THE AMERICAN JOURNAL OF GASTROENTEROLOGY
1, 2000
© 2000 by Am. Coll. of Gastroenterology
Published by Elsevier Science Inc.
Comparative, Open, Randomized Trial
of the Efficacy and Tolerance of Slow-
Release 5-ASA Suppositories Once Daily
Versus Conventional 5-ASA Suppositories Twice
Daily in the Treatment of Active Cryptogenic Proctitis
Philippe Marteau, M.D., Ph.D., Christian Florent, M.D., and the French Pentasa Study Group
Gastroenterology Department, Laënnec Hospital AP-HP, and Gastroenterology Department, Saint-Antoine
Hospital AP-HP, Paris, France
OBJECTIVE: The efficacy and tolerance of slow-release
5-ASA suppositories (Pentasa 1 g/day) were compared with
those of conventional 5-ASA suppositories (Rowasa 0.5 g
b.i.d.).
METHODS: Two hundred and fifty-one (251) patients pre-
senting with an exacerbation of cryptogenic proctitis were
randomized. Clinical activity and rectal lesions were mea-
sured at days 1 and 14 (and at day 21 for patients not in
remission at day 14), and each patient had to fill out a daily
diary card (checklist).
RESULTS: Results are given for slow-release and classical
suppositories, respectively. The reduction in symptoms and
lesions was identical in both groups. Treatment was contin-
ued until day 21 in 36% versus 33% of the patients, and
minor or moderate side effects occurred in 5.6% versus
6.3% (NS). The tolerance of the suppositories was rated as
satisfactory every day by 77% versus 54% (p ⫽ 0.001), and
early suppository expulsion occurred in 0.5% versus 3.4%
(p ⫽ 0.001).
CONCLUSIONS: The treatments were equally effective and
both were well tolerated. However, the advantages of the
slow-release suppositories were that patients exhibited
greater tolerance and early expulsion was less frequent. (Am
J Gastroenterol 2000;95:166 –170. © 2000 by Am. Coll. of
Gastroenterology)
INTRODUCTION
The treatment of cryptogenic colitis relies largely on the use
of topical antiinflammatory agents. Among the latter, 5-ami-
nosalicylic acid (5-ASA) derivatives seem to be the most
rapidly effective (1). 5-ASA suppositories are equivalent in
efficacy to 5-ASA enemas (2), but their therapeutic effect is
limited solely to the rectum. Two types of suppository have
been developed to release 5-ASA in the rectum. Conven-
tional glycerin suppositories melt quickly after insertion and
Vol. 95, No.
ISSN 0002-9270/00/$20.00
PII S0002-9270(99)00738-8
immediately release the active substance. A dosage of 500
mg twice daily has been shown to be equivalent to higher
doses (3). Their efficacy in achieving remission in exacer-
bations of distal cryptogenic colitis (UC) has been evaluated
at 42% and 28% at 2 wk (4, 5), 36% at 3 wk (6), 42– 85%
at 4 wk (range, 2–5), and 80% at 6 wk (6). The slow-release
suppository (Pentasa) contains 1 g of granulated mesalazine
with polyvidone, magnesium stearate, and macrogol 6000 as
vehicle. The galenic design provides a gradual release of the
active substance. These suppositories contain 1 g of 5-ASA,
and once-daily administration is sufficient (7). Their clinical
efficacy in treating exacerbations of distal UC was found to
be 64% and 69% at 2 wk (5, 8) and 84% at 4 wk (5); their
tolerance is satisfactory and the retention time in the rectum
usually exceeds the time required for dissolution (8). These
results suggest that slow-release suppositories might be
more rapidly effective than glycerin suppositories during
treatment lasting several days. Our study’s objective was to
confirm that slow-release suppositories were more effective
than traditional suppositories in inducing remission at 2 wk
in patients with acute cryptogenic proctitis and to evaluate
the tolerance of both treatments. While our study was still in
progress, the results of an initial comparative trial were
published and demonstrated the greater efficacy of slow-
release suppositories compared with that of conventional
Claversal suppositories, i.e., the clinical remission rate at 2
wk was 64% compared with 28% in 50 patients with distal
UC (5).
MATERIALS AND METHODS
Patients
The open study involving 56 investigators was carried out in
two parallel groups between March 3, 1994 and June 28,
1997. It was sponsored by the French pharmaceutical com-
pany, Ferring, and had been approved by the Comité Con-
sultatif de Protection de Personnes se prêtant à la Recherche
Biomédicale (C.C.P.P.R.B.; Advisory Committee for the
AJG – January, 2000
Protection of Persons Participating in Biomedical Research)
of Paris-Saint-Antoine. Written consent was obtained from
all subjects who agreed to participate in the study.
Inclusion criteria were as follows: outpatients with his-
tologically documented UC, Crohn’s disease, or nonspecific
inflammatory bowel disease; mild or moderate exacerba-
tion; presence of blood or mucus in stools; temperature
⬍38°C, endoscopic severity in the range of 2 (contact
bleeding from the mucous membrane) to 4 (superficial ul-
cerations) (8); lesions limited to the rectum. Patients receiv-
ing long-term oral treatment with 5-ASA or sulfasalazine
were eligible for inclusion, provided the doses administered
had not been increased during the previous month. Exclu-
sion criteria were as follows: patients aged ⬍18 or ⬎75 yr;
known hypersensitivity or resistance to salicyclate deriva-
tives; local or systemic antiinflammatory treatment for the
exacerbation in the 2 wk preceding the initial assessment;
patients taking anticoagulants, corticosteroid therapy, or im-
munosuppressive drugs or presenting another site of
Crohn’s disease or UC confirmed by endoscopic or radio-
logical examination within the previous year; pregnant or
lactating women; and the presence of proctitis of a different
origin (infectious or parasitic, drug- or radiation-induced,
etc.).
Outline of the Study
The patients were enrolled consecutively after a medical
evaluation of the initial clinical and endoscopic severity of
the condition and the performance of a rectal biopsy to
confirm the diagnosis. The clinical and endoscopic exami-
nations were performed by the same doctor before inclusion
in the trial (day 1) and at termination of the trial (day 14
and/or day 21 for patients treated for 21 days). At the initial
assessment at day 1, the following symptoms were evalu-
ated: daily frequency of daytime and nocturnal defecation;
presence of blood in stools; presence of mucus discharge
without fecal matter; and intensity of tenesmus and abdomi-
nopelvic pain rated on a 4-point scale from 0 to 3 (none,
mild, moderate, or severe). The endoscopic examination
(flexible proctosigmoidoscopy or proctoscopy) had to ex-
tend to the upper limit of the lesions. Lesions of the rectal
mucosa detected at endoscopy were scored on the following
scale: stage 0 ⫽ normal appearance or erythema; stage 1 ⫽
granulations and/or edema masking the submucosal vascu-
lar network; stage 2 ⫽ fragile mucosa (contact bleeding);
stage 3 ⫽ spontaneous bleeding; stage 4 ⫽ superficial
ulceration; and stage 5 ⫽ deep ulceration (8). Each patient
was provided with a daily diary card showing the number of
daytime and nocturnal stools, the presence of blood or
mucus discharge in the stools, the retention time of the
suppositories, and an assessment of the local tolerance of the
suppositories on a verbal 3-point scale (1 ⫽ good; 2 ⫽
moderate; 3 ⫽ poor).
Randomization was centralized and drawn up for each
investigator using a randomization table. Both treatments
provided 1 g daily of 5-ASA. The slow-release suppositories
Comparison of 5-ASA Suppositories 167
(SRS; Pentasa, Laboratoire Ferring, Gentilly, France) con-
tained 1 g. The dosage consisted of one suppository at
bedtime and the patient was advised to apply a small amount
of lubricant to the suppository (K-Y Lubricating Jelly, John-
son & Johnson, Arlington, TX), to insert it deep into the
ampulla recti, and to retain it in position as long as possible.
The conventional suppositories (CS) contained 500 mg of
5-ASA (Rowasa, Laboratoire Solvay, France) and their dos-
age consisted of two suppositories daily: one at bedtime and
one in the morning. The patient was advised to insert the
suppository flat end first into the ampulla recti and to retain
it as long as possible. The duration of treatment was 2 wk
(the primary endpoint was endoscopic response at that
time). However, failing remission by day 14, therapy was
continued for a third week. No other local or systemic
treatment was permitted throughout the trial, with the pos-
sible exception of orally administered 5-ASA or sulfasala-
zine if they had been prescribed more than a month earlier
and were taken at the same dosage.
The day-14 evaluation included the same clinical and
endoscopic examinations as at day 1 and the collection of
data from the diary cards. The criteria for remission and the
termination of treatment at day 14 were as follows: absence
of nocturnal defecation and blood in the stools; not more
than two mucus bowel movements per day; and lesions at an
endoscopic stage of ⱕ1. In the absence of these criteria,
treatment was continued for an additional week and a final
evaluation, identical to that performed at day14, was carried
out at day 21.
Evaluation Criteria and Statistical Methods
The primary evaluation criterion was an endoscopic re-
sponse defined as at least a one-stage reduction in the initial
score. Secondary criteria were an improvement in symp-
toms; the investigator’s end-of-trial global assessment, ex-
pressed on a verbal 5-point scale (recovery, major improve-
ment, moderate or mild improvement, condition unchanged,
or aggravation); the patient’s assessment of tolerance on a
3-point scale (mean and percentage of subjects reporting
tolerance every day as good compared with moderate or
poor); any adverse reactions; and the incidence of early
suppository expulsion recorded on the diary card and de-
fined as the expulsion of a suppository within 1 h of its
insertion.
Assuming that endoscopic remission would occur in 50%
of CS-treated patients and in 70% of SRS-treated patients,
and adopting a two-sided test with Type-I and Type-II errors
of 0.05 and 0.10, respectively, it was calculated that 122
subjects were required in each treatment group. The deci-
sion was therefore taken to include 125 subjects per group,
for a total of 250.
The results are expressed in terms of the mean ⫾ SD.
Group homogeneity before treatment was confirmed with
respect to demographic data, clinical symptoms, and endo-
scopic scores. The efficacy of the two treatments was com-
pared using Student’s t test for quantitative variables with a
168 Marteau et al. AJG – Vol. 95, No. 1, 2000

Table 1. Characteristics of Patients Suffering From Cryptogenic

Colitis and Treated With Slow-Release or Conventional 5-ASA
Suppositories
SRS CS
Number of subjects 125 126
Age (yr) 41 ⫾ 13 41 ⫾ 14
Percentage of women 57 52
Time since onset of episode (days) 50 ⫾ 219 46 ⫾ 158
First episode (%) 55 62
Previous episodes (number) 4.6 ⫾ 5.5 5.1 ⫾ 7.1
Onset of the disease (yr) 5.9 ⫾ 5.5 6.5 ⫾ 6.6
SRS ⫽ slow-release suppositories; CS ⫽ conventional suppositories; 5-ASA ⫽
5-aminosalicylic acid. None of the differences between the two groups was signifi-
cant.

normal distribution, the Mann-Whitney U test for ordinal

semiquantitative variables, and the ␹2 test for qualitative
variables (with adjustment of the endoscopic stage using the
Mantel-Haenszel method). The level of significance was set
at 5%.

RESULTS
Two hundred and fifty-one patients were included in the
trial: 125 in the SRS group and 126 in the CS group. Patient
characteristics are shown in Table 1. The two groups were
comparable in terms of age, gender, stage of clinical and
endoscopic gravity, and history of the proctitis (Table 1). A
diagnosis of UC was arrived at for 54% and 50% of patients
in the SRS and CS groups, respectively, Crohn’s disease in Figure 1. Rectal lesions at (A) D1 and (B) D14 among patients with
2.5% and 4.1%, and nonspecific proctitis in the remainder. cryptogenic colitis treated with 5-ASA suppositories: slow-release
There was no difference between the two groups in terms of suppositories (SRS, white bars, n ⫽ 125) or conventional suppos-
the stage of the initial rectal lesions (p ⫽ 0.78); their itories (CS, black bars, n ⫽ 126).
distribution is shown in Figure 1A,B. Throughout the trial,
12 patients in the SRS group (9.6%) and 18 patients in the and 14 (shown in Table 3); 36% and 33% of patients in the
CS group (14.3%, NS) continued to take an oral treatment SRS and CS groups, respectively, were treated for 3 wk
they had previously been taking for more than 1 month, i.e., (NS). At the end of the study, a decrease in the score of ⱖ1
salazopyrine (sulfasalazine) in three cases (all in the CS stage was observed in 95% and 94% of subjects in the SRS
group) and 5-ASA in 27 cases (12 and 15 in the SRS and CS and CS groups, respectively, in the per-protocol population
groups, respectively). Eight patients discontinued treatment (NS). Among the intention-to-treat population at day 21,
prematurely: two in the SRS group and six in the CS group blood had disappeared from the stools in 77% and 79%, and
(NS). Table 2 shows the reasons for these withdrawals. At mucus discharge had disappeared in 51% and 53% of sub-
day 14, the intention-to-treat population consisted of 244 jects in the SRS and CS groups, respectively, whereas the
patients. Two hundred and thirty-six patients were seen total number of stools had decreased by 1.4 ⫾ 1.8 stools/day
again at day 14 and satisfied all the follow-up criteria for
inclusion in the per-protocol analysis (115 and 121 in the Table 2. Number of Premature Withdrawals From the Study and
SRS and SC groups, respectively). Corresponding Reasons
Both the slow-release and conventional suppositories SRS CS
were significantly effective in treating the endoscopic le- Number of subjects 125 126
sions and clinical symptoms. The mean decrease in the Premature withdrawals (number) 2 6
endoscopic score at day 14 was 2.3 ⫾ 1.2 for both groups; Reasons
a decrease in the score of ⱖ1 stage was noted in 92% and Lost to follow-up 1 1
90% of patients in the SRS and CS groups, respectively (p ⫽ Noncompliance 1 0
Inefficacy 0 2
0.57); endoscopic lesions were at a stage ⱕ1 in 78% of Personal convenience 0 2
subjects in both groups. Figure 1 shows the endoscopic Adverse reactions 0 1
scores at day 1 and day 14. There was no difference between SRS ⫽ slow-release suppositories; CS ⫽ conventional suppositories. None of the
the two groups in terms of clinical signs noted at days 1, 7, differences between the two groups was significant.
AJG – January, 2000
Table 3. Variation in the Symptoms of Proctitis at Days 1, 7,
and 14 in Patients Treated With Slow-Release Suppositories or
Conventional Suppositories of 5-ASA*
Day SRS
Number of stools/day 1 2.8 ⫾ 1.6
7 1.7 ⫾ 1.1
14 1.7 ⫾ 1.1
Blood in stools (% of subjects) 1 88
7 29
14 17
Mucus discharge in stools 1 66
(% of subjects) 7 27
14 16
Tenesmus (% of subjects)† 1 66
7 26
14 20
* 5-ASA ⫽ 5-aminosalicylic acid. None of the differences between the two groups
was significant.
† The area under the tenesmus intensity curve is significantly smaller for SRS-
treated patients (p ⫽ 0.04), indicating that the mean intensity was lower in this group.
in both groups. Tenesmus decreased in intensity by 0.9 ⫾ 3
points in both groups. There was no difference between the
two groups in terms of the investigator’s global evaluation
(p ⫽ 0.54) at the termination of treatment: in the SRS group,
72 patients (59%) recovered, 43 (35%) improved, and the
condition was unchanged in seven (6%) and aggravated in
one patient. In the CS group, 69 patients (56%) recovered,
45 (36%) showed an improvement, and the condition of 10
patients (8%) was unchanged.
Fifteen patients complained of adverse reactions: seven in
the SRS group (5.6%) and eight in the CS group (6.3%, NS).
Twenty events were described: nine among seven patients in
the SRS group, and 11 among eight patients in the CS group.
It was considered possible, probable, or highly probable that
six of these events were attributable to treatment: two in the
SRS group (one case of skin rash and one of false urges) and
four in the CS group (one case of skin rash, which led to the
discontinuation of treatment, one case of anal pruritus, and
two cases of abdominal pain). The mean daily tolerance
score reported in the patient’s diary card (on a scale of 1 to
3, from good to poor, respectively) was 1.1 ⫾ 0.3 (SRS)
versus 1.2 ⫾ 0.03 (CS). Tolerance was reported as good
every day by 77% of SRS-treated patients as compared with
54% of CS-treated patients (p ⫽ 0.001). Early expulsion of
the suppositories was noted in 0.5% of subjects in the SRS
group versus 3.4% in the CS group (p ⫽ 0.001). In the CS
group, early expulsion occurred more frequently when the
suppository was inserted in the morning (5.8%) than in the
evening (1.0%) (p ⫽ 0.001). There was no significant cor-
relation between the tolerance score and the presence of
premature suppository expulsion.
DISCUSSION
The objective of the study was to compare the efficacy and
tolerance of two dosage forms of 5-ASA suppositories in the
Comparison of 5-ASA Suppositories 169
treatment of exacerbations of cryptogenic colitis, i.e., con-
ventional suppositories (CS) and slow-release suppositories
(SRS). Both treatments were highly effective and showed no
CS difference in efficacy in terms of inducing a reduction in
2.7 ⫾ 1.5 endoscopic lesions and clinical remission. However, treat-
1.8 ⫾ 1.3 ment with SRS had three significant advantages: half as
1.7 ⫾ 1.1 many suppositories were required (slow-release supposito-
93 ries are administered only once daily whereas conventional
27 suppositories must be administered twice daily); early ex-
17 pulsion occurred less frequently with the SRS than with the
62 CS administered in the morning; and tolerance was reported
29 as good every day by more SRS-treated subjects (77%) than
16 CS-treated subjects (54%).
71 Conventional suppositories containing glycerin melt rap-
34 idly once inserted and contain 500 mg of 5-ASA. Twice-
23 daily administration is recommended (3). The suppositories
containing slow-release microgranules (Pentasa) were de-
signed for sustained release of the active ingredient over a
7-h period. They contain 1 g of mesalazine and once-daily
administration is adequate; one study has shown that no
improvement in efficacy is achieved by increasing the dose
of local 5-ASA to ⬎1 g (7, 9). Our randomized, comparative
study was not carried out double blind. A double-blind study
would have avoided certain sources of bias in comparing the
efficacy of the two types of suppository, but it would have
entailed the administration of three suppositories daily, due
to the different consistency of the suppositories, and, quite
apart from any discomfort caused to the patient, comparison
of the tolerance of the two suppositories would have been
impossible. We acknowledge that a blinded assessment of
endoscopic lesions would have been a better design for our
study.
The results from other earlier studies and from the only
randomized, comparative study (which were published
while our own study was under way) would suggest that
slow-release suppositories are effective more rapidly than
conventional suppositories, with a higher remission rate at 2
wk (5). This finding was not confirmed by the results from
our study. The therapeutic efficacy of the slow-release sup-
positories noted in our patients was found to be identical to
that reported in the literature (5, 8); the efficacy of conven-
tional suppositories was, however, greater than that previ-
ously described, as remission rates previously reported were
only 42% and 28% at 2 wk (4, 5) and 36% at 3 wk (6). This
difference calls into question the nature and appropriateness
of the outcome measures and differences in study popula-
tions. In 1995 the Food and Drug Administration (FDA)
proposed guidelines for evaluation of therapies of crypto-
genic colitis to allow easier comparisons between trials (10).
The scoring system proposed by the FDA group to evaluate
endoscopic response would have been preferable, although
our scale is very close (8). In this system, progressive
inflammatory features include mucosal edema obscuring the
submucosal vessels, erythema, fine to coarse granularity and
friability (hemorrhage that may be either induced or spon-
taneous), and pinpoint to extensive mucosal ulceration (10).
170 Marteau et al.
Several other reasons might be put forward to explain the
difference. At inclusion, our patients had a mean stool count
of three per day, 91% had rectal bleeding, and 64% had
mucus discharges. These symptoms were apparently
slightly more severe than those exhibited by patients in the
study conducted by Gionchetti et al. (5) and, in addition,
41% of our patients were suffering from an initial episode of
proctitis, compared with 14% of Gionchetti et al.’s patients.
The most obvious difference between our patient population
and that studied by Farup et al. (4) concerned the time since
onset of symptoms of active proctitis, 48 days in our study
versus 12 months (range, 1–104.4 months). Moreover, pa-
tients in the Farup et al. trial were recruited in the hospital,
whereas our patients were monitored by physicians in pri-
vate practice. Finally, as our study and the trials mentioned
earlier were not blinded, it cannot be ruled out that aware-
ness of treatment assignment may have influenced the re-
porting of endpoints.
The tolerance of both treatments was satisfactory and
agreed with data so far published. However, it is interesting
to note that a higher percentage of subjects in the SRS group
reported tolerance as good every day. This refutes any
assumption that the hard consistency of slow-release sup-
positories might make them less well tolerated. The reasons
for the greater tolerance are not clear. It did not seem to be
explained by the increased tendency among CS patients to
expel their morning suppository, as there was no correlation
between early expulsion and tolerance. A lubricating jelly
was used to insert slow-release suppositories but not the
traditional suppositories, as proposed by the companies who
developed them, and this may have influenced the tolerance.
Hence, further studies will be required to confirm this
greater tolerance and to assess the role of suppository con-
sistency and the number of administrations.
In conclusion, 5-ASA slow-release and conventional sup-
positories were found to be equally effective at a dosage of
1 g/day. This fails to confirm the result obtained in the only
other randomized comparative study carried out so far (5).
The daily cost of treatment with slow-release suppositories
is slightly higher in France at present, but the following
factors argue in favor of using the slow-release form: fewer
administrations are required, early suppository expulsion
occurs less frequently, and a higher percentage of patients
report good tolerance.
AJG – Vol. 95, No. 1, 2000
ACKNOWLEDGMENT
This work was sponsored by Laboratoire Ferring, France.
Reprint requests and correspondence: Philippe Marteau, M.D.,
Ph.D, Service de Gastro-entérologie, Hôpital Laënnec, 42 rue de
Sèvres, 75007 Paris, France.
Received Aug. 17, 1999; accepted Aug. 18, 1999.
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