J Infect Chemother 24 (2018) 538e543

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Journal of Infection and Chemotherapy

journal homepage: http://www.elsevier.com/locate/jic

Original Article

Randomized controlled trial: PPI-based triple therapy containing

metronidazole versus clarithromycin as first-line treatment for
Helicobacter pylori in adolescents and young adults in Japan
Katushiro Mabe a, b, *, Masumi Okuda c, Shogo Kikuchi d, Kenji Amagai e, Rie Yoshimura f,
Mototsugu Kato a, b, Naoya Sakamoto g, Masahiro Asaka h, Japan Gast Study Group
a
Department of Gastroenterology, National Hospital Organization Hakodate Hospital, Hakodate, Hokkaido, Japan
b
Division of Endoscopy, Hokkaido University Hospital, Sapporo, Hokkaido, Japan
c
Department of Pediatrics, Aichi Medical University School of Medicine, Nagakute, Aichi, Japan
d
Department of Public Health, Aichi Medical University School of Medicine, Nagakute, Aichi, Japan
e
Division of Gastroenterology and G.I. Oncology, Ibaraki Prefectural Central Hospital and Cancer Centre, Kasama, Ibaraki, Japan
f
Department of Gastroenterology, Specific Medical Treatment Corporate Foundation Group, Hakuaikai Wellness Tenjin Clinic, Fukuoka, Japan
g
Department of Gastroenterology and Hepatology, Hokkaido University Graduate School of Medicine, Sapporo, Japan
h
Health Sciences University of Hokkaido, Tobetsu, Hokkaido, Japan

a r t i c l e i n f o a b s t r a c t

Article history: Background/Aims: Treating Helicobacter pylori infection in young people is effective for preventing gastric
Received 23 December 2017 cancer. This study compares the efficacy of triple therapies in adolescents and young adults in Japan.
Received in revised form Methods: This multicenter, randomized trial was conducted between February 2012 and March 2015.
7 February 2018
Infected participants were stratified into adolescents (13e19 years) and young adults (20e39 years).
Accepted 28 February 2018
Available online 28 March 2018
They were randomly assigned to a clarithromycin based (PAC) or metronidazole based (PAM) triple
therapy for 1 week.
Results: Overall, 137 and 169 participants received the PAC and PAM treatments, respectively. In ado-
Keywords:
Helicobacter pylori
lescents, the H. pylori eradication rates were 60.5% and 63.4% for PAC, and 98.3% and 100% for PAM in the
Adolescents intention-to-treat (ITT) and per-protocol (PP) analyses, respectively. In young adults, the eradication rates
Young adults were 67.0% and 66.7% for PAC, and 95.5% and 96.3% for PAM in ITT and PP analyses, respectively. The
Triple therapy eradication rate of PAM was significantly higher than that of PAC in both strata. No severe adverse events
Metronidazole were observed.
PPI Conclusion: In Japan, PAM may be selected as a first-line treatment for young people with H. pylori if
antibiotic susceptibility tests cannot be performed.
© 2018 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases.
Published by Elsevier Ltd. All rights reserved.

1. Introduction is approximately 45,000. H. pylori infection causes gastritis, which

Helicobacter pylori was first discovered in 1983 [1], and the In-
ternational Agency for Research on Cancer of the World Health
Organization classified H. pylori as a definite carcinogen in 1994 [2].
H. pylori in the East Asia area, including Japan, shows a clear
pathogenesis [3]. In Japan, gastric cancer is one of the most com-
mon cancers, and the annual number of deaths from gastric cancer
* Corresponding author. Department of Gastroenterology, National Hospital
Organization Hakodate Hospital, 18-16 Kawahara, Hakodate, 041-8512, Japan.
E-mail address: katsumabe@me.com (K. Mabe).
leads to atrophic gastritis and gastric cancer [4]. In a prospective
study, H. pylori-infected patients developed gastric cancer, whereas
few uninfected patients developed gastric cancer [5]. In addition, a
very low prevalence of H. pylori-negative gastric cancer was re-
ported in the Japanese population [6,7]. Several studies have
demonstrated that the treatment of H. pylori infection in the elderly
or in patients with gastric atrophy makes the incidence of gastric
cancer approximately a half [8,9]. However, eradication therapy in
younger patients or in those with mild gastric mucosal atrophy is
more effective for eliminating gastric cancer [10]. Therefore, to
prevent gastric cancer, the treatment of H. pylori in young people is
essential in areas such as Japan where gastric cancer is prevalent. A

https://doi.org/10.1016/j.jiac.2018.02.013
1341-321X/© 2018 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.
 K. Mabe et al. / J Infect Chemother 24 (2018) 538e543
screen-and-treat strategy for H. pylori infection has been initiated
for adolescents and young adults living in specific local areas with
the aim of preventing gastric cancer, and we expect it will be
implemented across Japan [11].
In the Japanese national health insurance system, proton pump
inhibitor (PPI)-based triple therapy containing clarithromycin
(CAM) and amoxicillin (AMPC) (PAC) is used as first-line treatment
for adult patients who are diagnosed as H. pylori gastritis by upper
endoscopy. A PPI-based triple therapy containing metronidazole
(MNZ) and AMPC (PAM) is used as a second-line treatment. The
prevalence of CAM-resistant H. pylori strain is increasing [12e14],
and the successful treatment rate of the PPI-based CAM containing
regimen has decreased, particularly in children and adolescents
[14]. Therefore, it is desirable to conduct antibiotic susceptibility
tests before treatment. In the ‘screen-and-treat of H. pylori’ strategy
of young people, however, it is difficult to perform upper endoscopy
and conduct antibiotic susceptibility tests for all patients who
receive eradication treatment. Therefore, the aim of the present
study was to compare the efficacy and tolerability of the two
PPI-based triple therapies for H. pylori-infected adolescents and
young adults for whom an antibiotics susceptibility test was not
performed.
2. Patients and methods
The protocol of this study was reviewed and approved by the
ethics committee of Hokkaido University Hospital and that of each
of the thirty participating institutions. Written informed consent
was obtained from all participants or their parents or guardians if
they were minors (under 20 years old).
2.1. Study design, participants
This multicenter, open-label, randomized trial of the ‘screen-
and-treat for H. pylori’ strategy was conducted between February
2012 and March 2015 (trial registry: UMIN000006949). Thirty
hospitals affiliated with the Japan Gast Study Group participated in
this study. Patients aged over thirteen and less than 40 years old
were included in the study. Participants were asked to provide
urine and/or serum samples for an assay of the anti-H. pylori
antibody. Exclusion criteria were prior treatment for H. pylori, an
allergy to antibiotics and PPI, history of gastrectomy, the presence
of gastric cancer, and those who were pregnant or lactating.
Participants who satisfied the inclusion criteria were registered
through the study website, and urine and/or serum antibody tests
were performed. Positive results in the urine and/or serum anti-
body test indicated H. pylori infection, and when the tests showed
discrepant results, each doctor determined the final infection status
using the 13C-urea breath test (UBT), stool antigen test, or rapid
urease test if necessary.
2.2. Urine and serum antibody test for diagnosing H. pylori and UBT
for determining treatment
Single-void urine samples were obtained at any time. The
presence of urinary immunoglobulin (Ig)-G antibodies to H. pylori
(u-Ab) was determined using immunochromatography (RAPIRUN,
Otsuka Pharmaceuticals Co., Ltd., Tokyo, Japan), a qualitative test, at
each clinic or hospital. This test was considered positive if red lines
appeared in both the control and test zones, and it was considered
negative if a red line was observed only in the control zone. When a
visible red line was not observed in the control zone, the test was
considered invalid.
Serum IgG antibodies to H. pylori (s-Ab) were quantified using a
serum H. pylori enzyme-linked immunosorbent assay (s-HpELISA)
539
kit (E-plate EIKEN H. pylori antibody, Eiken Chemical Co., Ltd.,
Tokyo, Japan). Serum antibody titers no less than 10 U/mL were
considered positive and ones less than 10 U/mL were considered
negative for H. pylori infection,. For the UBT, participants were
required to fast for 4 h before the test, and breath samples were
collected before and 20 min after the ingestion of 13C-urea (UBIT
tablet, 100 mg, Otsuka Pharmaceutical Co., Ltd.). When the UBT
value was <2.5‰, the treatment was considered a success.
2.3. Treatment and study outcomes
Using a central computer system, H. pylori-infected participants
were stratified into adolescents (13e19 years) and young adults
(20e39 years), and then randomly assigned to receive the PAC or
PAM treatment automatically. The primary and secondary out-
comes of this study were the efficacy and safety of PAC and PAM,
respectively, in adolescents and young adults in Japan. The PAC
treatment included lansoprazole (30 mg twice daily), AMPC
(750 mg twice daily), and CAM (200 mg twice daily) (Lansap® pack)
for a week. The PAM treatment included lansoprazole (30 mg twice
daily), AMPC (750 mg twice daily), and MNZ (250 mg twice daily)
(Lanpion® pack) for 1 week. Simultaneously, all participants
received 2 tablets of MIYA-BM® three times daily, which contains
Clostridium butyricum to prevent diarrhea [15]. During the treat-
ment, participants recorded the consumption of medicine and
adverse events if they occurred. Severe adverse events were
defined as death, life threatening, hospitalization, disability or
permanent damage. The treatment efficacy for H. pylori was eval-
uated using UBT more than 6 weeks after treatment was
completed. Eradication rates were determined using intention-to-
treat (ITT) and per-protocol (PP) analysis. For ITT, all patients
evaluated for treatment efficacy using UBT were analyzed. For PP,
only participants who completed the treatment (i.e. those who took
all medicine as prescribed) were included.
2.4. Statistical analysis and sample size
Statistical analyses were performed using Student's t-test for
continuous variables and chi-square test or Fisher's exact proba-
bility test for frequencies. Statistical analyses were performed using
HALBAU, version 7 (High Quality Analysis Libraries for Business and
Academic Users, Tokyo, Japan).
The required sample size was 39 for each arm, under the con-
dition that type I error was 5%, power was 80% by two-sided
analysis, and the expected successful eradication rates were 60%
with PAC and 90% with PAM. As separate analyses for adolescents
and young adults were planned, subjects were collected until all of
the four arms had 48 subjects (120% of the required sample size) for
random allocation.
3. Results
3.1. Participants' baseline characteristics
The flowchart of participants is shown in Fig. 1. We enrolled
1064 participants in this study, of whom 727 did not have H. pylori
infection, as assessed by negative urine and/or serum antibody
tests. No invalid result was observed in this study. Three hundred
and thirty-seven participants were diagnosed with H. pylori infec-
tion. Of these, 152 patients were randomly assigned by computer to
the PAC group, and 185 were assigned to the PAM group. From the
PAC and PAM groups, 15 and 16 patients were excluded respectively
(Fig. 1). Finally, 137 patients were treated with the PAC treatment,
and 169 were treated with the PAM treatment. Patient baseline
characteristics are shown in Table 1. There were no significant
540 K. Mabe et al. / J Infect Chemother 24 (2018) 538e543

Fig. 1. Flowchart of participants. Data are presented as the total number of adults (adolescents). PAC, lansoprazole (30 mg), amoxicillin (750 mg), and clarithromycin (200 mg) twice
daily; PAM, lansoprazole (30 mg), amoxicillin (750 mg), and metronidazole (250 mg) twice daily; Ab, antibodies.

Table 1
Participants' baseline characteristics.

ITT Adolescents p-value* Adults p-value

PAC PAM PAC PAM

n ¼ 43 n ¼ 58 n ¼ 94 n ¼ 111

Age, mean ± SD (years) 14.9 ± 1.6 14.9 ± 1.8 0.96 31.5 ± 5.9 32.6 ± 5.8 0.24
Sex (Male/Female) 23/20 28/30 0.69 52/42 54/57 0.40

PP Adolescents p-value Adults p-value

PAC PAM PAC PAM

n ¼ 41 n ¼ 55 n ¼ 93 n ¼ 107

Age, mean ± SD (years) 15.0 ± 1.6 14.9 ± 1.8 0.81 31.5 ± 5.9 32.7 ± 5.8 0.16
Sex (Male/Female) 21/20 26/29 0.87 51/42 52/55 0.40

Statistical analyses were performed using the Student t-test for continuous variables and the chi-square test or Fisher exact probability test for frequencies.
SD, standard deviation; PAC, lansoprazole (30 mg), amoxicillin (750 mg), and clarithromycin (200 mg) twice daily; PAM, lansoprazole (30 mg), amoxicillin (750 mg), and
metronidazole (250 mg) twice daily; ITT, intention-to-treat analysis; PP, per-protocol analysis.
There were no significant differences in age or gender distributions between the PAC and PAM groups, in either adolescent or young adult stratum.

differences in age or gender distributions between the PAC and
PAM groups, in either adolescent or young adult stratum.
Ninety of 101 participants in the adolescent group and 170 of
205 participants in the young adult group were both u-Ab and s-Ab
test positive. Discrepant results between u-Ab and s-Ab were
observed in 5 and 6 participants in the adolescent and young adult
groups, respectively. Six participants in the adolescent group and
29 in the young adult group underwent a single test.
3.2. Treatment outcomes of the PAC and PAM
In the adolescent group, the eradication rates of PAC were
60.5% in the ITT analysis and 63.4% in the PP analysis, and those of
PAM were 98.3% in the ITT analysis and 100% in the PP analysis
(Table 2). In the young adult group, the eradication rates of PAC
were 67.0% in the ITT analysis and 66.7% in the PP analysis, and
those of PAM were 95.5% in the ITT analysis and 96.3% in the PP
analysis (Table 2). The successful eradication rate of PAM was
significantly higher than that of PAC in adolescents and young
adults (p < 0.01).
3.3. Adverse events
The adverse events are shown in Table 3. Fifty-eight adverse
events were reported among 52 participants (17.0%) (PAC group: 23
[16.8%]; PAM group: 29 [17.2%]). Diarrhea was the most
 K. Mabe et al. / J Infect Chemother 24 (2018) 538e543 541

Table 2 system. In addition, the insurance coverage was only recently

Eradication rates and compliance of PAC and PAM. extended to the treatment of H. pylori of adults in 2007, and it was
PAC PAM p-valueb extended for the treatment of anaerobic bacterial infections and
Total
amoebic dysentery of adults in 2012. CAM was released in 1991 in
ITT 89/137 (65.0, 56.4e72.9)a 163/169 (96.4, 92.4e98.7) <0.01 Japan, and it has been used to treat various infections such as
PP 88/134 (65.7, 57.0e73.7) 157/162 (96.9, 92.9e99.0) <0.01 bronchitis, tonsillitis, acute otitis media, and enteritis in children
adolescents and adults covered by the national health insurance system. CAM
ITT 26/43 (60.5, 44.4e75.0) 57/58 (98.3, 90.8e100) <0.01
has been one of the most frequently used antibiotics, whereas MNZ
PP 26/41 (63.4, 46.9e77.9) 55/55 (100, 94.7e100) <0.01
adults has been a less frequently used antibiotic in Japan. This might
ITT 63/94 (67.0, 56.6e76.4) 106/111 (95.5, 89.8e98.5) <0.01 explain the excellent eradication rate of H. pylori using MNZ in the
PP 62/93 (66.7, 56.1e76.1) 103/107 (96.3, 90.7e99.0) <0.01 current study of a Japanese population. In another randomized,
PAC, lansoprazole (30 mg), amoxicillin (750 mg), and clarithromycin (200 mg) twice controlled study comparing PAC and PAM in 124 adult patients
daily; PAM, lansoprazole (30 mg), amoxicillin (750 mg), and metronidazole (aged 60.8 ± 13.5 years) [17] and 110 adults (aged 57.9 ± 14.9 years
(250 mg) twice daily; ITT, intention-to-treat analysis; PP, per-protocol analysis.
a
in PAC and aged 60.1 ± 12.2 years in PAM) [18] who were older than
Successful eradication/subjects (percent, 95% confidence interval).
b those in the present study, the eradication rates were 77.2% and
Calculated using Fisher exact probability.
80.4% for the PAC regimen and 93.5% and 100% for the PAM regimen
by PP analysis. The eradication rate of PAM treatment in the current
Table 3 study was superior to sequential therapy, which was reported to
Adverse events associated with PAC and PAM treatment. have high eradication rates in children and adults [19e21], and
Total PAC PAM p-valuea upon concomitant treatment [20,21]. Therefore, the treatment
n ¼ 306 n ¼ 137 n ¼ 169 regimen for H. pylori should be selected considering the specific
Total number of participants 52 (16) 23 (8) 29 (8) 1.00 (0.59) antibiotic use in the local area but not in other global locations. For
with adverse events PAC, the eradication rate was similar between adolescents and
Diarrhea 20 (6) 8 (2) 12 (4) 0.82 (1.00) adults (63.4% vs 66.7%). The prevalence of CAM resistance to
Skin rash 8 (3) 4 (2) 4 (1) 1.00 (0.57) H.pylori was reported to be high, particularly in young (57.9% in
Dysgeusia 8 (1) 4 (1) 4 (0) 1.00 (0.43)
Nausea 5 (2) 2 (2) 3 (0) 1.00 (0.18)
2012e2013) and middle-aged subjects (over 50% in 2008e2009)
Sense of abdominal distension 4 (1) 0 (0) 4 (1) 0.13 (1.00) [13]. The high resistance of CAM in both groups may have provoked
Epigastric discomfort 3 (1) 0 (0) 3 (1) 0.26 (1.00) the low eradication rate both in the adolescents and in young
Headache 2 (0) 1 (0) 1 (0) 1.00 (1.00) adults. In the present study, H. pylori strains were identified in 21
Candidal vaginitis 2 (0) 2 (0) 0 (0) 0.20 (1.00)
subjects with PAC treatment and CAM susceptibility tests were
Other 4 (3) 2 (1) 2 (2) 1.00 (1.00)
Unknown 2 (0) 1 (0) 1 (0) 1.00 (1.00) performed [22]. Overall, 15 and 6 subjects (strains) were CAM-
sensitive and resistant, respectively. Of 15 subjects with CAM-
Data are presented as the total number of adults (adolescents). PAC, lansoprazole
(30 mg), amoxicillin (750 mg), and clarithromycin (200 mg) twice daily; PAM, lan-
sensitive strains, 13 had successful PAC treatment. Of 6 subjects
soprazole (30 mg), amoxicillin (750 mg), and metronidazole (250 mg) twice daily. with CAM-resistant strains, only one had successful treatment.
a
Calculated using Fisher exact probability. Therefore, the treatment regimen must be selected according to the
susceptibility results if susceptibility tests are performed. As re-
ported previously [22], a non-invasive test that detects CAM
prevalent adverse event, followed by a skin rash and dysgeusia. No resistance using feces is desired.
remarkable differences in the occurrence of adverse events were Recently, a novel potassium-competitive acid blocker, vono-
observed between the PAC and PAM groups. An adult participant in prazan, has been used to treat H. pylori, and vonoprazan-based
the PAM group stopped treatment on the second day because of a triple therapy containing CAM was reported to have a better
headache, fever, and nausea. No severe adverse event was observed performance compared with PPI-based therapy [23,24]. The
in this study. No other participants stopped treatment because of eradication rates of triple therapy with vonoprazan, AMPC and
adverse events. CAM were 92.6% [23] and 91.2%, respectively [24] in adults, and
85.7% in junior high school students [25]. In the current study,
4. Discussion vonoprazan based triple therapy was not evaluated because it
was not available commercially during this study. However, the
Two PPI-based triple treatments were approved by the Japanese PAM regimen had a higher eradication rate than vonoprazan-
National Health Insurance system for adults in Japan. This is the based triple therapy containing CAM. High resistant rates of
first randomized trial comparing the two treatments in asymp- H. pylori to CAM were reported in Japan [12e14], and this ex-
tomatic adolescents and young adults in Japan. The results showed plains the low eradication rate of treatments including CAM. For
that the PAM regimen with MNZ had significantly higher eradica- the MNZ regimen, high resistant rates (2.8e40.2%) were also
tion rates than the PAC regimen with CAM; and the successful reported in Japan [12,14,26]. However, in the current study, the
eradication rate of PAC was too low to support its use for first-line PAM regimen had a high eradication rate. The reason for this
treatment. Surprisingly, the successful eradication rate (95% con- contradiction is unclear, but we speculate that MNZ resistance
fidence interval) of PAM treatment was 100% (94.7e100%) in ado- may exert less influence on eradication for H. pylori strains pre-
lescents and 95.3% (89.4e98.5%) in young adults, as assessed by PP vailing in Japan.
analysis. However, in areas other than Japan, results of a meta- In the current study, there were no remarkable differences in
analysis showed that PAM was less efficacious than PAC [16]. The the frequency of adverse events between the PAC and PAM treat-
high eradication rate in this study might be explained by the less ments, or between adolescents and adults. No severe adverse
frequent use of MNZ in these areas. MNZ was developed in France events were observed in our study, although an adult participant in
in 1957, and has been used worldwide to treat anaerobic bacterial the PAM group stopped treatment on the second day. Overall, both
infections, trichomoniasis and amebiasis. However, after the PAC and PAM treatments seem to be safe in adolescents and adults.
release of MNZ in Japan in 1961, it was only approved for treating The limitations of this study were as follows. First, the
trichomoniasis in adults by the Japanese national health insurance number of participants was relatively small because of the very
542 K. Mabe et al. / J Infect Chemother 24 (2018) 538e543
low H. pylori infection rate of young people in Japan. Second,
susceptibility to the antibiotic agents was not tested in this
study. Third, in most subjects, H. pylori infection was evaluated
using a urine and/or serum antibody test, which is the most
common screening method. The u-Ab test was developed in
Japan, and many studies have shown its efficacy for diagnosing
H. pylori infection [27e29]. In our study, the u-Ab test had 78.4%
sensitivity and 100% specificity with an accuracy of 92.1% when
using the UBT and H. pylori stool antigen test as standards [30].
Additionally, the s-Ab test used in this study has shown good
performance in adults and children [31,32]. Although the urine
antibody has been proven to have a high accuracy for H. pylori
infection, a small percent of misclassifications is expected.
Because its specificity is sufficiently high, false negative results
are likely to be rare. Additionally, when tests showed discrepant
results, the UBT, stool antigen test, or rapid urease test were
performed to make a final diagnosis. Thus, the effect of
misclassification may not affect our findings so much.
There was a difference in the numbers of subjects between the
two groups: 137 subjects in the PAC group and 169 in the PAM
group, the reason of which is not clear. Random allocation was
performed mechanically by a computer, and treatments were
prescribed according to the allocation, where no arbitrariness was
expected. Actually, there was no remarkable difference in back-
ground characteristics between the groups (Table 1). Thus, the
difference in numbers of subjects between the two groups may
have provoked little bias.
In summary, the eradication rate of PAM was significantly higher
than that of PAC in both adolescents and young adults in Japan. The PAM
regimen may be selected as a first-line treatment in Japanese for ado-
lescents and young adults if antibiotic susceptibility tests cannot be
performed. No severe adverse events were observed with PAC or PAM
treatment; thus, they are safe to use in adolescents and young adults.
Conflicts of interest
Mabe K reports a personal lecture fee (Takeda Pharmaceutical
Co and Ltd. and Eisai Co. LTD). Okuda M also reports a personal
lecture fee (Otsuka Pharmaceutical Co., Ltd. and Eisai Co. LTD).
Asaka M and Mabe K belong to the donation-funded Department of
Eizai Co. Ltd., at Cancer Preventive Medicine, Hokkaido University
Graduate School of Medicine. Kikuchi S, Amagai K, and Yoshimura R
declare no conflicts of interest.
ICMJE statement
All authors meet the ICMJE authorship criteria.
Acknowledgment
We thank J. Ludovic Croxford, PhD, from Edanz Group (www.
edanzediting.com/ac) for editing a draft of this manuscript.
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