ( 0.3) 1 1 ( 0.3) 1
嵌入爪 1 ( 0.7) 1 1 ( 0.7) 1
関節脱臼 1 ( 0.7) 1 1 ( 0.7) 1
裂傷 1 ( 0.3) 1 1 ( 0.3) 1
橈骨骨折 1 ( 0.3) 1 1 ( 0.3) 1

2.7.6 Summary of individual tests

肋骨骨折 1 ( 0.7) 1 1 ( 0.7) 1
手首関節骨折 1 ( 0.7) 1 1 ( 0.7) 1
擦過傷 1 ( 0.3) 1 1 ( 0.3) 1
創傷 1 ( 0.3) 1 1 ( 0.3) 1
半月板障害 1 ( 0.3) 1 1 ( 0.3) 1
冠動脈再狭窄 1 ( 0.3) 1 1 ( 0.3) 1
靱帯損傷 1 ( 0.3) 1 1 ( 0.3) 1
臨床検査 2 ( 0.6) 2 18 ( 5.6) 22 48 ( 15.0) 75 68 ( 21.2) 99 6 ( 2.0) 7 22 ( 7.2) 28 47 ( 15.4) 67 75 ( 24.5) 102 5 ( 3.4) 5 9 ( 6.2) 10 26 ( 17.9) 39 40 ( 27.6) 54
尿中白血球陽性 1 ( 0.3) 1 18 ( 5.6) 20 19 ( 5.9) 21 1 ( 0.3) 1 3 ( 1.0) 3 19 ( 6.2) 19 23 ( 7.5) 23 1 ( 0.7) 1 9 ( 6.3) 9 10 ( 7.0) 10
血中トリグリセリド増加 7 ( 2.2) 7 6 ( 1.9) 6 13 ( 4.1) 13 4 ( 1.3) 4 4 ( 1.3) 4 8 ( 2.6) 8 2 ( 1.4) 2 5 ( 3.5) 5 7 ( 4.9) 7
尿中赤血球陽性 8 ( 2.5) 8 8 ( 2.5) 8 11 ( 3.6) 11 11 ( 3.6) 11 4 ( 2.8) 4 4 ( 2.8) 4
γ-グルタミルトランスフェラーゼ増加 1 ( 0.3) 1 3 ( 0.9) 3 7 ( 2.2) 7 11 ( 3.4) 11 2 ( 0.7) 2 5 ( 1.6) 5 7 ( 2.3) 7 2 ( 1.4) 2 1 ( 0.7) 1 3 ( 2.1) 3
尿中ブドウ糖陽性 8 ( 2.5) 8 8 ( 2.5) 8 1 ( 0.3) 1 1 ( 0.3) 1 3 ( 2.1) 3 3 ( 2.1) 3
血中コレステロール増加 1 ( 0.3) 1 1 ( 0.3) 1 2 ( 0.7) 2 3 ( 1.0) 3 5 ( 1.6) 5 1 ( 0.7) 1 3 ( 2.1) 3 4 ( 2.8) 4
アラニン・アミノトランスフェラーゼ増加 2 ( 0.6) 2 4 ( 1.3) 4 6 ( 1.9) 6 1 ( 0.3) 1 1 ( 0.3) 1 2 ( 0.7) 2 1 ( 0.7) 1 1 ( 0.7) 1
白血球数減少 1 ( 0.3) 1 2 ( 0.6) 2 3 ( 0.9) 3 2 ( 0.7) 2 2 ( 0.7) 2 1 ( 0.3) 1 5 ( 1.6) 5 1 ( 0.7) 1 1 ( 0.7) 1
血中アルカリホスファターゼ増加 3 ( 0.9) 3 3 ( 0.9) 3 2 ( 0.7) 2 1 ( 0.3) 1 2 ( 0.7) 2 5 ( 1.6) 5 1 ( 0.7) 1 1 ( 0.7) 1
血圧上昇 3 ( 0.9) 3 3 ( 0.9) 3 4 ( 1.3) 4 4 ( 1.3) 4 2 ( 1.4) 3 2 ( 1.4) 3
残尿量 1 ( 0.3) 1 1 ( 0.3) 1 2 ( 0.6) 2 1 ( 0.3) 1 2 ( 0.7) 2 2 ( 0.7) 2 5 ( 1.6) 5 2 ( 1.4) 2 2 ( 1.4) 2
白血球数増加 1 ( 0.3) 1 1 ( 0.3) 1 1 ( 0.3) 1 3 ( 1.0) 3 4 ( 1.3) 4 1 ( 0.7) 1 2 ( 1.4) 2 3 ( 2.1) 3
アスパラギン酸アミノトランスフェラーゼ増加 4 ( 1.3) 4 4 ( 1.3) 4 1 ( 0.3) 1 1 ( 0.3) 1 2 ( 0.7) 2 1 ( 0.7) 1 1 ( 0.7) 1
尿中蛋白陽性 1 ( 0.3) 1 1 ( 0.3) 1 1 ( 0.3) 1 2 ( 0.7) 2 3 ( 1.0) 3 3 ( 2.1) 3 3 ( 2.1) 3
血中カリウム増加 1 ( 0.3) 1 1 ( 0.3) 1 1 ( 0.3) 1 3 ( 1.0) 3 4 ( 1.3) 4
血中尿酸増加 1 ( 0.3) 1 1 ( 0.3) 1 1 ( 0.3) 1 1 ( 0.3) 1 1 ( 0.3) 1 3 ( 1.0) 3 1 ( 0.7) 1 1 ( 0.7) 1
血中尿素増加 2 ( 0.7) 2 2 ( 0.7) 2 2 ( 1.4) 2 2 ( 1.4) 2
総蛋白減少 1 ( 0.3) 1 1 ( 0.3) 1 1 ( 0.3) 1 1 ( 0.3) 1 1 ( 0.7) 1 1 ( 0.7) 1
尿潜血陽性 1 ( 0.3) 1 1 ( 0.3) 1 2 ( 0.7) 2 1 ( 0.7) 1 1 ( 0.7) 1
血中乳酸脱水素酵素増加 1 ( 0.3) 1 1 ( 0.3) 1 1 ( 0.3) 1 1 ( 0.3) 1
血中カリウム減少 1 ( 0.3) 1 1 ( 0.3) 1 2 ( 0.6) 2
ヘマトクリット減少 1 ( 0.3) 1 1 ( 0.3) 1 1 ( 0.3) 1 1 ( 0.3) 1
ヘモグロビン減少 1 ( 0.3) 1 1 ( 0.3) 1 1 ( 0.3) 1 1 ( 0.3) 1

Causal relationship with the investigational drug: (1) clearly related, (2) probably related, (3) not related, (4) not related
 Table 2.7.6.3-19 List of adverse events by causal relationship (continued)
投与群 0.2 mg/日 プロピベリン プラセボ
安全性解析対象集団 321 306 145
因果関係 ① ② ③ ④ 計 ① ② ③ ④ 計 ① ② ③ ④ 計
有害事象項目 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数
赤血球数減少 1 ( 0.3) 1 1 ( 0.3) 1 1 ( 0.3) 1 1 ( 0.3) 1
血圧低下 1 ( 0.3) 1 1 ( 0.3) 1 1 ( 0.7) 1 1 ( 0.7) 1
尿沈渣陽性 1 ( 0.3) 1 1 ( 0.3) 1 1 ( 0.7) 1 1 ( 0.7) 1
血小板数減少 1 ( 0.3) 1 1 ( 0.3) 1
血中アルブミン減少 1 ( 0.3) 1 1 ( 0.3) 1
尿中ウロビリン陽性 1 ( 0.7) 1 1 ( 0.7) 1
血中クレアチンホスホキナーゼ増加 1 ( 0.3) 1 1 ( 0.3) 1
心電図Ｔ波逆転 1 ( 0.3) 1 1 ( 0.3) 1
代謝および栄養障害 1 ( 0.3) 1 3 ( 1.0) 3 1 ( 0.3) 1 5 ( 1.6) 5
食欲減退 1 ( 0.3) 1 1 ( 0.3) 1 2 ( 0.7) 2
低カリウム血症 1 ( 0.3) 1 1 ( 0.3) 1
食欲不振 1 ( 0.3) 1 1 ( 0.3) 1
痛風 1 ( 0.3) 1 1 ( 0.3) 1
筋骨格系および結合組織障害 1 ( 0.3) 1 12 ( 3.7) 16 13 ( 4.0) 17 1 ( 0.3) 1 8 ( 2.6) 8 9 ( 2.9) 9 6 ( 4.1) 6 6 ( 4.1) 6
背部痛 4 ( 1.2) 4 4 ( 1.2) 4 4 ( 1.3) 4 4 ( 1.3) 4 2 ( 1.4) 2 2 ( 1.4) 2
関節痛 2 ( 0.6) 2 2 ( 0.6) 2 2 ( 0.7) 2 2 ( 0.7) 2 2 ( 1.4) 2 2 ( 1.4) 2
筋骨格硬直 1 ( 0.3) 1 3 ( 0.9) 3 4 ( 1.2) 4
関節炎 1 ( 0.3) 1 1 ( 0.3) 1 1 ( 0.7) 1 1 ( 0.7) 1
頚部痛 1 ( 0.3) 1 1 ( 0.3) 1 2 ( 0.7) 2
関節腫脹 1 ( 0.3) 1 1 ( 0.3) 1
筋痙攣 1 ( 0.7) 1 1 ( 0.7) 1
筋痛 1 ( 0.3) 2 1 ( 0.3) 2
四肢痛 1 ( 0.3) 1 1 ( 0.3) 1
関節周囲炎 1 ( 0.3) 1 1 ( 0.3) 1
脊椎症 1 ( 0.3) 1 1 ( 0.3) 1
椎間板突出 1 ( 0.3) 1 1 ( 0.3) 1
良性、悪性および詳細不明の新生物（嚢胞およびポリープを含む） 1 ( 0.3) 1 1 ( 0.3) 1 1 ( 0.7) 1 1 ( 0.7) 1
皮膚乳頭腫 1 ( 0.7) 1 1 ( 0.7) 1
卵巣新生物 1 ( 0.3) 1 1 ( 0.3) 1
神経系障害 1 ( 0.3) 1 2 ( 0.6) 2 15 ( 4.7) 18 18 ( 5.6) 21 2 ( 0.7) 2 2 ( 0.7) 2 15 ( 4.9) 16 19 ( 6.2) 20 1 ( 0.7) 1 6 ( 4.1) 8 7 ( 4.8) 9
頭痛 1 ( 0.3) 1 10 ( 3.1) 12 11 ( 3.4) 13 8 ( 2.6) 9 8 ( 2.6) 9 3 ( 2.1) 3 3 ( 2.1) 3
浮動性めまい 1 ( 0.3) 1 1 ( 0.3) 1 3 ( 1.0) 3 3 ( 1.0) 3 2 ( 1.4) 2 2 ( 1.4) 2
1 ( 0.3) 1 1 ( 0.3) 1 2 ( 0.7) 2 1 ( 0.3) 1 3 ( 1.0) 3
2-
30
-

傾眠
脳梗塞 2 ( 0.6) 2 2 ( 0.6) 2
味覚異常 1 ( 0.3) 1 1 ( 0.3) 1 1 ( 0.3) 1 1 ( 0.3) 1
感覚減退 2 ( 0.7) 2 2 ( 0.7) 2
健忘 1 ( 0.3) 1 1 ( 0.3) 1
頚腕症候群 1 ( 0.7) 1 1 ( 0.7) 1
体位性めまい 1 ( 0.3) 1 1 ( 0.3) 1
意識消失 1 ( 0.7) 1 1 ( 0.7) 1
末梢性ニューロパシー 1 ( 0.7) 1 1 ( 0.7) 1
坐骨神経痛 1 ( 0.3) 1 1 ( 0.3) 1
失神 1 ( 0.3) 1 1 ( 0.3) 1
視野欠損 1 ( 0.7) 1 1 ( 0.7) 1
肋間神経痛 1 ( 0.3) 1 1 ( 0.3) 1

2.7.6 Summary of individual tests

精神障害 1 ( 0.3) 1 2 ( 0.6) 3 3 ( 0.9) 4 1 ( 0.3) 2 4 ( 1.3) 4 5 ( 1.6) 6
不眠症 2 ( 0.6) 2 2 ( 0.6) 2 4 ( 1.3) 4 4 ( 1.3) 4
抑うつ気分 1 ( 0.3) 1 1 ( 0.3) 1
リビドー減退 1 ( 0.3) 1 1 ( 0.3) 1
心身症 1 ( 0.3) 1 1 ( 0.3) 1
無為 1 ( 0.3) 1 1 ( 0.3) 1
腎および尿路障害 1 ( 0.3) 1 2 ( 0.6) 3 4 ( 1.2) 4 7 ( 2.2) 8 1 ( 0.3) 1 4 ( 1.3) 4 2 ( 0.7) 2 7 ( 2.3) 7 2 ( 1.4) 3 2 ( 1.4) 3
排尿困難 1 ( 0.3) 1 2 ( 0.6) 2 3 ( 0.9) 3 1 ( 0.3) 1 4 ( 1.3) 4 1 ( 0.3) 1 6 ( 2.0) 6 1 ( 0.7) 1 1 ( 0.7) 1
緊張性膀胱 1 ( 0.3) 1 1 ( 0.3) 1 1 ( 0.7) 1 1 ( 0.7) 1
膿尿 1 ( 0.3) 1 1 ( 0.3) 1 1 ( 0.3) 1 1 ( 0.3) 1
血尿 1 ( 0.3) 1 1 ( 0.3) 1
排尿異常 1 ( 0.7) 1 1 ( 0.7) 1
尿失禁 1 ( 0.3) 1 1 ( 0.3) 1
尿閉 1 ( 0.3) 1 1 ( 0.3) 1
生殖系および乳房障害 4 ( 1.3) 5 4 ( 1.3) 5
性器出血 2 ( 0.7) 3 2 ( 0.7) 3
閉経期症状 1 ( 0.3) 1 1 ( 0.3) 1
性器分泌物 1 ( 0.3) 1 1 ( 0.3) 1
呼吸器、胸郭および縦隔障害 1 ( 0.3) 1 21 ( 6.5) 23 22 ( 6.9) 24 1 ( 0.3) 1 14 ( 4.6) 17 15 ( 4.9) 18 1 ( 0.7) 1 7 ( 4.8) 8 8 ( 5.5) 9
上気道の炎症 9 ( 2.8) 10 9 ( 2.8) 10 4 ( 1.3) 4 4 ( 1.3) 4 3 ( 2.1) 3 3 ( 2.1) 3
咽喉頭疼痛 4 ( 1.2) 4 4 ( 1.2) 4 1 ( 0.3) 1 2 ( 0.7) 2 3 ( 1.0) 3 1 ( 0.7) 1 1 ( 0.7) 1
咳嗽 1 ( 0.3) 1 1 ( 0.3) 1 4 ( 1.3) 4 4 ( 1.3) 4 1 ( 0.7) 1 1 ( 0.7) 1
鼻漏 2 ( 0.6) 2 2 ( 0.6) 2 3 ( 1.0) 3 3 ( 1.0) 3
鼻出血 1 ( 0.3) 1 1 ( 0.3) 1 2 ( 1.4) 2 2 ( 1.4) 2
咽喉乾燥 1 ( 0.3) 1 1 ( 0.3) 1 1 ( 0.7) 1 1 ( 0.7) 1
咽頭不快感 2 ( 0.7) 2 2 ( 0.7) 2
喘息 1 ( 0.3) 1 1 ( 0.3) 1
呼吸困難 1 ( 0.3) 1 1 ( 0.3) 1
鼻閉 1 ( 0.3) 1 1 ( 0.3) 1
鼻乾燥 1 ( 0.7) 1 1 ( 0.7) 1
胸腔内出血 1 ( 0.3) 1 1 ( 0.3) 1
Causal relationship with the investigational drug: (1) clearly related, (2) probably related, (3) not related, (4) not related
 Table 2.7.6.3-19 List of adverse events by causal relationship (continued)
投与群 0.2 mg/日 プロピベリン プラセボ
安全性解析対象集団 321 306 145
因果関係 ① ② ③ ④ 計 ① ② ③ ④ 計 ① ② ③ ④ 計
有害事象項目 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数
湿性咳嗽 1 ( 0.3) 1 1 ( 0.3) 1
アレルギー性鼻炎 1 ( 0.3) 1 1 ( 0.3) 1
くしゃみ 1 ( 0.3) 1 1 ( 0.3) 1
皮膚および皮下組織障害 15 ( 4.7) 15 15 ( 4.7) 15 3 ( 1.0) 3 14 ( 4.6) 18 17 ( 5.6) 21 2 ( 1.4) 2 9 ( 6.2) 9 11 ( 7.6) 11
湿疹 3 ( 0.9) 3 3 ( 0.9) 3 1 ( 0.3) 1 2 ( 0.7) 2 3 ( 1.0) 3 1 ( 0.7) 1 2 ( 1.4) 2 3 ( 2.1) 3
皮下出血 3 ( 0.9) 3 3 ( 0.9) 3 3 ( 1.0) 5 3 ( 1.0) 5 2 ( 1.4) 2 2 ( 1.4) 2
そう痒症 2 ( 0.6) 2 2 ( 0.6) 2 3 ( 1.0) 3 3 ( 1.0) 3
発疹 1 ( 0.3) 1 1 ( 0.3) 1 1 ( 0.3) 1 1 ( 0.3) 1 1 ( 0.7) 1 1 ( 0.7) 1
皮膚嚢腫 1 ( 0.3) 1 1 ( 0.3) 1 1 ( 0.3) 1 1 ( 0.3) 1
皮膚炎 1 ( 0.3) 1 1 ( 0.3) 1 1 ( 0.7) 1 1 ( 0.7) 1
皮脂欠乏性湿疹 1 ( 0.3) 1 1 ( 0.3) 1 1 ( 0.3) 1 1 ( 0.3) 1
紅斑 1 ( 0.3) 1 1 ( 0.3) 1 1 ( 0.7) 1 1 ( 0.7) 1
蕁麻疹 1 ( 0.3) 1 1 ( 0.3) 1 1 ( 0.7) 1 1 ( 0.7) 1
擦過傷 2 ( 0.7) 3 2 ( 0.7) 3
全身性そう痒症 1 ( 0.3) 1 1 ( 0.3) 1 1 ( 0.7) 1 1 ( 0.7) 1
ざ瘡 1 ( 0.7) 1 1 ( 0.7) 1
薬剤性皮膚炎 1 ( 0.3) 1 1 ( 0.3) 1
顔面浮腫 1 ( 0.3) 1 1 ( 0.3) 1
過角化 1 ( 0.3) 1 1 ( 0.3) 1
皮膚線条 1 ( 0.3) 1 1 ( 0.3) 1
外科および内科処置 1 ( 0.3) 1 1 ( 0.3) 1
歯修復 1 ( 0.3) 1 1 ( 0.3) 1
血管障害 1 ( 0.3) 1 1 ( 0.3) 1 1 ( 0.3) 1 1 ( 0.3) 1
低血圧 1 ( 0.3) 1 1 ( 0.3) 1
ほてり 1 ( 0.3) 1 1 ( 0.3) 1

Causal relationship with the investigational drug: (1) clearly related, (2) probably related, (3) not related, (4) not related
The incidence of each laboratory measure may differ because cases with laboratory items present during the observation period and after the start of treatment were included in the total. The number of cases for each assay may vary, as cases with abnormal changes were included regardless of whether
the assay was missing or not.
2-
30
-

2.7.6 Summary of individual tests

 2.7.6 Summary of the individual tests

(4) Conclusion
Efficacy evaluations demonstrated superiority of ONO-8025 over placebo and non-
inferiority of ONO-8025 over propiverine hydrochloride in the primary endpoint of change
in the total number of urinary incontinences per week. In addition to urinary
incontinence, ONO-8025 was superior to placebo in the frequency of urination and the
frequency and severity of urinary urgency, which are the main clinical symptoms of
overactive bladder, indicating that the drug is effective in treating symptoms of urinary
incontinence, frequency and urinary urgency in overactive bladder.
In the safety evaluation, the incidence of adverse events and side effects was 72.9%
and 40.5% in the ONO-8025 group and 81.7% and 51.0% in the propiverine hydrochloride
group, respectively, both significantly lower in the ONO-8025 group than in the
propiverine hydrochloride group (Fisher's direct probability test: p = 0.0101 and p =
0.0102, respectively). The incidence and severity of dry mouth adverse events, which
may be due to anticholinergic effects, were both significantly lower in the ONO-8025
group than in the propiverine hydrochloride group (Fisher's direct probability test:
p=0.0302 and p=0.0433, respectively). The discontinuation rate due to adverse events
was 3.4% in the ONO-8025 group and 6.2% in the propiverine hydrochloride group, with
the ONO-8025 group having approximately half the rate of discontinuation compared to
the propiverine hydrochloride group. The rate of discontinuation due to dry mouth was
significantly lower in the ONO-8025 group than in the propiverine hydrochloride group
(Fisher's direct probability test: p=0.0181). There was no QTc prolongation in the ONO-
8025 group compared to the placebo group or before and after treatment. In contrast,
propiverine hydrochloride significantly prolonged QTc in the pre- and post-treatment
comparisons and in the comparison with the ONO-8025 group (corresponding t-test: p<0.0001,
t-test: p<0.0001, respectively).
This drug was developed from basic research as a bladder-selective antagonist of M3
and M1 muscarinic receptors, thereby reducing the side effects, mainly thirst, of
existing anticholinergic drugs. In this study, the drug was shown to be effective in
the treatment of various symptoms of urinary incontinence, frequency and urgency in
overactive bladder. Compared to propiverine hydrochloride, one of the most widely used
anticholinergic drugs on the market, it was found to reduce the incidence and severity
of adverse events and side effects thought to be based on anticholinergic effects,
mainly thirst, and to be a treatment for overactive bladder without QT prolongation. In
addition, it was found to be a treatment for overactive bladder without QT prolongation,
thus validating a series of development concepts from basic research.
Therefore, this drug showed similar efficacy compared to the existing anticholinergic
drug propiverine hydrochloride. It was also found to be a clinically useful bladder-
selective muscarinic M3 and M1 receptor antagonist that can be used safely compared with
existing anticholinergic drugs in patients who are unable to receive pharmacological
treatment for overactive bladder due to anticholinergic side effects, mainly dry mouth,
and the risk of QT prolongation.

- 317 -
 2.7.6 Summary of the individual tests

-4. Imidafenacin Long-Term Dose Study in Patients with Overactive Bladder [KRP197-
T301/ONO-8025-12]: Population Pharmacokinetic Analysis (Final Report)
............................... Attachment 5.3.3.5 #2
(1) Outline of the test
Title Imidafenacin long-term administration study Incremental dose long-term
administration study in patients with overactive bladder
(Study protocol No. KRP197-T301/ONO-8025-12): Population pharmacokinetic
analysis (final report)
Clinical trial
KRP197-T301/ONO-8025-12
protocol number
Test number Y08BG029
Testing period 9 December 2008 (date of fixation of the study protocol)
1 July 2009 (date of last analysis)
Objective The aim of this study was to estimate the population pharmacokinetic (PPK)
parameters of imidafenacin in patients with overactive bladder and healthy
adults, and to explore the factors that cause variability in pharmacokinetics.
The study also aimed to evaluate the relationship between plasma imidafenacin
concentrations and QTc. Furthermore, we aimed to evaluate the relationship
between exposure dose and efficacy and safety.
Method Plasma imidafenacin concentrations in patients with overactive bladder up to
52 weeks post-treatment (0.2 mg/day continuous group) or 64 weeks post-
treatment (0.4 mg/day increasing group) in the long-term dose escalation study
[KRP197-T301/ONO-8025-12] and in the long-term dose escalation study [ONO-
8025-07], and in healthy adults Plasma imidafenacin concentrations in 852
patients with overactive bladder (blood point 1983) and 90 healthy adults
(blood point 1983) were used in 7 studies in healthy adults [KRP197-T101,
KRP197-T102, KRP197-T103, KRP197-T104, KRP197-T105, ONO-8025-09, ONO-8025-
11]. Eighteen candidate covariates for PPK parameters were examined, and a
final model was constructed from the covariates that were judged to be
statistically significant. The relationship between plasma imidafenacin
concentration and QTc was also analysed by fitting a linear model. In addition,
Bayesian estimates of exposure (Cmax and AUC) and efficacy (total number of urge
incontinences per week, total number of urinary incontinences per week, average
number of urinations per day, average number of urinary urgencies per day)
were obtained for each 0.4 mg/day dose increase and 0.2 mg/day continuation
in the long-term dose increase study. urgency per day) by multiple linear
regression analysis, and the relationship between safety (occurrence of side
effects, occurrence of dry mouth (side effect), occurrence of moderate or
greater dry mouth (side effect)) by logistic regression analysis.

(2) Results
1) Plasma imidafenacin concentrations in a long-term dose escalation study
The plasma concentration-time plot of imidafenacin in the Incremental Long-Term Dose
Study is shown in Figure 2.7.6.4-1 and the summary statistics of the plasma concentration
data by time point of blood collection are shown in Table 2.7.6.4-1. Plasma imidafenacin
concentrations were high for approximately 1 to 3 hours after dosing and then disappeared.
The mean plasma concentrations of imidafenacin were 364 and 352 pg/mL in the 0.4 mg/day
dose escalation and 0.2 mg/day continuation groups, respectively, before 12 weeks (91
days) of treatment, when all patients received imidafenacin at 0.2 mg/day. The mean
plasma concentrations from 12 weeks (92 days) to 24 weeks (153 days) of treatment, from
24 weeks (154 days) to 40 weeks (265 days) of treatment, and from 40 weeks (266 days)
of treatment were 210, 425, and 242 pg/mL, respectively, for the 0.2 mg/day dose, and

- 318 -
 2.7.6 Summary of the individual tests

730, 1080, and 666 pg/mL, respectively, for the 0.4 mg/day dose. The mean plasma
concentrations since discontinuation were 210, 425, and 242 pg/mL at 0.2 mg/day and 730,
1080, and 666 pg/mL at 0.4 mg/day, respectively, indicating that plasma concentrations
increased with increasing dose. The mean plasma concentrations at discontinuation and
non-discontinuation were 401 and 352 pg/mL for the 0.2 mg/day dose and 975 and 900 pg/mL
for the 0.4 mg/day dose, respectively. 57 BLQ samples (including missing values) were
available.

3000
Plasma concentration of Imidafenacin (pg/mL)

0.2 mg/day
0.4 mg/day
2400

1800

1200

600

0
0 2 4 6 8 10 12 14
Time (h)
Figure 2.7.6.4-1 Plasma concentration versus time plot of imidafenacin in a long-term
dose escalation study

- 319 -
 2.7.6 Summary of the individual tests

Table 2.7.6.4-1 Summary statistics of plasma concentration data by time point of blood
collection in the Incremental Long-Term Dose Study
Blood
c
o
l
l
e
c
t
Dose
i
(mg / Time after
o
d adminis Plasma imidafenacin levels
n
a tration (pg/mL)
Numbe
y (h)
r
)
o
f
p
o
i
n
t
s
Maximum Minimum
Standar Standar
v v
d d
a a
Average Deviati Average Deviati Median
l l
o o
u u
n n
e e
Conti
n
u
i0.2 229 4.9 2.8 352 217 303 949 11.6
t
y
Cases
Incre
Bloo
12 weeks (91 a
d
days) s
c
Before e
o
d
l
v
l 0.2 172 4.9 2.7 364 229 331 1360 39.9
o
e
l
c
u
t
m
i
e
o
Cases
n
12 weeks (92 0.2 9 6.6 3.2 210 221 192 744 10.8
At
days)
Since
24 weeks (153 0.4 149 4.9 2.7 730 446 693 2130 31.1
days)
Before
After 24 weeks 0.2 12 2.5 2.1 425 242 447 938 82.8
(154
0.4 168 2.1 0.36 1080 436 1040 2840 16.2
days)

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 2.7.6 Summary of the individual tests

Before 40
weeks
(265
days)
40 weeks (266 0.2 3 5.1 3.9 242 109 296 314 116
days)
0.4 20 4.7 2.8 666 502 509 1570 54.4
Since
Except in case 0.2 401 4.9 2.8 352 223 303 1360 10.8
of
cancel 0.4 329 3.5 2.4 900 474 925 2840 16.2
lation
0.2 24 3.9 2.7 401 209 440 798 47.6
When to stop
0.4 8 4.5 2.8 975 659 817 2200 176
BLQ samples
(including missing 57
values)

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 2.7.6 Summary of the individual tests

2) Subject background
The number of blood samples, demographic and laboratory data of the analysed population
in the PPK analysis are shown in Table 2.7.6.4-2. Women were rarely included in the
healthy adult group and were older in the patient group. There was no significant bias
in the distribution of other demographic and laboratory data.

Table 2.7.6.4-2 Blood sampling points, demographic data and laboratory values for the
analysed population
of trials in patients. In
Full analysis population
Population for analysis Study po
Number of cases 942 852 90
Number of blood
3168 1983 1185
samples
Number of blood Number of blood
Number of cases Number of cases Number of
samples samples
(%) (%)
(%) (%)
Gender Men 258 (27.4) 1582(49.9) 171 (20.1) 415(20.9) 87 (96
Women 684 (72.6) 1586(50.1) 681 (79.9) 1568(79.1) 3 (3.
Drinking history I don't drink 466 (49.5) 1300(41.0) 445 (52.2) 1031(52.0) 21 (23
Drink 476 (50.5) 1868(59.0) 407 (47.8) 952(48.0) 69 (76
Smoking history I don't smoke 731 (77.6) 2091(66.0) 696 (81.7) 1628(82.1) 35 (38
Sip 211 (22.4) 1077(34.0) 156 (18.3) 355(17.9) 55 (61
Itrakona No combined use 942 a) (98.9) 3074(97.0) 852 (100.0) 1983(100.0) 90 a) (90
Combined use of Combined use a) a)
10 (1.1) 94(3.0) 0 (0.0) 0(0.0) 10 (10
zols available
CYP3A4 inhibitors No combined use 925 (98.2) 3133(98.9) 835 (98.0) 1948(98.2) 90 (100
Combination of With combination b) 17 (1.8) 35(1.1) 17 (2.0) 35(1.8) 0 (0.
CYP3A4 inducers No combined use 939 (99.7) 3164(99.9) 849 (99.6) 1979(99.8) 90 (100
Combination of With combination b) 3 (0.3) 4(0.1) 3 (0.4) 4(0.2) 0 (0.
Availability of a) a)
Fasting 84 (8.8) 886(28.0) 0 (0.0) 0(0.0) 84 (77
meals
a) a)
After the meal 876 (91.3) 2282(72.0) 852 (100.0) 1983(100.0) 24 (22
Weight (kg) Mean ± SD 57.2±9.9 56.7±10.0
Median (range) 56.0 (35.7 - 108.5) 55.4 (35.7 - 108.5) 61
Age (years) Mean ± SD 56±16 59±12
Median (range) 59 (20 - 85) 60 (20 - 85)
AST Mean ± SD 22±8 23±8
(IU/L) Median (range) 20 (8 - 69) 21 (9 - 69)
ALT Mean ± SD 19±11 20 ± 12
(IU/L) Median (range) 16 (4 - 96) 17 (4 - 96)
Total bilirubin Mean ± SD 0.53±0.22 0.52±0.21
(mg/dL) Median (range) 0.50 (0.20 - 2.10) 0.50 (0.20 - 2.10) 0.
Gamma-GTP Mean ± SD 27±27 29±28
(IU/L) Median (range) 19 (4 - 395) 20 (6 - 395)
Al-P Mean ± SD 224±76 230±76
(IU/L) Median (range) 215 (55 - 883) 220 (84 - 883)
LDH Mean ± SD 195±61 195±62
(IU/L) Median (range) 184 (91 - 717) 183 (91 - 717) 1
Albumin Mean ± SD 4.42±0.27 4.42±0.27
(g/dL) Median (range) 4.40 (3.60 - 5.40) 4.40 (3.60 - 5.40) 4.
Serum creatine Mean ± SD 0.70±0.16 0.68±0.15
Nin (mg/dL) Median (range) 0.67 (0.40 - 1.35) 0.65 (0.40 - 1.35) 0.
BUN Mean ± SD 14.9±4.0 15.1±4.1
(mg/dL) Median (range) 14.5 (5.7 - 31.9) 14.8 (5.7 - 31.9) 13
SD: Standard deviation
a)
: Some subjects are included in both categories.
b):
Patients with concomitant use of imidafenacin on the day of blood sampling for plasma imidafenacin
levels were considered to have concomitant use.
There were missing values for LDH (1 case) and albumin (3 cases) (both studies in patients), but no
other demographic or laboratory data were missing.

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 2.7.6 Summary of the individual tests

3) PPK analysis
The final model is shown in Table 2.7.6.4-3. The effects of age, Al-P and concomitant
use of itraconazole were detected as covariates of imidafenacin on CL, and the effect
of diet as a covariate on F and Ka. Body weight, sex, history of alcohol consumption,
smoking, concomitant use of CYP3A4 inhibitors, patient vs. healthy adult, AST, ALT,
total bilirubin, γ-GTP, LDH, albumin, serum creatinine and BUN were not incorporated
into the final model.
The PPK parameters in the final model are shown in Table 2.7.6.4-4. The estimated
values (95% confidence intervals) of the PPK parameters were 23.1 (21.2-25.0) L/h for
CL, 109 (102-116) L for V2, 3.50 (2.95-4.05) L/h for Q, 44.3 (33.8 54.8) L, Ka 3.07
h-1
(2.55 to 3.59) and ALAG 0.436 (0.422 to 0.450) h. The CV% of interindividual
variability was 32.4% for CL (ωCL2), 23.3% for V2 (ωv22) and 136.7% for Ka (ωKa2), and the

covariance of interindividual variability of CL and V2 (ωCLV2) was 0.0753. The effect of

age on CL (θ8) was -0.202 (95% CI: -0.279 to -0.125), the effect of Al-P (θ9) was -0.0961
(-0.134 to -0.0579) and the effect of itraconazole combination (θ10) was 0.665 (0.605 to
0.725). The CL of imidafenacin decreased with itraconazole concomitant use and with
increasing age and Al-P. The effect of diet on Ka (θ7) was 0.404 (0.313 to 0.495), and Ka
decreased with postprandial administration compared with fasting administration. The
effect of diet on F (θ11) was 1.17 ( The effect of food on F (θ11) was 1.17 (1.08 to
1.26) and F increased with postprandial compared with fasting.

Table 2.7.6.4-3 Final model

CL (L/h) = θ1 (AGE/59)θ8 (ALP/215)θ9 θ10 ITRA
V2 (L) = θ2
Q (L/h) = θ3
V3 (L) = θ4
F = 0.578 θ11 FOOD
Ka (h-1) = θ5 θ7 FOOD
ALAG (h) = θ6
CL: clearance, V2: distribution volume of the central compartment, and
Q: clearance between compartments, V3: volume of distribution of the peripheral
compartments, and
F: bioavailability, Ka: absorption rate constant, ALAG: lag time for absorption
AGE: Age (years), ALP: Al-P (IU/L)
FOOD: with or without food (fasting dose = 0, postprandial dose = 1)
ITRA: with or without concomitant use of itraconazole (no concomitant use = 0,
concomitant use = 1)

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 2.7.6 Summary of the individual tests

Table 2.7.6.4-4 PPK parameters in the final model

Estimated value Standard 95% confidence

error interval
CL (L/h) (θ1) 23.1 0.978 21.2 - 25.0
V2 (L) (θ2) 109 3.42 102 to 116
Q (L/h) (θ3) 3.50 0.282 2.95 - 4.05
V3 (L) (θ4) 44.3 5.34 33.8 - 54.8
F 0.578 (fixed)
Ka (h-1) (θ5) 3.07 0.266 2.55 - 3.59
ALAG (h) (θ6) 0.436 0.00720 0.422 - 0.450
Fixed effect Estimated value Standard 95% confidence
error interval
FOOD against Ka (θ7) 0.404 0.0466 0.313 - 0.495
AGE to CL (θ8) -0.202 0.0393 -0.279 - -0.125
ALP for CL (θ9) 0.0961 0.0195 -0.134 - -0.0579
ITRA against CL (θ10) 0.665 0.0305 0.605 - 0.725
FOOD against F (θ11) 1.17 0.0454 1.08 - 1.26
Inter-individual Estimated value Standard
variability (CV%) error
ωCL2
0.105 (32.4%) 0.0142
ωV22
0.0543 (23.3%) 0.0191
ωKa2
1.87 (136.7%) 0.448
ωCLV2 0.0753 0.0169
Intra-individual Estimated value Standard
variability (CV%) error
σ2
0.139 (37.3%) 0.0128

CL: clearance, V2: volume of distribution of the central compartment

Q: clearance between compartments, V3: volume of distribution of the peripheral compartments, and
F: bioavailability, Ka: absorption rate constant, ALAG: lag time of absorption
FOOD: presence of food (fasting = 0, postprandial = 1), AGE: age (years)
ALP: Al-P (IU/L), ITRA: with or without concomitant itraconazole (without concomitant = 0, with
concomitant = 1)

The effect of each covariate on the CL/F of imidafenacin is shown in Table 2.7.6.4-5.
CL/F was 33% lower with the combination than without itraconazole. Comparing CL/F at
the 95th percentile of age (77 years) and at the 5th percentile (37 years) in patients
with overactive bladder, CL/F at the 95th percentile was 14% lower than that at the 5th
percentile. Comparing the CL/F at the 95th percentile (355 IU/L) with the standard Al-
P value (220 IU/L) in patients with overactive bladder, the CL/F at the 95th percentile
was 4% lower than that at the standard value. Furthermore, CL/F was 15% lower at the
postprandial dose than at the fasting dose. The CL/F of the patients was 39.7 L/h,
calculated using the standard values for all covariates.

Table 2.7.6.4-5 Effect of covariates on CL/F of imidafenacin

Covariates CL/F CL/F ratio

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 2.7.6 Summary of the individual tests

Al-P Age (L/h)

Itraconazole Meals
(IU/L) (Age)
(1) No combined use Hunger 220 a) 60 a) 39.7
Combined use d)
(2) Hunger 220 60 26.4 0.67
available
After the d)
(3) No combined use 220 60 34.0 0.85
meal
(4) No combined use Hunger 355 b) 60 38.0 0.96 d)

(5) No combined use Hunger 220 37 c) 43.8

(6) No combined use Hunger 220 77 b) 37.8 0.86 e)

a): standard value (median value for patients with overactive bladder)

b): 95% points for patients with overactive bladder

c): 5% points in patients with overactive bladder

d): ratio to CL/F in (1)

e): ratio of (5) to CL/F

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 2.7.6 Summary of the individual tests

Comparison of CL/F in patients with overactive bladder with and without CYP3A4
inhibitors is shown in Figure 2.7.6.4-2 and Table 2.7.6.4-6. 17 and 835 patients were
treated with and without CYP3A4 inhibitors, respectively, and the concomitant CYP3A4
inhibitors were clarithromycin The mean values (standard deviations) of CL/F in patients
with and without CYP3A4 inhibitors were 31.5 (7.95) and 35.7 (11.95), respectively. The
mean CL/F values (standard deviation) for patients with and without CYP3A4 inhibitors
were 31.5 (7.95) and 35.7 (11.4) L/h, respectively.

150

120
Bayes CL/F (L/h)

90

60

30

0
. あり なし .
CYP3A4 阻害剤併用の有無
Figure 2.7.6.4-2. Comparison of CL/F in patients with overactive bladder
with and without CYP3A4 inhibitors

The white circles represent the values for each case and the solid lines represent
the mean ± standard deviation.
With: 17 patients, without: 835 patients

Table 2.7.6.4-6 Comparison of CL/F in patients with overactive bladder with and
without CYP3A4 inhibitors
CL/F (L/h)
Standard
Average
deviation
Cases with CYP3A4 inhibitors 31.5 7.95
No concomitant use of CYP3A4
35.7 11.4
inhibitors
With: 17 patients, without: 835 patients

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 2.7.6 Summary of the individual tests

4) Pharmacokinetic/pharmacodynamic analysis
(1) Evaluation of the relationship between imidafenacin concentration in plasma and QTc
The relationship between plasma imidafenacin concentration and QTc is shown in Figure
2.7.6.4-3. There was no prolongation of the QTc interval dependent on the plasma
imidafenacin concentration.
500

450
QTc (msec)

400

350

300
0 500 1000 1500 2000 2500 3000
Plasma concentration of Imidafenacin (pg/mL)

Figure 2.7.6.4-3 Relationship between plasma imidafenacin concentration

and QTc (measured and estimated)
The white circles represent measured values and the solid line represents the
relationship between the population mean estimate of QTc and the plasma concentration
of Clozapine.
Solid line: QTc = α + β Conc
(alpha: 395, beta: -0.00403, conc: plasma imidafenacin
concentration)
Analysed: 435 patients, at 1251

2) Assessing the relationship between exposure and efficacy

The relationship between exposure (Cmax and AUC) and efficacy endpoints (total number
of urinary urgency incontinence per week, total number of urinary incontinence per week,
average number of urination per day and average number of urinary urgency sensations
per day) in patients with overactive bladder in a long-term dose escalation study
calculated by Bayesian estimation was evaluated. The results of the multiple regression
analysis are presented below. The results of the analyses by multiple regression analysis
are shown in Tables 2.7.6.4-7 to 2.7.6.4-10, respectively: AUC as the explanatory
variable for the total number of urinary incontinence episodes per week in patients with
a 0.4 mg/day dose increase, and AUC as the explanatory variable for the mean number of
urinary urgency episodes per day in patients with a 0.4 mg/day dose increase. Cmax and
AUC were significant. For the other efficacy analysis items, Cmax and AUC were not

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 2.7.6 Summary of the individual tests

significant. On visual assessment, Cmax and AUC were not clearly related to any of the
efficacy analysis items.

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 2.7.6 Summary of the individual tests

Table 2.7.6.4-7. Cmax and AUC of imidafenacin (Bayesian estimates) and per week
Relationship with the total number of urge incontinence episodes
(results of multiple regression analysis)
Objective Explanatory Estimated value Standard p-value
variable variables error
Constants 0.324 0.463 0.4860
Total number
of urge
0.4 mg/day incontinences
Increased per week in 0.0437 0.00898 <0.0001
dose cases the
observation
period
Cmax 0.000032 0.000457 0.9443
Constants -0.453 0.434 0.2982
Total number
of urge
0.2 mg/day incontinences
Continuing per week in 0.0375 0.0103 0.0003
The final cases the
assessment observation
period period
Per week Cmax 0.001093 0.000900 0.2266
Total urgency
Urinary Constants 0.532 0.431 0.2190
incontinence Total number
frequency of urge
0.4 mg/day incontinences
Increased per week in 0.0442 0.00898 <0.0001
dose cases the
observation
period
AUC -0.000030 0.000069 0.6587
Constants -0.122 0.388 0.7542
Total number
of urge
0.2 mg/day incontinences
Continuing per week in 0.0380 0.0103 0.0003
cases the
observation
period
AUC 0.000061 0.000128 0.6331
Analysis: 321 patients (158 patients with 0.4 mg/day dose increase, 163 patients with 0.2 mg/day
continuation)

Table 2.7.6.4-8. Cmax and AUC of imidafenacin (Bayesian estimates) and per week
Relationship with total number of urinary incontinence (results of
analysis using multiple regression analysis)
Objective Explanatory Estimated value Standard p-value
variable variables error
Constants 0.378 0.480 0.4323
Total per
week of
The final 0.4 mg/day observation
assessment Increased period 0.0400 0.00837 <0.0001
period dose cases Urinary
Per week incontinence
Total number of frequency
urinary 0.000057 0.000473 0.9036
Cmax
incontinence
0.2 mg/day Constants 0.344 0.402 0.3932
Continuing Total per 0.0547 0.00728 <0.0001
cases week of

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 2.7.6 Summary of the individual tests

observation
period
Urinary
incontinence
frequency
Cmax 0.000480 0.000849 0.5726
Constants 0.636 0.447 0.1568
Total per
week of the
0.4 mg/day observation
Increased period 0.0406 0.00837 <0.0001
dose cases Urinary
incontinence
frequency
AUC -0.000034 0.00000071 0.6281
Constants 0.132 0.358 0.7122
Total per
week of the
0.2 mg/day observation
Continuing period 0.0552 0.00726 <0.0001
cases Urinary
incontinence
frequency
AUC 0.000003 0.000120 0.9801
Analysis: 321 patients (158 patients with 0.4 mg/day dose increase, 163 patients with 0.2 mg/day
continuation)

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 2.7.6 Summary of the individual tests

Table 2.7.6.4-9. Cmax and AUC (Bayesian estimates) of imidafenacin per day
Relationship with the average frequency of urination (results of
analysis by multiple regression analysis)
Objective Explanatory Estimated value Standard p-value
variable variables error
Constants 2.13 0.138 <0.0001
Average
number of
0.4 mg/day urinations
Increased per day in 0.0933 0.00941 <0.0001
dose cases the
observation
period
Cmax -0.000140 0.000096 0.1469
Constants 1.82 0.144 <0.0001
Average
number of
0.2 mg/day urinations
Continuing per day in 0.105 0.00928 <0.0001
cases the
The final observation
assessment period
period
Per day Cmax -0.000001 0.000249 0.9967
Average Constants 2.17 0.133 <0.0001
frequency of Average
urination number of
0.4 mg/day urinations
Increased per day in 0.0940 0.00935 <0.0001
dose cases the
observation
period
AUC -0.000029 0.000014 0.0440
Constants 1.85 0.136 <0.0001
Average
number of
0.2 mg/day urinations
Continuing per day in 0.105 0.00924 <0.0001
cases the
observation
period
AUC -0.000009 0.000035 0.8077
Analysis: 321 patients (158 patients with 0.4 mg/day dose increase, 163 patients with 0.2 mg/day
continuation)

Table 2.7.6.4-10. Cmax and AUC (Bayesian estimates) of imidafenacin per day
Relationship between the mean frequency of urinary urgency (results
of analysis using multiple regression analysis)
Objective Explanatory Estimated value Standard p-value
variable variables error
The final Constants 0.887 0.264 0.0010
Average
assessment 0.4 mg/day number of
urinary
period Increased urgencies per 0.108 0.0199 <0.0001
Per day day in the
dose cases observation
Urinary period
Cmax -0.000403 0.000252 0.1123
urgency 0.2 mg/day Constants 0.521 0.310 0.0942

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 2.7.6 Summary of the individual tests

Continuing Average
Average times cases number of
urinary
urgencies per 0.167 0.0220 <0.0001
day in the
observation
period
Cmax -0.000825 0.000645 0.2025
Constants 0.879 0.246 0.0005
Average
number of
0.4 mg/day urinary
Increased urgencies per 0.109 0.0199 <0.0001
dose cases day in the
observation
period
AUC -0.000065 0.000038 0.0888
Constants 0.627 0.274 0.0234
Average
number of
0.2 mg/day urinary
Continuing urgencies per 0.169 0.0219 <0.0001
cases day in the
observation
period
AUC -0.000171 0.000091 0.0620
Analysis: 321 patients (158 patients with 0.4 mg/day dose increase, 163 patients with 0.2 mg/day
continuation)

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 2.7.6 Summary of the individual tests

3) Assessment of the relationship between exposure and safety

The relationship between the exposure (Cmax and AUC) and the safety endpoints (occurrence
of adverse drug reactions, occurrence of dry mouth (adverse drug reaction), and
occurrence of moderate or greater dry mouth (adverse drug reaction)) in patients with
overactive bladder in a long-term dose escalation study calculated by Bayesian estimation
was evaluated. The results of the logistic regression analysis are shown in Table
2.7.6.4-11. Cmax and AUC were not significant as explanatory variables for the occurrence
of adverse reactions, dry mouth, and moderate or greater dry mouth in patients receiving
increasing doses of 0.4 mg/day or continuing doses of 0.2 mg/day. Visual assessment also
showed no clear association between Cmax and AUC and the incidence of adverse reactions,
dry mouth, or moderate or greater dry mouth.

Table 2.7.6.4-11 Relationship between Cmax and AUC (Bayesian estimates) and safety
of imidafenacin
(Results from logistic regression analysis)
Model equation
log(P/1-P) = α + β Cmax or AUC) P: Probability of occurrence
Parameter estimates
Safety Explanatory p-
variables Alpha Beta value
of β
0.4 mg/day
dose -0.326 0.000140 0.1655
increase AUC
0.2 mg/day
continuous -1.51 0.000391 0.1110
case
Side effects
Manifestation
0.4 mg/day
dose 0.483 0.001029 0.1348
increase Cmax
0.2 mg/day
continuous 0.779 0.000884 0.5783
case
0.4 mg/day
dose 0.715 0.000143 0.1429
increase AUC
0.2 mg/day
continuous -1.64 0.000261 0.3197
Dry mouth case
Manifestation 0.4 mg/day
dose 0.945 0.001121 0.0958
increase
Cmax
0.2 mg/day
continuous -0.852 -0.000062 0.9709
case
0.4 mg/day
dose -2.46 -0.000125 0.6204
increase AUC
0.2 mg/day
More than continuous -5.56 0.000802 0.1949
moderate case
Dry mouth 0.4 mg/day
Manifestation dose -3.63 0.000423 0.8016
increase
Cmax
0.2 mg/day
continuous -6.56 0.007042 0.0953
case
Analysis: 395 patients (185 patients with 0.4 mg/day dose increase, 210 patients with 0.2 mg/day

- 333 -
 2.7.6 Summary of the individual tests

continuation)

(3) Conclusion
It was suggested that the pharmacokinetics of imidafenacin was affected by concomitant
use of itraconazole, liver function parameters, age and diet. No plasma imidafenacin
concentration-dependent prolongation of the QTc interval was observed. Furthermore, no
clear relationship between exposure dose and efficacy or safety was observed in each of
the 0.4 mg/day dose escalation and 0.2 mg/day continuation cases in the long-term dose
escalation study.

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 2.7.6 Summary of the individual tests

-5. Imidafenacin long-term administration study Incremental dose long-term

administration study in patients with overactive bladder [KRP197-T301/ONO-
8025-12] (last report: at the time of assessment after 52 weeks of treatment
or 64 weeks of treatment)
............................... Attachment 5.3.5.2 #4
(1) Outline of the test
Title of the Imidafenacin long-term administration study Incremental dose long-term
clinical trial administration study in patients with overactive bladder
Clinical trial
KRP197-T301/ONO-8025-12
protocol number
Clinical trial
KYORIN Pharmaceutical Company Limited / Ono Pharmaceutical Co.
sponsors
Principal Medical Corporation Somakai Umeyama Clinic, Department of Urology, Tomokazu
Investigator Umeyama and others (total 38 people)
Clinical trial sites Medical Corporation Somakai Umeyama Clinic Urology and others (Total 38
facilities)
Trial Period 6 August 2007 (date of obtaining consent for the first subject)
24 March 2009 (date of last medication in last case)
Development phase Phase III
Objective A multicenter, open-label, uncontrolled study was conducted to evaluate the
safety and efficacy of long-term (52 weeks) treatment with imidafenacin 0.2
mg/day or 0.4 mg/day (increasing from 0.2 mg/day for 12 weeks) in patients
with overactive bladder.
Test design Multicentre, open-label, uncontrolled
Clinical Trial After a 2-week observation period, imidafenacin 0.1 mg tablets were orally
Method administered twice daily after breakfast and dinner for 12 weeks (0.2 mg/day)
in patients with overactive bladder. Subsequently, according to the dose
escalation criteria, patients were treated with imidafenacin 0.1 mg tablets
orally twice daily after breakfast and after dinner for 52 weeks (0.4 mg/day).
Non-supplemented patients continued to receive imidafenacin orally at a dose
of 0.2 mg/day for 40 weeks (0.2 mg/day for a total of 52 weeks).
Outline of the clinical trial design
Observa Treatment period
tion
period
-2 0 12 weeks 52 weeks 64 weeks
weeks week
0.2 mg/day 0.4 mg/day (52 weeks)
(12 weeks) 0.2 mg/day (40 weeks)
Number of subjects At the time of planning: 300-350 patients (at least 100 patients to be
evaluated after 52 weeks of dose increase)
Number of patients registered: 435
Number of patients included in the safety analysis: 435
Number of patients included in the efficacy analysis
Main analysis population Per Protocol Set (PPS) recruitment: 338 cases
Secondary analysis population Full Analysis Set (FAS) recruitment: 430
cases
Target Overactive bladder patients
Selection criteria Patients with overactive bladder who fulfilled all the criteria from 1) to 5)
below were selected.
1) Age: 20 years and over (at the time of obtaining consent)
2) Gender and inpatient/outpatient status: Not applicable
(3) Patients who fulfil all of the following criteria in the symptom diary for
the week prior to the end of the observation period
(1) A total of at least one urge incontinence episode per week

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 2.7.6 Summary of the individual tests

(2) The average number of times you urinate per day is 8 or more times.
(3) The average number of urinary urgencies per day is one or more.
(4) Patients who are judged by the investigator or sub-investigator to be able
to accurately record the symptom diary
(5) Patients who understand the purpose of the trial and can provide written
consent from themselves.
Exclusion criteria Patients who met any of the criteria 1) to 16) below were excluded.
1) Patients with genuine stress incontinence (GSI)
2) Patients with prostate cancer, bladder cancer, urinary tract stones
(ureteral stones, urethral stones, bladder stones, etc.), urinary tract
infections (cystitis, prostatitis, etc.) and interstitial cystitis, or with
a history of recurrent urinary tract infections (two or more occurrences
within 6 months prior to the observation period)
(3) Patients who have undergone urogenital surgery within 6 months prior to
the observation period
4) Patients with indwelling catheters or intermittent urinary continence
5) Patients who have undergone electrical stimulation therapy, magnetic
stimulation therapy or bladder training within 3 months prior to the
observation period
(6) Patients who have received concomitantly prohibited drugs within 2 weeks
prior to the observation period
(7) Patients with contraindications to the administration of anticholinergic
drugs (serious heart disease, angle-closure glaucoma, myasthenia gravis,
obstruction of the pylorus, duodenum or intestine, paralytic ileus, gastric
atony, intestinal atony)
Exclusion criteria (8) Patients with a history of serious allergy or serious adverse reactions
(cont'd) to drugs
9) Patients with a residual urine volume of more than 100 mL (measured by
transperitoneal echocardiography) or with clinically problematic lower
urinary tract obstructive diseases such as benign prostatic hyperplasia.
(10) Patients with polyuria with a daily urine output of 3000 mL or more in
the symptom diary during the observation period
(11) Patients with a total bilirubin of 3.0 mg/dL or higher or an AST (GOT)
or ALT (GPT) of institutional standard
Patients with levels above 2.5 times the upper limit (or above 100 IU/L)
(12) Patients with a serum creatinine of 2.0 mg/dL or more
(13) Patients with complications of malignancy that may affect general
condition and survival.
(14) Patients who are pregnant, lactating, or who may become pregnant, or who
wish to become pregnant during the study period.
(15) Four months have not elapsed since the completion of all other study
medications or the previous im
Patients treated with dafenacin (brand names: Uritos® Tablets 0.1 mg or
Staybla® Tablets 0.1 mg, development codes: KRP-197 or ONO-8025)
(16) Other cases that the investigator or sub-investigator considers
inappropriate for the study.
Patient
The inclusion and exclusion criteria 11) and 12) were determined using the
most recent laboratory test results available at the time of primary
enrollment, measured within 4 weeks (-30 days to 0 days) prior to primary
enrollment.
Test drug
Dosage and serial
Preparations Formulation Content Lot.No Expiry date
number
Imidafenacin Film Each tablet contains September
S746501
0.1 mg tablet Coated tablets 0.1 mg 2009

Control drug
Dosage and serial None
number

- 336 -
 2.7.6 Summary of the individual tests

Method of 0.2 mg/day (standard dose)

administration One 0.1 mg tablet was administered orally, twice daily, after breakfast and
dinner.
0.4 mg/day (increased dose)
Two 0.1 mg tablets were administered orally, twice daily, after breakfast
and after dinner.

Increase criteria
The dose should be increased if a) the investigator or subinvestigator
judges that a dose increase is necessary and b) the subject also wishes to
increase the dose, with reference to the case where none of the symptoms
of urinary urgency, frequency or urge urinary incontinence in overactive
bladder meets the following definition of normalization a) at the time of
visit after 12 weeks of treatment. However, patients who develop moderate
c)
or more adverse reactions by the time of the visit after 12 weeks of
treatment will be excluded.
(a): definition of normalisation Mean number of urinary urgency
sensations per day: 0 (disappearance)
Average number of urinations per day: less
than 8 times, and
Total number of urge incontinence episodes per
week: 0 (disappearance)
(b): If the dose was not increased to meet this criterion, or if
the dose was increased without meeting this criterion, the
reason for this should be stated in the case report.
(c): assessment criteria See degree of adverse event
Duration Observation period: 2 weeks
Duration of administration: 1 year
When increasing the dose: 64 weeks (normal dose period: 12 weeks, increasing
dose period: 52 weeks)
No dose increase: 52 weeks (normal dose period: 52 weeks)
Combination therapy 1) Treatment prohibited before the observation period
(1) Prohibited drugs before the observation period
The following drugs were not to be administered within 2 weeks before the
observation period
(1) Drugs for frequent urination and urinary incontinence, overactive
bladder
(2) Anticholinergicsa), cholinergic agonists
(a): The use of anticholinergic drugs, e.g. for pretreatment during
gastrointestinal examinations, is permitted.
(2) Prohibited therapies before the observation period
Therapy prohibited within 6 months before the observation period: urogenital
surgery
Therapy prohibited within 3 months before the observation period: electrical
stimulation, magnetic stimulation and bladder training.
2) Prohibited treatments from the observation phase to the treatment phase
(1) Contraindications
The following drugs are prohibited in combination
(1) Drugs for frequent urination and urinary incontinence, overactive
bladder
(2) Anticholinergicsb), cholinergic agonists

Combination therapy (iii) All other drugs currently under development and of undetermined
(continued) efficacy.
(b): The use of anticholinergic drugs for pre-treatment during
gastrointestinal examinations is permitted. However, the use of
anticholinergics during the symptom diary entry period was avoided.
(2) No concomitant therapy
During the study period (observation phase to treatment phase), concomitant

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 2.7.6 Summary of the individual tests

use of any of the therapies specified in the exclusion criteria (urogenital

surgery, indwelling catheters, intermittent urinary drainage, electrical
stimulation, magnetic stimulation or bladder training) was prohibited.
3) Concomitantly restricted medicines
Concomitant use of drugs other than the above-mentioned prohibited drugs was
allowed. However, for the following drugs, the same drug was used as much as
possible during the study period (observation phase to treatment phase), and
the dosage and administration were not changed.
(1) Drugs with anticholinergic effects among the following categories of drugs
1) Antidepressants
Anticonvulsants
3) Anti-Parkinson's drugs
Type I antiarrhythmic drugs
(2) Phenothiazines
(3) Monoamine oxidase inhibitors
(4) Estrogen preparations
(5) Ca antagonists
(6) Alpha 1 blockers
(7) Antihistamines (c)
(8) Loop diuretics
(c): Antihistamines may be used on a daily basis, but their use during the
symptom diary period is avoided where possible.
Evaluation criteria Efficacy and safety assessments were carried out according to the schedule
shown in Table 2.7.6.5-1.
Safety endpoints:.
Adverse events, side effects, laboratory tests, ECG (12-lead), blood
pressure and pulse rate, residual urine output

Adverse event indication

In order to compile and list the adverse events, the names of the adverse
events listed in the case report were replaced by the organ-specific major
category (SOC) and the basic term (PT) based on MedDRA ver 12.0J
(Pharmaceutical Terminology and Regulation).
Criteria for determining the severity of adverse events
1) Subjective symptoms (except dry mouth), other findings and laboratory
values
The following criteria were used to determine the severity of the disease
in three stages: mild, moderate and severe.
degree Judgement criteria (for reference)
Mild Transient and easily tolerated or not interfering with daily life
Moderate The extent to which it interferes with daily life
High The extent to which it makes daily life impossible
Thirst (dry mouth)
The following criteria were used to determine the severity of the disease
in three stages: mild, moderate and severe.
degree Judgement criteria (for reference)
Mild Almost unnoticeable
Moderate tolerable with drinking water, etc.
Ingestion of water or other substances is not tolerable
High
(discontinuation of the study drug)
Efficacy endpoints.
Total number of urge incontinences per week, total number of urge
incontinences per week, average number of urinations per day, average number
of urge incontinences per day, degree of urge incontinence, average amount
of urine voided per urge, quality of life (King Health Questionnaire)
Criteria for the degree of urinary urgency
degree Judgement criteria (for
reference)
No No urgency to urinate
Mild Weak

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 2.7.6 Summary of the individual tests

Moderat Strong
e
High Very strong
Pharmacokinetics: plasma unchanged drug concentrations

Statistical methods (1) Target population for analysis

The analysis population for the safety endpoint was the safety analysis
population. For the efficacy endpoints, PPS was the primary analysis population
and FAS was the secondary analysis population.
2) Efficacy analysis
The following analyses were carried out on the data from each patient group
in the 0.2 mg/day continuation and 0.4 mg/day dose escalation groups. Data up
to 12 weeks post-treatment were also analysed for all patients, where
appropriate.
(1) Summary statistics were calculated for the total number of urinary
incontinence episodes per week, the average number of urinary episodes
per day, the average number of urinary urgency episodes per day, the
average amount of urine voided per episodes, and the total number of
urinary urgency episodes per week. Comparisons between pre- and post-
treatment were made by means of a corresponding t-test.
(2) The total number of urinary incontinence episodes per week, the total
number of urinary incontinence episodes per week, the average number of
urination episodes per day, and the number of urinary urgency episodes
per day were examined over time by making a frequency distribution table
of normalized cases at each evaluation period.
(3) The frequency distributions of the measured values and the amount of change
in the degree of urinary urgency were made at each evaluation period, and
the changes over time were examined. Comparisons between the pre- and
post-dose periods were made using the Wilcoxon signed rank test.
(4) For each domain of the QOL score (King Health Questionnaire), summary
statistics of actual values and changes were calculated for each
assessment period, and changes over time were examined. Comparisons before
and after administration were made by corresponding t-tests.
3) Safety analysis
The following analyses were carried out on the data for each patient group,
in the 0.2 mg/day continuation and 0.4 mg/day dose escalation groups.
(1) The incidence of adverse events, side effects and dry mouth was calculated
and the cumulative incidence was estimated by the Kaplan-Meier method.
(2) The classification of adverse events (subjective symptoms, other sensory
findings and abnormal changes in clinical laboratory values) was
aggregated by causal relationship, degree, organ category, item, etc.
(3) Summary statistics were calculated for blood pressure, pulse rate and
residual urine volume at each time point of assessment, and changes over
time were examined. Comparisons between the pre- and post-dose periods
were made using a corresponding t-test.
(4) For electrocardiography, the presence of abnormal findings and the
percentage of abnormal variability were calculated. For QTc, summary
statistics and other data were calculated.
(5) For laboratory values, summary statistics were calculated for continuous
values and frequency distribution tables were prepared for ordinal values.
The presence or absence of abnormal findings and the proportion of abnormal
variations were also tabulated.

Date of report Interim report: 3 February 2009

Final report: 6 July 2009

- 339 -
 2.7.6 Summary of the individual tests

Table 2.7.6.5-1 Observation and inspection items and timing

Observat
Occasi
ion Treatment period

When to stop
on
period
W
e
-2 0 4 8 12 14 16 20 24 28 32 36 40 44 48 52 56 60 64
e
k
Obtaining
●
consent
Patient
● ●
background
ci ci ci ci
Medication ●a) ●a)
● ● ● rc ● ● ● ● ● ● ● ● ● ● rc rc rc ●
status le le le le
Considerat
ion of
●
increased
dosage
The symptom
ci
diary
● ● ● ● ● ● ● rc
Distributi le
on
The symptom
diary ci
Confirmati ● ● ● ● ● ● ● rc b)

on and le
collection
Degree of ci
urgency to ● ● ● ● ● ● ● rc ●
urinate le
QOL (King's
ci
Health
● ● ● ● ● rc ●
Questionna le
ire)
Amount of ci
urine ←●→ ● ● ● ● rc ●
remaining le
Blood
ci ci
pressure
←●→ ● ● rc ● ● ● ● rc ●
and pulse le le
rate
Electrocar
diogram c) circ circ
←●→ ● ● ● ● ● ● ●
(12 le le
Induction)
Laboratory
tests
ci
(Blood and
←●→ ● ● ● ● ● ● rc ●
urine le
collection
)
Adverse
● cir ●
events
cle

- 340 -
 2.7.6 Summary of the individual tests

Blood
sample for
drug
circ
concentrat ▲ ▲ (2) (2) (2) (2) (2) ●e)
le
ion
measuremen
t d)
○: only in the case of increased dosage.
▲: Implemented at any point; △: Implemented only in cases of increased dose, at any point
(a) Only investigate the use of other drugs.
(b) If there is an entry in the symptom diary at the time of discontinuation.
(c) Measurements are taken at any time, but after 24 weeks in cases where the dose has been increased,
measurements are taken 2 hours after taking the drug.
(d) A blood sample should be taken after the ECG test has been performed.
e) If the patient is not taking any medication on the day of the blood draw, it is not necessary to take
a blood sample.

- 341 -
 2.7.6 Summary of the individual tests

(2) Summary - Conclusion

1) Breakdown of subjects
The classification of cases is shown in Figure 2.7.6.5-1 and the breakdown of reasons
for non-adoption of cases in the analysis population is shown in Tables 2.7.6.5-2 to 3.
At the end of the observation period, 435 patients were primary enrolled in the study
and allocated study drug. The number of patients recruited to the safety analysis
population was 435, the number of patients recruited to FAS was 430 and the number of
patients recruited to PPS was 338.

一次登録症例

N=435
0.2 mg群 253
0.4 mg群 182

安全性
GCP不遵守例 未投与例 対象疾患外症例
解析対象集団
N=435 N=0 N=0 N=0
0.2 mg群 253 0.2 mg群 0 0.2 mg群 0 0.2 mg群 0
0.4 mg群 182 0.4 mg群 0 0.4 mg群 0 0.4 mg群 0

有効性評価項目
FAS 不適格例
未観察例
N=430 N=3 N=2
0.2 mg群 248 0.2 mg群 3 0.2 mg群 2
0.4 mg群 182 0.4 mg群 0 0.4 mg群 0

PPS 早期中止・脱落例† 処置違反例 服薬率違反例

N=338 N=83 N=12 N=20

0.2 mg群 179 0.2 mg群 63 0.2 mg群 8 0.2 mg群 17
0.4 mg群 159 0.4 mg群 20 0.4 mg群 4 0.4 mg群 3

※0.2 mg群：0.2 mg/日継続群

　0.4 mg群：0.4 mg/日増量群

†　　　 ：0.2 mg群は投与期間が48週未満，0.4 mg群は投与期間が60週未満

Figure 2.7.6.5-1 Classification of cases

Table 2.7.6.5-2 Breakdown of reasons for non-adoption of cases rejected in the

analysed population (FAS)

Reasons for rejection Number of cases

FAS Examples of Efficacy endpoints 0.2 mg/day 0.4 mg/day
ineligibility Unobserved cases Continuity Increased dose
group group
One reason
x 3
Rejected by

- 342 -
 2.7.6 Summary of the individual tests

x 2

Two reasons
x x
Rejected by

Total 5 0

Table 2.7.6.5-3 Breakdown of reasons for non-adoption of cases rejected in the

analysed population (PPS)

Reasons for rejection Number of cases

PPS Early termination Examples of Medication rates 0.2 mg/day 0.4 mg/day
Dropout examples treatment Examples of Continuity Increased dose
violations violations group group
One reason
Rejected by x 46 16

x 6 3

Two reasons
Rejected by x x 1

x x 15 3

x x

Three reasons
Rejected by x x x 2

Total 69 23

Figure 2.7.6.5-2 shows the number of discontinuations/withdrawals, the number of cases

where the dose was reduced after an increase and the reasons for discontinuation,
according to whether the dose was increased or not.

一次登録症例
（0.2mg/日）
435
中止
44

用量継続 増量あり
（0.2mg/日） （0.4mg/日）
209 182
中止 中止
24 19
0.2mg/日（減量）
10
中止
1
52週投与完了 64週投与完了 64週投与完了
185 153 9
中止理由 中止理由 中止理由 中止理由
①：14 ①：7 ⑥：1 ①：2
③：18 ③：9 ③：10
⑤：1 ④：2 投与群 投与量 例数 ⑥：4
⑥：2 ⑥：5 0.2 mg/日継続群 0.2 mg/日 253 ( 58.2) ⑨：3
⑧：4 ⑨：1 0.4 mg/日増量群 0.2 mg/日→0.4 mg/日 172 ( 39.5)
⑨：5 0.2 mg/日→0.4 mg/日→0.2 mg/日 10 ( 2.3)
( )内は割合（％）を示す． ＜中止理由＞
①同意が撤回されたため（有害事象発現）
②同意が撤回されたため（症状悪化）
③同意が撤回されたため（その他の理由による同意撤回）
④選択基準を満たしていなかったため
⑤除外基準に抵触していることが判明したため
⑥有害事象発現により継続困難なため
⑦症状悪化により継続困難なため
⑧来院せず，治験薬の投与が出来なくなったため
⑨その他，治験責任医師が継続困難と判断したため

Figure 2.7.6.5-2 Number of cases discontinued or dropped and reasons for

- 343 -
 2.7.6 Summary of the individual tests

discontinuation by whether the dose was increased

There were 44/435 (10.1%) patients who discontinued or withdrew by 12 weeks before
the decision to increase the dose to 0.4 mg/day. The main reasons for discontinuation
or withdrawal were withdrawal of consent (18 patients due to adverse events or other
reasons other than worsening symptoms) and withdrawal of consent (14 patients due to
adverse events).
Of the 391 patients who had completed 12 weeks of treatment, 77.0% (301/391) were
allowed to continue at an increased or normal dose according to the dose escalation
criteria. On the other hand, 7.9% (31/391) did not meet the definition of normalisation
but were satisfied with the effect and did not wish to increase the dose, 6.9% (27/391)
did not wish to increase the dose because of concerns about adverse events or
exacerbations, and 7.4% (27/391) met the definition of normalisation but were not
satisfied with the effect and wished to increase the dose. In 7.4% (29/391) of the cases,
the dose increase was requested due to unsatisfactory efficacy, and in 1.0% (4/391) of
the cases, the dose increase was not decided due to low adherence to the study medication.
After 12 weeks of treatment, 209/435 patients (48.0%) were continued at 0.2 mg/day (0.2
mg/day continuation group) and 182/435 patients (41.8%) were increased to 0.4 mg/day
(0.4 mg/day increase group). 10/182 (5.5%) of the 0.4 mg/day increase group had adverse
events. Of the patients in the 0.4 mg/day increase group, 10/182 (5.5%) had their dose
reduced to 0.2 mg/day because of the occurrence of an adverse event. 24/209 (11.5%) of
the patients in the 0.2 mg/day continuation group discontinued or dropped out after 12
weeks of treatment. In the 0.4 mg/day escalation group, 19/182 (10.4%) patients
discontinued or withdrew, and the main reason for discontinuation or withdrawal was
withdrawal of consent (other than the occurrence of an adverse event or worsening of
symptoms) in 10 cases. In the 0.4 mg/day dose escalation group, there was one case of
discontinuation or dropout after the dose was reduced to 0.2 mg/day, which was due to the
occurrence of an adverse event.
Important deviations excluded from the analysis population are shown in Table 2.7.6.5-
4. The analytical treatment of all cases, the acceptance or rejection of data and the
method of their analysis were decided at the case review meeting with reference to the
opinions of medical experts.

Table 2.7.6.5-4 Significant deviations excluded from the analysis population

Acceptance or
rejection a)
Safety
Number of cases (drug
Contents Analys
number)
PPS FAS is
Target
Group
Examples of
The average number of urinary urges per day
breaches of
2 cases (78, 79) during the week before the end of the observation x x circle
selection
period does not exceed 1
criteria
Examples of Patients with polyuria with a daily urine output
breaches of 1 case (83) of more than 3000 mL in the symptom diary during x x circle
exclusion the observation period

- 344 -
 2.7.6 Summary of the individual tests

criteria
Efficacy The study drug has been administered and the
assessment 2 cases (23, 71) efficacy endpoint has not been observed at least x x circle
unobserved once
Treatment duration of less than 48 weeks (336
88 cases (see footnote days) in the 0.2 mg/day continuous group and less circ
Examples of b) x circle
) than 60 weeks (420 days) in the 0.4 mg/day le
treatment
increased group
violations
22 cases (see footnote circ
c) Medication uptake less than 75%. x circle
) le
11 cases (208, 212,
Concomitant
223, 238, 361, 368, Use of contraindications from the observation circ
medications x circle
386, 411, 458, 531, phase to the treatment phase le
Combination
571)
therapy
No concomitant therapy from the observation circ
violations 1 case (578) x circle
phase to the treatment phase le
(a): Some cases were accepted or rejected differently due to deviations from other items.
(b): 9, 18, 22, 23, 25, 29, 32, 71, 78, 79, 83, 92, 97, 117, 121, 128, 130, 133, 142, 147, 148, 149, 158, 160, 162,
170, 214, 217, 224, 235, 243, 245, 251, 253, 255,. 269, 284, 285, 289, 291, 351, 358, 386, 398, 411, 425, 427,
431, 435, 436, 437, 438, 439, 446, 453, 455, 456, 457, 468, 472, 473, 474, 481, 486, 494, 498, 499,. 502, 503,
512, 516, 522, 527, 534, 541, 554, 557, 572, 575, 576, 577, 578, 585, 586, 592, 593, 605, 607
(c): 22, 23, 32, 71, 97, 128, 130, 149, 158, 243, 245, 386, 446, 486, 498, 499, 541, 578, 585, 593, 605, 607

2) Demographic and other reference value characteristics

Demographic data and other reference values for primary registration cases are shown
in Table 2.7.6.5-5.
The mean age (mean ± standard deviation, hereafter) was 57.1 ± 11.8 years and 58.0
± 12.7 years, respectively, and the mean body weight was 56.63 ± 10.54 kg and 56.53
± 10.48 kg, respectively, in the 0.2 mg/day continuous group and the 0.4 mg/day
increased group. .63±10.54 kg and 56.53±10.48 kg, respectively.
For each symptom of overactive bladder in the 0.2 mg/day continuous group and the 0.4
mg/day increased group, the total number of urge incontinence per week was 8.26±7.16
and 13.03±12.64, respectively; the total number of urinary incontinence per week was
9.39±8.98 and 14.96±15.04, respectively; the mean number of urinary urgency per day was
10.79±2.33 and 11.93±2.54, respectively; the mean number of urinary The mean number of
urinary incontinence per week was 9.39±8.98 and 14.96±15.04, respectively, the mean
number of urination per day was 10.79±2.33 and 11.93±2.54, respectively, and the mean
number of urinary urgency per day was 3.59±2.35 and 4.99±3.20, respectively. The 0.4
mg/day group had higher values at the end of the observation period for each symptom of
overactive bladder than the 0.2 mg/day group.

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 2.7.6 Summary of the individual tests

Table 2.7.6.5-5 Demographic data and other reference values

Population for analysis: primary registration cases
Item Classification 0.2 mg/day 0.4 mg/day Overall
continuous group increased dose
group
Number of cases covered 253 182 435
Gender Men 37 ( 14.6) 34 ( 18.7) 71 ( 16.3)
Women 216 ( 85.4) 148 ( 81.3) 364 ( 83.7)
Age <45 49 ( 19.4) 33 ( 18.1) 82 ( 18.9)
(Age) 45 - <55 46 ( 18.2) 33 ( 18.1) 79 ( 18.2)
55 - <65 84 ( 33.2) 52 ( 28.6) 136 ( 31.3)
65 - <75 61 ( 24.1) 50 ( 27.5) 111 ( 25.5)
>=75 13 ( 5.1) 14 ( 7.7) 27 ( 6.2)
Mean ± standard deviation 57.1±11.8 58.0±12.7 57.5±12.2
Median 58.0 59.0 58.0
Minimum to maximum value 28-81 22 to 85 22 to 85
Body weight <50.0 66 ( 26.1) 54 ( 29.7) 120 ( 27.6)
(kg) 50.0 - <55.0 58 ( 22.9) 35 ( 19.2) 93 ( 21.4)
55.0 - <60.0 48 ( 19.0) 30 ( 16.5) 78 ( 17.9)
60.0 - <65.0 31 ( 12.3) 27 ( 14.8) 58 ( 13.3)
>=65.0 50 ( 19.8) 36 ( 19.8) 86 ( 19.8)
Mean ± standard deviation 56.63±10.54 56.53±10.48 56.59±10.50
Median 55.00 55.25 55.00
Minimum to maximum value 35.7 - 100.6 37.5 to 99.4 35.7 - 100.6
Inpatient and outpatient Hospitalisation
Outpatient 248 ( 98.0) 178 ( 97.8) 426 ( 97.9)
Inpatient → Outpatient
Outpatient → Inpatient
Outpatient → Inpatient → 5 ( 2.0) 2 ( 1.1) 7 ( 1.6)
Outpatient
Outpatient → Inpatient → 2 ( 1.1) 2 ( 0.5)
Outpatient → Inpatient →
Outpatient
Smoking history 0 196 ( 77.5) 139 ( 76.4) 335 ( 77.0)
(Number of units/day) 1 - <5 7( 2.8) 2 ( 1.1) 9( 2.1)
5 - <20 34 ( 13.4) 28 ( 15.4) 62 ( 14.3)
>=20 16 ( 6.3) 13 ( 7.1) 29 ( 6.7)
Drinking history I don't drink 142 ( 56.1) 89 ( 48.9) 231 ( 53.1)
Several times a month 43 ( 17.0) 32 ( 17.6) 75 ( 17.2)
3 to 4 times a week 31 ( 12.3) 25 ( 13.7) 56 ( 12.9)
Almost every day 37 ( 14.6) 36 ( 19.8) 73 ( 16.8)
History of overactive bladder <6 8( 3.2) 2 ( 1.1) 10 ( 2.3)
(Subjective symptoms) 6 - <12 12 ( 4.7) 3 ( 1.6) 15 ( 3.4)
(Months) 12 - <36 85 ( 33.6) 51 ( 28.0) 136 ( 31.3)
>=36 148 ( 58.5) 126 ( 69.2) 274 ( 63.0)
Mean ± standard deviation 63.9±60.5 75.1±79.9 68.6±69.4
Median 46.0 48.0 47.0
Minimum to maximum value 2 to 423 1 to 557 1 to 557
Name of diagnosis Neurogenic bladder 2 ( 0.8) 2 ( 1.1) 4 ( 0.9)
Unstable bladder 251 ( 99.2) 180 ( 98.9) 431 ( 99.1)
Medical history No 120 ( 47.4) 80 ( 44.0) 200 ( 46.0)
Yes 133 ( 52.6) 102 ( 56.0) 235 ( 54.0)
Complications No 55 ( 21.7) 47 ( 25.8) 102 ( 23.4)
Yes 198 ( 78.3) 135 ( 74.2) 333 ( 76.6)
Within 30 days before the No 207 ( 81.8) 141 ( 77.5) 348 ( 80.0)
observation period
Previous treatment for Yes 46 ( 18.2) 41 ( 22.5) 87 ( 20.0)
overactive bladder
Combination treatment given No 46 ( 18.2) 33 ( 18.1) 79 ( 18.2)
in the treatment phase

- 346 -
 2.7.6 Summary of the individual tests

Yes 207 ( 81.8) 149 ( 81.9) 356 ( 81.8)

Presence or absence of No 249 ( 98.4) 177 ( 97.3) 426 ( 97.9)
complications from benign
prostatic hyperplasia
Yes 4 ( 1.6) 5 ( 2.7) 9 ( 2.1)
The figures in parentheses indicate the percentage (%).

- 347 -
 2.7.6 Summary of the individual tests

Table 2.7.6.5-5 Demographic data and other reference values (continued)

Population for analysis: primary registration cases
Item Classification 0.2 mg/day 0.4 mg/day Overall
continuous group increased dose
group
Total urgency per week <5.0 101 ( 39.9) 47 ( 25.8) 148 ( 34.0)
Urinary incontinence 5.0 - <7.0 28 ( 11.1) 26 ( 14.3) 54 ( 12.4)
frequency
(times) 7.0 - <14.0 75 ( 29.6) 42 ( 23.1) 117 ( 26.9)
14.0 - <21.0 31 ( 12.3) 31 ( 17.0) 62 ( 14.3)
>=21.0 18 ( 7.1) 36 ( 19.8) 54 ( 12.4)
Mean ± standard deviation 8.26±7.16 13.03±12.64 10.25±10.09
Median 6.00 9.00 7.00
Minimum to maximum value 1.0 - 47.0 1.0 - 75.0 1.0 - 75.0
Total number of urinary <5.0 93 ( 36.8) 42 ( 23.1) 135 ( 31.0)
incontinences per week
(times) 5.0 - <7.0 24 ( 9.5) 21 ( 11.5) 45 ( 10.3)
7.0 - <14.0 75 ( 29.6) 44 ( 24.2) 119 ( 27.4)
14.0 - <21.0 39 ( 15.4) 33 ( 18.1) 72 ( 16.6)
>=21.0 22 ( 8.7) 42 ( 23.1) 64 ( 14.7)
Mean ± standard deviation 9.39±8.98 14.96±15.04 11.72±12.20
Median 7.00 11.00 8.00
Minimum to maximum value 1.0 to 59.0 1.0 to 89.0 1.0 to 89.0
Average number of urinations <10.0 113 ( 44.7) 41 ( 22.5) 154 ( 35.4)
per day
(times) 10.0 - <12.0 76 ( 30.0) 59 ( 32.4) 135 ( 31.0)
12.0 - <14.0 44 ( 17.4) 52 ( 28.6) 96 ( 22.1)
>=14.0 20 ( 7.9) 30 ( 16.5) 50 ( 11.5)
Mean ± standard deviation 10.79±2.33 11.93±2.54 11.27±2.48
Median 10.29 11.43 10.86
Minimum to maximum value 8.0 - 19.2 8.0 - 22.0 8.0 - 22.0
Urinary urgency per day <2.0 63 ( 24.9) 28 ( 15.4) 91 ( 20.9)
Average times 2.0 - <4.0 108 ( 42.7) 49 ( 26.9) 157 ( 36.1)
(times) 4.0 - <6.0 44 ( 17.4) 48 ( 26.4) 92 ( 21.1)
>=6.0 38 ( 15.0) 57 ( 31.3) 95 ( 21.8)
Mean ± standard deviation 3.59±2.35 4.99±3.20 4.18±2.82
Median 3.00 4.43 3.43
Minimum to maximum value 0.6 to 16.9 1.0 - 21.3 0.6 to 21.3
Average amount of urine <100.0 31 ( 12.3) 26 ( 14.5) 57 ( 13.2)
voided per session
(mL) 100.0 - <150.0 85 ( 33.7) 89 ( 49.7) 174 ( 40.4)
150.0 - <200.0 100 ( 39.7) 45 ( 25.1) 145 ( 33.6)
>=200.0 36 ( 14.3) 19 ( 10.6) 55 ( 12.8)
lack of measurement 1 3 4
Mean ± standard deviation 153.68±45.81 142.35±43.39 148.97±45.12
Median 153.72 134.44 143.64
Minimum to maximum value 60.0 - 296.3 64.1 - 287.6 60.0 - 296.3
Degree of urgency to urinate Mild 49 ( 19.4) 23 ( 12.6) 72 ( 16.6)
Moderate 159 ( 62.8) 114 ( 62.6) 273 ( 62.8)
Altitude 45 ( 17.8) 45 ( 24.7) 90 ( 20.7)
Daily urine output (mL) <1500 78 ( 30.8) 50 ( 27.5) 128 ( 29.4)
1500 - <2000 87 ( 34.4) 61 ( 33.5) 148 ( 34.0)
2000 - <2500 57 ( 22.5) 48 ( 26.4) 105 ( 24.1)
>=2500 31 ( 12.3) 23 ( 12.6) 54 ( 12.4)
Mean ± standard deviation 1811.64±532.01 1862.97±509.52 1833.11±522.74
Median 1750.00 1820.00 1790.00
Minimum to maximum value 570.0 - 2930.0 560.0 - 2910.0 560.0 - 2930.0
Volume of urine remaining 0 116 ( 45.8) 86 ( 47.3) 202 ( 46.4)
(mL)
0< - <10 57 ( 22.5) 47 ( 25.8) 104 ( 23.9)
10 - <20 38 ( 15.0) 21 ( 11.5) 59 ( 13.6)

- 348 -
 2.7.6 Summary of the individual tests

20 - <50 31 ( 12.3) 23 ( 12.6) 54 ( 12.4)

>=50 11 ( 4.3) 5 ( 2.7) 16 ( 3.7)
Mean ± standard deviation 10.49±17.55 8.97±15.54 9.85±16.74
Median 2.00 1.72 2.00
Minimum to maximum value 0.0 - 88.8 0.0 to 89.0 0.0 to 89.0
The figures in parentheses indicate the percentage (%).

- 349 -
 2.7.6 Summary of the individual tests

3) Efficacy results
Total number of urge incontinences per week
Figure 2.7.6.5-3 shows the evolution of the measured total number of urge incontinence
episodes per week, and Table 2.7.6.5-6 shows the summary statistics of the measured
values, the change from the end of the observation period and the percentage change at
each evaluation period. The total number of urge incontinences per week at the end of
the observation period in the 0.2 mg/day group (mean ± standard deviation, hereafter)
was 8.37 ± 6.84. A significant reduction in the number of urge incontinences per week
was observed from the first assessment point at 4 weeks post-treatment compared to the
end of the observation period, and this reduction was maintained until 52 weeks post-
treatment. % reduction). In contrast, the total number of urge urinary incontinence
episodes per week at the end of the observation period in the 0.4 mg/day increase group
was 12.56 ± 11.96. There was a significant decrease in the number of urinary
incontinence episodes from the first assessment point, after 4 weeks of treatment,
compared with the end of the observation period, to 7.76 ± 8.32 episodes after 12 weeks
of treatment before the dose increase (after 12 weeks of treatment at 0.2 mg/day). 0.4
mg/day dose increase resulted in a decrease to 4.17 ± 6.74 episodes after 16 weeks of
treatment (after 4 weeks of dose increase). The total number of urge incontinences per
week after 64 weeks of treatment or at the time of discontinuation was 2.84±6.83 (9.72
±11.47 fewer urge incontinences, 77.85±50.49% reduction).

30.0
0.2 mg/日継続群
0.4 mg/日増量群

25.0
1週間あたりの合計切迫性尿失禁回数（回）

20.0
（平均値+標準偏差）

15.0

10.0

5.0

1）治療期52週後または中止時
（0.2 mg/日継続群）
0.0 治療期64週後または中止時
観察期
-2 48 52 最終 （0.4 mg/日増量群）
4 12 16 24 40 64 1）
終了時 評価時

観測時期（週後）

Figure 2.7.6.5-3 Measured total urge incontinence frequency per week (PPS)

- 350 -
 2.7.6 Summary of the individual tests

Table 2.7.6.5-6 Summary statistics for the total number of urge incontinence visits
per week
Population for analysis: PPS
Valuation period Item Summary statistics 0.2 mg/day 0.4 mg/day Overall
continuous increased dose
group group
At the end of the Measured value Number of cases 179 159 338
observation period
Mean ± standard 8.37±6.84 12.56±11.96 10.34±9.80
deviation
Median 7.00 9.00 7.00
Minimum to maximum 1.0 to 39.0 1.0 to 74.0 1.0 to 74.0
value
After 4 weeks of treatment Measured value Number of cases 178 156 334
Mean ± standard 3.43±4.43 8.55±11.39 5.82±8.80
deviation
Median 2.00 5.00 3.00
Minimum to maximum 0.0 to 21.0 0.0 to 93.0 0.0 to 93.0
value
Amount of Number of cases 178 156 334
change
Mean ± standard -4.88±5.56 -4.04±8.49 -4.49±7.08
deviation
Median -3.00 -2.50 -3.00
Minimum to maximum -26.0 to 7.0 -41.0 to 41.0 -41.0 to 41.0
value
Corresponding t-test1) p<0.0001 * p<0.0001 * p<0.0001 *
Rate of change Number of cases 178 156 334
Mean ± standard -55.57±69.81 -28.98±88.28 -43.15±79.96
deviation
Median -71.01 -43.17 -60.00
Minimum to maximum -100.0 to 600.0 -100.0 to 700.0 -100.0 to 700.0
value
Corresponding t-test1) p<0.0001 * p<0.0001 * p<0.0001 *
After 12 weeks of Measured value Number of cases 178 159 337
treatment
Mean ± standard 2.16 ± 4.30 7.76±8.32 4.80±7.08
deviation
Median 0.00 5.00 2.00
Minimum to maximum 0.0 to 38.0 0.0 to 47.0 0.0 to 47.0
value
Amount of Number of cases 178 159 337
change
Mean ± standard -6.18±6.95 -4.80±9.81 -5.53±8.44
deviation
Median -4.50 -3.00 -4.00
Minimum to maximum -31.0 to 31.0 -62.0 to 18.0 -62.0 to 31.0
value
Corresponding t-test1) p<0.0001 * p<0.0001 * p<0.0001 *
Rate of change Number of cases 178 159 337
Mean ± standard -72.80±61.34 -21.90±94.05 -48.78±82.40
deviation
Median -100.00 -38.10 -75.00
Minimum to maximum -100.0 to 442.9 -100.0 to 716.7 -100.0 to 716.7
value
Corresponding t-test1) p<0.0001 * p=0.0038 * p<0.0001 *
After 16 weeks of Measured value Number of cases 178 158
treatment
Mean ± standard 1.97±5.09 4.17±6.74
deviation
Median 0.00 1.20
Minimum to maximum 0.0 to 54.8 0.0 to 44.0
value
Amount of Number of cases 178 158
change
Mean ± standard -6.43±7.60 -8.39±10.33
deviation
Median -5.00 -5.00
Minimum to maximum -31.0 to 47.8 -69.0 to 9.0
value
Corresponding t-test1) p<0.0001 * p<0.0001 *
Rate of change Number of cases 178 158

- 351 -
 2.7.6 Summary of the individual tests

Mean ± standard -75.35±71.93 -67.40±42.05

deviation
Median -100.00 -83.33
Minimum to maximum -100.0 to 683.3 -100.0 to 114.3
value
Corresponding t-test1) p<0.0001 * p<0.0001 *
After 24 weeks of Measured value Number of cases 177 158
treatment
Mean ± standard 1.83±5.37 3.53±5.63
deviation
Median 0.00 1.00
Minimum to maximum 0.0 to 57.0 0.0 - 28.0
value
Amount of Number of cases 177 158
change
Mean ± standard -6.54±7.98 -8.89±10.51
deviation
Median -5.00 -5.60
Minimum to maximum -31.0 to 50.0 -68.0 to 6.0
value
Corresponding t-test1) p<0.0001 * p<0.0001 *
Rate of change Number of cases 177 158
Mean ± standard -75.22±78.63 -71.12±41.93
deviation
Median -100.00 -92.82
Minimum to maximum -100.0 to 714.3 -100.0 to 120.0
value
Corresponding t-test1) p<0.0001 * p<0.0001 *
1) Two-tailed test, *: p<0.05, N.S.: p≥0.05

- 352 -
 2.7.6 Summary of the individual tests

Table 2.7.6.5-6 Summary statistics for the total number of urge incontinence visits
per week (continued)
Population for analysis: PPS
Valuation period Item Summary statistics 0.2 mg/day 0.4 mg/day Overall
continuous increased dose
group group
After 40 weeks of Measured value Number of cases 177 159
treatment
Mean ± standard 0.86±3.10 2.40±5.32
deviation
Median 0.00 0.00
Minimum to maximum 0.0 to 32.0 0.0 to 35.0
value
Amount of Number of cases 177 159
change
Mean ± standard -7.56±7.11 -10.16±10.75
deviation
Median -5.20 -6.00
Minimum to maximum -37.0 to 25.0 -73.0 to 9.0
value
Corresponding t-test1) p<0.0001 * p<0.0001 *
Rate of change Number of cases 177 159
Mean ± standard -89.62±44.20 -81.39±34.51
deviation
Median -100.00 -100.00
Minimum to maximum -100.0 to 357.1 -100.0 to 100.0
value
Corresponding t-test1) p<0.0001 * p<0.0001 *
After 52 weeks of Measured value Number of cases 178 157
treatment
Mean ± standard 1.07±4.70 2.49±4.66
deviation
Median 0.00 0.00
Minimum to maximum 0.0 to 55.0 0.0 to 27.0
value
Amount of Number of cases 178 157
change
Mean ± standard -7.32±7.75 -10.12±11.16
deviation
Median -6.00 -6.00
Minimum to maximum -39.0 to 48.0 -74.0 to 9.0
value
Corresponding t-test1) p<0.0001 * p<0.0001 *
Rate of change Number of cases 178 157
Mean ± standard -88.14±62.71 -80.31±34.48
deviation
Median -100.00 -100.00
Minimum to maximum -100.0 to 685.7 -100.0 to 81.8
value
Corresponding t-test1) p<0.0001 * p<0.0001 *
After 64 weeks of Measured value Number of cases 159
treatment
Mean ± standard 2.84±6.83
deviation
Median 0.00
Minimum to maximum 0.0 to 52.0
value
Amount of Number of cases 159
change
Mean ± standard -9.72±11.47
deviation
Median -7.00
Minimum to maximum -74.0 to 38.0
value
Corresponding t-test1) p<0.0001 *
Rate of change Number of cases 159
Mean ± standard -77.85±50.49
deviation
Median -100.00
Minimum to maximum -100.0 to 271.4
value

- 353 -
 2.7.6 Summary of the individual tests

Corresponding t-test1) p<0.0001 *

After 52 weeks of Measured value Number of cases 178 159
treatment or at
discontinuation
(0.2 mg/day continuous Mean ± standard 1.07±4.70 2.84±6.83
group) deviation
After 64 weeks of Median 0.00 0.00
treatment or at
discontinuation
(0.4 mg/day increased dose Minimum to maximum 0.0 to 55.0 0.0 to 52.0
group) value
Amount of Number of cases 178 159
change
Mean ± standard -7.32±7.75 -9.72±11.47
deviation
Median -6.00 -7.00
Minimum to maximum -39.0 to 48.0 -74.0 to 38.0
value
Corresponding t-test1) p<0.0001 * p<0.0001 *
Rate of change Number of cases 178 159
Mean ± standard -88.14±62.71 -77.85±50.49
deviation
Median -100.00 -100.00
Minimum to maximum -100.0 to 685.7 -100.0 to 271.4
value
Corresponding t-test1) p<0.0001 * p<0.0001 *
1) Two-tailed test, *: p<0.05, N.S.: p≥0.05

- 354 -
 2.7.6 Summary of the individual tests

Total number of urinary incontinences per week

Figure 2.7.6.5-4 shows the change in the measured total number of urinary incontinence
episodes per week and Table 2.7.6.5-7 shows the summary statistics of the measured
values, the change from the end of the observation period and the percentage change at
each evaluation period. The total number of incontinences per week (mean ± standard
deviation) at the end of the observation period in the 0.2 mg/day continuation group
was 9.72 ± 9.05. There was a significant reduction in the number of urinary
incontinences per week from the first assessment point at 4 weeks post-treatment compared
to the end of the observation period, and this reduction continued until 52 weeks post-
treatment, with a total of 1.18 ± 4.77 urinary incontinences per week (a reduction of
8.57 ± 7.81 urinary incontinences, or 91.19 ± 27.77% reduction) at 52 weeks post-
treatment or discontinuation. reduction). In contrast, the total number of urinary
incontinences per week at the end of the observation period in the 0.4 mg/day increase
group was 14.01 ± 13.29. There was a significant decrease in the number of urinary
incontinence episodes from the first assessment point at 4 weeks post-treatment compared
to the end of the observation period, decreasing to 8.84 ± 9.82 episodes at 12 weeks
post-treatment before the dose increase (12 weeks post-treatment at 0.2 mg/day). 0.4
mg/day dose increase resulted in a decrease to 4.61 ± 7.21 episodes at 16 weeks post-
treatment (4 weeks post-treatment). The total number of urinary incontinences per week
after 64 weeks of treatment or at the time of discontinuation was 3.15±7.26 (10.86±
12.58 fewer urinary incontinences, 79.30±41.01% reduction).

30.0
0.2 mg/日継続群
0.4 mg/日増量群

25.0
1週間あたりの合計尿失禁回数（回）

20.0
（平均値+標準偏差）

15.0

10.0

5.0

1）治療期52週後または中止時
（0.2 mg/日継続群）
0.0 治療期64週後または中止時
観察期
-2 48 52 最終 （0.4 mg/日増量群）
4 12 16 24 40 64
終了時 評価時
1）

観測時期（週後）

Figure 2.7.6.5-4 Measured total number of urinary incontinence sessions per week (PPS)

- 355 -
 2.7.6 Summary of the individual tests

Table 2.7.6.5-7 Summary statistics for the total number of urinary incontinence
sessions per week
Population for analysis: PPS
Valuation period Item Summary statistics 0.2 mg/day 0.4 mg/day Overall
continuous increased dose
group group
At the end of the Measured value Number of cases 179 159 338
observation period
Mean ± standard 9.72±9.05 14.01±13.29 11.74±11.43
deviation
Median 7.00 11.00 8.00
Minimum to maximum 1.0 to 59.0 1.0 to 82.0 1.0 to 82.0
value
After 4 weeks of treatment Measured value Number of cases 178 156 334
Mean ± standard 3.73±4.56 9.52±11.88 6.44±9.22
deviation
Median 2.00 6.00 3.00
Minimum to maximum 0.0 to 21.0 0.0 to 93.0 0.0 to 93.0
value
Amount of Number of cases 178 156 334
change
Mean ± standard -5.93±7.40 -4.47±9.03 -5.25±8.22
deviation
Median -4.00 -3.00 -3.00
Minimum to maximum -45.0 to 7.0 -52.0 to 41.0 -52.0 to 41.0
value
Corresponding t-test1) p<0.0001 * p<0.0001 * p<0.0001 *
Rate of change Number of cases 178 156 334
Mean ± standard -56.43±74.09 -24.44±111.14 -41.49±94.46
deviation
Median -69.39 -41.43 -57.14
Minimum to maximum -100.0 to 700.0 -100.0 to -100.0 to
value 1100.0 1100.0
Corresponding t-test1) p<0.0001 * p=0.0067 * p<0.0001 *
After 12 weeks of Measured value Number of cases 178 159 337
treatment
Mean ± standard 2.43±4.45 8.84±9.82 5.45±8.13
deviation
Median 0.00 5.00 2.00
Minimum to maximum 0.0 to 38.0 0.0 to 67.0 0.0 to 67.0
value
Amount of Number of cases 178 159 337
change
Mean ± standard -7.27±7.49 -5.17±10.85 -6.28±9.27
deviation
Median -5.00 -3.00 -4.00
Minimum to maximum -45.0 to 6.0 -79.0 to 17.0 -79.0 to 17.0
value
Corresponding t-test1) p<0.0001 * p<0.0001 * p<0.0001 *
Rate of change Number of cases 178 159 337
Mean ± standard -75.02±44.94 -22.92±75.22 -50.44±66.36
deviation
Median -100.00 -33.33 -71.43
Minimum to maximum -100.0 to 250.0 -100.0 to 550.0 -100.0 to 550.0
value
Corresponding t-test1) p<0.0001 * p=0.0002 * p<0.0001 *
After 16 weeks of Measured value Number of cases 178 158
treatment
Mean ± standard 2.15±5.24 4.61±7.21
deviation
Median 0.00 2.00
Minimum to maximum 0.0 to 54.8 0.0 to 44.0
value
Amount of Number of cases 178 158
change
Mean ± standard -7.61±7.81 -9.39±11.60
deviation
Median -5.00 -6.00
Minimum to maximum -53.0 to 9.0 -82.0 to 10.0
value
Corresponding t-test1) p<0.0001 * p<0.0001 *
Rate of change Number of cases 178 158

- 356 -
 2.7.6 Summary of the individual tests

Mean ± standard -78.59±43.94 -68.11±37.68

deviation
Median -100.00 -78.84
Minimum to maximum -100.0 to 250.0 -100.0 to 60.0
value
Corresponding t-test1) p<0.0001 * p<0.0001 *
After 24 weeks of Measured value Number of cases 177 158
treatment
Mean ± standard 1.98±5.43 3.99±6.28
deviation
Median 0.00 1.00
Minimum to maximum 0.0 to 57.0 0.0 - 28.0
value
Amount of Number of cases 177 158
change
Mean ± standard -7.73±7.90 -9.86±11.70
deviation
Median -5.00 -6.00
Minimum to maximum -46.0 to 6.0 -82.0 to 6.0
value
Corresponding t-test1) p<0.0001 * p<0.0001 *
Rate of change Number of cases 177 158
Mean ± standard -79.71±41.87 -69.97±42.93
deviation
Median -100.00 -91.17
Minimum to maximum -100.0 to 114.3 -100.0 to 120.0
value
Corresponding t-test1) p<0.0001 * p<0.0001 *
1) Two-tailed test, *: p<0.05, N.S.: p≥0.05

- 357 -
 2.7.6 Summary of the individual tests

Table 2.7.6.5-7 Summary statistics for the total number of urinary incontinence
sessions per week (continued)
Population for analysis: PPS
Valuation period Item Summary statistics 0.2 mg/day 0.4 mg/day Overall
continuous increased dose
group group
After 40 weeks of Measured value Number of cases 177 159
treatment
Mean ± standard 0.94±3.13 2.75±5.72
deviation
Median 0.00 0.00
Minimum to maximum 0.0 to 32.0 0.0 to 35.0
value
Amount of Number of cases 177 159
change
Mean ± standard -8.85±8.23 -11.26±11.93
deviation
Median -7.00 -7.00
Minimum to maximum -55.0 to 4.0 -82.0 to 2.0
value
Corresponding t-test1) p<0.0001 * p<0.0001 *
Rate of change Number of cases 177 159
Mean ± standard -90.69±29.63 -80.12±33.60
deviation
Median -100.00 -100.00
Minimum to maximum -100.0 to 200.0 -100.0 to 100.0
value
Corresponding t-test1) p<0.0001 * p<0.0001 *
After 52 weeks of Measured value Number of cases 178 157
treatment
Mean ± standard 1.18±4.77 2.99±5.19
deviation
Median 0.00 0.00
Minimum to maximum 0.0 to 55.0 0.0 to 27.0
value
Amount of Number of cases 178 157
change
Mean ± standard -8.57±7.81 -10.93±12.35
deviation
Median -6.50 -7.00
Minimum to maximum -49.0 to 3.0 -82.0 to 14.0
value
Corresponding t-test1) p<0.0001 * p<0.0001 *
Rate of change Number of cases 178 157
Mean ± standard -91.19±27.77 -78.07±39.18
deviation
Median -100.00 -100.00
Minimum to maximum -100.0 to 150.0 -100.0 to 233.3
value
Corresponding t-test1) p<0.0001 * p<0.0001 *
After 64 weeks of Measured value Number of cases 159
treatment
Mean ± standard 3.15±7.26
deviation
Median 0.00
Minimum to maximum 0.0 to 58.0
value
Amount of Number of cases 159
change
Mean ± standard -10.86±12.58
deviation
Median -7.40
Minimum to maximum -82.0 to 32.0
value

- 358 -
 2.7.6 Summary of the individual tests

Corresponding t-test1) p<0.0001 *

Rate of change Number of cases 159
Mean ± standard -79.30±41.01
deviation
Median -100.00
Minimum to maximum -100.0 to 123.1
value
Corresponding t-test1) p<0.0001 *
After 52 weeks of Measured value Number of cases 178 159
treatment or at
discontinuation
(0.2 mg/day continuous Mean ± standard 1.18±4.77 3.15±7.26
group) deviation
After 64 weeks of Median 0.00 0.00
treatment or at
discontinuation
(0.4 mg/day increased dose Minimum to maximum 0.0 to 55.0 0.0 to 58.0
group) value
Amount of Number of cases 178 159
change
Mean ± standard -8.57±7.81 -10.86±12.58
deviation
Median -6.50 -7.40
Minimum to maximum -49.0 to 3.0 -82.0 to 32.0
value
Corresponding t-test1) p<0.0001 * p<0.0001 *
Rate of change Number of cases 178 159
Mean ± standard -91.19±27.77 -79.30±41.01
deviation
Median -100.00 -100.00
Minimum to maximum -100.0 to 150.0 -100.0 to 123.1
value
Corresponding t-test1) p<0.0001 * p<0.0001 *
1) Two-tailed test, *: p<0.05, N.S.: p≥0.05

Average number of urinations per day

In the 0.2 mg/day group, the mean daily urinary frequency (mean ± standard deviation,
hereafter) at the end of the observation period was 10.72 ± 2.19 times. The mean number
of voidings per day in the 0.2 mg/day group at the end of the observation period was
10.72 ± 2.19. A significant decrease in urinary frequency was observed after 4 weeks
of treatment, the first assessment point, and continued until 40 weeks of treatment,
with a mean daily frequency of 8.77 ± 2.04 urinations (a decrease of 1.91 ± 1.75
urinations) after 52 weeks of treatment or at discontinuation. In contrast, the mean
number of urinary diversions per day at the end of the observation period in the 0.4
mg/day dose escalation group was 11.86 ± 2.44. By increasing the dose to 0.4 mg/day,
the mean frequency decreased to 9.92 ± 2.23 urinary diversions after 16 weeks of
treatment (after 4 weeks of dose increase). The mean number of urinary diversions per
day after 64 weeks of treatment or at the time of discontinuation was 9.75±2.30 (a
decrease of 2.11±2.06).

- 359 -
 2.7.6 Summary of the individual tests

16.0
0.2 mg/日継続群
0.4 mg/日増量群

14.0
1日あたりの平均排尿回数（回）
（平均値+標準偏差）

12.0

10.0

1）治療期52週後または中止時
（0.2 mg/日継続群）
8.0 治療期64週後または中止時
観察期
-2 48 52 最終 （0.4 mg/日増量群）
4 12 16 24 40 64
終了時 評価時
1）

観測時期（週後）

Figure 2.7.6.5-5 Measured average number of urinations per day (PPS)

- 360 -
 2.7.6 Summary of the individual tests

Table 2.7.6.5-8 Summary statistics for the average number of urinations per day
Population for analysis: PPS
Valuation period Item Summary statistics 0.2 mg/day 0.4 mg/day Overall
continuous increased dose
group group
At the end of the Measured value Number of cases 179 159 338
observation period
Mean ± standard 10.72±2.19 11.86±2.44 11.26±2.38
deviation
Median 10.29 11.43 10.86
Minimum to maximum 8.0 - 19.0 8.0 - 20.1 8.0 - 20.1
value
After 4 weeks of treatment Measured value Number of cases 178 156 334
Mean ± standard 9.65±2.20 11.00±2.43 10.28±2.41
deviation
Median 9.36 10.71 10.00
Minimum to maximum 6.0 - 16.6 6.3 - 20.0 6.0 - 20.0
value
Amount of Number of cases 178 156 334
change
Mean ± standard -1.03±1.65 -0.87±1.64 -0.96±1.65
deviation
Median -1.00 0.71 0.86
Minimum to maximum -7.6 to 4.0 -6.7 to 3.9 -7.6 to 4.0
value
t-test1)
Corresponding p<0.0001 * p<0.0001 * p<0.0001 *
After 12 weeks of Measured value Number of cases 178 159 337
treatment
Mean ± standard 9.07±2.31 11.05±2.39 10.01±2.54
deviation
Median 8.71 10.71 9.57
Minimum to maximum 5.0 - 18.7 6.6 - 21.0 5.0 - 21.0
value
Amount of Number of cases 178 159 337
change
Mean ± standard -1.66±1.70 -0.82±1.70 -1.26±1.75
deviation
Median -1.57 0.71 -1.14
Minimum to maximum -7.6 to 2.4 -7.9 to 5.0 -7.9 to 5.0
value
t-test1)
Corresponding p<0.0001 * p<0.0001 * p<0.0001 *
After 16 weeks of Measured value Number of cases 178 158
treatment
Mean ± standard 9.13±2.20 9.92±2.23
deviation
Median 8.71 9.86
Minimum to maximum 5.1 to 18.7 6.3 - 17.4
value
Amount of Number of cases 178 158
change
Mean ± standard -1.56±1.66 -1.92±2.09
deviation
Median -1.57 -1.71
Minimum to maximum -7.6 to 3.4 -10.9 to 5.6
value
t-test1)
Corresponding p<0.0001 * p<0.0001 *
After 24 weeks of Measured value Number of cases 177 158
treatment
Mean ± standard 8.90±2.24 9.79±2.34
deviation

- 361 -
 2.7.6 Summary of the individual tests

Median 8.43 9.57

Minimum to maximum 4.7 - 19.1 5.6 - 17.3
value
Amount of Number of cases 177 158
change
Mean ± standard -1.84±1.81 -2.03±2.01
deviation
Median -1.86 -1.86
Minimum to maximum -7.9 to 3.3 -10.7 to 4.1
value
t-test1)
Corresponding p<0.0001 * p<0.0001 *
1) Two-tailed test, *: p<0.05, N.S.: p≥0.05

- 362 -
 2.7.6 Summary of the individual tests

Table 2.7.6.5-8 Summary statistics for the average number of urinations per day
(continued)
Population for analysis: PPS
Valuation period Item Summary statistics 0.2 mg/day 0.4 mg/day Overall
continuous increased dose
group group
After 40 weeks of Measured value Number of cases 177 159
treatment
Mean ± standard 8.46±2.26 9.16±2.10
deviation
Median 8.14 9.00
Minimum to maximum 4.0 - 20.6 5.0 - 17.1
value
Amount of Number of cases 177 159
change
Mean ± standard -2.23±2.01 -2.70±2.11
deviation
Median -2.14 -2.57
Minimum to maximum -8.4 to 4.4 -10.3 to 3.0
value
Corresponding t-test1) p<0.0001 * p<0.0001 *
After 52 weeks of Measured value Number of cases 178 157
treatment
Mean ± standard 8.77±2.04 9.64±2.22
deviation
Median 8.50 9.29
Minimum to maximum 4.7 to 18.1 4.4 - 17.3
value
Amount of Number of cases 178 157
change
Mean ± standard -1.91±1.75 -2.24±2.07
deviation
Median -1.71 -2.00
Minimum to maximum -8.3 to 2.1 -11.4 to 2.3
value
Corresponding t-test1) p<0.0001 * p<0.0001 *
After 64 weeks of Measured value Number of cases 159
treatment
Mean ± standard 9.75±2.30
deviation
Median 9.43
Minimum to maximum 6.0 - 17.9
value
Amount of Number of cases 159
change
Mean ± standard -2.11±2.06
deviation
Median -1.86
Minimum to maximum -11.0 to 2.4
value
Corresponding t-test1) p<0.0001 *
After 52 weeks of Measured value Number of cases 178 159
treatment or at
discontinuation
(0.2 mg/day continuous Mean ± standard 8.77±2.04 9.75±2.30
group) deviation
After 64 weeks of Median 8.50 9.43
treatment or at
discontinuation
(0.4 mg/day increased dose Minimum to maximum 4.7 to 18.1 6.0 - 17.9
group) value
Amount of Number of cases 178 159
change
Mean ± standard -1.91±1.75 -2.11±2.06
deviation

- 363 -
 2.7.6 Summary of the individual tests

Median -1.71 -1.86

Minimum to maximum -8.3 to 2.1 -11.0 to 2.4
value
Corresponding t-test1) p<0.0001 * p<0.0001 *
1) Two-tailed test, *: p<0.05, N.S.: p≥0.05

Average number of urinary urgency per day

The mean number of urinary urgency episodes per day in the 0.2 mg/day group at the
end of the observation period (mean ± standard deviation; hereafter the same) was 3.72
± 2.34. The mean number of urinary urgencies per day (mean ± standard deviation,
hereafter) in the 0.2 mg/day group was 3.72 ± 2.34. A significant reduction in urinary
urgency was observed after 4 weeks of treatment, the first assessment time point,
compared with the end of the observation period, and the reduction continued until 52
weeks of treatment, with a mean of 1.14 ± 1.79 urinary urgency per day (a reduction of
2.59 ± 2.07 urinary urgency per day, 68.67 ± 67.77% reduction) after 52 weeks of
treatment or at the time of discontinuation. reduction). In contrast, the mean number
of urinary urgency episodes per day at the end of the observation period in the 0.4
mg/day increase group was 4.96 ± 2.99 episodes. There was a significant decrease in
the number of urinary urgency episodes from the first assessment time point, 4 weeks
into the treatment period, compared with the end of the observation period, to 3.56 ±
2.66 episodes at 12 weeks into the treatment period before the dose increase (12 weeks
after the 0.2 mg/day dose). The mean number of urinary urgency episodes per day after
64 weeks of treatment or at the time of discontinuation was 1.68±2.28 (a decrease of
3.28±2.91 episodes, a reduction rate of 65.62±38.69%).
10.0
0.2 mg/日継続群
0.4 mg/日増量群

8.0
1日あたりの尿意切迫感の平均回数（回）

6.0
（平均値+標準偏差）

4.0

2.0

1）治療期52週後または中止時
（0.2 mg/日継続群）
0.0 治療期64週後または中止時
観察期
-2 48 52 最終 （0.4 mg/日増量群）
4 12 16 24 40 64
終了時 評価時
1）

観測時期（週後）

Figure 2.7.6.5-6 Measured average number of urinary urgency sensations per day (PPS)

- 364 -
 2.7.6 Summary of the individual tests

Table 2.7.6.5-9 Summary statistics of the mean number of urinary urgency episodes
per day
Population for analysis: PPS
Valuation period Item Summary statistics 0.2 mg/day 0.4 mg/day Overall
continuous increased dose
group group
At the end of the Measured value Number of cases 179 159 338
observation period
Mean ± standard 3.72±2.34 4.96±2.99 4.30±2.73
deviation
Median 3.00 4.57 3.69
Minimum to maximum 1.0 - 16.9 1.0 - 17.1 1.0 - 17.1
value
After 4 weeks of treatment Measured value Number of cases 178 156 334
Mean ± standard 2.44±2.28 3.59±2.85 2.98±2.62
deviation
Median 1.71 2.93 2.14
Minimum to maximum 0.0 to 14.6 0.0 to 15.6 0.0 to 15.6
value
Amount of Number of cases 178 156 334
change
Mean ± standard -1.26±1.83 -1.34±1.94 -1.30±1.88
deviation
Median -1.14 -1.14 -1.14
Minimum to maximum -7.4 to 5.4 -8.1 to 4.4 -8.1 to 5.4
value
Corresponding t-test1) p<0.0001 * p<0.0001 * p<0.0001 *
Rate of change Number of cases 178 156 334
Mean ± standard -31.36±63.97 -25.99±46.91 -28.85±56.63
deviation
Median -40.40 -33.33 -36.18
Minimum to maximum -100.0 to 475.0 -100.0 to 312.5 -100.0 to 475.0
value
Corresponding t-test1) p<0.0001 * p<0.0001 * p<0.0001 *
After 12 weeks of Measured value Number of cases 178 159 337
treatment
Mean ± standard 1.59±1.98 3.56±2.66 2.52 ± 2.52
deviation
Median 0.86 2.86 1.86
Minimum to maximum 0.0 to 13.7 0.3 to 14.0 0.0 to 14.0
value
Amount of Number of cases 178 159 337
change
Mean ± standard -2.12±1.98 -1.39±2.08 -1.78±2.06
deviation
Median -1.86 -1.14 -1.57
Minimum to maximum -8.6 to 5.3 -10.0 to 3.9 -10.0 to 5.3
value
Corresponding t-test1) p<0.0001 * p<0.0001 * p<0.0001 *
Rate of change Number of cases 178 159 337
Mean ± standard -55.91±59.69 -23.67±43.29 -40.70±54.94
deviation
Median -64.97 -30.95 -48.78
Minimum to maximum -100.0 to 528.6 -87.9 to 237.5 -100.0 to 528.6
value
Corresponding t-test1) p<0.0001 * p<0.0001 * p<0.0001 *
After 16 weeks of Measured value Number of cases 178 158
treatment
Mean ± standard 1.50±1.96 2.32±2.33
deviation
Median 0.86 1.64
Minimum to maximum 0.0 to 12.5 0.0 to 10.9
value
Amount of Number of cases 178 158
change
Mean ± standard -2.23±1.97 -2.65±2.43
deviation
Median -1.86 -2.29
Minimum to maximum -7.7 to 6.8 -13.0 to 3.7
value
Corresponding t-test1) p<0.0001 * p<0.0001 *
Rate of change Number of cases 178 158

- 365 -
 2.7.6 Summary of the individual tests

Mean ± standard -59.58±68.48 -53.79±36.50

deviation
Median -72.22 -57.44
Minimum to maximum -100.0 to 683.3 -100.0 to 77.3
value
Corresponding t-test1) p<0.0001 * p<0.0001 *
After 24 weeks of Measured value Number of cases 177 158
treatment
Mean ± standard 1.30±1.98 2.03±2.41
deviation
Median 0.60 1.29
Minimum to maximum 0.0 - 11.7 0.0 to 13.3
value
Amount of Number of cases 177 158
change
Mean ± standard -2.41±2.15 -2.88±2.62
deviation
Median -2.00 -2.70
Minimum to maximum -8.4 to 7.1 -14.0 to 3.6
value
Corresponding t-test1) p<0.0001 * p<0.0001 *
Rate of change Number of cases 177 158
Mean ± standard -63.95±70.07 -58.58±40.25
deviation
Median -80.00 -66.15
Minimum to maximum -100.0 to 714.3 -100.0 to 187.5
value
Corresponding t-test1) p<0.0001 * p<0.0001 *
1) Two-tailed test, *: p<0.05, N.S.: p≥0.05

- 366 -
 2.7.6 Summary of the individual tests

Table 2.7.6.5-9 Summary statistics of the average number of urinary urgency

sensations per day (continued)
Population for analysis: PPS
Valuation period Item Summary statistics 0.2 mg/day 0.4 mg/day Overall
continuous increased dose
group group
After 40 weeks of Measured value Number of cases 177 159
treatment
Mean ± standard 1.01±1.67 1.54±2.07
deviation
Median 0.29 0.86
Minimum to maximum 0.0 to 10.6 0.0 to 13.4
value
Amount of Number of cases 177 159
change
Mean ± standard -2.71±2.05 -3.42±2.76
deviation
Median -2.29 -3.00
Minimum to maximum -8.1 to 3.6 -17.1 to 3.4
value
Corresponding t-test1) p<0.0001 * p<0.0001 *
Rate of change Number of cases 177 159
Mean ± standard -73.79±45.59 -68.63±34.98
deviation
Median -89.80 -79.41
Minimum to maximum -100.0 to 357.1 -100.0 to 109.1
value
Corresponding t-test1) p<0.0001 * p<0.0001 *
After 52 weeks of Measured value Number of cases 178 157
treatment
Mean ± standard 1.14±1.79 1.63±2.07
deviation
Median 0.43 1.00
Minimum to maximum 0.0 to 11.6 0.0 to 12.3
value
Amount of Number of cases 178 157
change
Mean ± standard -2.59±2.07 -3.35±2.81
deviation
Median -2.29 -2.86
Minimum to maximum -8.0 to 6.9 -17.1 to 3.0
value
Corresponding t-test1) p<0.0001 * p<0.0001 *
Rate of change Number of cases 178 157
Mean ± standard -68.67±67.77 -65.75±35.99
deviation
Median -88.12 -73.33
Minimum to maximum -100.0 to 685.7 -100.0 to 95.5
value
Corresponding t-test1) p<0.0001 * p<0.0001 *
After 64 weeks of Measured value Number of cases 159
treatment
Mean ± standard 1.68±2.28
deviation
Median 1.00
Minimum to maximum 0.0 to 11.3
value
Amount of Number of cases 159
change
Mean ± standard -3.28±2.91
deviation
Median -2.79
Minimum to maximum -17.1 to 5.3
value
Corresponding t-test1) p<0.0001 *
Rate of change Number of cases 159
Mean ± standard -65.60±38.68
deviation
Median -75.00
Minimum to maximum -100.0 to 168.2
value

- 367 -
 2.7.6 Summary of the individual tests

Corresponding t-test1) p<0.0001 *

After 52 weeks of Measured value Number of cases 178 159
treatment or at
discontinuation
(0.2 mg/day continuous Mean ± standard 1.14±1.79 1.68±2.28
group) deviation
After 64 weeks of Median 0.43 1.00
treatment or at
discontinuation
(0.4 mg/day increased dose Minimum to maximum 0.0 to 11.6 0.0 to 11.3
group) value
Amount of Number of cases 178 159
change
Mean ± standard -2.59±2.07 -3.28±2.91
deviation
Median -2.29 -2.79
Minimum to maximum -8.0 to 6.9 -17.1 to 5.3
value
Corresponding t-test1) p<0.0001 * p<0.0001 *
Rate of change Number of cases 178 159
Mean ± standard -68.67±67.77 -65.62±38.69
deviation
Median -88.12 -75.00
Minimum to maximum -100.0 to 685.7 -100.0 to 168.2
value
Corresponding t-test1) p<0.0001 * p<0.0001 *
1) Two-tailed test, *: p<0.05, N.S.: p≥0.05

Percentage of cases with normalization of symptoms of overactive bladder (normalization

rate)
Normalisation was defined as zero total urge incontinence per week, zero total urinary
incontinence per week, less than eight urinary diversions per day, and zero urinary
urgency per day at each assessment period. The proportion of patients with normalisation
of each endpoint (normalisation rate) was calculated for each treatment group. The
normalization rate was calculated for each treatment group.
a) Normalisation rate of total urge incontinence frequency per week
The normalization rate of total urge incontinence per week in the 0.2 mg/day group
was 38.2% after 4 weeks of treatment, 58.4% after 12 weeks of treatment, and increased
over time until 52 weeks of treatment. The normalization rate was 81.5% after 52 weeks
of treatment or at the time of discontinuation. On the other hand, the normalization
rate of the total number of urge urinary incontinence episodes per week in the 0.4
mg/day dose increase group was 18.6% after 4 weeks of treatment and 9.4% after 12 weeks
of treatment before the dose increase (after 12 weeks of treatment with 0.2 mg/day),
but increased to 39.2% after 16 weeks of treatment (after 4 weeks of dose increase) and
remained normalized until 64 weeks of treatment (after 52 weeks of dose increase). The
normalisation rate continued to increase until 64 weeks post-treatment (52 weeks post-
treatment), with a normalisation rate of 62.9% at 64 weeks post-treatment or
discontinuation.

Table 2.7.6.5-10 Normalisation rate of total urge incontinence

- 368 -
 2.7.6 Summary of the individual tests

frequency per week

Population for analysis: PPS
0.2 mg/day continuous 0.4 mg/day increased Overall
group dose group
Valuation period Normalised Normalisat Normalised Normalisat Normalised Normalisat
ion rate ion rate ion rate
Number of (%) Number of (%) Number of (%)
cases cases cases
After 4 weeks of treatment 68 /178 ( 38.2) 29 /156 ( 18.6) 97 /334 ( 29.0)
After 12 weeks of 104 /178 ( 58.4) 15 /159 ( 9.4) 119 /337 ( 35.3)
treatment
After 16 weeks of 110 /178 ( 61.8) 62 /158 ( 39.2)
treatment
After 24 weeks of 118 /177 ( 66.7) 71 /158 ( 44.9)
treatment
After 40 weeks of 141 /177 ( 79.7) 99 /159 ( 62.3)
treatment
After 52 weeks of 145 /178 ( 81.5) 92 /157 ( 58.6)
treatment
After 64 weeks of 100 /159 ( 62.9)
treatment
1)
at final assessment 145 /178 ( 81.5) 100 /159 ( 62.9)
Definition of normalisation of urge incontinence frequency: zero total urge incontinence frequency per
week at each assessment period
(1) 0.2 mg/day continuous group: after 52 weeks of treatment or at discontinuation; 0.4 mg/day increased
group: after 64 weeks of treatment or at discontinuation

(b) Normalisation rate of total number of urinary incontinence sessions per week
The normalization rate of the total number of urinary incontinence sessions per week
in the 0.2 mg/day group was 35.4% after 4 weeks of treatment, 54.5% after 12 weeks of
treatment, and increased over time until 52 weeks of treatment. The normalization rate
was 80.3% after 52 weeks of treatment or at the time of discontinuation. On the other
hand, the normalization rate of the total number of urinary incontinences per week in
the 0.4 mg/day dose increase group was 16.0% after 4 weeks of treatment and 7.5% after
12 weeks of treatment before the dose increase (after 12 weeks of treatment with 0.2
mg/day), but increased to 36.7% after 16 weeks of treatment (after 4 weeks of dose
increase) and remained normalized until 64 weeks of treatment (after 52 weeks of dose
increase). After 64 weeks of treatment (52 weeks after dose escalation), the
normalization rate increased to 59.1%.

Table 2.7.6.5-11 Normalisation rate of total number of urinary

incontinence sessions per week
Population for analysis: PPS
0.2 mg/day continuous 0.4 mg/day increased Overall
group dose group
Valuation period Normalised Normalisat Normalised Normalisat Normalised Normalisat
ion rate ion rate ion rate
Number of (%) Number of (%) Number of (%)
cases cases cases

- 369 -
 2.7.6 Summary of the individual tests

After 4 weeks of treatment 63 /178 ( 35.4) 25 /156 ( 16.0) 88 /334 ( 26.3)

After 12 weeks of 97 /178 ( 54.5) 12 /159 ( 7.5) 109 /337 ( 32.3)
treatment
After 16 weeks of 103 /178 ( 57.9) 58 /158 ( 36.7)
treatment
After 24 weeks of 112 /177 ( 63.3) 68 /158 ( 43.0)
treatment
After 40 weeks of 137 /177 ( 77.4) 93 /159 ( 58.5)
treatment
After 52 weeks of 143 /178 ( 80.3) 86 /157 ( 54.8)
treatment
After 64 weeks of 94 /159 ( 59.1)
treatment
1)
at final assessment 143 /178 ( 80.3) 94 /159 ( 59.1)
Definition of normalisation of urinary incontinence frequency: 0 total urinary incontinence frequency
per week at each assessment period
(1) 0.2 mg/day continuous group: after 52 weeks of treatment or at discontinuation; 0.4 mg/day increased
group: after 64 weeks of treatment or at discontinuation

(c) normalisation rate of the average number of urinations per day

Table 2.7.6.5-12 shows the percentages of normalization of the mean daily voiding
frequency in the 0.2 mg/day group after 4 weeks of treatment, 34.3% after 12 weeks of
treatment, and increasing until 52 weeks of treatment. After 52 weeks of treatment or
at the time of discontinuation, the normalization rate was 35.4%. On the other hand, in
the 0.4 mg/day dose increase group, the normalization rate of the mean daily frequency
of urination was 6.4% after 4 weeks of treatment and 6.3% after 12 weeks of treatment
before the dose increase (after 12 weeks of treatment with 0.2 mg/day), but it increased
to 20.3% after 16 weeks of treatment (after 4 weeks of dose increase), and the
normalization rate increased until 64 weeks of treatment (after 52 weeks of dose
increase). The normalization rate increased to 20.3% after 16 weeks of treatment (4
weeks after dose increase) and continued to increase until 64 weeks of treatment (52
weeks after dose increase), when the normalization rate was 20.8%.

Table 2.7.6.5-12 Normalisation rate of average number of urinations

per day
Population for analysis: PPS
0.2 mg/day continuous 0.4 mg/day increased Overall
group dose group
Valuation period Normalised Normalisat Normalised Normalisat Normalised Normalisat
ion rate ion rate ion rate
Number of (%) Number of (%) Number of (%)
cases cases cases
After 4 weeks of treatment 40 /178 ( 22.5) 10 /156 ( 6.4) 50 /334 ( 15.0)
After 12 weeks of 61 /178 ( 34.3) 10 /159 ( 6.3) 71 /337 ( 21.1)
treatment
After 16 weeks of 54 /178 ( 30.3) 32 /158 ( 20.3)
treatment
After 24 weeks of 70 /177 ( 39.5) 33 /158 ( 20.9)
treatment
After 40 weeks of 80 /177 ( 45.2) 48 /159 ( 30.2)
treatment
After 52 weeks of 63 /178 ( 35.4) 35 /157 ( 22.3)
treatment
After 64 weeks of 33 /159 ( 20.8)
treatment
1)
at final assessment 63 /178 ( 35.4) 33 /159 ( 20.8)
Definition of normalisation of the mean frequency of urination: cases with a mean frequency of urination
of less than 8 times per day at each assessment period
(1) 0.2 mg/day continuous group: after 52 weeks of treatment or at discontinuation; 0.4 mg/day increased
group: after 64 weeks of treatment or at discontinuation

- 370 -
 2.7.6 Summary of the individual tests

(d) Normalisation rate of the average number of urinary urgencies per day
Table 2.7.6.5-13 shows the normalization rate of the mean number of urinary urgency
episodes per day at each assessment period. After 52 weeks of treatment or at the time
of discontinuation, the normalization rate was 33.1%. On the other hand, in the 0.4
mg/day dose increase group, the normalization rate of the mean frequency of urinary
urgency per day was 0.6% after 4 weeks of treatment and 0.0% after 12 weeks of treatment
before the dose increase (after 12 weeks of treatment with 0.2 mg/day), but it increased
to 5.7% after 16 weeks of treatment (after 4 weeks of dose increase), and the
normalization rate increased until 64 weeks of treatment (after 52 weeks of dose
increase). After 64 weeks of treatment (52 weeks of dose escalation), the normalization
rate increased to 5.7%, and the normalization rate was 22.6% after 64 weeks of treatment
or at the time of discontinuation.

Table 2.7.6.5-13 Normalisation rate of the average number of urinary

urgencies per day
Population for analysis: PPS
0.2 mg/day continuous 0.4 mg/day increased Overall
group dose group
Valuation period Normalised Normalisat Normalised Normalisat Normalised Normalisat
ion rate ion rate ion rate
Number of (%) Number of (%) Number of (%)
cases cases cases
After 4 weeks of treatment 12 /178 ( 6.7) 1 /156 ( 0.6) 13 /334 ( 3.9)
After 12 weeks of 27 /178 ( 15.2) 0 /159 ( 0.0) 27 /337 ( 8.0)
treatment
After 16 weeks of 40 /178 ( 22.5) 9 /158 ( 5.7)
treatment
After 24 weeks of 53 /177 ( 29.9) 19 /158 ( 12.0)
treatment
After 40 weeks of 62 /177 ( 35.0) 33 /159 ( 20.8)
treatment
After 52 weeks of 59 /178 ( 33.1) 31 /157 ( 19.7)
treatment
After 64 weeks of 36 /159 ( 22.6)
treatment
1)
at final assessment 59 /178 ( 33.1) 36 /159 ( 22.6)
Definition of normalisation of urinary urgency frequency: cases with an average of zero urinary urgency
per day at each assessment period
(1) 0.2 mg/day continuous group: after 52 weeks of treatment or at discontinuation; 0.4 mg/day increased
group: after 64 weeks of treatment or at discontinuation

(6) Degree of urgency to urinate

In the 0.2 mg/day continuation group, the percentage of patients with at least a 1-
step improvement in urinary urgency was 46.1% after 4 weeks of treatment and 68.9% after
12 weeks of treatment, and the percentage of patients with improvement increased until
52 weeks of treatment, with 84.2% of patients having improvement after 52 weeks of
treatment or at the time of discontinuation. On the other hand, in the 0.4 mg/day dose
increase group, the percentage of patients with at least a 1-step improvement in urinary
urgency was 33.5% after 4 weeks of treatment, 39.9% after 12 weeks of treatment before

- 371 -
 2.7.6 Summary of the individual tests

the dose increase (12 weeks after 0.2 mg/day), and increased to 69.4% after 16 weeks of
treatment (4 weeks after the dose increase). The percentage of patients who improved
after 64 weeks of treatment or at the time of discontinuation was 82.4%.

(7) Average amount of urine voided per session

In the 0.2 mg/day group, the mean voided volume (mean ± standard deviation) at the
end of the observation period was 153.09 ± 44.49 mL. The change in the mean voided
volume from the end of the observation period is shown in Table 2.7.6.5-14. The mean
volume of urine voided (mean ± standard deviation) at the end of the observation period
was 153.09 ± 44.49 mL. There was a significant increase in urine output from the first
assessment point, 4 weeks after treatment, compared with the end of the observation
period, and this increase remained significant until 52 weeks after treatment, when it
was 183.02 ± 60.04 mL (an increase of 29.44 ± 41.72 mL) at 52 weeks after treatment
or at the time of discontinuation. In contrast, the mean volume of urine voided per
urination at the end of the observation period in the 0.4 mg/day dose escalation group
was 144.60±42.62 mL. There was a significant increase in urine output from the first
assessment point, after 4 weeks of treatment, compared with the end of the observation
period, to 164.48±53.50 mL after 12 weeks of treatment before the dose increase (after
12 weeks of treatment with 0.2 mg/day). 0.4 mg/day increased the urine output to 179.64
±59.36 mL after 16 weeks of treatment (after 4 weeks of dose increase). By increasing
the dose to 0.4 mg/day, the mean daily urine output increased to 179.64±59.36 mL after
16 weeks of treatment (after 4 weeks of dose increase) and remained significantly higher
until 64 weeks of treatment (after 52 weeks of dose increase), with a mean daily urine
output of 182.19±59.91 mL (an increase of 38.07±45.38 mL) after 64 weeks of treatment
or at discontinuation.

260.0
0.2 mg/日継続群
0.4 mg/日増量群

230.0
（平均値+標準偏差）
平均1回排尿量（ml）

200.0

170.0

1）治療期52週後または中止時
（0.2 mg/日継続群）
140.0 治療期64週後または中止時
観察期-2 48 52 最終 （0.4 mg/日増量群）
4 12 16 24 40 64
終了時 評価時
1）

観測時期（週後）

- 372 -
 2.7.6 Summary of the individual tests

Figure 2.7.6.5-7 Measured average volume of urine voided per session (PPS)

- 373 -
 2.7.6 Summary of the individual tests

Table 2.7.6.5-14 Summary statistics for mean single urination volume

Population for analysis: PPS
Valuation period Item Summary statistics 0.2 mg/day 0.4 mg/day Overall
continuous increased dose
group group
At the end of the Measured value Number of cases 178 157 335
observation period
Mean ± standard 153.09±44.49 144.60±42.62 149.11±43.76
deviation
Median 152.98 135.79 143.64
Minimum to maximum 60.0 - 288.1 64.1 - 287.6 60.0 - 288.1
value
After 4 weeks of treatment Measured value Number of cases 178 155 333
Mean ± standard 176.10±57.03 164.16±52.00 170.54±54.99
deviation
Median 173.10 155.36 164.67
Minimum to maximum 59.7 - 391.6 79.1 - 308.9 59.7 - 391.6
value
Amount of Number of cases 177 153 330
change
Mean ± standard 22.58±36.02 20.12±31.98 21.44±34.18
deviation
Median 19.82 16.48 18.09
Minimum to maximum -75.8 to 178.2 -73.8 to 110.8 -75.8 to 178.2
value
t-test1)
Corresponding p<0.0001 * p<0.0001 * p<0.0001 *
After 12 weeks of Measured value Number of cases 177 158 335
treatment
Mean ± standard 181.91±62.29 164.48±53.50 173.69±58.87
deviation
Median 180.74 162.95 170.50
Minimum to maximum 57.0 - 423.6 63.8 - 384.5 57.0 - 423.6
value
Amount of Number of cases 177 156 333
change
Mean ± standard 28.66±42.34 21.30±34.58 25.21±39.02
deviation
Median 24.33 19.47 21.60
Minimum to maximum -79.7 to 210.2 -84.9 to 158.4 -84.9 to 210.2
value
t-test1)
Corresponding p<0.0001 * p<0.0001 * p<0.0001 *
After 16 weeks of Measured value Number of cases 177 157
treatment
Mean ± standard 182.43±62.46 179.64±59.36
deviation
Median 178.42 171.43
Minimum to maximum 52.1 to 405.7 67.4 - 380.5
value
Amount of Number of cases 177 155
change
Mean ± standard 28.85±45.90 35.93±44.47
deviation
Median 19.58 31.69
Minimum to maximum -93.9 to 192.4 -118.4 to 191.6
value
t-test1)
Corresponding p<0.0001 * p<0.0001 *
After 24 weeks of Measured value Number of cases 176 157
treatment
Mean ± standard 184.14±57.55 183.44±60.04
deviation

- 374 -
 2.7.6 Summary of the individual tests

Median 177.73 177.24

Minimum to maximum 79.2 - 396.4 61.1 - 353.1
value
Amount of Number of cases 176 155
change
Mean ± standard 31.25±42.51 39.26±42.21
deviation
Median 26.82 33.25
Minimum to maximum -71.3 to 193.1 -74.4 to 169.7
value
t-test1)
Corresponding p<0.0001 * p<0.0001 *
1) Two-tailed test, *: p<0.05, N.S.: p≥0.05

- 375 -
 2.7.6 Summary of the individual tests

Table 2.7.6.5-14 Summary statistics of mean single urinary output (continued)

Population for analysis: PPS
Valuation period Item Summary statistics 0.2 mg/day 0.4 mg/day Overall
continuous increased dose
group group
After 40 weeks of Measured value Number of cases 176 159
treatment
Mean ± standard 179.91±58.48 174.45±59.18
deviation
Median 174.51 164.74
Minimum to maximum 59.1 - 405.0 66.3-367.6
value
Amount of Number of cases 176 157
change
Mean ± standard 26.56±46.06 30.31±46.32
deviation
Median 24.38 20.52
Minimum to maximum -186.7 to 191.7 -62.3 to 237.6
value
t-test1)
Corresponding p<0.0001 * p<0.0001 *
After 52 weeks of Measured value Number of cases 177 157
treatment
Mean ± standard 183.04±60.04 179.16±56.70
deviation
Median 181.29 175.80
Minimum to maximum 68.9 - 372.4 46.5 - 363.3
value
Amount of Number of cases 177 155
change
Mean ± standard 29.46±41.66 35.14±47.45
deviation
Median 25.16 32.15
Minimum to maximum -82.9 to 191.6 -123.2 to 233.3
value
t-test1)
Corresponding p<0.0001 * p<0.0001 *
After 64 weeks of Measured value Number of cases 158
treatment
Mean ± standard 182.19±59.91
deviation
Median 177.21
Minimum to maximum 43.1 to 414.7
value
Amount of Number of cases 156
change
Mean ± standard 38.07±45.38
deviation
Median 28.11
Minimum to maximum -96.8 to 217.1
value
t-test1)
Corresponding p<0.0001 *
After 52 weeks of Measured value Number of cases 177 158
treatment or at
discontinuation
(0.2 mg/day continuous Mean ± standard 183.02±60.04 182.19±59.91
group) deviation
After 64 weeks of Median 180.95 177.21
treatment or at
discontinuation
(0.4 mg/day increased dose Minimum to maximum 68.9 - 372.4 43.1 to 414.7
group) value

- 376 -
 2.7.6 Summary of the individual tests

Amount of Number of cases 177 156

change
Mean ± standard 29.44±41.72 38.07±45.38
deviation
Median 25.16 28.11
Minimum to maximum -86.5 to 191.6 -96.8 to 217.1
value
t-test1)
Corresponding p<0.0001 * p<0.0001 *
1) Two-tailed test, *: p<0.05, N.S.: p≥0.05

⑧ King's Health Questionnaire (Quality of Life Score)

Figure 2.7.6.5-8 shows the change from the end of the observation period in each
domain of the King Health Questionnaire at each assessment period. 0.2 mg/day continued
to improve QOL in all domains of the King Health Questionnaire used to assess QOL from
12 weeks of treatment until 52 weeks of treatment or until discontinuation. In the King
study, the improvement in quality of life was sustained from 12 weeks of treatment to
52 weeks of treatment or until discontinuation. In contrast, the 0.4 mg/day group showed
significant improvements in all eight domains except general health (impact of urinary
problems on life, work/household limitations, physical limitations, social limitations,
personal relationships, psychological problems, sleep and energy, and subjective
severity of illness). There were also significant improvements in general health. There
was also a significant improvement in overall health status after 64 weeks of treatment
or at discontinuation. Furthermore, there was a further improvement in quality of life
in all domains after the dose increase compared with before the dose increase.

排尿の問題
全般的な が生活に 仕事・家事 個人的な
健康状態 与える影響 の制限 身体的制限 社会的制限 人間関係 心の問題 睡眠・活力 自覚的重症度
10

-10

-20

-30

-40

-50

-60
治療期12週後 治療期24週後 治療期40週後

治療期52週後 治療期52週後または中止時
-70

Figure 2.7.6.5-8 Changes in each domain of the King Health Questionnaire (0.2 mg/day
continuous group)

- 377 -
 2.7.6 Summary of the individual tests

排尿の問題
全般的な が生活に 仕事・家事 個人的な
健康状態 与える影響 の制限 身体的制限 社会的制限 人間関係 心の問題 睡眠・活力 自覚的重症度
10

-10

-20

-30

-40

-50

-60
治療期12週後 治療期24週後 治療期40週後

治療期52週後 治療期64週後 治療期64週後または中止時

-70

Figure 2.7.6.5-8 Changes in each domain of the King's Health Questionnaire (0.4 mg/day
increase group)

3) Assessment of safety
(i) Indication of adverse events
Safety was assessed in terms of adverse events occurring from the start of the
treatment period to 52 weeks (0.2 mg/day continuation group) and 64 weeks (0.4 mg/day
dose increase group) of the treatment period or at discontinuation. The 10 patients who
received a dose reduction to 0.2 mg after a dose increase to 0.4 mg were included in
the analysis of the 0.4 mg/day dose increase group.
When the same event occurred more than once in the same patient, the number of cases
was counted as one, and the number of incidents was counted as one per occurrence.

Adverse events
A summary of adverse events is shown in Table 2.7.6.5-15. The incidence of adverse
events was 84.4% (367/435) in all patients, 80.2% (203/253) in the 0.2 mg/day
continuation group and 90.1% (164/182) in the 0.4 mg/day dose increase group. The
incidence of adverse reactions was 49.4% (215/435) in all patients, 39.9% (101/253) in
the 0.2 mg/day continuous group and 62.6% (114/182) in the 0.4 mg/day increased group.
There were no deaths. The incidence of serious adverse events was 3.7% (16/435) in all
patients, 3.2% (8/253) in the 0.2 mg/day continuation group and 4.4% (8/182) in the 0.4
mg/day increase group. The incidence of adverse events leading to discontinuation
(including withdrawal of consent due to adverse events) was 7.8% (34/435) of all patients,
compared with 11.1% (28/253) in the 0.2 mg/day continuation group and 3.3% (6/182) in
the 0.4 mg/day increase group.

Table 2.7.6.5-15 Summary of adverse events

- 378 -
 2.7.6 Summary of the individual tests

解析対象集団：安全性解析対象集団
投与群 0.2 mg/日継続群 0.4 mg/日増量群 全体
対象例数 253 182 435
有害事象発現例 203 ( 80.2) 164 ( 90.1) 367 ( 84.4)
重篤な有害事象発現例 8 ( 3.2) 8 ( 4.4) 16 ( 3.7)
投与中止の原因となった有害事象発現例 28 ( 11.1) 6 ( 3.3)a） 34 ( 7.8) a）
有害事象による減量例 0 ( 0.0) 10 ( 5.5) 10 ( 2.3)
副作用発現例 101 ( 39.9) 114 ( 62.6) 215 ( 49.4)
重篤な副作用発現例 0 ( 0.0) 0 ( 0.0) 0 ( 0.0)
投与中止の原因となった副作用発現例 16 ( 6.3) 4 ( 2.2) b） 20 ( 4.6) b）
副作用による減量例 0 ( 0.0) 8 ( 4.4) 8 ( 1.8)
死亡例 0 ( 0.0) 0 ( 0.0) 0 ( 0.0)
（ ）内は割合（％）を示す。
a）有害事象による投与中止例である薬剤番号512番の被験者は、投与中止の原因となった有害事象が特定され
なかったために、投与中止の原因となった有害事象が発現しなかった被験者として集計した。
b）副作用による投与中止例である薬剤番号512番の被験者は、投与中止の原因となった副作用が特定されな
かったために、投与中止の原因となった副作用が発現しなかった被験者として集計した。

Figure 2.7.6.5-9 and Figure 2.7.6.5-10 show the results of Kaplan-Meier analysis of
the cumulative incidence of adverse events and adverse reactions, respectively. The
cumulative incidence of adverse events and adverse reactions was 60.9% (63.3% in the
0.2 mg/day continuous group and 57.7% in the 0.4 mg/day increased group) and 32.5%
(33.7% in the 0.2 mg/day continuous group and 30.8% in the 0.4 mg/day increased group),
respectively, after 12 weeks of treatment in all patients. The cumulative incidence of
adverse events and adverse reactions at the final evaluation was 85.4% and 43.3% after
52 weeks of treatment or discontinuation, respectively, in the 0.2 mg/day continuous
group and 90.7% and 63.2% after 64 weeks of treatment or discontinuation in the 0.4
mg/day increased group.

- 379 -
 2.7.6 Summary of the individual tests

100.0

90.0

0.2 mg
80.0

70.0

0.2 mg/日継続群
累積発現率（％）

60.0 0.4 mg/日増量群

　　 全体
50.0

40.0

30.0

20.0 累積発現率
12週時 最終評価時1）
0.2 mg/日継続群 63.3％ 85.4％
10.0
0.4 mg/日増量群 57.7％ 90.7％
全体 60.9％
0.0
0 8 16 24 32 40 48 56 64

時期（週）
at-risk例数 0週 4週 8週 12週 16週 20週 24週 28週 32週 36週 40週 44週 48週 52週 56週 60週 64週
0.2 mg/日継続群 253 147 108 86 69 60 53 47 46 42 39 38 38 22
0.4 mg/日増量群 182 128 100 81 48 41 36 30 29 28 26 25 22 20 18 18 10
全体 435 275 208 167 117 101 89 77 75 70 65 63 60 42 18 18 10
1）治療期52週後または中止時
（0.2 mg/日継続群）
治療期64週後または中止時
（0.4 mg/日増量群）
解析対象集団：安全性解析対象集団
Figure 2.7.6.5-9 Cumulative incidence of adverse events

- 380 -
 2.7.6 Summary of the individual tests

100.0

90.0
0.2 mg/日継続群
0.4 mg/日増量群 0.2 mg
80.0 　　 全体

70.0
累積発現率（％）

60.0

50.0

40.0

30.0

20.0 累積発現率
12週時 最終評価時1）
0.2 mg/日継続群 33.7％ 43.3％
10.0
0.4 mg/日増量群 30.8％ 63.2％
全体 32.5％
0.0
0 8 16 24 32 40 48 56 64

時期（週）
at-risk例数 0週 4週 8週 12週 16週 20週 24週 28週 32週 36週 40週 44週 48週 52週 56週 60週 64週
0.2 mg/日継続群 253 178 159 145 136 131 129 122 120 119 116 114 114 69
0.4 mg/日増量群 182 145 135 130 85 80 73 69 69 69 67 63 62 62 60 60 33
全体 435 323 294 275 221 211 202 191 189 188 183 177 176 131 60 60 33
1）治療期52週後または中止時
（0.2 mg/日継続群）
治療期64週後または中止時
（0.4 mg/日増量群）
解析対象集団：安全性解析対象集団
Figure 2.7.6.5-10 Cumulative incidence of adverse reactions

The frequency of adverse events and adverse reactions by SOC category is shown in
Table 2.7.6.5-16 and Table 2.7.6.5-17, respectively. The frequency of adverse events
and adverse reactions by symptom is shown in Tables 2.7.6.5-18 and 2.7.6.5-19,
respectively.
The most frequent adverse event among all patients by SOC category was gastrointestinal
disorders in 53.8% (234/435 patients), compared with 44.3% (112/253 patients) in the
0.2 mg/day continuation group and 67.0% (122/182 patients) in the 0.4 mg/day increase
group. Other relatively frequent adverse events by SOC category (incidence of 10% or
more in all patients) were infections and parasitism in 42.8% (41.1% in the 0.2 mg/day
continuous group and 45.1% in the 0.4 mg/day increased group), laboratory tests in 22.1%
(22.1% in the 0.2 mg/day continuous group and 22.0% in the 0.4 mg/day ), musculoskeletal

- 381 -
 2.7.6 Summary of the individual tests

and connective tissue disorders in 14.3% (11.5% in the 0.2 mg/day continuous group and
18.1% in the 0.4 mg/day increased group), nervous system disorders in 12.0% (12.3% in
the 0.2 mg/day continuous group and 11.5% in the 0.4 mg/day increased group), skin and
subcutaneous tissue disorders in 10.6% (10.7% in the 0.2 mg The most frequent adverse
reactions in all patients by SOC category were gastrointestinal disorders in 44.8%
(195/435), 34.4% (87/253) in the 0.2 mg/day group and 59.3% (108/182) in the 0.4 mg/day
group. 108/182). Other adverse reactions by SOC category that occurred relatively
frequently (≥3% of all patients) were laboratory tests in 4.8% of patients (4.7% in the
0.2 mg/day continuous group and 4.9% in the 0.4 mg/day increased group).
The most frequent adverse event by symptom was dry mouth. Dry mouth occurred in 38.6%
(168/435) of all patients, 27.7% (70/253) in the 0.2 mg/day continuation group and 53.8%
(98/182) in the 0.4 mg/day increase group. Other relatively frequent adverse events
(incidence of 5% or more in all patients) were nasopharyngitis in 31.3% (27.7% in the
0.2 mg/day continuous group and 36.3% in the 0.4 mg/day increased group), constipation
in 15.4% (11.9% in the 0.2 mg/day continuous group and 20.3% in the 0.4 mg/day increased
group), positive urine leukocytes in 8.3% (9.2% in the 0.2 mg/day continuous group, 7.1%
in the 0.4 mg/day increased group), headache 6.2% (6.3% in the 0.2 mg/day continuous
group, 6.0% in the 0.4 mg/day increased group), cystitis 5.1% (6.3% in the 0.2 mg/day
continuous group, 3.3% in the 0.4 mg/day increased group), back pain 5.1% (3.6% in the
0.2 mg/day continued group). ) and back pain in 5.1% (3.6% in the 0.2 mg/day continuous
group and 7.1% in the 0.4 mg/day increased group).
The most frequent symptom-specific adverse reaction was dry mouth. Dry mouth was
judged to be an adverse effect in 37.7% (164/435) of all patients, 26.5% (67/253) in
the 0.2 mg/day continuation group and 53.3% (97/182) in the 0.4 mg/day increase group.
Other side effects that occurred relatively frequently (incidence of 5% or more) were
constipation in 13.6% of patients (9.9% in the 0.2 mg/day continuous group and 18.7% in
the 0.4 mg/day increased group).

Table 2.7.6.5-16 Frequency of adverse events by SOC classification

Population for analysis: Safety analysis population

Dose group 0.2 mg/day continuous group 0.4 mg/day increased dose Overall
group
Adverse event items Manif Targe Expressi Manif Manif Targe Expressi Manif Manif Targe Expressi Manif
(SOC classification by MedDRA) estat t on rate estat estat t on rate estat estat t on rate estat
ion Numbe (%) ion ion Numbe (%) ion ion Numbe (%) ion
Numbe r of Numbe Numbe r of Numbe Numbe r of Numbe
r of cases r of r of cases r of r of cases r of
cases cases cases cases cases cases
Overall 203 /253 ( 80.2) 623 164 /182 ( 90.1) 718 367 /435 ( 84.4) 1341
Blood and lymphatic disorders 1 /253 ( 0.4) 1 2 /182 ( 1.1) 2 3 /435 ( 0.7) 3
Heart problems 6 /253 ( 2.4) 8 7 /182 ( 3.8) 9 13 /435 ( 3.0) 17
Ear and maze disorders 3 /253 ( 1.2) 3 6 /182 ( 3.3) 6 9 /435 ( 2.1) 9
Endocrine disorders 1 /253 ( 0.4) 1 1 /435 ( 0.2) 1
Eye disorders 16 /253 ( 6.3) 17 14 /182 ( 7.7) 18 30 /435 ( 6.9) 35
Gastrointestinal disorders 112 /253 ( 44.3) 159 122 /182 ( 67.0) 235 234 /435 ( 53.8) 394
Systemic disorders and local conditions of 11 /253 ( 4.3) 12 7 /182 ( 3.8) 8 18 /435 ( 4.1) 20
administration
Hepatobiliary system disorders 1 /253 ( 0.4) 1 1 /435 ( 0.2) 1
Immune system disorders 3 /253 ( 1.2) 3 5 /182 ( 2.7) 5 8 /435 ( 1.8) 8

- 382 -
 2.7.6 Summary of the individual tests

Infectious and parasitic diseases 104 /253 ( 41.1) 161 82 /182 ( 45.1) 166 186 /435 ( 42.8) 327
Injuries, poisoning and treatment 14 /253 ( 5.5) 16 21 /182 ( 11.5) 28 35 /435 ( 8.0) 44
complications
Laboratory tests 56 /253 ( 22.1) 98 40 /182 ( 22.0) 80 96 /435 ( 22.1) 178
Metabolic and nutritional disorders 5 /253 ( 2.0) 5 1 /182 ( 0.5) 1 6 /435 ( 1.4) 6
Musculoskeletal and connective tissue 29 /253 ( 11.5) 35 33 /182 ( 18.1) 40 62 /435 ( 14.3) 75
disorders
Benign, malignant and unspecified 2 /182 ( 1.1) 2 2 /435 ( 0.5) 2
neoplasms (including cysts and polyps)
Nervous system disorders 31 /253 ( 12.3) 32 21 /182 ( 11.5) 49 52 /435 ( 12.0) 81
Mental disorder 5 /253 ( 2.0) 5 5 /182 ( 2.7) 5 10 /435 ( 2.3) 10
Renal and urinary tract disorders 5 /253 ( 2.0) 6 4 /182 ( 2.2) 5 9 /435 ( 2.1) 11
Reproductive system and breast disorders 4 /253 ( 1.6) 7 3 /182 ( 1.6) 3 7 /435 ( 1.6) 10
Respiratory, thoracic and mediastinal 15 /253 ( 5.9) 17 20 /182 ( 11.0) 26 35 /435 ( 8.0) 43
disorders
Skin and subcutaneous tissue disorders 27 /253 ( 10.7) 30 19 /182 ( 10.4) 25 46 /435 ( 10.6) 55
Surgical and medical procedures 3 /253 ( 1.2) 3 1 /182 ( 0.5) 1 4 /435 ( 0.9) 4
Vascular disorders 3 /253 ( 1.2) 3 4 /182 ( 2.2) 4 7 /435 ( 1.6) 7

- 383 -
 2.7.6 Summary of the individual tests

Table 2.7.6.5-17 Frequency of adverse reactions by SOC category

Population for analysis: Safety analysis population
Dose group 0.2 mg/day continuous group 0.4 mg/day increased dose Overall
group
Side effects Manif Targe Expressi Manif Manif Targe Expressi Manif Manif Targe Expressi Manif
(SOC classification by MedDRA) estat t on rate estat estat t on rate estat estat t on rate estat
ion Numbe (%) ion ion Numbe (%) ion ion Numbe (%) ion
Numbe r of Numbe Numbe r of Numbe Numbe r of Numbe
r of cases r of r of cases r of r of cases r of
cases cases cases cases cases cases
Overall 101 /253 ( 39.9) 143 114 /182 ( 62.6) 200 215 /435 ( 49.4) 343
Blood and lymphatic disorders 1 /182 ( 0.5) 1 1 /435 ( 0.2) 1
Heart problems 2 /253 ( 0.8) 3 2 /182 ( 1.1) 4 4 /435 ( 0.9) 7
Eye disorders 2 /253 ( 0.8) 2 3 /182 ( 1.6) 3 5 /435 ( 1.1) 5
Gastrointestinal disorders 87 /253 ( 34.4) 106 108 /182 ( 59.3) 153 195 /435 ( 44.8) 259
Systemic disorders and local conditions of 1 /253 ( 0.4) 1 1 /182 ( 0.5) 1 2 /435 ( 0.5) 2
administration
Infectious and parasitic diseases 6 /253 ( 2.4) 7 1 /182 ( 0.5) 1 7 /435 ( 1.6) 8
Laboratory tests 12 /253 ( 4.7) 14 9 /182 ( 4.9) 15 21 /435 ( 4.8) 29
Musculoskeletal and connective tissue 2 /182 ( 1.1) 2 2 /435 ( 0.5) 2
disorders
Nervous system disorders 6 /253 ( 2.4) 7 4 /182 ( 2.2) 5 10 /435 ( 2.3) 12
Mental disorder 1 /182 ( 0.5) 1 1 /435 ( 0.2) 1
Renal and urinary tract disorders 1 /253 ( 0.4) 1 4 /182 ( 2.2) 5 5 /435 ( 1.1) 6
Reproductive system and breast disorders 1 /182 ( 0.5) 1 1 /435 ( 0.2) 1
Respiratory, thoracic and mediastinal 1 /253 ( 0.4) 1 3 /182 ( 1.6) 6 4 /435 ( 0.9) 7
disorders
Skin and subcutaneous tissue disorders 1 /253 ( 0.4) 1 1 /182 ( 0.5) 2 2 /435 ( 0.5) 3

- 384 -
 2.7.6 Summary of the individual tests

Table 2.7.6.5-18 Frequency of adverse events by symptom (Part 1)

Population for analysis: Safety analysis population
Dose group 0.2 mg/day continuous 0.4 mg/day increased Overall
group dose group
Adverse event items Mani Targ Expres Mani Mani Targ Expres Mani Mani Targ Expres Mani
(MedDRA classification of SOC and PT) fest et sion fest fest et sion fest fest et sion fest
atio Numb rate atio atio Numb rate atio atio Numb rate atio
n er (%) n n er (%) n n er (%) n
Numb of Numb Numb of Numb Numb of Numb
er case er er case er er case er
of s of of s of of s of
case case case case case case
s s s s s s
Overall 203 /253 ( 80.2 623 164 /182 ( 90.1 718 367 /435 ( 84.4 1341
) ) )
Blood and lymphatic disorders 1 /253 ( 0.4) 1 2 /182 ( 1.1) 2 3 /435 ( 0.7) 3
Anaemia 1 /253 ( 0.4) 1 1 /435 ( 0.2) 1
Iron deficiency anaemia 1 /182 ( 0.5) 1 1 /435 ( 0.2) 1
Lymphadenopathy 1 /182 ( 0.5) 1 1 /435 ( 0.2) 1
Heart problems 6 /253 ( 2.4) 8 7 /182 ( 3.8) 9 13 /435 ( 3.0) 17
Arrhythmia 1 /253 ( 0.4) 2 1 /182 ( 0.5) 1 2 /435 ( 0.5) 3
Atrial Fibrillation 1 /182 ( 0.5) 1 1 /435 ( 0.2) 1
Myocardial ischaemia 1 /253 ( 0.4) 1 1 /435 ( 0.2) 1
Throbbing 4 /253 ( 1.6) 4 2 /182 ( 1.1) 2 6 /435 ( 1.4) 6
Sinus bradycardia 1 /182 ( 0.5) 1 1 /435 ( 0.2) 1
Supraventricular extrasystoles 1 /182 ( 0.5) 1 1 /435 ( 0.2) 1
Ventricular extrasystoles 1 /253 ( 0.4) 1 2 /182 ( 1.1) 3 3 /435 ( 0.7) 4
Ear and maze disorders 3 /253 ( 1.2) 3 6 /182 ( 3.3) 6 9 /435 ( 2.1) 9
Sensorineural hearing loss 1 /253 ( 0.4) 1 1 /435 ( 0.2) 1
earache 1 /182 ( 0.5) 1 1 /435 ( 0.2) 1
Meniere's disease 1 /253 ( 0.4) 1 1 /435 ( 0.2) 1
Tinnitus 1 /182 ( 0.5) 1 1 /435 ( 0.2) 1
Rotatory vertigo 1 /253 ( 0.4) 1 2 /182 ( 1.1) 2 3 /435 ( 0.7) 3
Pruritus 1 /182 ( 0.5) 1 1 /435 ( 0.2) 1
sudden hearing loss 1 /182 ( 0.5) 1 1 /435 ( 0.2) 1
Endocrine disorders 1 /253 ( 0.4) 1 1 /435 ( 0.2) 1
Graves' disease 1 /253 ( 0.4) 1 1 /435 ( 0.2) 1
Eye disorders 16 /253 ( 6.3) 17 14 /182 ( 7.7) 18 30 /435 ( 6.9) 35
eyestrain 3 /253 ( 1.2) 3 3 /435 ( 0.7) 3
Blepharitis 1 /182 ( 0.5) 1 1 /435 ( 0.2) 1
Cataracts 1 /182 ( 0.5) 2 1 /435 ( 0.2) 2
Conjunctival haemorrhage 1 /253 ( 0.4) 1 1 /435 ( 0.2) 1
Conjunctivitis 2 /253 ( 0.8) 2 2 /182 ( 1.1) 2 4 /435 ( 0.9) 4
Allergic conjunctivitis 4 /253 ( 1.6) 4 4 /182 ( 2.2) 4 8 /435 ( 1.8) 8
eye discharge 1 /182 ( 0.5) 1 1 /435 ( 0.2) 1
Eyelid oedema 1 /182 ( 0.5) 3 1 /435 ( 0.2) 3
eye redness 1 /253 ( 0.4) 1 1 /435 ( 0.2) 1
photophobia 1 /253 ( 0.4) 1 1 /435 ( 0.2) 1
Posterior capsule opacity 1 /182 ( 0.5) 1 1 /435 ( 0.2) 1
Presbyopia 1 /182 ( 0.5) 1 1 /435 ( 0.2) 1
Foggy vision 2 /253 ( 0.8) 2 3 /182 ( 1.6) 3 5 /435 ( 1.1) 5
Ocular dryness 2 /253 ( 0.8) 2 2 /435 ( 0.5) 2
Foreign body sensation in the eye 1 /253 ( 0.4) 1 1 /435 ( 0.2) 1

- 385 -
 2.7.6 Summary of the individual tests

Table 2.7.6.5-18 Frequency of adverse events by symptom (Part 2)

Population for analysis: Safety analysis population
Dose group 0.2 mg/day continuous 0.4 mg/day increased Overall
group dose group
Adverse event items Mani Targ Expres Mani Mani Targ Expres Mani Mani Targ Expres Mani
(MedDRA classification of SOC and PT) fest et sion fest fest et sion fest fest et sion fest
atio Numb rate atio atio Numb rate atio atio Numb rate atio
n er (%) n n er (%) n n er (%) n
Numb of Numb Numb of Numb Numb of Numb
er case er er case er er case er
of s of of s of of s of
case case case case case case
s s s s s s
Gastrointestinal disorders 112 /253 ( 44.3 159 122 /182 ( 67.0 235 234 /435 ( 53.8 394
) ) )
Abdominal discomfort 14 /253 ( 5.5) 15 5 /182 ( 2.7) 5 19 /435 ( 4.4) 20
Abdominal distension 3 /253 ( 1.2) 3 3 /435 ( 0.7) 3
Abdominal pain 1 /253 ( 0.4) 1 2 /182 ( 1.1) 2 3 /435 ( 0.7) 3
Lower abdominal pain 1 /182 ( 0.5) 1 1 /435 ( 0.2) 1
Upper abdominal pain 3 /253 ( 1.2) 3 5 /182 ( 2.7) 6 8 /435 ( 1.8) 9
Change in stool habits 1 /253 ( 0.4) 1 1 /435 ( 0.2) 1
Cheilitis 2 /182 ( 1.1) 2 2 /435 ( 0.5) 2
Constipation 30 /253 ( 11.9 31 37 /182 ( 20.3 42 67 /435 ( 15.4 73
) ) )
tooth decay 2 /253 ( 0.8) 2 5 /182 ( 2.7) 5 7 /435 ( 1.6) 7
Diarrhoea 8 /253 ( 3.2) 8 11 /182 ( 6.0) 12 19 /435 ( 4.4) 20
Dry mouth 70 /253 ( 27.7 71 98 /182 ( 53.8 111 168 /435 ( 38.6 182
) ) )
Indigestion 2 /253 ( 0.8) 2 7 /182 ( 3.8) 15 9 /435 ( 2.1) 17
Stomach ulcers 1 /182 ( 0.5) 1 1 /435 ( 0.2) 1
Haemorrhagic gastric ulcer 1 /182 ( 0.5) 1 1 /435 ( 0.2) 1
Gastritis 6 /253 ( 2.4) 7 3 /182 ( 1.6) 5 9 /435 ( 2.1) 12
Erosive Gastritis 1 /182 ( 0.5) 1 1 /435 ( 0.2) 1
Gastro-oesophageal reflux disease 1 /253 ( 0.4) 1 1 /435 ( 0.2) 1
Gastrointestinal disorders 1 /253 ( 0.4) 1 1 /435 ( 0.2) 1
Gingivitis 1 /253 ( 0.4) 1 5 /182 ( 2.7) 6 6 /435 ( 1.4) 7
Excretion of blood and faeces 1 /182 ( 0.5) 1 1 /435 ( 0.2) 1
Inguinal hernia 1 /182 ( 0.5) 1 1 /435 ( 0.2) 1
Irritable bowel syndrome 1 /182 ( 0.5) 1 1 /435 ( 0.2) 1
Dry lips 1 /253 ( 0.4) 1 1 /182 ( 0.5) 1 2 /435 ( 0.5) 2
Nausea 4 /253 ( 1.6) 4 4 /182 ( 2.2) 4 8 /435 ( 1.8) 8
Periodontal disease 1 /253 ( 0.4) 1 1 /435 ( 0.2) 1
Periodontitis 3 /253 ( 1.2) 3 2 /182 ( 1.1) 2 5 /435 ( 1.1) 5
Mouth ulcers 1 /253 ( 0.4) 1 5 /182 ( 2.7) 5 6 /435 ( 1.4) 6
Toothache 1 /253 ( 0.4) 1 1 /182 ( 0.5) 1 2 /435 ( 0.5) 2
Vomiting 1 /253 ( 0.4) 1 3 /182 ( 1.6) 4 4 /435 ( 0.9) 5
Systemic disorders and local conditions of 11 /253 ( 4.3) 12 7 /182 ( 3.8) 8 18 /435 ( 4.1) 20
administration
Chest discomfort 1 /253 ( 0.4) 2 1 /182 ( 0.5) 1 2 /435 ( 0.5) 3
Chest pain 2 /253 ( 0.8) 2 1 /182 ( 0.5) 1 3 /435 ( 0.7) 3
Fatigue 2 /253 ( 0.8) 2 2 /435 ( 0.5) 2
Abnormal sensations 1 /253 ( 0.4) 1 1 /435 ( 0.2) 1
Fatigue 2 /253 ( 0.8) 2 1 /182 ( 0.5) 2 3 /435 ( 0.7) 4
Edema 1 /253 ( 0.4) 1 1 /435 ( 0.2) 1
Peripheral oedema 1 /253 ( 0.4) 1 1 /182 ( 0.5) 1 2 /435 ( 0.5) 2
Fever 2 /182 ( 1.1) 2 2 /435 ( 0.5) 2
dry mouth 1 /253 ( 0.4) 1 1 /182 ( 0.5) 1 2 /435 ( 0.5) 2
Hepatobiliary system disorders 1 /253 ( 0.4) 1 1 /435 ( 0.2) 1
Alcoholic liver disease 1 /253 ( 0.4) 1 1 /435 ( 0.2) 1
Immune system disorders 3 /253 ( 1.2) 3 5 /182 ( 2.7) 5 8 /435 ( 1.8) 8
Food allergies 1 /182 ( 0.5) 1 1 /435 ( 0.2) 1

- 386 -
 2.7.6 Summary of the individual tests

Seasonal allergies 3 /253 ( 1.2) 3 4 /182 ( 2.2) 4 7 /435 ( 1.6) 7

- 387 -
 2.7.6 Summary of the individual tests

Table 2.7.6.5-18 Frequency of adverse events by symptom (Part 3)

Population for analysis: Safety analysis population
Dose group 0.2 mg/day continuous 0.4 mg/day increased Overall
group dose group
Adverse event items Mani Targ Expres Mani Mani Targ Expres Mani Mani Targ Expres Mani
(MedDRA classification of SOC and PT) fest et sion fest fest et sion fest fest et sion fest
atio Numb rate atio atio Numb rate atio atio Numb rate atio
n er (%) n n er (%) n n er (%) n
Numb of Numb Numb of Numb Numb of Numb
er case er er case er er case er
of s of of s of of s of
case case case case case case
s s s s s s
Infectious and parasitic diseases 104 /253 ( 41.1 161 82 /182 ( 45.1 166 186 /435 ( 42.8 327
) ) )
Acute tonsillitis 1 /253 ( 0.4) 1 1 /435 ( 0.2) 1
Appendicitis 1 /253 ( 0.4) 1 1 /435 ( 0.2) 1
Bacteriuria 1 /253 ( 0.4) 1 1 /435 ( 0.2) 1
Bronchitis 3 /253 ( 1.2) 3 1 /182 ( 0.5) 1 4 /435 ( 0.9) 4
Chronic sinusitis 1 /253 ( 0.4) 1 1 /435 ( 0.2) 1
Cystitis 16 /253 ( 6.3) 16 6 /182 ( 3.3) 9 22 /435 ( 5.1) 25
Infectious Dermatitis 1 /253 ( 0.4) 1 1 /435 ( 0.2) 1
Endocarditis 1 /253 ( 0.4) 1 1 /435 ( 0.2) 1
Folliculitis 1 /253 ( 0.4) 1 1 /435 ( 0.2) 1
Gastroenteritis 3 /253 ( 1.2) 3 9 /182 ( 4.9) 9 12 /435 ( 2.8) 12
Viral gastroenteritis 2 /253 ( 0.8) 2 1 /182 ( 0.5) 1 3 /435 ( 0.7) 3
Herpes Simplex 1 /182 ( 0.5) 1 1 /435 ( 0.2) 1
Shingles 1 /253 ( 0.4) 1 1 /182 ( 0.5) 1 2 /435 ( 0.5) 2
Granuloma 1 /253 ( 0.4) 1 1 /435 ( 0.2) 1
Influenza 2 /253 ( 0.8) 2 3 /182 ( 1.6) 3 5 /435 ( 1.1) 5
Nasopharyngitis 70 /253 ( 27.7 98 66 /182 ( 36.3 122 136 /435 ( 31.3 220
) ) )
Esophageal candidiasis 1 /182 ( 0.5) 1 1 /435 ( 0.2) 1
Onychomycosis 1 /253 ( 0.4) 1 1 /435 ( 0.2) 1
Otitis externa 1 /253 ( 0.4) 1 1 /435 ( 0.2) 1
Middle ear infection 1 /253 ( 0.4) 1 2 /182 ( 1.1) 2 3 /435 ( 0.7) 3
Sore throat 7 /253 ( 2.8) 9 4 /182 ( 2.2) 4 11 /435 ( 2.5) 13
Pneumonia 1 /253 ( 0.4) 1 1 /435 ( 0.2) 1
Pyelonephritis 1 /253 ( 0.4) 1 1 /435 ( 0.2) 1
Rhinitis 1 /182 ( 0.5) 1 1 /435 ( 0.2) 1
Sinusitis 2 /253 ( 0.8) 2 2 /435 ( 0.5) 2
Tinea pedis 1 /253 ( 0.4) 1 1 /182 ( 0.5) 1 2 /435 ( 0.5) 2
Tonsillitis 1 /182 ( 0.5) 1 1 /435 ( 0.2) 1
Upper respiratory tract infection 2 /182 ( 1.1) 3 2 /435 ( 0.5) 3
Urinary tract infection 4 /253 ( 1.6) 5 1 /182 ( 0.5) 1 5 /435 ( 1.1) 6
Vulvovaginitis 1 /253 ( 0.4) 1 1 /435 ( 0.2) 1
Ringworm infection 3 /253 ( 1.2) 3 1 /182 ( 0.5) 2 4 /435 ( 0.9) 5
Oral herpes 2 /253 ( 0.8) 2 3 /182 ( 1.6) 3 5 /435 ( 1.1) 5
Injuries, poisoning and treatment 14 /253 ( 5.5) 16 21 /182 ( 11.5 28 35 /435 ( 8.0) 44
complications )
Complex fractures 1 /182 ( 0.5) 1 1 /435 ( 0.2) 1
Epicondylitis 1 /182 ( 0.5) 1 1 /435 ( 0.2) 1
Broken leg 1 /253 ( 0.4) 1 2 /182 ( 1.1) 2 3 /435 ( 0.7) 3
Forearm fracture 1 /253 ( 0.4) 1 1 /435 ( 0.2) 1
Hand fracture 1 /253 ( 0.4) 1 1 /435 ( 0.2) 1
Head injury 2 /182 ( 1.1) 2 2 /435 ( 0.5) 2
Scar Hernia 1 /182 ( 0.5) 1 1 /435 ( 0.2) 1
Joint dislocation 1 /182 ( 0.5) 2 1 /435 ( 0.2) 2
Sprained joints 2 /253 ( 0.8) 2 4 /182 ( 2.2) 4 6 /435 ( 1.4) 6
Fractured ribs 1 /253 ( 0.4) 1 1 /435 ( 0.2) 1
Whiplash injuries 1 /253 ( 0.4) 1 1 /435 ( 0.2) 1
Traumatic fractures 1 /253 ( 0.4) 1 1 /435 ( 0.2) 1
abrasions 1 /253 ( 0.4) 1 1 /435 ( 0.2) 1
Muscle sprain 1 /182 ( 0.5) 1 1 /435 ( 0.2) 1
bruise 2 /253 ( 0.8) 2 5 /182 ( 2.7) 5 7 /435 ( 1.6) 7
Wounds 1 /253 ( 0.4) 1 1 /182 ( 0.5) 1 2 /435 ( 0.5) 2
Burns 2 /253 ( 0.8) 3 2 /435 ( 0.5) 3
Meniscus disorders 1 /253 ( 0.4) 1 1 /435 ( 0.2) 1

- 388 -
 2.7.6 Summary of the individual tests

Ligament injury 1 /182 ( 0.5) 1 1 /435 ( 0.2) 1

Limb injuries 1 /182 ( 0.5) 1 1 /435 ( 0.2) 1
Fractured tooth 2 /182 ( 1.1) 2 2 /435 ( 0.5) 2
Pain due to treatment 2 /182 ( 1.1) 4 2 /435 ( 0.5) 4

- 389 -
 2.7.6 Summary of the individual tests

Table 2.7.6.5-18 Frequency of adverse events by symptom (Part 4)

Population for analysis: Safety analysis population
Dose group 0.2 mg/day continuous 0.4 mg/day increased Overall
group dose group
Adverse event items Mani Targ Expres Mani Mani Targ Expres Mani Mani Targ Expres Mani
(MedDRA classification of SOC and PT) fest et sion fest fest et sion fest fest et sion fest
atio Numb rate atio atio Numb rate atio atio Numb rate atio
n er (%) n n er (%) n n er (%) n
Numb of Numb Numb of Numb Numb of Numb
er case er er case er er case er
of s of of s of of s of
case case case case case case
s s s s s s
Laboratory tests 56 /253 ( 22.1 98 40 /182 ( 22.0 80 96 /435 ( 22.1 178
) ) )
Increase in alanine aminotransferase 3 /250 ( 1.2) 3 5 /182 ( 2.7) 5 8 /432 ( 1.9) 8
Increased aspartate aminotransferase 4 /250 ( 1.6) 4 5 /182 ( 2.7) 5 9 /432 ( 2.1) 9
Increased bilirubin in the blood 2 /250 ( 0.8) 2 1 /182 ( 0.5) 1 3 /432 ( 0.7) 3
Reduction of cholesterol in the blood 1 /250 ( 0.4) 1 1 /432 ( 0.2) 1
Increased blood cholesterol 1 /182 ( 0.5) 1 1 /432 ( 0.2) 1
Increased lactate dehydrogenase in the 1 /250 ( 0.4) 1 2 /182 ( 1.1) 2 3 /432 ( 0.7) 3
blood
Increased blood pressure 1 /253 ( 0.4) 1 2 /182 ( 1.1) 4 3 /435 ( 0.7) 5
Increased triglycerides in the blood 7 /250 ( 2.8) 8 4 /182 ( 2.2) 4 11 /432 ( 2.5) 12
ECG T-wave inversion 1 /182 ( 0.5) 1 1 /435 ( 0.2) 1
Increased gamma-glutamyltransferase 3 /250 ( 1.2) 3 4 /182 ( 2.2) 4 7 /432 ( 1.6) 7
Glucose positive in urine 4 /250 ( 1.6) 4 4 /432 ( 0.9) 4
Increased glycohaemoglobin 1 /253 ( 0.4) 1 1 /435 ( 0.2) 1
Corneoscopy abnormalities 1 /253 ( 0.4) 1 1 /435 ( 0.2) 1
Reduced haematocrit 1 /250 ( 0.4) 1 1 /432 ( 0.2) 1
Reduced haemoglobin 1 /250 ( 0.4) 1 1 /182 ( 0.5) 1 2 /432 ( 0.5) 2
Positive red blood cells in urine 14 /250 ( 5.6) 17 7 /182 ( 3.8) 9 21 /432 ( 4.9) 26
Decreased white blood cell count 2 /250 ( 0.8) 2 2 /182 ( 1.1) 2 4 /432 ( 0.9) 4
Increased white blood cell count 2 /250 ( 0.8) 2 3 /182 ( 1.6) 3 5 /432 ( 1.2) 5
Positive urinary white blood cell count 23 /250 ( 9.2) 28 13 /182 ( 7.1) 21 36 /432 ( 8.3) 49
Amount of urine remaining 7 /253 ( 2.8) 8 4 /182 ( 2.2) 4 11 /435 ( 2.5) 12
positive for protein in urine 4 /250 ( 1.6) 4 4 /182 ( 2.2) 4 8 /432 ( 1.9) 8
Positive urine for urobilin 2 /250 ( 0.8) 2 1 /182 ( 0.5) 1 3 /432 ( 0.7) 3
Increase in blood alkaline phosphatase 2 /250 ( 0.8) 2 2 /182 ( 1.1) 2 4 /432 ( 0.9) 4
Detection of bacteria in urine 1 /253 ( 0.4) 2 2 /182 ( 1.1) 5 3 /435 ( 0.7) 7
Positive bacterial DNA test 1 /182 ( 0.5) 1 1 /435 ( 0.2) 1
Metabolic and nutritional disorders 5 /253 ( 2.0) 5 1 /182 ( 0.5) 1 6 /435 ( 1.4) 6
loss of appetite 3 /253 ( 1.2) 3 1 /182 ( 0.5) 1 4 /435 ( 0.9) 4
Diabetes 1 /253 ( 0.4) 1 1 /435 ( 0.2) 1
Hyperlipidaemia 1 /253 ( 0.4) 1 1 /435 ( 0.2) 1
Musculoskeletal and connective tissue 29 /253 ( 11.5 35 33 /182 ( 18.1 40 62 /435 ( 14.3 75
disorders ) ) )
Joint pain 3 /253 ( 1.2) 3 2 /182 ( 1.1) 2 5 /435 ( 1.1) 5
Arthritis 1 /253 ( 0.4) 1 1 /182 ( 0.5) 2 2 /435 ( 0.5) 3
Back pain 9 /253 ( 3.6) 9 13 /182 ( 7.1) 13 22 /435 ( 5.1) 22
Lateral abdominal pain 1 /253 ( 0.4) 1 1 /435 ( 0.2) 1
Joint exudates 1 /182 ( 0.5) 1 1 /435 ( 0.2) 1
Muscle spasm 1 /253 ( 0.4) 1 1 /182 ( 0.5) 1 2 /435 ( 0.5) 2
Musculoskeletal pain 1 /253 ( 0.4) 1 1 /182 ( 0.5) 1 2 /435 ( 0.5) 2
Myalgia 1 /253 ( 0.4) 1 1 /435 ( 0.2) 1
Neck pain 1 /253 ( 0.4) 1 1 /182 ( 0.5) 1 2 /435 ( 0.5) 2
Osteoarthritis 2 /253 ( 0.8) 2 5 /182 ( 2.7) 5 7 /435 ( 1.6) 7
Limb pain 2 /253 ( 0.8) 2 2 /182 ( 1.1) 2 4 /435 ( 0.9) 4
Periprosthetic Arthritis 3 /253 ( 1.2) 3 4 /182 ( 2.2) 4 7 /435 ( 1.6) 7
Spondylitis Osteoarthritis 2 /253 ( 0.8) 2 2 /435 ( 0.5) 2
Tendonitis 1 /253 ( 0.4) 1 2 /182 ( 1.1) 2 3 /435 ( 0.7) 3
Bullet finger 1 /182 ( 0.5) 1 1 /435 ( 0.2) 1
Muscle tension 1 /182 ( 0.5) 1 1 /435 ( 0.2) 1
Disc protrusion 1 /253 ( 0.4) 1 1 /435 ( 0.2) 1
Musculoskeletal rigidity 5 /253 ( 2.0) 5 2 /182 ( 1.1) 2 7 /435 ( 1.6) 7
Spondylolisthesis 1 /253 ( 0.4) 1 1 /182 ( 0.5) 1 2 /435 ( 0.5) 2
Tendon pain 1 /182 ( 0.5) 1 1 /435 ( 0.2) 1

- 390 -
 2.7.6 Summary of the individual tests

Benign, malignant and unspecified neoplasms 2 /182 ( 1.1) 2 2 /435 ( 0.5) 2

(including cysts and polyps)
Bladder cancer 1 /182 ( 0.5) 1 1 /435 ( 0.2) 1
Cancer of the cervix 1 /182 ( 0.5) 1 1 /435 ( 0.2) 1

- 391 -
 2.7.6 Summary of the individual tests

Table 2.7.6.5-18 Frequency of adverse events by symptom (Part 5)

Population for analysis: Safety analysis population
Dose group 0.2 mg/day continuous 0.4 mg/day increased Overall
group dose group
Adverse event items Mani Targ Expres Mani Mani Targ Expres Mani Mani Targ Expres Mani
(MedDRA classification of SOC and PT) fest et sion fest fest et sion fest fest et sion fest
atio Numb rate atio atio Numb rate atio atio Numb rate atio
n er (%) n n er (%) n n er (%) n
Numb of Numb Numb of Numb Numb of Numb
er case er er case er er case er
of s of of s of of s of
case case case case case case
s s s s s s
Nervous system disorders 31 /253 ( 12.3 32 21 /182 ( 11.5 49 52 /435 ( 12.0 81
) ) )
Cervico-omo-brachial syndrome 1 /253 ( 0.4) 1 1 /182 ( 0.5) 1 2 /435 ( 0.5) 2
Floating vertigo 3 /253 ( 1.2) 3 5 /182 ( 2.7) 5 8 /435 ( 1.8) 8
Taste disorders 1 /253 ( 0.4) 1 1 /182 ( 0.5) 1 2 /435 ( 0.5) 2
Headache 16 /253 ( 6.3) 16 11 /182 ( 6.0) 33 27 /435 ( 6.2) 49
Sensory deprivation 2 /253 ( 0.8) 2 2 /182 ( 1.1) 2 4 /435 ( 0.9) 4
Migraine 1 /182 ( 0.5) 2 1 /435 ( 0.2) 2
Neuralgia 1 /253 ( 0.4) 1 1 /182 ( 0.5) 1 2 /435 ( 0.5) 2
Peripheral neuropathy 2 /253 ( 0.8) 2 1 /182 ( 0.5) 1 3 /435 ( 0.7) 3
Sciatica 1 /253 ( 0.4) 1 1 /182 ( 0.5) 2 2 /435 ( 0.5) 3
drowsiness 2 /253 ( 0.8) 2 2 /435 ( 0.5) 2
Transient ischaemic attack 1 /253 ( 0.4) 1 1 /435 ( 0.2) 1
tremor 1 /253 ( 0.4) 1 1 /435 ( 0.2) 1
Lacunar infarction 1 /182 ( 0.5) 1 1 /435 ( 0.2) 1
Parkinson's disease 1 /253 ( 0.4) 1 1 /435 ( 0.2) 1
Mental disorder 5 /253 ( 2.0) 5 5 /182 ( 2.7) 5 10 /435 ( 2.3) 10
Depression 3 /253 ( 1.2) 3 3 /435 ( 0.7) 3
Insomnia 1 /253 ( 0.4) 1 2 /182 ( 1.1) 2 3 /435 ( 0.7) 3
Panic attacks 1 /182 ( 0.5) 1 1 /435 ( 0.2) 1
Schizophrenia 1 /253 ( 0.4) 1 1 /435 ( 0.2) 1
Anxiety disorders 2 /182 ( 1.1) 2 2 /435 ( 0.5) 2
Renal and urinary tract disorders 5 /253 ( 2.0) 6 4 /182 ( 2.2) 5 9 /435 ( 2.1) 11
Ureteral calculus 1 /253 ( 0.4) 1 1 /435 ( 0.2) 1
Difficulty in urination 4 /253 ( 1.6) 4 4 /182 ( 2.2) 4 8 /435 ( 1.8) 8
Hydronephrosis 1 /253 ( 0.4) 1 1 /435 ( 0.2) 1
Urine Residue 1 /182 ( 0.5) 1 1 /435 ( 0.2) 1
Reproductive system and breast disorders 4 /253 ( 1.6) 7 3 /182 ( 1.6) 3 7 /435 ( 1.6) 10
Atrophic vulvovaginitis 1 /253 ( 0.4) 1 1 /435 ( 0.2) 1
Dysmenorrhoea 1 /253 ( 0.4) 1 1 /435 ( 0.2) 1
Menopausal symptoms 1 /253 ( 0.4) 1 2 /182 ( 1.1) 2 3 /435 ( 0.7) 3
Irregular uterine bleeding 1 /253 ( 0.4) 1 1 /435 ( 0.2) 1
Prostatitis 1 /182 ( 0.5) 1 1 /435 ( 0.2) 1
Pruritus Vulvae 1 /253 ( 0.4) 3 1 /435 ( 0.2) 3
Respiratory, thoracic and mediastinal 15 /253 ( 5.9) 17 20 /182 ( 11.0 26 35 /435 ( 8.0) 43
disorders )
Asthma 2 /253 ( 0.8) 2 2 /435 ( 0.5) 2
Cough 1 /253 ( 0.4) 1 5 /182 ( 2.7) 5 6 /435 ( 1.4) 6
Dry throat 1 /182 ( 0.5) 1 1 /435 ( 0.2) 1
Speech impediment 1 /253 ( 0.4) 1 1 /182 ( 0.5) 2 2 /435 ( 0.5) 3
Pneumothorax 1 /182 ( 0.5) 1 1 /435 ( 0.2) 1
Allergic Rhinitis 2 /253 ( 0.8) 2 2 /182 ( 1.1) 2 4 /435 ( 0.9) 4
Seasonal Rhinitis 1 /182 ( 0.5) 1 1 /435 ( 0.2) 1
Vasomotor rhinitis 1 /182 ( 0.5) 1 1 /435 ( 0.2) 1
Inflammation of the upper airway 7 /253 ( 2.8) 8 5 /182 ( 2.7) 5 12 /435 ( 2.8) 13
Allergic cough 1 /182 ( 0.5) 1 1 /435 ( 0.2) 1
Oropharyngeal discomfort 1 /253 ( 0.4) 1 2 /182 ( 1.1) 3 3 /435 ( 0.7) 4
oropharyngeal pain 2 /253 ( 0.8) 2 2 /182 ( 1.1) 4 4 /435 ( 0.9) 6

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 2.7.6 Summary of the individual tests

Table 2.7.6.5-18 Frequency of adverse events by symptom (Part 6)

Population for analysis: Safety analysis population
Dose group 0.2 mg/day continuous 0.4 mg/day increased Overall
group dose group
Adverse event items Mani Targ Expres Mani Mani Targ Expres Mani Mani Targ Expres Mani
(MedDRA classification of SOC and PT) fest et sion fest fest et sion fest fest et sion fest
atio Numb rate atio atio Numb rate atio atio Numb rate atio
n er (%) n n er (%) n n er (%) n
Numb of Numb Numb of Numb Numb of Numb
er case er er case er er case er
of s of of s of of s of
case case case case case case
s s s s s s
Skin and subcutaneous tissue disorders 27 /253 ( 10.7 30 19 /182 ( 10.4 25 46 /435 ( 10.6 55
) ) )
acne 1 /182 ( 0.5) 1 1 /435 ( 0.2) 1
Acrodermatitis 3 /253 ( 1.2) 3 3 /435 ( 0.7) 3
Skin cysts 1 /182 ( 0.5) 1 1 /435 ( 0.2) 1
Dermatitis 6 /253 ( 2.4) 7 2 /182 ( 1.1) 2 8 /435 ( 1.8) 9
Contact dermatitis 2 /253 ( 0.8) 2 1 /182 ( 0.5) 2 3 /435 ( 0.7) 4
Skin dryness 1 /253 ( 0.4) 1 1 /435 ( 0.2) 1
Sweating disorders 1 /253 ( 0.4) 1 1 /435 ( 0.2) 1
Eczema 7 /253 ( 2.8) 7 6 /182 ( 3.3) 6 13 /435 ( 3.0) 13
Seborrheic Dermatitis 1 /253 ( 0.4) 1 1 /435 ( 0.2) 1
Red sweat rash 3 /182 ( 1.6) 3 3 /435 ( 0.7) 3
hyperkeratosis 2 /253 ( 0.8) 2 1 /182 ( 0.5) 1 3 /435 ( 0.7) 3
Fitted claws 1 /182 ( 0.5) 1 1 /435 ( 0.2) 1
Allergic photosensitivity reactions 1 /253 ( 0.4) 1 1 /435 ( 0.2) 1
Pruritus 2 /253 ( 0.8) 2 2 /435 ( 0.5) 2
Psoriasis 1 /182 ( 0.5) 1 1 /435 ( 0.2) 1
Rash 1 /253 ( 0.4) 1 2 /182 ( 1.1) 3 3 /435 ( 0.7) 4
Urticaria 1 /253 ( 0.4) 1 3 /182 ( 1.6) 4 4 /435 ( 0.9) 5
Angiokeratoma Corporis 1 /253 ( 0.4) 1 1 /435 ( 0.2) 1
Surgical and medical procedures 3 /253 ( 1.2) 3 1 /182 ( 0.5) 1 4 /435 ( 0.9) 4
Blepharoplasty 1 /253 ( 0.4) 1 1 /435 ( 0.2) 1
Tympanoplasty 1 /182 ( 0.5) 1 1 /435 ( 0.2) 1
Surgical spinal fusion 1 /253 ( 0.4) 1 1 /435 ( 0.2) 1
Vertebroplasty 1 /253 ( 0.4) 1 1 /435 ( 0.2) 1
Vascular disorders 3 /253 ( 1.2) 3 4 /182 ( 2.2) 4 7 /435 ( 1.6) 7
High blood pressure 1 /253 ( 0.4) 1 2 /182 ( 1.1) 2 3 /435 ( 0.7) 3
Low blood pressure 1 /253 ( 0.4) 1 1 /435 ( 0.2) 1
Orthostatic hypotension 2 /182 ( 1.1) 2 2 /435 ( 0.5) 2
Hot flashes 1 /253 ( 0.4) 1 1 /435 ( 0.2) 1

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 2.7.6 Summary of the individual tests

Table 2.7.6.5-19 Frequency of adverse reactions by symptom (Part 1)

Population for analysis: Safety analysis population
Dose group 0.2 mg/day continuous 0.4 mg/day increased Overall
group dose group
Side effects Mani Targ Expres Mani Mani Targ Expres Mani Mani Targ Expres Mani
(MedDRA classification of SOC and PT) fest et sion fest fest et sion fest fest et sion fest
atio Numb rate atio atio Numb rate atio atio Numb rate atio
n er (%) n n er (%) n n er (%) n
Numb of Numb Numb of Numb Numb of Numb
er case er er case er er case er
of s of of s of of s of
case case case case case case
s s s s s s
Overall 101 /253 ( 39.9 143 114 /182 ( 62.6 200 215 /435 ( 49.4 343
) ) )
Blood and lymphatic disorders 1 /182 ( 0.5) 1 1 /435 ( 0.2) 1
Lymphadenopathy 1 /182 ( 0.5) 1 1 /435 ( 0.2) 1
Heart problems 2 /253 ( 0.8) 3 2 /182 ( 1.1) 4 4 /435 ( 0.9) 7
Arrhythmia 1 /253 ( 0.4) 2 1 /435 ( 0.2) 2
Atrial Fibrillation 1 /182 ( 0.5) 1 1 /435 ( 0.2) 1
Ventricular extrasystoles 1 /253 ( 0.4) 1 2 /182 ( 1.1) 3 3 /435 ( 0.7) 4
Eye disorders 2 /253 ( 0.8) 2 3 /182 ( 1.6) 3 5 /435 ( 1.1) 5
Foggy vision 1 /253 ( 0.4) 1 3 /182 ( 1.6) 3 4 /435 ( 0.9) 4
Ocular dryness 1 /253 ( 0.4) 1 1 /435 ( 0.2) 1
Gastrointestinal disorders 87 /253 ( 34.4 106 108 /182 ( 59.3 153 195 /435 ( 44.8 259
) ) )
Abdominal discomfort 4 /253 ( 1.6) 5 2 /182 ( 1.1) 2 6 /435 ( 1.4) 7
Abdominal distension 2 /253 ( 0.8) 2 2 /435 ( 0.5) 2
Upper abdominal pain 1 /182 ( 0.5) 1 1 /435 ( 0.2) 1
Change in stool habits 1 /253 ( 0.4) 1 1 /435 ( 0.2) 1
Constipation 25 /253 ( 9.9) 26 34 /182 ( 18.7 36 59 /435 ( 13.6 62
) )
Diarrhoea 1 /182 ( 0.5) 1 1 /435 ( 0.2) 1
Dry mouth 67 /253 ( 26.5 68 97 /182 ( 53.3 110 164 /435 ( 37.7 178
) ) )
Gastritis 1 /253 ( 0.4) 1 1 /435 ( 0.2) 1
Dry lips 1 /253 ( 0.4) 1 1 /182 ( 0.5) 1 2 /435 ( 0.5) 2
Nausea 1 /253 ( 0.4) 1 1 /182 ( 0.5) 1 2 /435 ( 0.5) 2
Mouth ulcers 1 /253 ( 0.4) 1 1 /182 ( 0.5) 1 2 /435 ( 0.5) 2
Systemic disorders and local conditions of 1 /253 ( 0.4) 1 1 /182 ( 0.5) 1 2 /435 ( 0.5) 2
administration
Edema 1 /253 ( 0.4) 1 1 /435 ( 0.2) 1
dry mouth 1 /182 ( 0.5) 1 1 /435 ( 0.2) 1
Infectious and parasitic diseases 6 /253 ( 2.4) 7 1 /182 ( 0.5) 1 7 /435 ( 1.6) 8
Cystitis 1 /253 ( 0.4) 1 1 /182 ( 0.5) 1 2 /435 ( 0.5) 2
Pyelonephritis 1 /253 ( 0.4) 1 1 /435 ( 0.2) 1
Urinary tract infection 4 /253 ( 1.6) 5 4 /435 ( 0.9) 5
Laboratory tests 12 /253 ( 4.7) 14 9 /182 ( 4.9) 15 21 /435 ( 4.8) 29
Increase in alanine aminotransferase 2 /182 ( 1.1) 2 2 /432 ( 0.5) 2
Increased aspartate aminotransferase 2 /182 ( 1.1) 2 2 /432 ( 0.5) 2
Increased blood cholesterol 1 /182 ( 0.5) 1 1 /432 ( 0.2) 1
Increased lactate dehydrogenase in the 1 /182 ( 0.5) 1 1 /432 ( 0.2) 1
blood
Increased gamma-glutamyltransferase 1 /182 ( 0.5) 1 1 /432 ( 0.2) 1
Positive red blood cells in urine 1 /250 ( 0.4) 1 2 /182 ( 1.1) 2 3 /432 ( 0.7) 3
Positive urinary white blood cell count 6 /250 ( 2.4) 7 1 /182 ( 0.5) 2 7 /432 ( 1.6) 9
Amount of urine remaining 5 /253 ( 2.0) 6 3 /182 ( 1.6) 3 8 /435 ( 1.8) 9
Increase in blood alkaline phosphatase 1 /182 ( 0.5) 1 1 /432 ( 0.2) 1
Musculoskeletal and connective tissue 2 /182 ( 1.1) 2 2 /435 ( 0.5) 2
disorders
Back pain 2 /182 ( 1.1) 2 2 /435 ( 0.5) 2
Nervous system disorders 6 /253 ( 2.4) 7 4 /182 ( 2.2) 5 10 /435 ( 2.3) 12
Floating vertigo 2 /253 ( 0.8) 2 2 /435 ( 0.5) 2
Taste disorders 1 /182 ( 0.5) 1 1 /435 ( 0.2) 1
Headache 3 /253 ( 1.2) 3 2 /182 ( 1.1) 2 5 /435 ( 1.1) 5
Migraine 1 /182 ( 0.5) 2 1 /435 ( 0.2) 2
drowsiness 2 /253 ( 0.8) 2 2 /435 ( 0.5) 2
Mental disorder 1 /182 ( 0.5) 1 1 /435 ( 0.2) 1
Insomnia 1 /182 ( 0.5) 1 1 /435 ( 0.2) 1
Renal and urinary tract disorders 1 /253 ( 0.4) 1 4 /182 ( 2.2) 5 5 /435 ( 1.1) 6
Difficulty in urination 1 /253 ( 0.4) 1 4 /182 ( 2.2) 4 5 /435 ( 1.1) 5
Urine Residue 1 /182 ( 0.5) 1 1 /435 ( 0.2) 1
Reproductive system and breast disorders 1 /182 ( 0.5) 1 1 /435 ( 0.2) 1

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 2.7.6 Summary of the individual tests

Prostatitis 1 /182 ( 0.5) 1 1 /435 ( 0.2) 1

Respiratory, thoracic and mediastinal 1 /253 ( 0.4) 1 3 /182 ( 1.6) 6 4 /435 ( 0.9) 7
disorders
Cough 1 /253 ( 0.4) 1 1 /435 ( 0.2) 1
Dry throat 1 /182 ( 0.5) 1 1 /435 ( 0.2) 1
Speech impediment 1 /182 ( 0.5) 2 1 /435 ( 0.2) 2
Oropharyngeal discomfort 2 /182 ( 1.1) 3 2 /435 ( 0.5) 3

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 2.7.6 Summary of the individual tests

Table 2.7.6.5-19 Frequency of adverse reactions by symptom (Part 2)

Population for analysis: Safety analysis population
Dose group 0.2 mg/day continuous 0.4 mg/day increased Overall
group dose group
Side effects Mani Targ Expres Mani Mani Targ Expres Mani Mani Targ Expres Mani
(MedDRA classification of SOC and PT) fest et sion fest fest et sion fest fest et sion fest
atio Numb rate atio atio Numb rate atio atio Numb rate atio
n er (%) n n er (%) n n er (%) n
Numb of Numb Numb of Numb Numb of Numb
er case er er case er er case er
of s of of s of of s of
case case case case case case
s s s s s s
Skin and subcutaneous tissue disorders 1 /253 ( 0.4) 1 1 /182 ( 0.5) 2 2 /435 ( 0.5) 3
Allergic photosensitivity reactions 1 /253 ( 0.4) 1 1 /435 ( 0.2) 1
Rash 1 /182 ( 0.5) 2 1 /435 ( 0.2) 2

Figure 2.7.6.5-11 and Figure 2.7.6.5-12 show the results of the Kaplan-Meier analysis
of the cumulative incidence of adverse events and adverse reactions for dry mouth, the
most frequently occurring adverse reaction, respectively.
The cumulative incidence of dry mouth adverse events and adverse reactions was 25.1%
and 24.4%, respectively, after 12 weeks of treatment in all patients. At the final
evaluation, the cumulative incidence of dry mouth adverse events and adverse reactions
was 29.9% and 28.7% after 52 weeks of treatment or at discontinuation in the 0.2 mg/day
continuation group, respectively, and 54.5% and 53.9% after 64 weeks of treatment or at
discontinuation in the 0.4 mg/day dose increase group, respectively.
In terms of the incidence of dry mouth (adverse event) by severity, there were no
cases of severe dry mouth. The incidence of moderate dry mouth was 3.9% (17/435) in all
patients, 4.0% (10/253) in the 0.2 mg/day continuation group and 3.8% (7/182) in the
0.4 mg/day dose increase group. All 17 cases of moderate mouth dryness were judged to
be adverse reactions.

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 2.7.6 Summary of the individual tests

100.0

90.0
0.2 mg/日継続群
0.4 mg/日増量群 0.2 mg
80.0 　　 全体

70.0
累積発現率（％）

60.0

50.0

40.0

30.0

20.0 累積発現率
12週時 最終評価時1）
0.2 mg/日継続群 24.8％ 29.9％
10.0
0.4 mg/日増量群 25.3％ 54.5％
全体 25.1％
0.0
0 8 16 24 32 40 48 56 64

時期（週）
at-risk例数 0週 4週 8週 12週 16週 20週 24週 28週 32週 36週 40週 44週 48週 52週 56週 60週 64週
0.2 mg/日継続群 253 187 171 160 149 148 146 138 136 134 133 132 131 83
0.4 mg/日増量群 182 151 143 138 100 94 87 82 82 82 80 76 75 75 73 72 43
全体 435 338 314 298 249 242 233 220 218 216 213 208 206 158 73 72 43
1）治療期52週後または中止時
（0.2 mg/日継続群）
治療期64週後または中止時
（0.4 mg/日増量群）
解析対象集団：安全性解析対象集団
Figure 2.7.6.5-11 Cumulative incidence of dry mouth (adverse event)

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 2.7.6 Summary of the individual tests

100.0

90.0
0.2 mg/日継続群
0.4 mg/日増量群 0.2 mg
80.0 　　 全体

70.0
累積発現率（％）

60.0

50.0

40.0

30.0

20.0 累積発現率
12週時 最終評価時1）
0.2 mg/日継続群 23.6％ 28.7％
10.0
0.4 mg/日増量群 25.3％ 53.9％
全体 24.4％
0.0
0 8 16 24 32 40 48 56 64

時期（週）
at-risk例数 0週 4週 8週 12週 16週 20週 24週 28週 32週 36週 40週 44週 48週 52週 56週 60週 64週
0.2 mg/日継続群 253 190 174 163 152 151 149 141 139 137 136 135 134 85
0.4 mg/日増量群 182 151 143 138 100 94 87 82 82 82 80 77 76 76 74 73 43
全体 435 341 317 301 252 245 236 223 221 219 216 212 210 161 74 73 43
1）治療期52週後または中止時
（0.2 mg/日継続群）
治療期64週後または中止時
（0.4 mg/日増量群）
解析対象集団：安全性解析対象集団
Figure 2.7.6.5-12 Cumulative incidence of dry mouth (side effect)

With regard to the incidence of adverse events and adverse reactions by severity of
constipation (13.6%), for which the incidence of adverse reactions was 5% or more in
all patients except dry mouth, there were no cases of severe constipation. The incidence
of moderate constipation (adverse events) was 0.9% (4/435) in all patients, 0.4% (1/253)
in the 0.2 mg/day continuation group and 1.6% (3/182) in the 0.4 mg/day increase group.
All four cases of moderate constipation were judged to be adverse reactions.

Death, other serious adverse events and other significant adverse events
There were no deaths in this study.
A list of other serious adverse events is given in Table 2.7.6.5-20. Other serious
adverse events were observed in 8 patients in the 0.2 mg/day continuation group and in
8 patients in the 0.4 mg/day dose increase group (11 events). No serious adverse event

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 2.7.6 Summary of the individual tests

occurred in more than one patient. All of these serious adverse events were considered
to be complication-related or incidental and were not causally related to the study
drug.

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 2.7.6 Summary of the individual tests

Table 2.7.6.5-20 List of other serious adverse events

Population for analysis: Safety analysis population
number Causal relationship to
name* Time of
group of Adverse event [MedDRA base word the investigational
manifestation
pairs drug
Lumbar vertebroplasty
576 29 days later No relation
[Vertebroplasty].
Worsening of depression in
435 schizophrenia 83 days later No relation
Schizophrenia.
527 Graves' disease [Graves' disease 102 days later No relation
0.2 mg/day 170 Infective endocarditis [endocarditis After 105 days No relation
continuous group 147 Worsening of diabetes [Diabetes]. 114 days later No relation
534 Left hydronephrosis [hydronephrosis 193 days later No relation
Parkinson's disease
496 286 days later No relation
Parkinson's disease.
Posterior decompression fixation of After 330 days
455 the lumbar spine (10 days after the No relation
Surgical spinal fusion end of the trial)
Haemorrhagic gastric ulcer
After 120 days No relation
[haemorrhagic gastric ulcer
202
Acute gastroenteritis
231 days later No relation
[Gastroenteritis
446 Left hiatal hernia [Inguinal hernia After 125 days No relation
Fracture (medial part of left ankle
joint, proximal part of left foot
489 After 157 days No relation
fibula)
0.4 mg/day Complex fracture.
increased dose
Worsening of back pain [backache]. After 190 days No relation
group 549
Tympanoplasty [tympanoplasty]. 272 days later No relation
Increased blood pressure [Increased
407 259 days later No relation
blood pressure
404 Head trauma [Head injury After 289 days No relation
Headache [Headache After 319 days No relation
214 Cancer of the cervix [Cancer of the
327 days later No relation
cervix
284 Bladder cancer [Bladder cancer 364 days later No relation
Name of the event reported in the case report

Other important adverse events included non-serious adverse events that were judged
to be severe, adverse events that resulted in dose discontinuation, and adverse events
that resulted in dose reduction. Tables 2.7.6.5-21, 2.7.6.5-22, and 2.7.6.5-23 list
cases of non-serious but severe adverse events, adverse events leading to discontinuation,
and adverse events leading to weight loss, respectively.
The only non-serious adverse event judged to be severe was one case of lymphadenopathy
(MedDRA Baseline: lymphadenopathy) in the 0.4 mg/day dose escalation group. The
possibility of malignant lymphoma was ruled out, and the investigator concluded that
the lymphadenopathy was not causally related to the study drug because the cause could
not be determined, although it could be a reaction to the concomitant medication
methotrexate. The event resolved after discontinuation of the study drug.
The incidence of adverse events leading to discontinuation (including withdrawal of
consent due to adverse events) was 7.8% (34/435) of all patients, 11.1% (28/253) in the
0.2 mg/day continuation group, and 3.3% (6/182) in the 0.4 mg/day dose increase group.
The incidence of adverse drug reactions causing discontinuation of treatment was 4.6%
(20/435) in all patients, 6.3% (16/253) in the 0.2 mg/day continuous group and 2.2%

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 2.7.6 Summary of the individual tests

(4/182) in the 0.4 mg/day increased group. Among the adverse events that led to
discontinuation of treatment, those that occurred relatively frequently (incidence of
0.5% or more in all patients) were dry mouth in 1.4% (1.6% in the 0.2 mg/day continuous
group and 1.1% in the 0.4 mg/day increased group), constipation in 0.9% (1.6% in the
0.2 mg/day continuous group and 0.0% in the 0.4 mg/day increased group), residual The
incidence of urinary retention was 0.7% (1.2% in the 0.2 mg/day continuous group and
0.0% in the 0.4 mg/day increased group), most likely due to anticholinergic effects.
All of the adverse events that led to discontinuation of treatment resolved or resolved
with discontinuation of the study drug, observation, or appropriate treatment. The
incidence of adverse events leading to dose reduction was 5.5% (10/182 patients) in the
0.4 mg/day dose increase group. The most frequent adverse event resulting in dose
reduction was dry mouth in 2.7% (5/182) of patients, most likely due to anticholinergic
effects. All of the adverse events that caused a reduction in the dose of the study drug
disappeared or resolved with discontinuation of the study drug, follow-up or drug
treatment.

Table 2.7.6.5-21 Adverse events judged to be severe other than serious

Population for analysis: Safety analysis population
Causal relationship to
number of Name of adverse event Time of
group the investigational
pairs MedDRA Basic Terms manifestation
drug
0.4 mg/day
Lymphadenopathy Not necessarily
increased dose 358 161
Lymphadenopathy. related
group
Name of the event reported in the case report

Table 2.7.6.5-22 Adverse events resulting in discontinuation of treatment

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 2.7.6 Summary of the individual tests

解析対象集団：安全性解析対象集団
投与群 0.2 mg/日継続群 0.4 mg/日増量群 全体
有害事象項目 発現 対象 発現率 発現 対象 発現率 発現 対象 発現率
（MedDRAによるSOC･PT分類） 例数 例数 (％) 例数a) 例数 (％) 例数a) 例数 (％)
全体 28 /253 ( 11.1) 6 /182 ( 3.3) 34 /435 ( 7.8)
血液およびリンパ系障害 1 /182 ( 0.5) 1 /435 ( 0.2)
リンパ節症 1 /182 ( 0.5) 1 /435 ( 0.2)
心臓障害 2 /253 ( 0.8) 1 /182 ( 0.5) 3 /435 ( 0.7)
心房細動 1 /182 ( 0.5) 1 /435 ( 0.2)
動悸 1 /253 ( 0.4) 1 /435 ( 0.2)
心室性期外収縮 1 /253 ( 0.4) 1 /435 ( 0.2)
内分泌障害 1 /253 ( 0.4) 1 /435 ( 0.2)
バセドウ病 1 /253 ( 0.4) 1 /435 ( 0.2)
胃腸障害 13 /253 ( 5.1) 2 /182 ( 1.1) 15 /435 ( 3.4)
腹部不快感 2 /253 ( 0.8) 2 /435 ( 0.5)
腹部膨満 1 /253 ( 0.4) 1 /435 ( 0.2)
便秘 4 /253 ( 1.6) 4 /435 ( 0.9)
口内乾燥 4 /253 ( 1.6) 2 /182 ( 1.1) 6 /435 ( 1.4)
胃腸障害 1 /253 ( 0.4) 1 /435 ( 0.2)
悪心 1 /253 ( 0.4) 1 /435 ( 0.2)
全身障害および投与局所様態 1 /253 ( 0.4) 1 /435 ( 0.2)
胸部不快感 1 /253 ( 0.4) 1 /435 ( 0.2)
感染症および寄生虫症 3 /253 ( 1.2) 3 /435 ( 0.7)
膀胱炎 1 /253 ( 0.4) 1 /435 ( 0.2)
心内膜炎 1 /253 ( 0.4) 1 /435 ( 0.2)
尿路感染 1 /253 ( 0.4) 1 /435 ( 0.2)
臨床検査 4 /253 ( 1.6) 4 /435 ( 0.9)
尿中白血球陽性 1 /250 ( 0.4) 1 /432 ( 0.2)
残尿量 3 /253 ( 1.2) 3 /435 ( 0.7)
代謝および栄養障害 1 /253 ( 0.4) 1 /435 ( 0.2)
糖尿病 1 /253 ( 0.4) 1 /435 ( 0.2)
筋骨格系および結合組織障害 1 /253 ( 0.4) 1 /435 ( 0.2)
脊椎すべり症 1 /253 ( 0.4) 1 /435 ( 0.2)
良性、悪性および詳細不明の新生物（嚢胞およびポ 2 /182 ( 1.1) 2 /435 ( 0.5)
リープを含む）
膀胱癌 1 /182 ( 0.5) 1 /435 ( 0.2)
子宮頚部癌 1 /182 ( 0.5) 1 /435 ( 0.2)
神経系障害 4 /253 ( 1.6) 4 /435 ( 0.9)
浮動性めまい 1 /253 ( 0.4) 1 /435 ( 0.2)
頭痛 1 /253 ( 0.4) 1 /435 ( 0.2)
神経痛 1 /253 ( 0.4) 1 /435 ( 0.2)
傾眠 1 /253 ( 0.4) 1 /435 ( 0.2)
振戦 1 /253 ( 0.4) 1 /435 ( 0.2)
精神障害 2 /253 ( 0.8) 2 /435 ( 0.5)
うつ病 1 /253 ( 0.4) 1 /435 ( 0.2)
統合失調症 1 /253 ( 0.4) 1 /435 ( 0.2)
腎および尿路障害 2 /253 ( 0.8) 2 /435 ( 0.5)
尿管結石 1 /253 ( 0.4) 1 /435 ( 0.2)
排尿困難 1 /253 ( 0.4) 1 /435 ( 0.2)
水腎症 1 /253 ( 0.4) 1 /435 ( 0.2)
a）有害事象による投与中止例である薬剤番号512番の被験者は、投与中止の原因となった有害事象が特定されなかっ
たために、投与中止の原因となった有害事象発現例に含めなかった。

Table 2.7.6.5-23 Adverse events causing weight loss

Population for analysis: Safety analysis population
number Adverse event name* [MedDRA Time of Causal relationship to
group
of pairs base word manifestation the investigational drug
7 days
355 Dry mouth [dry mouth]. Probably related
later
Worsening of dry mouth (dry
9 days
357 mouth) Probably related
later
0.4 mg/day [Dry mouth]
increased dose Exacerbation of dry mouth After 54
Clearly relevant
group [dry mouth]. days
363
After 90
Stomatitis [Stomatitis]. Probably related
days
Spring finger of right 91 days
214 No relation
middle finger (hypertrophic later

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 2.7.6 Summary of the individual tests

tendinopathy)
[Bullet finger]
Thirst (dry mouth) 94 days
Clearly relevant
[Dry mouth] later
491
After 95
Skin rash [Eruption] Not necessarily related
days
Ventricular extrasystoles After 95
290 Not necessarily related
[ventricular extrasystoles] days
Gastrointestinal discomfort 102 days
Probably related
[abdominal discomfort] later
539
Constipation After 115
Probably related
[constipation]. days
Increased residual urine After 168
433 Not necessarily related
[amount of residual urine]. days
After 180
Vomiting [emesis]. No relation
days
401
After 190
Vomiting [emesis]. No relation
days
Thirst (dry mouth) 238 days
Probably related
[Dry mouth] later
238 days
426 Hoarseness [dysphonia]. Probably related
later
Pharyngeal Discomfort 238 days
Probably related
[Oropharyngeal Discomfort] later
Name of the event reported in the case report

4) Clinical laboratory values

There were scattered abnormal changes in clinical laboratory values, but no clinically
problematic changes were observed.

(5) Vital signs, physical findings and other observations relevant to safety
There were some abnormalities in blood pressure, pulse rate, ECG and residual urine
output, but no clinically problematic changes were observed. There was no prolongation
of the mean value of QTc and change in QTc calculated by the Bazett equation at the time
of the ECG QTc assessment, and the results of the categorical analysis showed no
significant difference in the proportion of patients at each assessment. The maximum
QTc value was 495.0 msec, and there were no cases of clinical concern exceeding 500 msec
at any time. The maximum QTc was 495.0 msec. In the 0.4 mg/day escalation group, QT was
measured at 24 weeks post-treatment and at 2 hours post-dose, around the time of maximum
plasma concentration, and, as in the other assessment periods, there were no clinically
relevant changes in QTc.

4) Conclusion
In patients for whom the usual dose of 0.2 mg/day was not sufficiently effective,
increasing the dose to 0.4 mg/day improved symptoms of urinary urgency, frequency, and
urge urinary incontinence in overactive bladder and patient quality of life, and the
effect was maintained without diminution up to 1 year after the dose increase. After
increasing the dose to 0.4 mg/day, there was no increase in side effects due to long-
term administration or new clinically problematic side effects, and the drug can be
administered safely for a long time.
In addition to the usual dose of this drug, the dose can be increased to 0.4 mg/day
as appropriate, which is considered to provide an effective and safe opportunity to

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 2.7.6 Summary of the individual tests

treat overactive bladder in a larger number of patients, including those who are not
fully satisfied with the effect of the usual dose (0.2 mg/day) in clinical practice.

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 2.7.6 Summary of the individual tests

-6 ONO-8025 Long-term administration study Long-term administration study in patients

with overactive bladder [ONO-8025-07
(1) Outline of the test
Title of the ONO-8025 Long-term administration study Long-term administration study in
clinical trial patients with overactive bladder
Clinical trial
ONO-8025-07
protocol number
Clinical trial
Ono Pharmaceutical Industry Co.
sponsors
Principal Taketoshi Saka, Department of Urology, Saka Urological Hospital, Kitanrenkai
Investigator Medical Corporation, and others (74 persons in total)
Clinical trial sites Kitanrenkai Saka Urological Hospital Urology and others (74 facilities in
total)
Trial Period 11 July 2003 (date of consent for the first case)
24 November 2004 (date of last medication for last subject)
Development phase Phase III
Objective To investigate the safety and efficacy of long-term treatment with ONO-8025
in patients with overactive bladder in a multicenter, open-label, uncontrolled
study.
Test design Multicentre, open-label, uncontrolled
Clinical Trial After a 2-week observation period, ONO-8025 0.1 mg tablets were orally
Method administered twice daily after breakfast and dinner for 52 weeks in patients
with overactive bladder. An interim analysis was performed on the data up to
28 weeks after the treatment period.
Number of subjects At the time of planning At least 400 cases (at least 300 cases to be evaluated
after 28 weeks of treatment, of which at least 100 cases to be evaluated after
52 weeks of treatment)
Number of patients in this registry: 481
Number of cases analysed for safety: 478
Number of patients analysed for efficacy (number of PPS patients): 364
Number of patients analysed for efficacy (number of patients with FAS): 474
Target Overactive bladder patients
Selection criteria Patients with overactive bladder who fulfilled all of the following 1) to 4)
were selected.
1) Age: 20 years and over (at the time of obtaining consent)
2) Gender and inpatient/outpatient status: Not applicable
(3) Patients who fulfil all of the following criteria in the symptom diary for
the week prior to the end of the observation period
(1) Frequency of urinary incontinence: Total number of urge incontinence
episodes per week of 1 or more
(2) Frequency of urination: average of 8 or more urinations per day
(3) Frequency of urinary urgency: average of at least one urinary urgency per
day
(4) Patients who are judged by the investigator (or sub-investigator) to be
able to accurately record the symptom diary
Exclusion criteria Patients with any of the following 1) to 16) were excluded.
1) Patients with genuine stress incontinence (GSI)
2) Patients with prostate cancer, bladder tumours, bladder stones, urinary
tract infections (cystitis, prostatitis, etc.) and interstitial cystitis,
or a history of recurrent urinary tract infections (two or more within 6
months prior to the observation period)
(3) Patients who have undergone urogenital surgery within 6 months prior to
the observation period
4) Patients with indwelling catheters or intermittent urinary continence
5) Patients who have undergone electrical stimulation therapy or bladder
training within 3 months prior to the observation period and have shown a
positive response

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 2.7.6 Summary of the individual tests

(6) Patients who have received concomitantly prohibited drugs within 2 weeks
prior to the observation period
(7) Patients with contraindications to the administration of anticholinergic
drugs (severe heart disease, glaucoma, myasthenia gravis, obstruction of
the pylorus, duodenum or intestinal tract, gastric atony, intestinal
atony).
(8) Patients with a history of serious allergy or serious adverse reactions
to drugs
9) Patients with a residual urine volume of 100 mL or more, or with clinically
problematic obstructive diseases of the lower urinary tract such as benign
prostatic hyperplasia
(10) Patients with polyuria with a daily urine output of 3000 mL or more in
the symptom diary during the observation period
(11) Patients with total bilirubin greater than 3.0 mg/dL or AST (GOT) and ALT
(GPT) greater than 2.5 times the institutional normal (or greater than 100
IU/L)
(12) Patients with a serum creatinine of 2.0 mg/dL or more
(13) Patients with malignancies that may affect their general condition and
survival.
(14) Patients who are pregnant, lactating, or who may become pregnant, or who
wish to become pregnant during the study period.
(15) Patients who have not yet completed 4 months of treatment with all other
investigational drugs or who have previously received ONO-8025 (KRP-197)

Exclusion criteria (16) Other patients who are judged by the investigator (or sub-investigator)
(cont'd) to be unsuitable for the study
Test drug
Preparations Formulation Content Lot.No Expiry date
Dosage and serial
ONO-8025 Film Each tablet contains
number S320440 January 2006
1.0 mg tablet Coated tablets 0.05 mg

Control drug
Dosage and serial None
number
Method of One tablet was administered orally twice a day after breakfast and after
administration dinner.
Duration 52 weeks
Combination therapy Prohibited treatments before the observation period
(1) Medication prohibited within 8 weeks prior to observation period
Estrogen preparations (but allowed if the same dose has been used for at least
8 weeks prior to the observation period).
(2) Medication prohibited within 13 days prior to the observation period
1) Drugs for frequent urination and urinary incontinence
2) Anticholinergics and cholinergic agonists
3) Tricyclic antidepressants
4) Anticonvulsants
5) Anti-Parkinson's drugs

Prohibited treatments from the observation phase to the treatment phase

(1) Contraindications
1) Drugs for frequent urination and urinary incontinence
2) Anticholinergics and cholinergic agonists
3) Tricyclic antidepressants
4) Anticonvulsants
5) Anti-Parkinson's drugs
6) Estrogen preparations
(7) All other medicines currently under development and of undefined efficacy.
However, estrogen preparations could be used in combination if they had
been used at the same dose for at least 8 weeks prior to the observation

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 2.7.6 Summary of the individual tests

period. No change in dosage and administration was made during the study
period (observation phase to treatment phase).
(2) No concomitant therapy
During the trial period (observation phase to treatment phase), concomitant
use of the therapies specified in the exclusion criteria (urogenital surgery,
indwelling catheters, intermittent urinary continence, electrical stimulation
therapy, bladder training) was prohibited.

(3) Possible concomitant medications

Other than the above-mentioned concomitantly prohibited drugs, concomitant use
was allowed. However, for Ca antagonists, alpha 1 blockers, and antihistamines,
the same drug was used during the study period (observation phase to treatment
phase), and the dosage and administration were not changed whenever possible.
Evaluation criteria Safety, efficacy and pharmacokinetic evaluations were carried out according
to the schedule shown in Table 2.7.6.6-1.
Safety endpoints
Adverse events, side effects, general clinical examination,
electrocardiogram (12-lead), blood pressure and pulse rate, and residual urine
were evaluated. Thirst was graded as mild, moderate or severe according to the
following criteria

Degree Judgement criteria (for reference)

1. mild Almost unnoticeable
2. moderate tolerable with drinking water, etc.
3. altitude Ingestion of water or other substances is not
tolerable (discontinuation of the study drug)

The names of adverse events listed in the case report form have been
translated into major organ categories and basic terms based on MedDRA ver
7.0J (Pharmaceutical Regulatory Terminology).
Efficacy endpoints
The total number of urinary incontinences per week, the average number of
urinations per day, the average number of urinary urgencies per day, the
average amount of urine voided per urination, the degree of urinary urgency
and the quality of life score (King Health Questionnaire) were assessed.

Assessment criteria Pharmacokinetics

(continued) The concentration of the unchanged drug in plasma was determined.
Statistical methods 1) Interim analysis
An interim analysis of data up to 28 weeks post-treatment was performed.
(2) Target population for analysis
The primary analysis population for efficacy was the Per Protocol Set (PPS).
Where appropriate, Full Analysis Set (FAS) analyses were also performed. For
the safety endpoints, the analysis population consisted of patients with the
target disease who had received at least one dose of the treatment.
3) Safety analysis
The following analyses were performed on data up to 52 weeks post-treatment.
A secondary analysis was also performed in the population with a treatment
duration of at least 48 weeks and a medication adherence rate of at least 75%.
(1) The incidence of adverse events, side effects and dry mouth was calculated.
The cumulative incidence was estimated by the Kaplan-Meier method. The
number of days until the onset of each adverse event, side effect, and
dry mouth was calculated as the number of days until the first occurrence
of each event after the start of study drug administration.
(2) Adverse events (subjective symptoms, subjective findings, and abnormal
changes in laboratory values) were aggregated by causal relationship,
degree, organ category, and item.
(3) Summary statistics were calculated for blood pressure, pulse rate, and
residual urine volume at each time point, and changes over time were

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 2.7.6 Summary of the individual tests

examined. Comparisons between pre- and post-treatment were made by means

of a corresponding t-test.
(4) For the ECG, the percentage of patients with or without abnormal findings
was calculated for each evaluation period, and changes over time were
examined. In addition, the amount of change in QTc was also analyzed.
(5) Summary statistics were calculated for each time point and changes in
laboratory values were examined over time. Comparisons between pre- and
post-treatment were made by corresponding t-test or Wilcoxon signed rank
test, depending on the characteristics of the data.
4) Efficacy analysis
The following analyses were performed on the data up to 52 weeks after the
treatment period.
(1) Summary statistics were calculated for each assessment period for the
total number of urinary incontinence episodes per week, the average number
of urination episodes per day, the average number of urinary urgency
episodes per day, the average volume of urination per episodes, the total
number of urinary urgency episodes per week, and the number of days with
zero urinary incontinence episodes per week. Changes over time were
examined. Comparisons between the pre- and post-treatment periods were
made using a corresponding t-test.
(2) The disappearance rate of urinary incontinence frequency was calculated
for each evaluation period, and changes over time were examined.
(3) The frequency distribution of urinary urgency and the amount of change in
urinary urgency were examined over time. Comparisons between the pre- and
post-treatment periods were made using the Wilcoxon signed-rank test.
(4) Summary statistics were calculated for the measured QOL scores and the
change in QOL scores at each evaluation period, and the changes over time
were examined. Comparisons between the pre- and post-treatment periods
were made using a corresponding t-test.
(5) For (1) and (2). The same analysis was performed for patients with a total
number of urinary incontinence of 5 or more times per week at the end of
the observation period.
Date of report 22 February 2005

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 2.7.6 Summary of the individual tests

Table 2.7.6.6-1 Observation and inspection items and timing

Wash
観察期 治療期 中
out 期
時期 止
-4 -2 0 4 8 12 16 20 24 28 32 36 40 44 48 52
時
週 週 週 週 週 週 週 週 週 週 週 週 週 週 週 週

同意取得 ○ ○1)
患者背景
合併症，既往歴 ○
など

服薬状況 ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○

症状日誌の配布 ○ ○ ○ ○ ○ ○

症状日誌の

確認・回収
①尿失禁回数

②排尿回数 ○ ○ ○ ○ ○ ○ ○2)
③尿意切迫感の

回数

④1 回排尿量

尿意切迫感の
○ ○ ○ ○ ○ ○ ○
程度

QOL（キング健
○ ○ ○ ○ ○
康調査票）

残尿量 ○ ○ ○ ○ ○

血圧・脈拍数 ○ ○ ○ ○ ○ ○

心電図（12 誘導） ○ ○ ○ ○ ○

一般臨床検査 ○ ○ ○ ○ ○ ○ ○

有害事象

薬物濃度測定用
○ ○3) ○ ○4) ○ ○
採血

1）Wash out 開始前に同意を取得した場合は不要

2）中止時において症状日誌の記載がある場合
3）治療期 4 週後に採血した場合は不要
4）治療期 28 週後に採血した場合は不要

(2) Summary and conclusion

1) Breakdown of subjects
A total of 481 subjects were enrolled in the study, with 479 receiving study drug,
105 discontinuing or dropping out (including 2 non-treated subjects), and 376 receiving
treatment after 52 weeks of treatment. The number of patients included in the safety
analysis was 478, the number of patients included in the primary analysis of efficacy
(PPS) was 364, and the number of patients included in the secondary analysis (FAS) was
474 (see Figure 2.7.6.6-1), and the treatment of cases is shown in Table 2.7.6.6-2.

- 409 -
 2.7.6 Summary of the individual tests

登録症例

481

安全性解析対象集団 GCP不遵守例 未投与例 対象疾患外症例

478 1 2 0

FAS 不適格例 有効性評価項目未観察例

474 4 0

処置違反††・
PPS 早期中止・脱落例†
服薬率違反例†††
364 95 110

完全症例†††† 中止・脱落例 評価データ不完備例

291 2 73

† ：投与期間が治療期28週後の評価時に24週未満，治療期52週後の評価時に48週未満の症例
†† ：併用禁止薬による治療を実施した症例
††† ：治療期の服薬率が75％未満の症例
††††：治験実施計画書完全遵守例

Figure 2.7.6.6-1 Breakdown of subjects

- 410 -
 2.7.6 Summary of the individual tests

Table 2.7.6.6-2 Treatment of cases

該当 PPS FAS 安全性
問題項目 内容 該当症例の薬剤No.
例数 採否 採否 採否

口頭同意のみでWash outを開始し，観察期開始前に 1)
GCP不遵守 1 × × × 629
文書同意を取得した症例

未投与 治験薬が投与されなかった症例 2 × × × 2)
175 ，559
3)

前立腺癌，膀胱腫瘍，膀胱結石，尿路感染症（膀胱
炎，前立腺炎など）および間質性膀胱炎を合併する
患者，または再発性尿路感染症（観察期前6ヶ月以 3 × × ○ 4) 2)
150 ，175 ，559
3)

内に2回以上発症）の既往のある症例
除外基準違反
観察期前2週間以内に併用禁止薬の投与を受けた症
2 × × ○ 5)
413 ，645
6)
例

一般状態，生存期間に影響を及ぼす可能性のある悪
1 × × ○ 365
7)
性腫瘍を合併する症例

8) 9)
1，11，19 ，27，36，43 ，51，53，54，71，
10)
83，85，86 ，94，95，96，100，102，112，
115，117，122，139，143，144，147，148，
4) 2)
150 ，151，161，163，166，173，175 ，
11) 12)
182 ，190，196，201，202，207 ，253，
13) 14)
255 ，256，257，262，264，269，271 ，
中止・脱落
治療期の投与期間が48週間（336日間）未満の症例 102 × ○ ○ 15)
281，296，299 ，304，329，333，337，339，
（48週未満）
7) 5)
353，363，365 ，378，403，404，413 ，
415，423，426，434，454，463，483，485，
3)
487，493，510，514，538，559 ，569，575，
585，586，587，593，615，616，625，627，
1) 6)
629 ，630，634，636，645 ，650，652，
655，684，687，704，707，720，730，769

服薬率が75％未満の症例 3 × ○ ○ 8) 11)
19 ，182 ，299
15)

11) 12)
21，41，93，125，182 ，198，207 ，224，
処置違反・評価
データ不完備 観察期から治療期に併用禁止薬が投与された症例 ○ ○ 13) 14) 5)
18 × 255 ，271 ，340，364，413 ，447，548，
596，705，721

観察期から治療期に併用療法が施行された症例 4 × ○ ○ 9) 10)
43 ，86 ，342，526

1) to 15) indicate the same case.

(2) Safety results

A list of adverse events by severity, a list of adverse effects by severity and a list
of adverse events by causality are presented in Tables 2.7.6-9 to 2.7.6-11.
There was no difference in the incidence of adverse events or side effects, or in the
incidence of dry mouth, due to long-term exposure, or in the nature, severity or timing
of symptoms. The incidence of adverse events was 90.4% (432/478 patients) (see Table
2.7.6.6-3), and the cumulative incidence after 12, 28 and 52 weeks of treatment was
estimated to be 73.8%, 85.9% and 91.9%, respectively (Kaplan-Meier method, see Figure
2.7.6.6-2). The most frequent adverse event was dry mouth, with an incidence of 40.2%
(192/478) (see Table 2.7.6.6-3), and the cumulative incidence after 12, 28 and 52 weeks
of treatment was estimated to be 37.3%, 39.6% and 40.9%, respectively (Kaplan-Meier
method, see Figure 2.7.6.6-2). The severity was high in 3 cases, moderate in 30 cases
and mild in 159 cases (176 cases). Other than dry mouth, adverse events with an incidence
of 5% or more occurred in 30.8% (147/478) of patients with nasopharyngitis, 14.4%
(69/478) with constipation, 11.5% (55/478) with positive urinary white blood cells, 7.7%
(37/478) with headache, 6.5% (31/478) with cystitis, 5.4% (26/478) with back pain, and

- 411 -
 2.7.6 Summary of the individual tests

5.4% (26/478) with upper respiratory pain. 478), inflammation of the upper respiratory
tract 5.2% (25/478), diarrhoea 5.0% (24/478) (see Table 2.7.6.6-4), and the degree of
nasopharyngitis 8.8% (13/147), constipation 4.3% (3/69), positive urine leukocytes 10.9%
(6/55), headache 13.5% (5/37) Cystitis in 16.1% (5/31), back pain in 23.1% (6/26), upper
respiratory tract inflammation in 8.0% (2/25), diarrhoea in 16.7% (4/24) were moderate
and all others were mild.

Table 2.7.6.6-3 Incidence of adverse events, side effects and dry mouth

項目 有 無
有害事象 432 (90.4) 46 (9.6)
副作用 223 (46.7) 255 (53.3)
口渇 192 (40.2) 286 (59.8)
口渇（因果関係が否定できないもの） 164 (34.3) 314 (65.7)
（）内は％を示す．

Table 2.7.6.6-4 Adverse events with an incidence of 5% or more

項目 発現頻度
対象例数 478
有害事象項目
口渇 192 (209)
鼻咽頭炎 147 (234)
便秘 69 ( 84)
尿中白血球陽性 55 ( 70)
頭痛 37 ( 48)
膀胱炎 31 ( 44)
背部痛 26 ( 27)
上気道の炎症 25 ( 40)
下痢 24 ( 32)
（）内は件数を示す．

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 2.7.6 Summary of the individual tests

100.0

80.0
累積発現率（％）

60.0

40.0

有害事象

20.0 副作用

口渇

口渇
（因果関係否定できないもの）
0.0
0 28 56 84 112 140 168 196 224
196 252 280 308 336 364
364
(28週) (52週)

発現時期（日後）

Figure 2.7.6-2 Cumulative incidence of adverse events, side effects and dry mouth

- 413 -
 2.7.6 Summary of the individual tests

The incidence of adverse events that could not be ruled out as causally related to
ONO-8025 was 46.7% (223/478 patients) (see Table 2.7.6.6-3), and the cumulative incidence
was estimated to be 41.7%, 45.3% and 47.3% after 12, 28 and 52 weeks of treatment,
respectively (see Kaplan-Meier method, Figure 2.7.6.6-2). Adverse reactions with an
incidence of 5% or more were dry mouth (34.3%, 164/478 patients) and constipation (9.0%,
43/478 patients) (see Table 2.7.6.6-5).

Table 2.7.6.6-5 Adverse reactions with an incidence of 5% or more

項目 発現頻度
対象例数 478
有害事象項目
口渇 164 (177)
便秘 43 ( 50)
（）内は件数を示す．

Apart from one death, 41 serious adverse events were observed in 35 patients (7.3%).
One of these (acute glaucoma in the right eye) could not be ruled out as being causally
related to ONO-8025, but the other serious adverse events were all considered to be
complication-related or incidental events and were ruled out as being causally related
to the drug. The new adverse reactions observed after 12 weeks of treatment in the Phase
III comparative study, from 12 weeks to 52 weeks of treatment, were tongue disorder,
abnormal urine odour, pharyngeal discomfort, choking sensation, and decreased blood
sodium in five cases (choking sensation was moderate, others were mild), all of which
were not observed up to 12 weeks of the study and These were all observed up to 12 weeks
of the study and in the phase II and phase III comparative studies. Furthermore, the
mean QTc was not prolonged after 12, 28, 52 or 52 weeks of treatment or at discontinuation
(see Table 2.7.6.6-6). There were six patients with a QTc prolongation of 60 ms or more
at any time point, but the maximum QTc was 478.6 ms and did not exceed 500 ms, which is
of particular clinical concern, at any time point (see Table 2.7.6.6-7).

Table 2.7.6.6-6 Summary statistics for QTc

Number
Valuation Mean ± standard Correspondence t-
Item of Median
period deviation test
cases
At the end of
Absolute ±
the observation 477 402.30 24.44 400.18
value (%)
period
After 12 weeks Absolute ±
437 402.83 25.11 400.56
of treatment value (%)
±
Difference 436 0.75 21.67 1.64 p=0.4682 N.S.
(%)
After 28 weeks Absolute ±
412 399.41 25.43 398.29
of treatment value (%)

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 2.7.6 Summary of the individual tests

±
Difference 412 -2.15 22.09 -2.06 p=0.0490 *
(%)
After 52 weeks Absolute ±
374 397.05 23.85 396.18
of treatment value (%)
±
Difference 374 -3.67 24.28 -2.81 p=0.0037 *
(%)
After 52 weeks Absolute ±
444 399.00 24.66 397.98
of treatment value (%)
or at the time ±
Difference 444 -3.50 24.37 -2.81 p=0.0026 *
of cancellation (%)
Two-tailed, p<0.05, N.S.: Not significant

Table 2.7.6-7 Frequency of differences in QTc by category

Less than 30 to
Less than 30 ms More than 60 ms
60 ms Total
Time of
Number Number Number (Number of
measurement
of % of of % of of % of cases)
cases cases cases
After 12 weeks
397 ( 91.1) 37 ( 8.5) 2 ( 0.5) 436
of treatment
After 28 weeks
387 ( 93.9) 23 ( 5.6) 2 ( 0.5) 412
of treatment
After 52 weeks
349 ( 93.3) 23 ( 6.1) 2 ( 0.5) 374
of treatment
After 52 weeks
of treatment
413 ( 93.0) 28 ( 6.3) 3 ( 0.7) 444
or at the time
of cancellation

The rate of discontinuation due to adverse events (including subjects who withdrew
consent because of an adverse event) was 10.3% (49/478) after 52 weeks of treatment,
and the rate of discontinuation due to adverse events was 5.6% (27/478).
The most common adverse reactions that led to discontinuation of treatment were those
thought to be based on anticholinergic effects, including 8 cases of ocular dysregulation
(foggy vision, photophobia, abnormal eye sensations), 6 cases of thirst, and 2 cases of
residual urine.
There was a significant increase in residual urine volume at all assessment periods
compared with the end of the observation period, but not to a clinically problematic
extent, with a mean increase of 2.30-3.11 mL. There were no clinically problematic

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 2.7.6 Summary of the individual tests

changes in blood pressure or pulse rate. There were no clinically problematic changes
in laboratory values (Table 2.7.6.6-8). There were no abnormal changes in individual
laboratory values that were judged to be severe, and most were mild. Subgroup analyses
of adverse events showed no difference in the incidence of adverse events, adverse
reactions or dry mouth between elderly and non-elderly patients, or between patients
taking Clozapine concomitantly with drugs that inhibit CYP3A4, the main metabolising
enzyme of Clozapine.
In conclusion, ONO-8025 0.2 mg/day can be used safely for long-term treatment without
any increase in side effects or development of new clinically relevant side effects due
to long-term treatment.

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 2.7.6 Summary of the individual tests

Table 2.7.6-8 Pre- and post-dose changes in clinical laboratory values

解析対象集団：安全性解析対象集団
検査項目 時期 症例数 平均±標準偏差 最小値 25％点 中央値 75％点 最大値 対応のあるt検定1)
白血球数 観察期 478 5710.7 ± 1472.9 2400 4700.0 5600.0 6600.0 12400 － 　
治療期4週後 457 5568.5 ± 1499.2 2500 4500.0 5400.0 6300.0 11900 p=0.0062 *
治療期12週後 439 5581.3 ± 1546.2 2300 4530.0 5400.0 6400.0 13000 p=0.0126 *
治療期28週後 416 5382.9 ± 1469.4 1500 4300.0 5200.0 6150.0 11400 p<0.0001 *
治療期40週後 382 5538.0 ± 1433.9 2700 4400.0 5400.0 6400.0 11200 p=0.0044 *
治療期52週後 378 5500.2 ± 1519.4 2300 4500.0 5400.0 6200.0 12000 p=0.0004 *
52週後または中止時 450 5552.6 ± 1651.0 2300 4500.0 5360.0 6200.0 17800 p=0.0113 *
赤血球数 観察期 478 429.7 ± 38.2 322 404.0 428.0 454.0 550 － 　
治療期4週後 457 430.4 ± 37.4 332 406.0 426.0 456.0 540 p=0.6840 N.S.
治療期12週後 439 429.9 ± 38.7 328 402.0 429.0 457.0 550 p=0.8545 N.S.
治療期28週後 416 422.4 ± 37.6 309 396.0 419.5 447.0 554 p<0.0001 *
治療期40週後 382 418.8 ± 37.7 313 393.0 416.0 444.0 530 p<0.0001 *
治療期52週後 378 418.0 ± 36.6 308 391.0 417.5 439.0 550 p<0.0001 *
52週後または中止時 450 419.4 ± 38.0 302 391.0 419.0 444.0 550 p<0.0001 *
ヘモグロビン 観察期 478 13.18 ± 1.29 8.2 12.40 13.10 14.00 17.0 － 　
治療期4週後 457 13.20 ± 1.23 8.3 12.40 13.10 14.00 17.2 p=0.8698 N.S.
治療期12週後 439 13.19 ± 1.29 8.3 12.40 13.10 14.00 17.2 p=0.9753 N.S.
治療期28週後 416 13.33 ± 1.29 6.9 12.55 13.30 14.10 16.8 p<0.0001 *
治療期40週後 382 13.34 ± 1.28 8.5 12.40 13.30 14.20 17.4 p<0.0001 *
治療期52週後 378 13.31 ± 1.25 8.4 12.50 13.25 14.10 16.9 p=0.0004 *
52週後または中止時 450 13.31 ± 1.29 8.4 12.50 13.30 14.10 17.3 p=0.0011 *
ヘマトクリット値 観察期 478 40.06 ± 3.47 28.1 37.80 40.00 42.10 50.0 － 　
治療期4週後 457 40.22 ± 3.34 30.5 38.10 40.20 42.30 51.3 p=0.1261 N.S.
治療期12週後 439 40.23 ± 3.49 30.6 37.80 40.30 42.60 51.4 p=0.1007 N.S.
治療期28週後 416 39.45 ± 3.42 23.8 37.30 39.20 41.50 48.6 p<0.0001 *
治療期40週後 382 39.32 ± 3.34 30.3 36.90 39.30 41.50 47.7 p<0.0001 *
治療期52週後 378 39.33 ± 3.26 29.0 37.10 39.15 41.50 48.4 p<0.0001 *
52週後または中止時 450 39.40 ± 3.40 29.0 37.10 39.30 41.70 49.4 p<0.0001 *
血小板数 観察期 476 22.29 ± 4.84 11.1 19.05 22.10 24.95 46.3 － 　
治療期4週後 455 22.41 ± 4.77 10.2 19.00 22.10 25.60 42.7 p=0.1580 N.S.
治療期12週後 437 22.67 ± 4.82 10.4 19.30 22.70 25.50 39.1 p=0.0047 *
治療期28週後 414 22.70 ± 5.03 9.7 19.00 22.55 26.10 37.6 p=0.0064 *
治療期40週後 380 22.53 ± 4.97 11.1 19.00 22.45 25.70 48.7 p=0.2324 N.S.
治療期52週後 376 22.50 ± 5.19 11.0 18.80 22.20 25.45 52.6 p=0.2214 N.S.
52週後または中止時 448 22.45 ± 5.03 11.0 18.85 22.10 25.40 52.6 p=0.0877 N.S.
総蛋白 観察期 478 7.365 ± 0.459 6.00 7.000 7.400 7.700 8.60 － 　
治療期4週後 456 7.326 ± 0.435 6.10 7.000 7.300 7.600 9.30 p=0.0117 *
治療期12週後 438 7.258 ± 0.400 5.80 7.000 7.250 7.500 9.00 p<0.0001 *
治療期28週後 416 7.223 ± 0.420 6.00 6.900 7.200 7.500 8.80 p<0.0001 *
治療期40週後 382 7.269 ± 0.438 6.10 7.000 7.300 7.600 9.00 p<0.0001 *
治療期52週後 378 7.223 ± 0.453 6.00 6.900 7.200 7.500 8.70 p<0.0001 *
52週後または中止時 450 7.221 ± 0.451 6.00 6.900 7.200 7.500 8.70 p<0.0001 *
アルブミン 観察期 475 4.477 ± 0.279 3.60 4.300 4.500 4.700 5.40 － 　
治療期4週後 453 4.444 ± 0.266 3.50 4.300 4.400 4.600 5.20 p=0.0002 *
治療期12週後 435 4.367 ± 0.262 3.60 4.200 4.400 4.500 5.10 p<0.0001 *
治療期28週後 414 4.363 ± 0.256 3.50 4.200 4.400 4.500 5.40 p<0.0001 *
治療期40週後 382 4.398 ± 0.261 3.70 4.200 4.400 4.600 5.20 p<0.0001 *
治療期52週後 377 4.348 ± 0.265 3.30 4.200 4.300 4.500 5.20 p<0.0001 *
52週後または中止時 447 4.339 ± 0.281 2.80 4.200 4.300 4.500 5.20 p<0.0001 *

1）両側検定、*：p<0.05　N.S.：p≧ 0.05

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 2.7.6 Summary of the individual tests

Table 2.7.6-8 Pre- and post-dose changes in clinical laboratory values (continued)
解析対象集団：安全性解析対象集団
検査項目 時期 症例数 平均±標準偏差 最小値 25％点 中央値 75％点 最大値 対応のあるt検定1)
アルブミン 観察期 3 61.37 ± 3.42 59.1 59.10 59.70 65.30 65.3 － 　
（％） 治療期4週後 3 60.37 ± 1.36 59.1 59.10 60.20 61.80 61.8 p=0.6860 N.S.
治療期12週後 3 61.90 ± 1.21 60.6 60.60 62.10 63.00 63.0 p=0.7467 N.S.
治療期28週後 2 62.25 ± 1.06 61.5 61.50 62.25 63.00 63.0 p=0.2247 N.S.
治療期40週後 0 ± － 　
治療期52週後 1 63.60 ± 63.6 63.60 63.60 63.60 63.6 － 　
52週後または中止時 2 63.60 ± 0.00 63.6 63.60 63.60 63.60 63.6 p=0.0454 *
総ビリルビン 観察期 478 0.504 ± 0.216 0.20 0.400 0.500 0.600 2.10 － 　
治療期4週後 456 0.493 ± 0.204 0.20 0.400 0.500 0.600 1.70 p=0.0915 N.S.
治療期12週後 438 0.482 ± 0.197 0.10 0.400 0.400 0.600 2.00 p=0.0032 *
治療期28週後 416 0.514 ± 0.189 0.20 0.400 0.500 0.600 1.50 p=0.2692 N.S.
治療期40週後 382 0.554 ± 0.208 0.20 0.400 0.500 0.600 1.80 p<0.0001 *
治療期52週後 378 0.533 ± 0.206 0.20 0.400 0.500 0.600 2.10 p=0.0029 *
52週後または中止時 450 0.526 ± 0.203 0.20 0.400 0.500 0.600 2.10 p=0.0100 *
AST(GOT) 観察期 478 23.1 ± 8.2 9 18.0 22.0 26.0 69 － 　
治療期4週後 456 22.2 ± 6.8 10 18.0 21.0 25.0 64 p=0.0003 *
治療期12週後 438 22.7 ± 7.5 12 18.0 21.0 25.0 79 p=0.0463 *
治療期28週後 416 21.4 ± 7.0 10 17.0 20.0 24.0 71 p<0.0001 *
治療期40週後 382 21.0 ± 6.8 7 17.0 20.0 23.0 69 p<0.0001 *
治療期52週後 378 22.0 ± 15.9 5 16.0 20.0 24.0 298 p=0.1233 N.S.
52週後または中止時 450 22.6 ± 20.9 5 17.0 20.0 24.0 336 p=0.5824 N.S.
ALT(GPT) 観察期 478 20.8 ± 12.5 4 13.0 17.5 24.0 96 － 　
治療期4週後 456 20.0 ± 11.6 4 13.0 17.0 24.0 94 p=0.0171 *
治療期12週後 438 20.3 ± 11.8 2 13.0 17.0 22.0 101 p=0.1161 N.S.
治療期28週後 416 18.4 ± 9.6 4 12.0 16.0 21.0 74 p<0.0001 *
治療期40週後 382 18.1 ± 9.3 4 12.0 16.0 21.0 63 p<0.0001 *
治療期52週後 378 19.2 ± 15.3 3 12.0 16.0 22.0 239 p=0.0219 *
52週後または中止時 450 19.6 ± 16.7 3 12.0 16.0 22.0 239 p=0.0728 N.S.
γ-GTP 観察期 478 31.3 ± 32.1 6 15.0 21.0 34.0 395 － 　
治療期4週後 456 29.6 ± 28.7 7 15.0 20.0 32.0 342 p=0.0052 *
治療期12週後 438 29.1 ± 28.1 7 15.0 20.0 32.0 330 p=0.0001 *
治療期28週後 416 27.6 ± 25.6 4 14.0 19.0 30.0 265 p=0.0005 *
治療期40週後 382 27.1 ± 23.2 5 14.0 19.0 30.0 159 p<0.0001 *
治療期52週後 378 28.7 ± 26.2 3 14.0 19.0 32.0 196 p=0.0687 N.S.
52週後または中止時 450 29.7 ± 30.2 3 14.0 20.0 32.0 330 p=0.0549 N.S.
Al-P 観察期 478 233.9 ± 81.9 84 183.0 221.0 274.0 883 － 　
治療期4週後 456 234.2 ± 82.3 89 179.5 222.0 274.0 871 p=0.2843 N.S.
治療期12週後 438 232.8 ± 85.4 69 177.0 220.0 268.0 815 p=0.4710 N.S.
治療期28週後 416 228.4 ± 80.5 95 177.0 217.5 266.5 804 p=0.3080 N.S.
治療期40週後 382 223.9 ± 69.4 84 176.0 212.5 266.0 600 p=0.0019 *
治療期52週後 378 221.1 ± 70.0 84 173.0 207.0 260.0 566 p=0.0001 *
52週後または中止時 450 225.1 ± 75.1 84 173.0 212.0 265.0 751 p=0.0005 *

1）両側検定、*：p<0.05　N.S.：p≧ 0.05

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 2.7.6 Summary of the individual tests

Table 2.7.6-8 Pre- and post-dose changes in clinical laboratory values (continued)
解析対象集団：安全性解析対象集団
検査項目 時期 症例数 平均±標準偏差 最小値 25％点 中央値 75％点 最大値 対応のあるt検定1)
LDH 観察期 477 207.8 ± 75.1 91 165.0 191.0 222.0 717 － 　
治療期4週後 455 199.2 ± 62.3 104 163.0 185.0 214.0 672 p<0.0001 *
治療期12週後 437 201.5 ± 65.8 96 164.0 187.0 216.0 557 p=0.0002 *
治療期28週後 415 192.0 ± 56.3 104 162.0 180.0 207.0 598 p<0.0001 *
治療期40週後 381 193.4 ± 56.8 98 160.0 187.0 210.0 596 p<0.0001 *
治療期52週後 377 193.1 ± 57.1 90 161.0 184.0 207.0 514 p<0.0001 *
52週後または中止時 449 196.0 ± 71.0 90 160.0 184.0 208.0 936 p=0.0003 *
クレアチニン 観察期 478 0.710 ± 0.166 0.40 0.600 0.670 0.810 1.35 － 　
治療期4週後 456 0.704 ± 0.166 0.36 0.590 0.670 0.800 1.40 p=0.1354 N.S.
治療期12週後 438 0.690 ± 0.166 0.39 0.580 0.660 0.770 1.36 p<0.0001 *
治療期28週後 416 0.680 ± 0.162 0.40 0.570 0.650 0.755 1.48 p<0.0001 *
治療期40週後 382 0.699 ± 0.156 0.40 0.590 0.670 0.780 1.55 p=0.3574 N.S.
治療期52週後 378 0.686 ± 0.150 0.40 0.580 0.660 0.770 1.30 p=0.0003 *
52週後または中止時 450 0.694 ± 0.166 0.40 0.580 0.660 0.780 1.55 p=0.0007 *
BUN 観察期 478 15.74 ± 4.21 5.7 12.80 15.30 18.00 31.9 － 　
治療期4週後 456 15.25 ± 3.99 6.4 12.35 15.00 17.60 31.3 p=0.0020 *
治療期12週後 438 15.31 ± 4.11 4.8 12.50 14.90 17.60 28.8 p=0.0118 *
治療期28週後 416 15.24 ± 3.79 6.0 12.40 15.00 17.45 28.6 p=0.0068 *
治療期40週後 382 15.75 ± 4.11 6.3 13.00 15.10 18.30 30.4 p=0.8004 N.S.
治療期52週後 378 14.98 ± 3.79 6.0 12.30 14.50 17.20 28.5 p=0.0001 *
52週後または中止時 450 15.09 ± 3.97 6.0 12.30 14.60 17.30 29.3 p=0.0003 *
トリグリセライド 観察期 477 139.2 ± 95.1 21 80.0 117.0 171.0 947 － 　
治療期4週後 455 138.5 ± 86.8 25 84.0 115.0 167.0 626 p=0.7376 N.S.
治療期12週後 437 129.2 ± 71.9 11 79.0 112.0 157.0 488 p=0.0041 *
治療期28週後 415 132.4 ± 81.5 22 82.0 111.0 159.0 802 p=0.0855 N.S.
治療期40週後 381 139.5 ± 79.9 29 86.0 122.0 172.0 651 p=0.9831 N.S.
治療期52週後 377 132.0 ± 74.5 28 82.0 114.0 161.0 560 p=0.0493 *
52週後または中止時 449 131.2 ± 74.0 28 80.0 113.0 161.0 560 p=0.0309 *
総コレステロール 観察期 478 210.6 ± 35.3 112 188.0 211.5 234.0 349 － 　
治療期4週後 456 208.5 ± 34.2 120 186.0 210.0 228.0 320 p=0.0078 *
治療期12週後 438 208.2 ± 33.7 116 186.0 208.0 229.0 315 p=0.0059 *
治療期28週後 416 205.0 ± 34.7 110 184.0 203.0 227.0 344 p<0.0001 *
治療期40週後 382 203.4 ± 33.8 105 181.0 203.0 227.0 287 p<0.0001 *
治療期52週後 378 202.6 ± 33.0 113 180.0 203.5 225.0 312 p<0.0001 *
52週後または中止時 450 202.4 ± 33.6 113 179.0 204.5 226.0 312 p<0.0001 *
尿酸 観察期 478 4.85 ± 1.20 2.1 4.00 4.70 5.60 8.5 － 　
治療期4週後 456 4.83 ± 1.19 2.0 4.00 4.80 5.60 9.2 p=0.9476 N.S.
治療期12週後 438 4.76 ± 1.16 1.9 4.00 4.70 5.50 8.7 p=0.0475 *
治療期28週後 416 4.78 ± 1.18 1.9 4.00 4.70 5.50 9.5 p=0.1773 N.S.
治療期40週後 382 4.85 ± 1.22 2.1 4.00 4.80 5.60 9.2 p=0.4007 N.S.
治療期52週後 378 4.80 ± 1.23 1.9 4.00 4.60 5.50 8.9 p=0.8786 N.S.
52週後または中止時 450 4.83 ± 1.22 1.9 4.00 4.70 5.60 8.9 p=0.7563 N.S.

1）両側検定、*：p<0.05　N.S.：p≧ 0.05

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 2.7.6 Summary of the individual tests

Table 2.7.6-8 Pre- and post-dose changes in clinical laboratory values (continued)
解析対象集団：安全性解析対象集団
検査項目 時期 症例数 平均±標準偏差 最小値 25％点 中央値 75％点 最大値 対応のあるt検定1)
Na 観察期 478 141.60 ± 2.15 127.0 140.00 142.00 143.00 148.0 － 　
治療期4週後 456 141.17 ± 2.24 132.0 140.00 141.00 143.00 151.0 p<0.0001 *
治療期12週後 438 140.94 ± 2.09 131.0 140.00 141.00 142.00 148.0 p<0.0001 *
治療期28週後 416 140.89 ± 2.53 113.0 140.00 141.00 142.00 147.0 p<0.0001 *
治療期40週後 382 141.50 ± 2.19 135.0 140.00 141.00 143.00 148.0 p=0.4470 N.S.
治療期52週後 378 141.24 ± 2.05 134.0 140.00 141.00 143.00 147.0 p=0.0018 *
52週後または中止時 450 141.24 ± 2.12 131.0 140.00 141.00 143.00 147.0 p=0.0005 *
K 観察期 478 4.131 ± 0.358 2.70 3.900 4.100 4.300 5.30 － 　
治療期4週後 456 4.142 ± 0.343 2.60 3.900 4.100 4.300 5.40 p=0.5848 N.S.
治療期12週後 438 4.116 ± 0.342 2.90 3.900 4.100 4.400 5.20 p=0.6783 N.S.
治療期28週後 416 4.112 ± 0.333 3.00 3.900 4.100 4.300 5.20 p=0.6635 N.S.
治療期40週後 382 4.150 ± 0.354 2.80 3.900 4.100 4.400 5.70 p=0.1451 N.S.
治療期52週後 378 4.143 ± 0.322 2.90 3.900 4.100 4.400 5.30 p=0.2933 N.S.
52週後または中止時 450 4.130 ± 0.335 2.80 3.900 4.100 4.310 5.30 p=0.7399 N.S.
Cl 観察期 478 104.73 ± 2.67 93.0 103.00 105.00 106.00 112.0 － 　
治療期4週後 456 104.25 ± 2.70 94.0 103.00 104.00 106.00 113.0 p<0.0001 *
治療期12週後 437 103.72 ± 2.59 94.0 102.00 104.00 105.00 114.0 p<0.0001 *
治療期28週後 416 103.64 ± 2.83 81.0 102.00 104.00 106.00 112.0 p<0.0001 *
治療期40週後 382 104.34 ± 2.57 97.0 103.00 104.00 106.00 112.0 p=0.0072 *
治療期52週後 378 103.98 ± 2.44 95.0 102.00 104.00 105.00 112.0 p<0.0001 *
52週後または中止時 450 103.95 ± 2.48 94.0 102.00 104.00 105.90 112.0 p<0.0001 *

1）両側検定、*：p<0.05　N.S.：p≧ 0.05

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 2.7.6 Summary of the individual tests

Table 2.7.6-8 Pre- and post-dose changes in clinical laboratory values (continued)
解析対象集団：安全性解析対象集団
Wilcoxon符号付
検査項目 時期 症例数 - ± + ++ +++ ++++
順位検定1)
観察期 476 425 37 9 3 2 0 －
治療期4週後 453 413 24 12 4 0 0 p=0.5916 N.S.
尿蛋白 治療期12週後 439 397 25 10 7 0 0 p=0.8451 N.S.
治療期28週後 416 380 23 8 3 2 0 p=0.6234 N.S.
治療期40週後 383 342 28 7 5 1 0 p=0.6151 N.S.
治療期52週後 378 346 19 8 3 2 0 p=0.8075 N.S.
52週後または中止時 450 410 22 11 4 3 0 p=0.9577 N.S.
観察期 476 435 7 11 7 11 5 －
治療期4週後 453 412 9 9 4 14 5 p=1.0000 N.S.
尿糖 治療期12週後 439 392 13 11 8 12 3 p=0.7491 N.S.
治療期28週後 416 381 11 6 5 8 5 p=0.8569 N.S.
治療期40週後 383 357 9 4 5 4 4 p=0.1956 N.S.
治療期52週後 378 350 10 5 5 4 4 p=0.3456 N.S.
52週後または中止時 451 418 12 5 7 5 4 p=0.1280 N.S.
観察期 468 61 403 4 0 0 0 －
治療期4週後 445 61 380 4 0 0 0 p=0.7656 N.S.
尿ウロビリノゲン 治療期12週後 431 55 370 5 1 0 0 p=0.3535 N.S.
治療期28週後 408 58 345 5 0 0 0 p=1.0000 N.S.
治療期40週後 376 49 322 5 0 0 0 p=0.9844 N.S.
治療期52週後 371 49 317 5 0 0 0 p=0.9727 N.S.
52週後または中止時 443 62 376 5 0 0 0 p=0.9727 N.S.

1）両側検定、*：p<0.05　N.S.：p≧ 0.05

- 421 -
 2.7.6 Summary of the individual tests

Table 2.7.6-9 List of adverse events by severity

投与群 0.2 mg/日
安全性解析対象集団 478
重症度 軽度 中等度 高度 計
有害事象項目 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数
全例 278 ( 58.2) 1606 139 ( 29.1) 242 15 ( 3.1) 15 432 ( 90.4) 1863
血液およびリンパ系障害 3 ( 0.6) 3 1 ( 0.2) 1 4 ( 0.8) 4
貧血 1 ( 0.2) 1 1 ( 0.2) 1
鉄欠乏性貧血 1 ( 0.2) 1 1 ( 0.2) 1
リンパ節炎 1 ( 0.2) 1 1 ( 0.2) 1
リンパ節症 1 ( 0.2) 1 1 ( 0.2) 1
心臓障害 10 ( 2.1) 10 2 ( 0.4) 2 2 ( 0.4) 2 14 ( 2.9) 14
動悸 6 ( 1.3) 6 1 ( 0.2) 1 7 ( 1.5) 7
心不全 2 ( 0.4) 2 2 ( 0.4) 2
狭心症 1 ( 0.2) 1 1 ( 0.2) 1
徐脈 1 ( 0.2) 1 1 ( 0.2) 1
左脚ブロック 1 ( 0.2) 1 1 ( 0.2) 1
上室性期外収縮 1 ( 0.2) 1 1 ( 0.2) 1
心室性期外収縮 1 ( 0.2) 1 1 ( 0.2) 1
耳および迷路障害 7 ( 1.5) 7 2 ( 0.4) 2 9 ( 1.9) 9
回転性眩暈 2 ( 0.4) 2 1 ( 0.2) 1 3 ( 0.6) 3
耳閉感 1 ( 0.2) 1 1 ( 0.2) 1 2 ( 0.4) 2
メニエール病 1 ( 0.2) 1 1 ( 0.2) 1
耳鳴 1 ( 0.2) 1 1 ( 0.2) 1
頭位性眩暈 1 ( 0.2) 1 1 ( 0.2) 1
突発難聴 1 ( 0.2) 1 1 ( 0.2) 1
内分泌障害 1 ( 0.2) 1 1 ( 0.2) 1
甲状腺結節 1 ( 0.2) 1 1 ( 0.2) 1
眼障害 66 ( 13.8) 81 13 ( 2.7) 14 79 ( 16.5) 95
霧視 13 ( 2.7) 13 1 ( 0.2) 1 14 ( 2.9) 14
眼球乾燥 13 ( 2.7) 13 1 ( 0.2) 1 14 ( 2.9) 14
羞明 10 ( 2.1) 10 3 ( 0.6) 3 13 ( 2.7) 13
白内障 6 ( 1.3) 6 3 ( 0.6) 3 9 ( 1.9) 9
眼精疲労 7 ( 1.5) 7 7 ( 1.5) 7
硝子体浮遊物 4 ( 0.8) 4 4 ( 0.8) 4
アレルギー性結膜炎 3 ( 0.6) 3 3 ( 0.6) 3
眼痛 3 ( 0.6) 3 3 ( 0.6) 3
眼の異常感 2 ( 0.4) 2 2 ( 0.4) 2
複視 2 ( 0.4) 2 2 ( 0.4) 2
眼瞼浮腫 2 ( 0.4) 3 2 ( 0.4) 3
角膜炎 1 ( 0.2) 1 1 ( 0.2) 1 2 ( 0.4) 2
光視症 2 ( 0.4) 2 2 ( 0.4) 2
水晶体嚢の偽落屑 1 ( 0.2) 1 1 ( 0.2) 1 2 ( 0.4) 2
閉塞隅角緑内障 1 ( 0.2) 1 1 ( 0.2) 1
乱視 1 ( 0.2) 1 1 ( 0.2) 1
結膜炎 1 ( 0.2) 1 1 ( 0.2) 1
眼脂 1 ( 0.2) 1 1 ( 0.2) 1
眼の障害 1 ( 0.2) 1 1 ( 0.2) 1
眼出血 1 ( 0.2) 1 1 ( 0.2) 1
涙液分泌低下 1 ( 0.2) 1 1 ( 0.2) 1
流涙増加 1 ( 0.2) 1 1 ( 0.2) 1
黄斑変性 1 ( 0.2) 1 1 ( 0.2) 1
老視 1 ( 0.2) 1 1 ( 0.2) 1
屈折障害 1 ( 0.2) 1 1 ( 0.2) 1
網膜剥離 1 ( 0.2) 1 1 ( 0.2) 1
視力低下 1 ( 0.2) 1 1 ( 0.2) 1
視覚障害 1 ( 0.2) 1 1 ( 0.2) 1
眼そう痒症 1 ( 0.2) 1 1 ( 0.2) 1
胃腸障害 143 ( 29.9) 270 28 ( 5.9) 36 171 ( 35.8) 306
便秘 66 ( 13.8) 80 3 ( 0.6) 4 69 ( 14.4) 84
下痢 20 ( 4.2) 28 4 ( 0.8) 4 24 ( 5.0) 32
上腹部痛 16 ( 3.3) 18 6 ( 1.3) 7 22 ( 4.6) 25
悪心 16 ( 3.3) 17 2 ( 0.4) 2 18 ( 3.8) 19
嘔吐 13 ( 2.7) 16 2 ( 0.4) 2 15 ( 3.1) 18
胃不快感 11 ( 2.3) 18 2 ( 0.4) 2 13 ( 2.7) 20
胃炎 10 ( 2.1) 14 2 ( 0.4) 2 12 ( 2.5) 16
歯痛 8 ( 1.7) 8 2 ( 0.4) 2 10 ( 2.1) 10
口内炎 7 ( 1.5) 12 1 ( 0.2) 2 8 ( 1.7) 14
腹部膨満 7 ( 1.5) 8 7 ( 1.5) 8
消化不良 7 ( 1.5) 7 7 ( 1.5) 7
腹痛 5 ( 1.0) 5 1 ( 0.2) 1 6 ( 1.3) 6
歯周炎 4 ( 0.8) 4 2 ( 0.4) 2 6 ( 1.3) 6
口唇炎 4 ( 0.8) 4 1 ( 0.2) 1 5 ( 1.0) 5
胃潰瘍 5 ( 1.0) 5 5 ( 1.0) 5
歯肉炎 3 ( 0.6) 3 1 ( 0.2) 1 4 ( 0.8) 4
下腹部痛 1 ( 0.2) 1 2 ( 0.4) 2 3 ( 0.6) 3
歯肉腫脹 3 ( 0.6) 3 3 ( 0.6) 3
痔核 3 ( 0.6) 4 3 ( 0.6) 4
歯周病 2 ( 0.4) 2 1 ( 0.2) 1 3 ( 0.6) 3
口唇乾燥 2 ( 0.4) 2 2 ( 0.4) 2
舌障害 2 ( 0.4) 2 2 ( 0.4) 2
結腸ポリープ 1 ( 0.2) 1 1 ( 0.2) 1
十二指腸潰瘍 1 ( 0.2) 1 1 ( 0.2) 1
嚥下障害 1 ( 0.2) 1 1 ( 0.2) 1
腸炎 1 ( 0.2) 1 1 ( 0.2) 1
食中毒 1 ( 0.2) 1 1 ( 0.2) 1
舌炎 1 ( 0.2) 1 1 ( 0.2) 1
舌苔 1 ( 0.2) 1 1 ( 0.2) 1
歯の障害 1 ( 0.2) 1 1 ( 0.2) 1
心窩部不快感 1 ( 0.2) 1 1 ( 0.2) 1
口の感覚鈍麻 1 ( 0.2) 1 1 ( 0.2) 1
全身障害および投与局所様態 184 ( 38.5) 231 37 ( 7.7) 37 3 ( 0.6) 3 224 ( 46.9) 271
口渇 159 ( 33.3) 176 30 ( 6.3) 30 3 ( 0.6) 3 192 ( 40.2) 209
末梢性浮腫 10 ( 2.1) 11 1 ( 0.2) 1 11 ( 2.3) 12
発熱 7 ( 1.5) 8 2 ( 0.4) 2 9 ( 1.9) 10
倦怠感 8 ( 1.7) 10 8 ( 1.7) 10
胸部不快感 6 ( 1.3) 6 1 ( 0.2) 1 7 ( 1.5) 7

- 422 -
 2.7.6 Summary of the individual tests

Table 2.7.6-9 List of adverse events by severity (continued)

投与群 0.2 mg/日
安全性解析対象集団 478
重症度 軽度 中等度 高度 計
有害事象項目 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数
胸痛 4 ( 0.8) 4 4 ( 0.8) 4
浮腫 4 ( 0.8) 5 4 ( 0.8) 5
無力症 2 ( 0.4) 2 1 ( 0.2) 1 3 ( 0.6) 3
疼痛 2 ( 0.4) 2 1 ( 0.2) 1 3 ( 0.6) 3
疲労 2 ( 0.4) 2 2 ( 0.4) 2
歩行異常 1 ( 0.2) 1 1 ( 0.2) 1
局所の炎症 1 ( 0.2) 1 1 ( 0.2) 1
圧迫感 1 ( 0.2) 1 1 ( 0.2) 1
腫脹 1 ( 0.2) 1 1 ( 0.2) 1
圧痛 1 ( 0.2) 1 1 ( 0.2) 1
炎症 1 ( 0.2) 1 1 ( 0.2) 1
免疫系障害 2 ( 0.4) 2 2 ( 0.4) 2
季節性アレルギー 2 ( 0.4) 2 2 ( 0.4) 2
感染症および寄生虫症 170 ( 35.6) 327 28 ( 5.9) 33 4 ( 0.8) 4 202 ( 42.3) 364
鼻咽頭炎 134 ( 28.0) 220 13 ( 2.7) 14 147 ( 30.8) 234
膀胱炎 26 ( 5.4) 37 5 ( 1.0) 7 31 ( 6.5) 44
咽喉頭炎 7 ( 1.5) 10 7 ( 1.5) 10
細菌尿 5 ( 1.0) 6 5 ( 1.0) 6
気管支炎 3 ( 0.6) 5 1 ( 0.2) 1 1 ( 0.2) 1 5 ( 1.0) 7
インフルエンザ 2 ( 0.4) 2 3 ( 0.6) 3 5 ( 1.0) 5
齲歯 3 ( 0.6) 3 1 ( 0.2) 1 4 ( 0.8) 4
胃腸炎 2 ( 0.4) 2 1 ( 0.2) 1 1 ( 0.2) 1 4 ( 0.8) 4
単純ヘルペス 4 ( 0.8) 8 4 ( 0.8) 8
ウイルス性胃腸炎 2 ( 0.4) 2 1 ( 0.2) 1 3 ( 0.6) 3
帯状疱疹 1 ( 0.2) 1 2 ( 0.4) 2 3 ( 0.6) 3
足部白癬 3 ( 0.6) 3 3 ( 0.6) 3
尿路感染 3 ( 0.6) 5 3 ( 0.6) 5
急性気管支炎 2 ( 0.4) 2 2 ( 0.4) 2
外耳炎 2 ( 0.4) 2 2 ( 0.4) 2
中耳炎 2 ( 0.4) 3 2 ( 0.4) 3
鼻炎 2 ( 0.4) 2 2 ( 0.4) 2
白癬 2 ( 0.4) 2 2 ( 0.4) 2
扁桃炎 1 ( 0.2) 1 1 ( 0.2) 1 2 ( 0.4) 2
化膿 2 ( 0.4) 2 2 ( 0.4) 2
虫垂炎 1 ( 0.2) 1 1 ( 0.2) 1
気管支肺炎 1 ( 0.2) 1 1 ( 0.2) 1
毛包炎 1 ( 0.2) 1 1 ( 0.2) 1
ヘルペスウイルス感染 1 ( 0.2) 1 1 ( 0.2) 1
麦粒腫 1 ( 0.2) 1 1 ( 0.2) 1
耳下腺炎 1 ( 0.2) 1 1 ( 0.2) 1
肺炎 1 ( 0.2) 1 1 ( 0.2) 1
肺水腫 1 ( 0.2) 1 1 ( 0.2) 1
急性腎盂腎炎 1 ( 0.2) 1 1 ( 0.2) 1
腟炎 1 ( 0.2) 1 1 ( 0.2) 1
トリコモナス性外陰部腟炎 1 ( 0.2) 1 1 ( 0.2) 1
ヘリコバクター感染 1 ( 0.2) 1 1 ( 0.2) 1
ウイルス性腸炎 1 ( 0.2) 1 1 ( 0.2) 1
傷害、中毒および処置合併症 30 ( 6.3) 33 14 ( 2.9) 15 2 ( 0.4) 2 46 ( 9.6) 50
背部損傷 5 ( 1.0) 5 2 ( 0.4) 2 7 ( 1.5) 7
熱傷 5 ( 1.0) 5 2 ( 0.4) 2 7 ( 1.5) 7
関節捻挫 4 ( 0.8) 5 2 ( 0.4) 2 6 ( 1.3) 7
擦過傷 4 ( 0.8) 4 4 ( 0.8) 4
創傷 3 ( 0.6) 3 3 ( 0.6) 3
節足動物咬傷 2 ( 0.4) 2 2 ( 0.4) 2
鎖骨骨折 2 ( 0.4) 2 2 ( 0.4) 2
肋骨骨折 1 ( 0.2) 1 1 ( 0.2) 1 2 ( 0.4) 2
半月板障害 1 ( 0.2) 1 1 ( 0.2) 1 2 ( 0.4) 2
靱帯損傷 1 ( 0.2) 1 1 ( 0.2) 1 2 ( 0.4) 2
動物咬傷 1 ( 0.2) 1 1 ( 0.2) 1
節足動物刺傷 1 ( 0.2) 1 1 ( 0.2) 1
圧迫骨折 1 ( 0.2) 1 1 ( 0.2) 1
上顆炎 1 ( 0.2) 1 1 ( 0.2) 1
骨折 1 ( 0.2) 1 1 ( 0.2) 1
手骨折 1 ( 0.2) 1 1 ( 0.2) 1
上腕骨骨折 1 ( 0.2) 1 1 ( 0.2) 1
顎の骨折 1 ( 0.2) 1 1 ( 0.2) 1
橈骨骨折 1 ( 0.2) 1 1 ( 0.2) 1
歯牙損傷 1 ( 0.2) 1 1 ( 0.2) 1
尾骨骨折 1 ( 0.2) 1 1 ( 0.2) 1
処置後痛 1 ( 0.2) 1 1 ( 0.2) 1
臨床検査 109 ( 22.8) 211 19 ( 4.0) 34 128 ( 26.8) 245
尿中白血球陽性 49 ( 10.3) 63 6 ( 1.3) 7 55 ( 11.5) 70
γ-グルタミルトランスフェラーゼ増加 18 ( 3.8) 19 1 ( 0.2) 1 19 ( 4.0) 20
アラニン・アミノトランスフェラーゼ増加 12 ( 2.5) 14 3 ( 0.6) 3 15 ( 3.1) 17
血中トリグリセリド増加 11 ( 2.3) 12 2 ( 0.4) 2 13 ( 2.7) 14
尿中赤血球陽性 12 ( 2.5) 13 1 ( 0.2) 1 13 ( 2.7) 14
白血球数増加 10 ( 2.1) 11 3 ( 0.6) 3 13 ( 2.7) 14
アスパラギン酸アミノトランスフェラーゼ増加 8 ( 1.7) 10 3 ( 0.6) 3 11 ( 2.3) 13
血中乳酸脱水素酵素増加 8 ( 1.7) 8 2 ( 0.4) 2 10 ( 2.1) 10
血中アルカリホスファターゼ増加 5 ( 1.0) 5 3 ( 0.6) 3 8 ( 1.7) 8
残尿量 5 ( 1.0) 6 2 ( 0.4) 2 7 ( 1.5) 8
尿中ブドウ糖陽性 6 ( 1.3) 6 6 ( 1.3) 6
ヘマトクリット減少 5 ( 1.0) 5 1 ( 0.2) 1 6 ( 1.3) 6
ヘモグロビン減少 5 ( 1.0) 5 1 ( 0.2) 1 6 ( 1.3) 6
赤血球数減少 5 ( 1.0) 5 1 ( 0.2) 1 6 ( 1.3) 6
尿中蛋白陽性 5 ( 1.0) 6 5 ( 1.0) 6
血圧上昇 4 ( 0.8) 4 1 ( 0.2) 1 5 ( 1.0) 5
白血球数減少 4 ( 0.8) 4 1 ( 0.2) 1 5 ( 1.0) 5
血中コレステロール増加 2 ( 0.4) 2 2 ( 0.4) 2
血中ナトリウム減少 2 ( 0.4) 2 2 ( 0.4) 2
血中尿素増加 2 ( 0.4) 2 2 ( 0.4) 2
血中尿酸増加 2 ( 0.4) 2 2 ( 0.4) 2

- 423 -
 2.7.6 Summary of the individual tests

Table 2.7.6-9 List of adverse events by severity (continued)

投与群 0.2 mg/日
安全性解析対象集団 478
重症度 軽度 中等度 高度 計
有害事象項目 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数
血小板数減少 1 ( 0.2) 1 1 ( 0.2) 1
血中塩化物減少 1 ( 0.2) 1 1 ( 0.2) 1
血中クレアチンホスホキナーゼ増加 1 ( 0.2) 1 1 ( 0.2) 1
血中カリウム減少 1 ( 0.2) 1 1 ( 0.2) 1
Ｃ－反応性蛋白増加 1 ( 0.2) 1 1 ( 0.2) 1
心電図ＳＴ部分異常 1 ( 0.2) 1 1 ( 0.2) 1
心電図Ｔ波逆転 1 ( 0.2) 1 1 ( 0.2) 1
心電図異常Ｔ波 1 ( 0.2) 1 1 ( 0.2) 1
尿検査異常 1 ( 0.2) 1 1 ( 0.2) 1
代謝および栄養障害 5 ( 1.0) 5 2 ( 0.4) 2 7 ( 1.5) 7
食欲不振 2 ( 0.4) 2 1 ( 0.2) 1 3 ( 0.6) 3
糖尿病 2 ( 0.4) 2 2 ( 0.4) 2
食欲減退 1 ( 0.2) 1 1 ( 0.2) 1 2 ( 0.4) 2
筋骨格系および結合組織障害 63 ( 13.2) 91 12 ( 2.5) 15 2 ( 0.4) 2 77 ( 16.1) 108
背部痛 20 ( 4.2) 21 6 ( 1.3) 6 26 ( 5.4) 27
関節痛 16 ( 3.3) 20 1 ( 0.2) 3 1 ( 0.2) 1 18 ( 3.8) 24
筋骨格硬直 7 ( 1.5) 9 7 ( 1.5) 9
限局性骨関節炎 4 ( 0.8) 4 1 ( 0.2) 1 5 ( 1.0) 5
筋痛 5 ( 1.0) 6 5 ( 1.0) 6
筋痙攣 4 ( 0.8) 6 4 ( 0.8) 6
四肢痛 2 ( 0.4) 3 1 ( 0.2) 1 3 ( 0.6) 4
関節周囲炎 2 ( 0.4) 2 1 ( 0.2) 1 3 ( 0.6) 3
椎間板突出 2 ( 0.4) 2 1 ( 0.2) 1 3 ( 0.6) 3
関節炎 2 ( 0.4) 2 2 ( 0.4) 2
単関節炎 1 ( 0.2) 1 1 ( 0.2) 1 2 ( 0.4) 2
脊柱管狭窄症 1 ( 0.2) 1 1 ( 0.2) 1 2 ( 0.4) 2
脊椎症 2 ( 0.4) 2 2 ( 0.4) 2
腱炎 2 ( 0.4) 2 2 ( 0.4) 2
骨痛 1 ( 0.2) 1 1 ( 0.2) 1
骨棘 1 ( 0.2) 1 1 ( 0.2) 1
ガングリオン 1 ( 0.2) 1 1 ( 0.2) 1
関節硬直 1 ( 0.2) 2 1 ( 0.2) 2
関節腫脹 1 ( 0.2) 1 1 ( 0.2) 1
筋力低下 1 ( 0.2) 1 1 ( 0.2) 1
筋骨格痛 1 ( 0.2) 1 1 ( 0.2) 1
頚部痛 1 ( 0.2) 1 1 ( 0.2) 1
後天性脊椎すべり症 1 ( 0.2) 1 1 ( 0.2) 1
狭窄性腱鞘炎 1 ( 0.2) 1 1 ( 0.2) 1
良性、悪性および詳細不明の新生物（嚢胞およびポリープを含む） 2 ( 0.4) 2 1 ( 0.2) 1 3 ( 0.6) 3
肺の良性新生物 1 ( 0.2) 1 1 ( 0.2) 1
肺転移 1 ( 0.2) 1 1 ( 0.2) 1
皮膚乳頭腫 1 ( 0.2) 1 1 ( 0.2) 1
神経系障害 71 ( 14.9) 105 16 ( 3.3) 20 87 ( 18.2) 125
頭痛 32 ( 6.7) 41 5 ( 1.0) 7 37 ( 7.7) 48
浮動性めまい 14 ( 2.9) 22 5 ( 1.0) 5 19 ( 4.0) 27
傾眠 13 ( 2.7) 13 2 ( 0.4) 2 15 ( 3.1) 15
感覚減退 9 ( 1.9) 11 2 ( 0.4) 2 11 ( 2.3) 13
意識消失 2 ( 0.4) 2 2 ( 0.4) 2 4 ( 0.8) 4
味覚異常 3 ( 0.6) 3 3 ( 0.6) 3
坐骨神経痛 2 ( 0.4) 2 1 ( 0.2) 1 3 ( 0.6) 3
緊張性頭痛 2 ( 0.4) 2 2 ( 0.4) 2
肋間神経痛 2 ( 0.4) 2 2 ( 0.4) 2
自律神経失調 1 ( 0.2) 2 1 ( 0.2) 2
脳梗塞 1 ( 0.2) 1 1 ( 0.2) 1
体位性めまい 1 ( 0.2) 1 1 ( 0.2) 1
眼振 1 ( 0.2) 1 1 ( 0.2) 1
視野欠損 1 ( 0.2) 1 1 ( 0.2) 1
パーキンソン病 1 ( 0.2) 1 1 ( 0.2) 1
顔面痙攣 1 ( 0.2) 1 1 ( 0.2) 1
精神障害 10 ( 2.1) 12 3 ( 0.6) 3 1 ( 0.2) 1 14 ( 2.9) 16
不眠症 9 ( 1.9) 11 9 ( 1.9) 11
うつ病 1 ( 0.2) 1 2 ( 0.4) 2 1 ( 0.2) 1 4 ( 0.8) 4
不安 1 ( 0.2) 1 1 ( 0.2) 1
腎および尿路障害 9 ( 1.9) 12 2 ( 0.4) 2 11 ( 2.3) 14
排尿困難 4 ( 0.8) 6 4 ( 0.8) 6
尿閉 1 ( 0.2) 1 1 ( 0.2) 1 2 ( 0.4) 2
遺尿 1 ( 0.2) 1 1 ( 0.2) 1
血尿 1 ( 0.2) 1 1 ( 0.2) 1
膿尿 1 ( 0.2) 2 1 ( 0.2) 2
尿流量減少 1 ( 0.2) 1 1 ( 0.2) 1
尿臭異常 1 ( 0.2) 1 1 ( 0.2) 1
生殖系および乳房障害 9 ( 1.9) 11 2 ( 0.4) 2 11 ( 2.3) 13
前立腺炎 1 ( 0.2) 1 2 ( 0.4) 2 3 ( 0.6) 3
女性陰部そう痒症 2 ( 0.4) 3 2 ( 0.4) 3
不規則月経 2 ( 0.4) 3 2 ( 0.4) 3
月経困難症 1 ( 0.2) 1 1 ( 0.2) 1
閉経期症状 1 ( 0.2) 1 1 ( 0.2) 1
卵巣嚢胞 1 ( 0.2) 1 1 ( 0.2) 1
腟粘膜びらん 1 ( 0.2) 1 1 ( 0.2) 1
呼吸器、胸郭および縦隔障害 69 ( 14.4) 97 7 ( 1.5) 12 76 ( 15.9) 109
上気道の炎症 23 ( 4.8) 37 2 ( 0.4) 3 25 ( 5.2) 40
咳嗽 11 ( 2.3) 13 1 ( 0.2) 2 12 ( 2.5) 15
咽喉頭疼痛 11 ( 2.3) 12 1 ( 0.2) 2 12 ( 2.5) 14
嗄声 7 ( 1.5) 8 7 ( 1.5) 8
鼻漏 6 ( 1.3) 6 6 ( 1.3) 6
鼻出血 5 ( 1.0) 7 5 ( 1.0) 7
咽頭不快感 4 ( 0.8) 4 4 ( 0.8) 4
喘息 2 ( 0.4) 3 2 ( 0.4) 3
湿性咳嗽 2 ( 0.4) 2 2 ( 0.4) 2
息詰まり感 1 ( 0.2) 1 1 ( 0.2) 1
咽喉乾燥 1 ( 0.2) 1 1 ( 0.2) 1
呼吸困難 1 ( 0.2) 1 1 ( 0.2) 1

- 424 -
 2.7.6 Summary of the individual tests

Table 2.7.6-9 List of adverse events by severity (continued)

投与群 0.2 mg/日
安全性解析対象集団 478
重症度 軽度 中等度 高度 計
有害事象項目 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数
喀血 1 ( 0.2) 1 1 ( 0.2) 1
鼻閉 1 ( 0.2) 1 1 ( 0.2) 1
鼻乾燥 1 ( 0.2) 1 1 ( 0.2) 1
アレルギー性鼻炎 1 ( 0.2) 1 1 ( 0.2) 1
喀痰増加 1 ( 0.2) 1 1 ( 0.2) 1
アレルギー性気管支炎 1 ( 0.2) 1 1 ( 0.2) 1
喉頭不快感 1 ( 0.2) 1 1 ( 0.2) 1
皮膚および皮下組織障害 68 ( 14.2) 91 10 ( 2.1) 12 78 ( 16.3) 103
皮下出血 21 ( 4.4) 25 2 ( 0.4) 2 23 ( 4.8) 27
湿疹 15 ( 3.1) 15 2 ( 0.4) 2 17 ( 3.6) 17
そう痒症 11 ( 2.3) 12 11 ( 2.3) 12
発疹 8 ( 1.7) 8 1 ( 0.2) 1 9 ( 1.9) 9
接触性皮膚炎 7 ( 1.5) 7 1 ( 0.2) 1 8 ( 1.7) 8
紅斑 2 ( 0.4) 2 2 ( 0.4) 2 4 ( 0.8) 4
皮膚炎 2 ( 0.4) 2 1 ( 0.2) 1 3 ( 0.6) 3
蕁麻疹 3 ( 0.6) 3 3 ( 0.6) 3
円形脱毛症 2 ( 0.4) 2 2 ( 0.4) 2
ざ瘡 1 ( 0.2) 1 1 ( 0.2) 1
皮膚嚢腫 1 ( 0.2) 2 1 ( 0.2) 2
アレルギー性皮膚炎 1 ( 0.2) 1 1 ( 0.2) 1
薬剤性皮膚炎 1 ( 0.2) 1 1 ( 0.2) 1
皮膚乾燥 1 ( 0.2) 1 1 ( 0.2) 1
発汗障害 1 ( 0.2) 1 1 ( 0.2) 1
結節性紅斑 1 ( 0.2) 1 1 ( 0.2) 1
顔面浮腫 1 ( 0.2) 1 1 ( 0.2) 1
紅色汗疹 1 ( 0.2) 1 1 ( 0.2) 1
爪の障害 1 ( 0.2) 1 1 ( 0.2) 1
皮膚疼痛 1 ( 0.2) 1 1 ( 0.2) 1
乾癬 1 ( 0.2) 1 1 ( 0.2) 1
脂漏性皮膚炎 1 ( 0.2) 1 1 ( 0.2) 1
ひび・あかぎれ 1 ( 0.2) 1 1 ( 0.2) 1
皮膚潰瘍 1 ( 0.2) 1 1 ( 0.2) 1
汗腺障害 1 ( 0.2) 1 1 ( 0.2) 1
挫傷 1 ( 0.2) 1 1 ( 0.2) 1
血管障害 4 ( 0.8) 4 4 ( 0.8) 4
高血圧 1 ( 0.2) 1 1 ( 0.2) 1
末梢血管障害 1 ( 0.2) 1 1 ( 0.2) 1
静脈瘤 1 ( 0.2) 1 1 ( 0.2) 1
ほてり 1 ( 0.2) 1 1 ( 0.2) 1
The incidence of each laboratory measure may vary because the number of cases with laboratory items present during the observation period and after the start of treatment was included in
the total.
However, items that were judged to have abnormal variations were included regardless of whether the test value was missing or not.

- 425 -
 2.7.6 Summary of the individual tests

Table 2.7.6-10 List of adverse reactions by severity

投与群 0.2 mg/日
安全性解析対象集団 478
重症度 軽度 中等度 高度 計
有害事象項目 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数
全例 177 ( 37.0) 294 43 ( 9.0) 59 3 ( 0.6) 3 223 ( 46.7) 356
心臓障害 2 ( 0.4) 2 2 ( 0.4) 2 4 ( 0.8) 4
動悸 1 ( 0.2) 1 1 ( 0.2) 1 2 ( 0.4) 2
左脚ブロック 1 ( 0.2) 1 1 ( 0.2) 1
心室性期外収縮 1 ( 0.2) 1 1 ( 0.2) 1
眼障害 27 ( 5.6) 29 6 ( 1.3) 6 33 ( 6.9) 35
羞明 10 ( 2.1) 10 2 ( 0.4) 2 12 ( 2.5) 12
眼球乾燥 6 ( 1.3) 6 1 ( 0.2) 1 7 ( 1.5) 7
霧視 6 ( 1.3) 6 6 ( 1.3) 6
眼精疲労 3 ( 0.6) 3 3 ( 0.6) 3
眼の異常感 2 ( 0.4) 2 2 ( 0.4) 2
閉塞隅角緑内障 1 ( 0.2) 1 1 ( 0.2) 1
複視 1 ( 0.2) 1 1 ( 0.2) 1
眼痛 1 ( 0.2) 1 1 ( 0.2) 1
眼瞼浮腫 1 ( 0.2) 2 1 ( 0.2) 2
胃腸障害 51 ( 10.7) 61 5 ( 1.0) 10 56 ( 11.7) 71
便秘 41 ( 8.6) 47 2 ( 0.4) 3 43 ( 9.0) 50
腹部膨満 4 ( 0.8) 4 4 ( 0.8) 4
上腹部痛 1 ( 0.2) 1 2 ( 0.4) 3 3 ( 0.6) 4
胃不快感 2 ( 0.4) 2 1 ( 0.2) 1 3 ( 0.6) 3
胃炎 2 ( 0.4) 2 2 ( 0.4) 2
悪心 1 ( 0.2) 1 1 ( 0.2) 1 2 ( 0.4) 2
口唇炎 1 ( 0.2) 1 1 ( 0.2) 1
消化不良 1 ( 0.2) 1 1 ( 0.2) 1
舌炎 1 ( 0.2) 1 1 ( 0.2) 1
口内炎 1 ( 0.2) 2 1 ( 0.2) 2
舌障害 1 ( 0.2) 1 1 ( 0.2) 1
全身障害および投与局所様態 132 ( 27.6) 149 29 ( 6.1) 29 3 ( 0.6) 3 164 ( 34.3) 181
口渇 133 ( 27.8) 146 28 ( 5.9) 28 3 ( 0.6) 3 164 ( 34.3) 177
無力症 1 ( 0.2) 1 1 ( 0.2) 1 2 ( 0.4) 2
倦怠感 1 ( 0.2) 1 1 ( 0.2) 1
浮腫 1 ( 0.2) 1 1 ( 0.2) 1
感染症および寄生虫症 2 ( 0.4) 2 1 ( 0.2) 1 3 ( 0.6) 3
膀胱炎 2 ( 0.4) 2 1 ( 0.2) 1 3 ( 0.6) 3
臨床検査 16 ( 3.3) 26 2 ( 0.4) 2 18 ( 3.8) 28
残尿量 3 ( 0.6) 4 2 ( 0.4) 2 5 ( 1.0) 6
γ-グルタミルトランスフェラーゼ増加 4 ( 0.8) 4 4 ( 0.8) 4
血中乳酸脱水素酵素増加 2 ( 0.4) 2 2 ( 0.4) 2
血中トリグリセリド増加 2 ( 0.4) 2 2 ( 0.4) 2
尿中白血球陽性 2 ( 0.4) 2 2 ( 0.4) 2
尿中蛋白陽性 2 ( 0.4) 2 2 ( 0.4) 2
血小板数減少 1 ( 0.2) 1 1 ( 0.2) 1
尿中ブドウ糖陽性 1 ( 0.2) 1 1 ( 0.2) 1
アスパラギン酸アミノトランスフェラーゼ増加 1 ( 0.2) 1 1 ( 0.2) 1
血中コレステロール増加 1 ( 0.2) 1 1 ( 0.2) 1
血中ナトリウム減少 1 ( 0.2) 1 1 ( 0.2) 1
ヘマトクリット減少 1 ( 0.2) 1 1 ( 0.2) 1
ヘモグロビン減少 1 ( 0.2) 1 1 ( 0.2) 1
赤血球数減少 1 ( 0.2) 1 1 ( 0.2) 1
白血球数減少 1 ( 0.2) 1 1 ( 0.2) 1
血中アルカリホスファターゼ増加 1 ( 0.2) 1 1 ( 0.2) 1
代謝および栄養障害 1 ( 0.2) 1 1 ( 0.2) 1 2 ( 0.4) 2
食欲不振 1 ( 0.2) 1 1 ( 0.2) 1 2 ( 0.4) 2
筋骨格系および結合組織障害 1 ( 0.2) 1 1 ( 0.2) 1
背部痛 1 ( 0.2) 1 1 ( 0.2) 1
神経系障害 11 ( 2.3) 11 3 ( 0.6) 3 14 ( 2.9) 14
傾眠 8 ( 1.7) 8 2 ( 0.4) 2 10 ( 2.1) 10
味覚異常 2 ( 0.4) 2 2 ( 0.4) 2
浮動性めまい 1 ( 0.2) 1 1 ( 0.2) 1
頭痛 1 ( 0.2) 1 1 ( 0.2) 1
腎および尿路障害 4 ( 0.8) 4 1 ( 0.2) 1 5 ( 1.0) 5
排尿困難 2 ( 0.4) 2 2 ( 0.4) 2
尿閉 1 ( 0.2) 1 1 ( 0.2) 1 2 ( 0.4) 2
尿臭異常 1 ( 0.2) 1 1 ( 0.2) 1
呼吸器、胸郭および縦隔障害 5 ( 1.0) 5 2 ( 0.4) 2 7 ( 1.5) 7
咽喉頭疼痛 2 ( 0.4) 2 2 ( 0.4) 2
息詰まり感 1 ( 0.2) 1 1 ( 0.2) 1
咽喉乾燥 1 ( 0.2) 1 1 ( 0.2) 1
嗄声 1 ( 0.2) 1 1 ( 0.2) 1
咽頭不快感 1 ( 0.2) 1 1 ( 0.2) 1
湿性咳嗽 1 ( 0.2) 1 1 ( 0.2) 1
皮膚および皮下組織障害 4 ( 0.8) 4 1 ( 0.2) 1 5 ( 1.0) 5
そう痒症 2 ( 0.4) 2 2 ( 0.4) 2
皮膚乾燥 1 ( 0.2) 1 1 ( 0.2) 1
発疹 1 ( 0.2) 1 1 ( 0.2) 1
顔面浮腫 1 ( 0.2) 1 1 ( 0.2) 1

The incidence of each laboratory measure may vary because the number of cases with laboratory items present during the observation period and after the start of treatment was included in
the total.
However, items that were judged to have abnormal variations were included regardless of whether the test value was missing or not.

- 426 -
 2.7.6 Summary of the individual tests

Table 2.7.6-11 List of adverse events by causal relationship

投与群 0.2 mg/日
安全性解析対象集団 478
因果関係 ① ② ③ ④ 計
有害事象項目 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数
全例 40 ( 8.4) 59 114 ( 23.8) 160 69 ( 14.4) 137 209 ( 43.7) 1507 432 ( 90.4) 1863
血液およびリンパ系障害 4 ( 0.8) 4 4 ( 0.8) 4
貧血 1 ( 0.2) 1 1 ( 0.2) 1
鉄欠乏性貧血 1 ( 0.2) 1 1 ( 0.2) 1
リンパ節炎 1 ( 0.2) 1 1 ( 0.2) 1
リンパ節症 1 ( 0.2) 1 1 ( 0.2) 1
心臓障害 1 ( 0.2) 1 3 ( 0.6) 3 10 ( 2.1) 10 14 ( 2.9) 14
動悸 2 ( 0.4) 2 5 ( 1.0) 5 7 ( 1.5) 7
心不全 2 ( 0.4) 2 2 ( 0.4) 2
狭心症 1 ( 0.2) 1 1 ( 0.2) 1
徐脈 1 ( 0.2) 1 1 ( 0.2) 1
左脚ブロック 1 ( 0.2) 1 1 ( 0.2) 1
上室性期外収縮 1 ( 0.2) 1 1 ( 0.2) 1
心室性期外収縮 1 ( 0.2) 1 1 ( 0.2) 1
耳および迷路障害 9 ( 1.9) 9 9 ( 1.9) 9
回転性眩暈 3 ( 0.6) 3 3 ( 0.6) 3
耳閉感 2 ( 0.4) 2 2 ( 0.4) 2
メニエール病 1 ( 0.2) 1 1 ( 0.2) 1
耳鳴 1 ( 0.2) 1 1 ( 0.2) 1
頭位性眩暈 1 ( 0.2) 1 1 ( 0.2) 1
突発難聴 1 ( 0.2) 1 1 ( 0.2) 1
内分泌障害 1 ( 0.2) 1 1 ( 0.2) 1
甲状腺結節 1 ( 0.2) 1 1 ( 0.2) 1
眼障害 5 ( 1.0) 5 10 ( 2.1) 10 18 ( 3.8) 20 46 ( 9.6) 60 79 ( 16.5) 95
霧視 1 ( 0.2) 1 5 ( 1.0) 5 8 ( 1.7) 8 14 ( 2.9) 14
眼球乾燥 1 ( 0.2) 1 1 ( 0.2) 1 5 ( 1.0) 5 7 ( 1.5) 7 14 ( 2.9) 14
羞明 2 ( 0.4) 2 7 ( 1.5) 7 3 ( 0.6) 3 1 ( 0.2) 1 13 ( 2.7) 13
白内障 9 ( 1.9) 9 9 ( 1.9) 9
眼精疲労 1 ( 0.2) 1 2 ( 0.4) 2 4 ( 0.8) 4 7 ( 1.5) 7
硝子体浮遊物 4 ( 0.8) 4 4 ( 0.8) 4
アレルギー性結膜炎 3 ( 0.6) 3 3 ( 0.6) 3
眼痛 1 ( 0.2) 1 2 ( 0.4) 2 3 ( 0.6) 3
眼の異常感 2 ( 0.4) 2 2 ( 0.4) 2
複視 1 ( 0.2) 1 1 ( 0.2) 1 2 ( 0.4) 2
眼瞼浮腫 1 ( 0.2) 2 1 ( 0.2) 1 2 ( 0.4) 3
角膜炎 2 ( 0.4) 2 2 ( 0.4) 2
光視症 2 ( 0.4) 2 2 ( 0.4) 2
水晶体嚢の偽落屑 2 ( 0.4) 2 2 ( 0.4) 2
閉塞隅角緑内障 1 ( 0.2) 1 1 ( 0.2) 1
乱視 1 ( 0.2) 1 1 ( 0.2) 1
結膜炎 1 ( 0.2) 1 1 ( 0.2) 1
眼脂 1 ( 0.2) 1 1 ( 0.2) 1
眼の障害 1 ( 0.2) 1 1 ( 0.2) 1
眼出血 1 ( 0.2) 1 1 ( 0.2) 1
涙液分泌低下 1 ( 0.2) 1 1 ( 0.2) 1
流涙増加 1 ( 0.2) 1 1 ( 0.2) 1
黄斑変性 1 ( 0.2) 1 1 ( 0.2) 1
老視 1 ( 0.2) 1 1 ( 0.2) 1
屈折障害 1 ( 0.2) 1 1 ( 0.2) 1
網膜剥離 1 ( 0.2) 1 1 ( 0.2) 1
視力低下 1 ( 0.2) 1 1 ( 0.2) 1
視覚障害 1 ( 0.2) 1 1 ( 0.2) 1
眼そう痒症 1 ( 0.2) 1 1 ( 0.2) 1
胃腸障害 5 ( 1.0) 8 24 ( 5.0) 32 27 ( 5.6) 31 115 ( 24.1) 235 171 ( 35.8) 306
便秘 3 ( 0.6) 3 20 ( 4.2) 24 20 ( 4.2) 23 26 ( 5.4) 34 69 ( 14.4) 84
下痢 24 ( 5.0) 32 24 ( 5.0) 32
上腹部痛 1 ( 0.2) 1 1 ( 0.2) 2 1 ( 0.2) 1 19 ( 4.0) 21 22 ( 4.6) 25
悪心 1 ( 0.2) 1 1 ( 0.2) 1 16 ( 3.3) 17 18 ( 3.8) 19
嘔吐 15 ( 3.1) 18 15 ( 3.1) 18
胃不快感 1 ( 0.2) 1 2 ( 0.4) 2 10 ( 2.1) 17 13 ( 2.7) 20
胃炎 2 ( 0.4) 2 10 ( 2.1) 14 12 ( 2.5) 16
歯痛 10 ( 2.1) 10 10 ( 2.1) 10
口内炎 1 ( 0.2) 2 7 ( 1.5) 12 8 ( 1.7) 14
腹部膨満 1 ( 0.2) 1 3 ( 0.6) 3 3 ( 0.6) 4 7 ( 1.5) 8
消化不良 1 ( 0.2) 1 6 ( 1.3) 6 7 ( 1.5) 7
腹痛 6 ( 1.3) 6 6 ( 1.3) 6
歯周炎 6 ( 1.3) 6 6 ( 1.3) 6
口唇炎 1 ( 0.2) 1 4 ( 0.8) 4 5 ( 1.0) 5
胃潰瘍 5 ( 1.0) 5 5 ( 1.0) 5
歯肉炎 4 ( 0.8) 4 4 ( 0.8) 4
下腹部痛 3 ( 0.6) 3 3 ( 0.6) 3
歯肉腫脹 3 ( 0.6) 3 3 ( 0.6) 3
痔核 3 ( 0.6) 4 3 ( 0.6) 4
歯周病 3 ( 0.6) 3 3 ( 0.6) 3
口唇乾燥 2 ( 0.4) 2 2 ( 0.4) 2
舌障害 1 ( 0.2) 1 1 ( 0.2) 1 2 ( 0.4) 2
結腸ポリープ 1 ( 0.2) 1 1 ( 0.2) 1
十二指腸潰瘍 1 ( 0.2) 1 1 ( 0.2) 1
嚥下障害 1 ( 0.2) 1 1 ( 0.2) 1
腸炎 1 ( 0.2) 1 1 ( 0.2) 1
食中毒 1 ( 0.2) 1 1 ( 0.2) 1
舌炎 1 ( 0.2) 1 1 ( 0.2) 1
舌苔 1 ( 0.2) 1 1 ( 0.2) 1
歯の障害 1 ( 0.2) 1 1 ( 0.2) 1
心窩部不快感 1 ( 0.2) 1 1 ( 0.2) 1
口の感覚鈍麻 1 ( 0.2) 1 1 ( 0.2) 1
全身障害および投与局所様態 39 ( 8.2) 42 96 ( 20.1) 101 29 ( 6.1) 38 60 ( 12.6) 90 224 ( 46.9) 271
口渇 39 ( 8.2) 41 96 ( 20.1) 101 29 ( 6.1) 35 28 ( 5.9) 32 192 ( 40.2) 209
末梢性浮腫 11 ( 2.3) 12 11 ( 2.3) 12
発熱 9 ( 1.9) 10 9 ( 1.9) 10
倦怠感 1 ( 0.2) 1 7 ( 1.5) 9 8 ( 1.7) 10
胸部不快感 7 ( 1.5) 7 7 ( 1.5) 7
胸痛 4 ( 0.8) 4 4 ( 0.8) 4
浮腫 1 ( 0.2) 1 3 ( 0.6) 4 4 ( 0.8) 5
無力症 2 ( 0.4) 2 1 ( 0.2) 1 3 ( 0.6) 3
疼痛 3 ( 0.6) 3 3 ( 0.6) 3
疲労 2 ( 0.4) 2 2 ( 0.4) 2
歩行異常 1 ( 0.2) 1 1 ( 0.2) 1
局所の炎症 1 ( 0.2) 1 1 ( 0.2) 1
圧迫感 1 ( 0.2) 1 1 ( 0.2) 1
腫脹 1 ( 0.2) 1 1 ( 0.2) 1
圧痛 1 ( 0.2) 1 1 ( 0.2) 1
炎症 1 ( 0.2) 1 1 ( 0.2) 1
免疫系障害 2 ( 0.4) 2 2 ( 0.4) 2
季節性アレルギー 2 ( 0.4) 2 2 ( 0.4) 2
感染症および寄生虫症 3 ( 0.6) 3 199 ( 41.6) 361 202 ( 42.3) 364
鼻咽頭炎 147 ( 30.8) 234 147 ( 30.8) 234
膀胱炎 3 ( 0.6) 3 28 ( 5.9) 41 31 ( 6.5) 44
Causal relationship with the investigational drug: (1) clearly related, (2) probably related, (3) not related, (4) not related

- 427 -
 2.7.6 Summary of the individual tests

Table 2.7.6-11 List of adverse events by causal relationship (continued)

投与群 0.2 mg/日
安全性解析対象集団 478
因果関係 ① ② ③ ④ 計
有害事象項目 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数
咽喉頭炎 7 ( 1.5) 10 7 ( 1.5) 10
細菌尿 5 ( 1.0) 6 5 ( 1.0) 6
気管支炎 5 ( 1.0) 7 5 ( 1.0) 7
インフルエンザ 5 ( 1.0) 5 5 ( 1.0) 5
齲歯 4 ( 0.8) 4 4 ( 0.8) 4
胃腸炎 4 ( 0.8) 4 4 ( 0.8) 4
単純ヘルペス 4 ( 0.8) 8 4 ( 0.8) 8
ウイルス性胃腸炎 3 ( 0.6) 3 3 ( 0.6) 3
帯状疱疹 3 ( 0.6) 3 3 ( 0.6) 3
足部白癬 3 ( 0.6) 3 3 ( 0.6) 3
尿路感染 3 ( 0.6) 5 3 ( 0.6) 5
急性気管支炎 2 ( 0.4) 2 2 ( 0.4) 2
外耳炎 2 ( 0.4) 2 2 ( 0.4) 2
中耳炎 2 ( 0.4) 3 2 ( 0.4) 3
鼻炎 2 ( 0.4) 2 2 ( 0.4) 2
白癬 2 ( 0.4) 2 2 ( 0.4) 2
扁桃炎 2 ( 0.4) 2 2 ( 0.4) 2
化膿 2 ( 0.4) 2 2 ( 0.4) 2
虫垂炎 1 ( 0.2) 1 1 ( 0.2) 1
気管支肺炎 1 ( 0.2) 1 1 ( 0.2) 1
毛包炎 1 ( 0.2) 1 1 ( 0.2) 1
ヘルペスウイルス感染 1 ( 0.2) 1 1 ( 0.2) 1
麦粒腫 1 ( 0.2) 1 1 ( 0.2) 1
耳下腺炎 1 ( 0.2) 1 1 ( 0.2) 1
肺炎 1 ( 0.2) 1 1 ( 0.2) 1
肺水腫 1 ( 0.2) 1 1 ( 0.2) 1
急性腎盂腎炎 1 ( 0.2) 1 1 ( 0.2) 1
腟炎 1 ( 0.2) 1 1 ( 0.2) 1
トリコモナス性外陰部腟炎 1 ( 0.2) 1 1 ( 0.2) 1
ヘリコバクター感染 1 ( 0.2) 1 1 ( 0.2) 1
ウイルス性腸炎 1 ( 0.2) 1 1 ( 0.2) 1
傷害、中毒および処置合併症 46 ( 9.6) 50 46 ( 9.6) 50
背部損傷 7 ( 1.5) 7 7 ( 1.5) 7
熱傷 7 ( 1.5) 7 7 ( 1.5) 7
関節捻挫 6 ( 1.3) 7 6 ( 1.3) 7
擦過傷 4 ( 0.8) 4 4 ( 0.8) 4
創傷 3 ( 0.6) 3 3 ( 0.6) 3
節足動物咬傷 2 ( 0.4) 2 2 ( 0.4) 2
鎖骨骨折 2 ( 0.4) 2 2 ( 0.4) 2
肋骨骨折 2 ( 0.4) 2 2 ( 0.4) 2
半月板障害 2 ( 0.4) 2 2 ( 0.4) 2
靱帯損傷 2 ( 0.4) 2 2 ( 0.4) 2
動物咬傷 1 ( 0.2) 1 1 ( 0.2) 1
節足動物刺傷 1 ( 0.2) 1 1 ( 0.2) 1
圧迫骨折 1 ( 0.2) 1 1 ( 0.2) 1
上顆炎 1 ( 0.2) 1 1 ( 0.2) 1
骨折 1 ( 0.2) 1 1 ( 0.2) 1
手骨折 1 ( 0.2) 1 1 ( 0.2) 1
上腕骨骨折 1 ( 0.2) 1 1 ( 0.2) 1
顎の骨折 1 ( 0.2) 1 1 ( 0.2) 1
橈骨骨折 1 ( 0.2) 1 1 ( 0.2) 1
歯牙損傷 1 ( 0.2) 1 1 ( 0.2) 1
尾骨骨折 1 ( 0.2) 1 1 ( 0.2) 1
処置後痛 1 ( 0.2) 1 1 ( 0.2) 1
臨床検査 4 ( 0.8) 4 14 ( 2.9) 24 110 ( 23.0) 217 128 ( 26.8) 245
尿中白血球陽性 2 ( 0.4) 2 53 ( 11.1) 68 55 ( 11.5) 70
γ-グルタミルトランスフェラーゼ増加 1 ( 0.2) 1 3 ( 0.6) 3 15 ( 3.1) 16 19 ( 4.0) 20
アラニン・アミノトランスフェラーゼ増加 15 ( 3.1) 17 15 ( 3.1) 17
血中トリグリセリド増加 2 ( 0.4) 2 11 ( 2.3) 12 13 ( 2.7) 14
尿中赤血球陽性 13 ( 2.7) 14 13 ( 2.7) 14
白血球数増加 13 ( 2.7) 14 13 ( 2.7) 14
アスパラギン酸アミノトランスフェラーゼ増加 1 ( 0.2) 1 10 ( 2.1) 12 11 ( 2.3) 13
血中乳酸脱水素酵素増加 2 ( 0.4) 2 8 ( 1.7) 8 10 ( 2.1) 10
血中アルカリホスファターゼ増加 1 ( 0.2) 1 7 ( 1.5) 7 8 ( 1.7) 8
残尿量 3 ( 0.6) 3 2 ( 0.4) 3 2 ( 0.4) 2 7 ( 1.5) 8
尿中ブドウ糖陽性 1 ( 0.2) 1 5 ( 1.0) 5 6 ( 1.3) 6
ヘマトクリット減少 1 ( 0.2) 1 5 ( 1.0) 5 6 ( 1.3) 6
ヘモグロビン減少 1 ( 0.2) 1 5 ( 1.0) 5 6 ( 1.3) 6
赤血球数減少 1 ( 0.2) 1 5 ( 1.0) 5 6 ( 1.3) 6
尿中蛋白陽性 2 ( 0.4) 2 3 ( 0.6) 4 5 ( 1.0) 6
血圧上昇 5 ( 1.0) 5 5 ( 1.0) 5
白血球数減少 1 ( 0.2) 1 4 ( 0.8) 4 5 ( 1.0) 5
血中コレステロール増加 1 ( 0.2) 1 1 ( 0.2) 1 2 ( 0.4) 2
血中ナトリウム減少 1 ( 0.2) 1 1 ( 0.2) 1 2 ( 0.4) 2
血中尿素増加 2 ( 0.4) 2 2 ( 0.4) 2
血中尿酸増加 2 ( 0.4) 2 2 ( 0.4) 2
血小板数減少 1 ( 0.2) 1 1 ( 0.2) 1
血中塩化物減少 1 ( 0.2) 1 1 ( 0.2) 1
血中クレアチンホスホキナーゼ増加 1 ( 0.2) 1 1 ( 0.2) 1
血中カリウム減少 1 ( 0.2) 1 1 ( 0.2) 1
Ｃ－反応性蛋白増加 1 ( 0.2) 1 1 ( 0.2) 1
心電図ＳＴ部分異常 1 ( 0.2) 1 1 ( 0.2) 1
心電図Ｔ波逆転 1 ( 0.2) 1 1 ( 0.2) 1
心電図異常Ｔ波 1 ( 0.2) 1 1 ( 0.2) 1
尿検査異常 1 ( 0.2) 1 1 ( 0.2) 1
代謝および栄養障害 1 ( 0.2) 1 1 ( 0.2) 1 5 ( 1.0) 5 7 ( 1.5) 7
食欲不振 1 ( 0.2) 1 1 ( 0.2) 1 1 ( 0.2) 1 3 ( 0.6) 3
糖尿病 2 ( 0.4) 2 2 ( 0.4) 2
食欲減退 2 ( 0.4) 2 2 ( 0.4) 2
筋骨格系および結合組織障害 1 ( 0.2) 1 76 ( 15.9) 107 77 ( 16.1) 108
背部痛 1 ( 0.2) 1 25 ( 5.2) 26 26 ( 5.4) 27
関節痛 18 ( 3.8) 24 18 ( 3.8) 24
筋骨格硬直 7 ( 1.5) 9 7 ( 1.5) 9
限局性骨関節炎 5 ( 1.0) 5 5 ( 1.0) 5
筋痛 5 ( 1.0) 6 5 ( 1.0) 6
筋痙攣 4 ( 0.8) 6 4 ( 0.8) 6
四肢痛 3 ( 0.6) 4 3 ( 0.6) 4
関節周囲炎 3 ( 0.6) 3 3 ( 0.6) 3
椎間板突出 3 ( 0.6) 3 3 ( 0.6) 3
関節炎 2 ( 0.4) 2 2 ( 0.4) 2
単関節炎 2 ( 0.4) 2 2 ( 0.4) 2
脊柱管狭窄症 2 ( 0.4) 2 2 ( 0.4) 2
脊椎症 2 ( 0.4) 2 2 ( 0.4) 2
腱炎 2 ( 0.4) 2 2 ( 0.4) 2
骨痛 1 ( 0.2) 1 1 ( 0.2) 1
骨棘 1 ( 0.2) 1 1 ( 0.2) 1
ガングリオン 1 ( 0.2) 1 1 ( 0.2) 1
関節硬直 1 ( 0.2) 2 1 ( 0.2) 2

Causal relationship with the investigational drug: (1) clearly related, (2) probably related, (3) not related, (4) not related

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 2.7.6 Summary of the individual tests

Table 2.7.6-11 List of adverse events by causal relationship (continued)

投与群 0.2 mg/日
安全性解析対象集団 478
因果関係 ① ② ③ ④ 計
有害事象項目 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数 例数 （％） 件数
関節腫脹 1 ( 0.2) 1 1 ( 0.2) 1
筋力低下 1 ( 0.2) 1 1 ( 0.2) 1
筋骨格痛 1 ( 0.2) 1 1 ( 0.2) 1
頚部痛 1 ( 0.2) 1 1 ( 0.2) 1
後天性脊椎すべり症 1 ( 0.2) 1 1 ( 0.2) 1
狭窄性腱鞘炎 1 ( 0.2) 1 1 ( 0.2) 1
良性、悪性および詳細不明の新生物（嚢胞およびポリープを含む） 3 ( 0.6) 3 3 ( 0.6) 3
肺の良性新生物 1 ( 0.2) 1 1 ( 0.2) 1
肺転移 1 ( 0.2) 1 1 ( 0.2) 1
皮膚乳頭腫 1 ( 0.2) 1 1 ( 0.2) 1
神経系障害 3 ( 0.6) 3 5 ( 1.0) 5 6 ( 1.3) 6 73 ( 15.3) 111 87 ( 18.2) 125
頭痛 1 ( 0.2) 1 36 ( 7.5) 47 37 ( 7.7) 48
浮動性めまい 1 ( 0.2) 1 18 ( 3.8) 26 19 ( 4.0) 27
傾眠 3 ( 0.6) 3 3 ( 0.6) 3 4 ( 0.8) 4 5 ( 1.0) 5 15 ( 3.1) 15
感覚減退 11 ( 2.3) 13 11 ( 2.3) 13
意識消失 4 ( 0.8) 4 4 ( 0.8) 4
味覚異常 2 ( 0.4) 2 1 ( 0.2) 1 3 ( 0.6) 3
坐骨神経痛 3 ( 0.6) 3 3 ( 0.6) 3
緊張性頭痛 2 ( 0.4) 2 2 ( 0.4) 2
肋間神経痛 2 ( 0.4) 2 2 ( 0.4) 2
自律神経失調 1 ( 0.2) 2 1 ( 0.2) 2
脳梗塞 1 ( 0.2) 1 1 ( 0.2) 1
体位性めまい 1 ( 0.2) 1 1 ( 0.2) 1
眼振 1 ( 0.2) 1 1 ( 0.2) 1
視野欠損 1 ( 0.2) 1 1 ( 0.2) 1
パーキンソン病 1 ( 0.2) 1 1 ( 0.2) 1
顔面痙攣 1 ( 0.2) 1 1 ( 0.2) 1
精神障害 14 ( 2.9) 16 14 ( 2.9) 16
不眠症 9 ( 1.9) 11 9 ( 1.9) 11
うつ病 4 ( 0.8) 4 4 ( 0.8) 4
不安 1 ( 0.2) 1 1 ( 0.2) 1
腎および尿路障害 1 ( 0.2) 1 1 ( 0.2) 1 3 ( 0.6) 3 6 ( 1.3) 9 11 ( 2.3) 14
排尿困難 1 ( 0.2) 1 1 ( 0.2) 1 2 ( 0.4) 4 4 ( 0.8) 6
尿閉 2 ( 0.4) 2 2 ( 0.4) 2
遺尿 1 ( 0.2) 1 1 ( 0.2) 1
血尿 1 ( 0.2) 1 1 ( 0.2) 1
膿尿 1 ( 0.2) 2 1 ( 0.2) 2
尿流量減少 1 ( 0.2) 1 1 ( 0.2) 1
尿臭異常 1 ( 0.2) 1 1 ( 0.2) 1
生殖系および乳房障害 11 ( 2.3) 13 11 ( 2.3) 13
前立腺炎 3 ( 0.6) 3 3 ( 0.6) 3
女性陰部そう痒症 2 ( 0.4) 3 2 ( 0.4) 3
不規則月経 2 ( 0.4) 3 2 ( 0.4) 3
月経困難症 1 ( 0.2) 1 1 ( 0.2) 1
閉経期症状 1 ( 0.2) 1 1 ( 0.2) 1
卵巣嚢胞 1 ( 0.2) 1 1 ( 0.2) 1
腟粘膜びらん 1 ( 0.2) 1 1 ( 0.2) 1
呼吸器、胸郭および縦隔障害 4 ( 0.8) 4 3 ( 0.6) 3 69 ( 14.4) 102 76 ( 15.9) 109
上気道の炎症 25 ( 5.2) 40 25 ( 5.2) 40
咳嗽 12 ( 2.5) 15 12 ( 2.5) 15
咽喉頭疼痛 2 ( 0.4) 2 10 ( 2.1) 12 12 ( 2.5) 14
嗄声 1 ( 0.2) 1 6 ( 1.3) 7 7 ( 1.5) 8
鼻漏 6 ( 1.3) 6 6 ( 1.3) 6
鼻出血 5 ( 1.0) 7 5 ( 1.0) 7
咽頭不快感 1 ( 0.2) 1 3 ( 0.6) 3 4 ( 0.8) 4
喘息 2 ( 0.4) 3 2 ( 0.4) 3
湿性咳嗽 1 ( 0.2) 1 1 ( 0.2) 1 2 ( 0.4) 2
息詰まり感 1 ( 0.2) 1 1 ( 0.2) 1
咽喉乾燥 1 ( 0.2) 1 1 ( 0.2) 1
呼吸困難 1 ( 0.2) 1 1 ( 0.2) 1
喀血 1 ( 0.2) 1 1 ( 0.2) 1
鼻閉 1 ( 0.2) 1 1 ( 0.2) 1
鼻乾燥 1 ( 0.2) 1 1 ( 0.2) 1
アレルギー性鼻炎 1 ( 0.2) 1 1 ( 0.2) 1
喀痰増加 1 ( 0.2) 1 1 ( 0.2) 1
アレルギー性気管支炎 1 ( 0.2) 1 1 ( 0.2) 1
喉頭不快感 1 ( 0.2) 1 1 ( 0.2) 1
皮膚および皮下組織障害 1 ( 0.2) 1 4 ( 0.8) 4 73 ( 15.3) 98 78 ( 16.3) 103
皮下出血 23 ( 4.8) 27 23 ( 4.8) 27
湿疹 17 ( 3.6) 17 17 ( 3.6) 17
そう痒症 2 ( 0.4) 2 9 ( 1.9) 10 11 ( 2.3) 12
発疹 1 ( 0.2) 1 8 ( 1.7) 8 9 ( 1.9) 9
接触性皮膚炎 8 ( 1.7) 8 8 ( 1.7) 8
紅斑 4 ( 0.8) 4 4 ( 0.8) 4
皮膚炎 3 ( 0.6) 3 3 ( 0.6) 3
蕁麻疹 3 ( 0.6) 3 3 ( 0.6) 3
円形脱毛症 2 ( 0.4) 2 2 ( 0.4) 2
ざ瘡 1 ( 0.2) 1 1 ( 0.2) 1
皮膚嚢腫 1 ( 0.2) 2 1 ( 0.2) 2
アレルギー性皮膚炎 1 ( 0.2) 1 1 ( 0.2) 1
薬剤性皮膚炎 1 ( 0.2) 1 1 ( 0.2) 1
皮膚乾燥 1 ( 0.2) 1 1 ( 0.2) 1
発汗障害 1 ( 0.2) 1 1 ( 0.2) 1
結節性紅斑 1 ( 0.2) 1 1 ( 0.2) 1
顔面浮腫 1 ( 0.2) 1 1 ( 0.2) 1
紅色汗疹 1 ( 0.2) 1 1 ( 0.2) 1
爪の障害 1 ( 0.2) 1 1 ( 0.2) 1
皮膚疼痛 1 ( 0.2) 1 1 ( 0.2) 1
乾癬 1 ( 0.2) 1 1 ( 0.2) 1
脂漏性皮膚炎 1 ( 0.2) 1 1 ( 0.2) 1
ひび・あかぎれ 1 ( 0.2) 1 1 ( 0.2) 1
皮膚潰瘍 1 ( 0.2) 1 1 ( 0.2) 1
汗腺障害 1 ( 0.2) 1 1 ( 0.2) 1
挫傷 1 ( 0.2) 1 1 ( 0.2) 1
血管障害 4 ( 0.8) 4 4 ( 0.8) 4
高血圧 1 ( 0.2) 1 1 ( 0.2) 1
末梢血管障害 1 ( 0.2) 1 1 ( 0.2) 1
静脈瘤 1 ( 0.2) 1 1 ( 0.2) 1
ほてり 1 ( 0.2) 1 1 ( 0.2) 1
Causal relationship with the investigational drug: (1) clearly related, (2) probably related, (3) not related, (4) not related
The incidence of each laboratory measure may vary because the number of cases with laboratory items present during the observation period and after the start of treatment was
included in the total.
However, items that were judged to have abnormal variations were included regardless of whether the test value was missing or not.

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 2.7.6 Summary of the individual tests

3) Efficacy results
The percentage change (mean ± standard deviation) in the total number of urinary
incontinence sessions per week compared to the end of the observation period was 48.58
± 57.08, 55.92 ± 72.52, 70.83 ± 50.56, 81.30 ± 40.74, 83.59 ± 35.54 and 83.51 ±
35.48 after 4, 12, 28, 40, 52 and 52 weeks of treatment (or at discontinuation),
respectively. .74, 83.59±35.54 and 83.51±35.48, respectively, indicating a significant
reduction in the number of urinary incontinence episodes at all assessment times compared
to the end of the observation period (PPS, corresponding t-test, both p<0.0001, see
Table 2.7.6.6-12).

Table 2.7.6-12 Summary statistics for the total number of urinary incontinence
sessions per week (PPS)

評価時期 項目 症例数 平均±標準偏差 最小値 25％点 中央値 75％点 最大値 対応のあるt検定

観察期終了時 実測値 364 14.53 ± 14.47 1.0 5.00 9.50 19.00 109.0
治療期4週後 実測値 358 7.26 ± 10.83 0.0 1.00 3.00 9.00 103.0
差 358 -7.36 ± 10.68 -86.6 -11.00 -5.00 -2.00 20.0 p<0.0001 *
変化率 358 -48.58 ± 57.08 -100.0 -94.12 -61.32 -22.22 350.0 p<0.0001 *
治療期12週後 実測値 355 5.53 ± 9.62 0.0 0.00 2.00 7.00 93.0
差 355 -8.96 ± 11.97 -88.6 -12.40 -6.00 -2.00 17.0 p<0.0001 *
変化率 355 -55.92 ± 72.52 -100.0 -100.00 -75.86 -42.86 566.7 p<0.0001 *
治療期28週後 実測値 355 4.03 ± 8.39 0.0 0.00 1.00 4.00 83.0
差 355 -10.30 ± 12.55 -94.0 -13.00 -7.20 -3.00 25.0 p<0.0001 *
変化率 355 -70.83 ± 50.56 -100.0 -100.00 -90.91 -60.47 400.0 p<0.0001 *
治療期40週後 実測値 361 2.97 ± 7.05 0.0 0.00 0.00 2.00 55.0
差 361 -11.55 ± 12.32 -86.6 -15.00 -8.00 -4.00 8.0 p<0.0001 *
変化率 361 -81.30 ± 40.74 -100.0 -100.00 -100.00 -75.00 400.0 p<0.0001 *
治療期52週後 実測値 354 2.88 ± 7.22 0.0 0.00 0.00 3.00 54.0
差 354 -11.67 ± 12.81 -91.0 -15.00 -8.00 -3.50 32.0 p<0.0001 *
変化率 354 -83.59 ± 35.54 -100.0 -100.00 -100.00 -81.33 300.0 p<0.0001 *
治療期52週後 実測値 363 2.84 ± 7.14 0.0 0.00 0.00 3.00 54.0
または中止時 差 363 -11.66 ± 12.72 -91.0 -15.00 -8.00 -3.50 32.0 p<0.0001 *
変化率 363 -83.51 ± 35.48 -100.0 -100.00 -100.00 -81.33 300.0 p<0.0001 *
両側検定、p<0.05

The change in mean daily urinary frequency (times) (mean ± standard deviation)
compared to the end of the observation period was 1.21 ± 1.84, 1.65 ± 2.12, 2.05 ±
2.26, 2.55 ± 2.31, 2.34 ± 2.15, and 2.35 ± 2.14 after 4, 12, 28, 40, and 52 weeks of
treatment (or at discontinuation), respectively. 2.15, and 2.35±2.14, respectively,
and there was a significant reduction at all assessment times compared with the end of
the observation period (PPS, corresponding t-test, both p<0.0001, see Table 2.7.6.6-13).

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 2.7.6 Summary of the individual tests

Table 2.7.6-13 Summary statistics for the average number of urinations per day (PPS)
評価時期 項目 症例数 平均±標準偏差 最小値 25％点 中央値 75％点 最大値 対応のあるt検定
観察期終了時 実測値 364 11.56 ± 2.81 8.0 9.57 11.00 13.00 29.4
治療期4週後 実測値 358 10.35 ± 2.46 4.9 8.57 10.00 11.60 21.0
差 358 -1.21 ± 1.84 -15.1 -2.00 -1.00 -0.14 3.5 p<0.0001 *
治療期12週後 実測値 355 9.92 ± 2.43 5.1 8.14 9.43 11.57 19.4
差 355 -1.65 ± 2.12 -13.4 -2.71 -1.43 -0.43 3.6 p<0.0001 *
治療期28週後 実測値 355 9.52 ± 2.34 5.0 7.86 9.14 10.86 16.7
差 355 -2.05 ± 2.26 -14.6 -3.14 -1.86 -0.71 3.7 p<0.0001 *
治療期40週後 実測値 361 9.02 ± 2.29 3.9 7.29 8.71 10.40 16.1
差 361 -2.55 ± 2.31 -17.3 -3.71 -2.21 -1.00 3.1 p<0.0001 *
治療期52週後 実測値 354 9.22 ± 2.38 4.7 7.43 8.71 10.57 20.4
差 354 -2.34 ± 2.15 -13.9 -3.43 -2.14 -1.00 2.1 p<0.0001 *
治療期52週後 実測値 363 9.21 ± 2.36 4.7 7.57 8.71 10.57 20.4
または中止時 差 363 -2.35 ± 2.14 -13.9 -3.43 -2.14 -1.00 2.1 p<0.0001 *

両側検定、p<0.05

The percentage change (%) (mean ± standard deviation) in the mean number of urinary
urgency per day compared to the end of the observation period was 35.01 ± 48.51, 45.81
± 53.37, 55.67 ± 48.65, 71.54 ± 37.85, 70.39 ± 38.67 and 70.53 ± 38.37 after 4,
12, 28, 40 and 52 weeks of treatment (or at discontinuation), respectively. ±37.85,
70.39±38.67 and 70.53±38.37, respectively, a significant decrease compared to the end
of the observation period (PPS, corresponding t-test, both p<0.0001, see Table 2.7.6.6-
14).

Table 2.7.6-14 Summary statistics of the mean number of urinary urgency sensations per
day (PPS)

評価時期 項目 症例数 平均±標準偏差 最小値 25％点 中央値 75％点 最大値 対応のあるt検定

観察期終了時 実測値 364 4.84 ± 3.18 1.0 2.57 4.00 6.21 18.6
治療期4週後 実測値 358 3.14 ± 3.02 0.0 1.00 2.29 4.57 17.9
変化率 358 -35.01 ± 48.51 -100.0 -69.57 -42.51 -12.07 323.1 p<0.0001 *
治療期12週後 実測値 355 2.53 ± 2.79 0.0 0.57 1.71 3.43 19.3
変化率 355 -45.81 ± 53.37 -100.0 -82.50 -55.26 -25.00 323.1 p<0.0001 *
治療期28週後 実測値 355 2.11 ± 2.64 0.0 0.29 1.29 2.71 15.9
変化率 355 -55.67 ± 48.65 -100.0 -92.06 -68.42 -34.78 292.3 p<0.0001 *
治療期40週後 実測値 361 1.46 ± 2.26 0.0 0.00 0.71 1.71 14.6
変化率 361 -71.54 ± 37.85 -100.0 -100.00 -83.78 -57.14 259.0 p<0.0001 *
治療期52週後 実測値 354 1.56 ± 2.46 0.0 0.00 0.71 1.86 18.7
変化率 354 -70.39 ± 38.67 -100.0 -100.00 -81.70 -58.33 238.5 p<0.0001 *
治療期52週後 実測値 363 1.54 ± 2.43 0.0 0.00 0.71 1.86 18.7
または中止時 変化率 363 -70.53 ± 38.37 -100.0 -100.00 -81.58 -58.33 238.5 p<0.0001 *

両側検定、p<0.05

The change in mean single voiding volume (mL) (mean ± standard deviation) compared

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 2.7.6 Summary of the individual tests

to the end of the observation period was 27.87 ± 33.45, 34.10 ± 35.70, 33.08 ± 39.08,
24.09 ± 41.23, 29.67 ± 39.77 and 28.99 ± 40.09 after 4, 12, 28, 40, 52 and 52 weeks
of treatment (or at discontinuation), respectively. 23, 29.67±39.77 and 28.99±40.09,
respectively, a significant increase compared with the end of the observation period
(PPS, corresponding t-test, both p<0.0001, see Table 2.7.6.6-15).

Table 2.7.6-15 Summary statistics of mean single urination volume (PPS)

評価時期 項目 症例数 平均±標準偏差 最小値 25％点 中央値 75％点 最大値 対応のあるt検定1)
観察期終了時 実測値 357 145.77 ± 49.43 41.2 110.63 138.18 177.00 341.4
治療期4週後 実測値 356 173.48 ± 59.54 44.7 129.69 168.56 208.06 420.0
差 350 27.87 ± 33.45 -67.6 6.14 23.64 44.87 211.9 p<0.0001 *
治療期12週後 実測値 352 179.52 ± 57.68 41.3 137.39 172.96 216.20 391.2
差 346 34.10 ± 35.70 -58.6 9.23 31.63 53.97 162.2 p<0.0001 *
治療期28週後 実測値 354 178.26 ± 58.27 46.7 136.11 173.56 218.33 393.8
差 348 33.08 ± 39.08 -64.4 8.05 28.79 53.20 217.9 p<0.0001 *
治療期40週後 実測値 360 169.06 ± 59.40 38.9 127.32 163.42 205.92 381.1
差 353 24.09 ± 41.23 -102.0 -2.75 21.25 47.81 170.9 p<0.0001 *
治療期52週後 実測値 353 174.91 ± 58.78 45.6 133.59 168.33 213.64 387.1
差 347 29.67 ± 39.77 -76.8 3.66 26.22 51.40 179.0 p<0.0001 *
治療期52週後 実測値 362 174.49 ± 58.37 45.6 132.96 168.25 211.92 387.1
または中止時 差 355 28.99 ± 40.09 -76.8 3.13 25.80 51.15 179.0 p<0.0001 *

両側検定、p<0.05

The percentage change (%) (mean ± standard deviation) in the total number of urge
urinary incontinence per week compared to the end of the observation period was -49.58
± 71.35, -58.91 ± 76.07, -71.56 ± 61.24, -49.58 ± 71.35, -58.91 ± 76.07, -71.56
± 61.24, -71.56 ± 61.24, -71.56 ± 61.24, -71.56 ± 61.24, and -71.56 ± 61.24 after
4, 12, 28, 40, and 52 weeks of treatment (or at discontinuation), respectively. 83.54±
39.89, -84.44±38.57, and -84.21±38.71, respectively, showing a significant decrease
compared to the end of the observation period (PPS, corresponding t-test, both p<0.0001,
see Table 2.7.6.6-16).

Table 2.7.6-16 Summary statistics for the total number of urge incontinence visits per
week (PPS)

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 2.7.6 Summary of the individual tests

評価時期 項目 症例数 平均±標準偏差 最小値 25％点 中央値 75％点 最大値 対応のあるt検定1)

観察期終了時 実測値 364 11.88 ± 11.59 0.0 4.00 8.08 16.00 89.6
治療期4週後 実測値 358 5.76 ± 8.55 0.0 0.00 2.00 7.00 50.0
差 358 -6.23 ± 9.43 -86.6 -9.00 -4.00 -1.00 30.0 p<0.0001 *
変化率 357 -49.58 ± 71.35 -100.0 -100.00 -65.00 -25.00 600.0 p<0.0001 *
治療期12週後 実測値 355 4.23 ± 7.19 0.0 0.00 1.00 5.00 59.0
差 355 -7.66 ± 10.45 -88.6 -10.00 -5.00 -2.00 24.0 p<0.0001 *
変化率 354 -58.91 ± 76.07 -100.0 -100.00 -80.26 -50.00 566.7 p<0.0001 *
治療期28週後 実測値 355 3.20 ± 7.25 0.0 0.00 0.00 3.00 74.0
差 355 -8.53 ± 10.48 -85.4 -12.00 -7.00 -2.00 38.0 p<0.0001 *
変化率 354 -71.56 ± 61.24 -100.0 -100.00 -100.00 -66.67 500.0 p<0.0001 *
治療期40週後 実測値 361 2.15 ± 5.60 0.0 0.00 0.00 2.00 49.0
差 361 -9.74 ± 10.49 -86.6 -14.00 -7.00 -3.00 14.0 p<0.0001 *
変化率 360 -83.54 ± 39.89 -100.0 -100.00 -100.00 -81.88 400.0 p<0.0001 *
治療期52週後 実測値 354 2.13 ± 5.43 0.0 0.00 0.00 2.00 48.0
差 354 -9.79 ± 10.59 -87.6 -14.00 -7.00 -3.00 34.0 p<0.0001 *
変化率 353 -84.44 ± 38.57 -100.0 -100.00 -100.00 -85.29 300.0 p<0.0001 *
治療期52週後 実測値 363 2.11 ± 5.38 0.0 0.00 0.00 2.00 48.0
または中止時 差 363 -9.77 ± 10.52 -87.6 -14.00 -7.00 -3.00 34.0 p<0.0001 *
変化率 362 -84.21 ± 38.71 -100.0 -100.00 -100.00 -84.62 300.0 p<0.0001 *

1)両側検定，*：
Two-tailed p<0.05p<0.05
test,

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 2.7.6 Summary of the individual tests

Of the nine domains of the King Health Questionnaire used to assess quality of life,
all items (general health status, impact of urinary problems on life, work/household
limitations, physical limitations, social limitations, personal relationships, mental
problems, sleep/vitality (energy) and subjective severity) showed a significant decrease
compared to the end of the observation period. (PPS, corresponding t-test, p=0.0125
after 12 weeks of treatment for general health, p=0.0078 after 28 weeks of treatment,
p<0.0001 for all others). In the PPS, 282 (77.5%) of 364 patients had a total of 5 or
more urinary incontinence episodes per week at the end of the observation period (the
selection criteria for urinary incontinence episodes were the same as in the late phase
II and III comparative studies). The percentage change (%) (mean ± standard deviation)
in the total number of urinary incontinence sessions per week in these patients relative
to the end of the observation period was 62.49 ± 44.40, 74.64 ± 36.55, 82.65 ± 30.29,
82.65 ± 30.29, and 82.76 ± 30.21 after 12 and 28 weeks of treatment and after 52 weeks
(or at discontinuation), respectively. There was a significant reduction in the number
of urinary incontinences compared with the end of the observation period at all
assessment times (PPS, corresponding t-test, both p<0.0001), and the drug effect was
maintained without diminution until after 52 weeks of treatment.
Thus, the 0.2 mg/day group showed improvement in the main clinical symptoms (urinary
incontinence, frequency and urgency) in patients with overactive bladder from 4 weeks
after the treatment period, and the efficacy was maintained without diminution until 52
weeks after the treatment period.

(4) Conclusion
This study was conducted at 74 centres in Japan to investigate the efficacy and safety
of long-term treatment with a single dose of 0.2 mg/day of the drug orally for 52 weeks
after a 2-week observation period in patients with overactive bladder. A total of 481
patients were enrolled in the study, 364 of whom were in the primary efficacy population
(PPS). According to the Ministry of Health, Labour and Welfare (MHLW) Notification of
the Director-General of the Pharmaceutical Affairs Bureau of the Ministry of Health,
Labour and Welfare, "Regarding the number of patients and the duration of administration
required to evaluate the safety of new drugs at the clinical trial stage that are
expected to be administered for a long period of time for non-fatal diseases" (NHI No.
592, May 24, 1995), the number of patients required for evaluation during the 28-week
treatment period is Since the number of patients who had completed 28 weeks of treatment
in this study met this criterion, an application for approval was submitted based on
the results of the interim results up to 28 weeks of treatment. Since the number of
patients in the study met this criterion, an application for approval was submitted
based on the interim results after 28 weeks of treatment.
In selecting patients with overactive bladder, the late Phase II and Phase III
comparative studies included patients with a total of five or more urinary incontinence
episodes per week in the week prior to the end of the observation period. Since another
main objective of this study, as well as the investigation of the efficacy of the drug
in long-term treatment, was to confirm the safety of long-term treatment, the patient

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 2.7.6 Summary of the individual tests

population was expanded to include patients with at least one total urge urinary
incontinence per week. Safety was assessed by examining the incidence, timing, nature
and severity of adverse events and side effects, and efficacy was assessed by examining
the temporal changes in symptoms of overactive bladder, such as the number of urinary
incontinence, frequency of urination, and frequency of urinary urgency, and by comparing
each symptom before and after treatment using a corresponding t-test. The safety and
efficacy of the drug were analyzed in terms of long-term administration. A population
pharmacokinetic analysis report was also prepared separately for the results of the
study on plasma unchanged drug concentrations and efficacy and safety by PPK (population
pharmacokinetic) analysis.
In terms of safety, there was no increase in side effects or development of new
clinically concerning side effects attributable to long-term treatment. The new adverse
reactions observed after 12 weeks of treatment in the Phase III comparative study were
tongue disorder, abnormal urine odour, pharyngeal discomfort, choking sensation, and
decreased blood sodium in 5 cases (choking sensation was moderate, others were mild),
all of which were observed up to and including 12 weeks of treatment in the study. All
other adverse events were observed up to 12 weeks post-treatment and in the Phase II
and Phase III comparative studies. The incidence of adverse events and adverse reactions
was 91.9% and 47.3%, respectively, after 52 weeks of treatment, compared with 73.8% and
41.7%, respectively, after 12 weeks of treatment, with approximately 80% or more of
adverse events and adverse reactions occurring by 12 weeks of treatment. Furthermore,
there was no difference in QTc between the pre- and post-treatment QT prolongation
periods at 12, 28, 52 and 52 weeks (or at discontinuation). Although there were six
patients with QTc prolongation of more than 60 ms at any time point in the study, the
maximum QTc was 478.6 ms and did not exceed 500 ms, which is of particular clinical
concern, at any time point in the study. Among serious adverse events, there was one
death, which was considered to be an incidental complication and was not related to the
study drug. Other than acute glaucoma in the right eye, all other serious adverse events
(41 in 35 patients) were considered to be complication-related or accidental and were
not causally related to the study drug. The acute glaucoma in the right eye recovered
quickly with appropriate treatment. The discontinuation rate due to adverse events
(including subjects who withdrew consent due to the occurrence of adverse events) was
10.3% (49/478), and the discontinuation rate due to adverse drug reactions was 5.6%
(27/478). There was a significant increase in residual urine volume at all assessment
periods compared with the end of the observation period, but the mean increase was 2.30-
3.11 mL, which was not clinically relevant. There were no clinically problematic changes
in blood pressure, pulse rate or laboratory values. Subgroup analysis of adverse events
showed that the incidence of adverse events, side effects and dry mouth did not differ
between elderly and non-elderly patients, or between patients taking Clozapine in
combination with drugs that inhibit CYP3A4, the main metabolizing enzyme of Clozapine.
These results indicate that this drug can be safely administered for a long time in
patients with overactive bladder.
In terms of efficacy, the drug was found to be effective against the main symptoms of

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 2.7.6 Summary of the individual tests

urinary incontinence, frequency and urinary urgency in patients with overactive bladder.
08, 55.92 ± 72.52, 70.83 ± 50.56, 81.30 ± 40.74, 83.59 ± 35.54, and 83.51 ± 35.48,
respectively, and the change in the mean number of urinary voidings per day (times)
(mean±standard deviation) was 1.00 ± 0.01 after 4, 12, 28, 40, 52, and 52 weeks of
treatment (or at discontinuation), respectively. or at discontinuation) by 1.21 ± 1.84,
1.65 ± 2.12, 2.05 ± 2.26, 2.55 ± 2.31, 2.34 ± 2.15 and 2.35 ± 2.14, respectively,
and by the percentage reduction in urinary urgency per day (%) after 4, 12, 28, 40, 52
and 52 weeks of treatment ( or at the time of discontinuation) were 35.01±48.51, 45.81
±53.37, 55.67±48.65, 71.54±37.85, 70.39±38.67, and 70.53±38.37, respectively,
indicating a significant improvement from 4 weeks post-treatment compared to the pre-
treatment period (corresponding t (corresponding t-test, both p<0.0001), and the effect
was maintained without diminution until 52 weeks after treatment. When the selection
criteria for frequency of urinary incontinence in this study were the same as in the
late phase II and III comparative studies (PPS and a total of 5 or more urinary
incontinence episodes per week at the end of the observation period), the percentage
reduction in urinary incontinence was 51% after 4, 12, 28, 40, 52 and 52 weeks of
treatment ( or at discontinuation) were 51.68±44.67, 62.49±44.40, 74.64±36.55, 82.56
±27.52, 82.65±30.29 and 82.76±30.21, respectively. effect (PPS, corresponding t-test,
both p<0.0001). The King's Health Questionnaire, a previously validated urinary
incontinence-specific questionnaire, was used to assess quality of life in patients with
overactive bladder. ONO-8025 0.2 mg/day showed a significant improvement in all endpoints,
including the impact of urinary problems on life, limitations in work and housework,
physical limitations and psychological problems.
In conclusion, ONO-8025 0.2 mg/day is a drug that can be safely administered for a
long period of time in patients with overactive bladder, without any increase in side
effects due to long-term administration or development of new clinically problematic
side effects, and has a sustained effect on the main symptoms of patients with overactive
bladder. The drug can be safely administered for a long period of time without the
development of new clinically problematic side effects, and showed a sustained effect
on the main symptoms of patients with overactive bladder.

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