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GASTROENTEROLOGY 1988;95:1449-53
ALIMENTARY TRACT
Double .. Blind Comparison of Slow.. Release
5 .. Aminosalicylate and Sulfasalazine in
Remission Maintenance in Ulcerative
Colitis
CBRIS J. J. MULDER, GUIDO N. J. TYTGAT, IRENE T. WETERMAN,
WILLEM DEKKER, PAUL BLOK, MAX SCHRIJVER, and
HERBERT v.o. HEIDE
pepartment of Gastroenterology-Hepatology, Academic Medical Center, Amsterdam; Department
of Gastroenterology, Academic Hospital, Leiden; Department of Gastroenterology, Elisabeth
Gasthuis, Haarlem; Department of Pathology, Municipal Medical and Health Center, Haarlem;
and Department of Internal Medicine, Bronovo Hospital, The Hague, the Netherlands
The results of a clinical tri al comparing slowrelease 5-aminosalicylic acid tablets (Pentasa) and
enteric-coated sulfasalazine tablets (Salazopyrin)
with regard to the effica,cy of maintaining ulcerative
colitis patients in remission for 12 mo and with
regard to safety of tre&tment are reported. Seventyfive patients with ulcerative colitis in remission for
between 1 mo and 5 yr were included for analysis.
Forty-nine men and 26 women, aged between 18
and 79 yr, received either Pentasa t.i.d. (1500 mg)
plus Salazopyrin placebo 01' Salazopyrin t.i.d. (3 g)
plus Pentasa placebo daily. Patients were assessed
clinically, endoscopically, and histologically before
and 3, 6, 9, and 12 mo afier the start of treatment.
Life-table analysi& showed ongoing remission afier
6 and 12 mo for Pentasa to be 63% (26 of 41) and
54% (22 of 41) and for Salazopyrin 72% (22 of 31)
and 46% (14 of 31). These differences were not
statistically significant. Three patients treated with
Salazopyrin were withdrawn because of severe
erythrodermia, anxiety and backache, and pregnancy, respectively. One patient on Salazopyrin experienced transient rises in serum urea, creatinine,
and lactic dehydrogenase and another patient in
this group reported slight reversible loss of hair. In
the Pentasa group no side effects were recorded. We
conclude that Pentasa is a well-tolerated drug,
equally effective as Salazopyrin in maintenance of
remission of ulcerative colitis.
T
he natural history of ulcerative colitis (De) is
characterized by periods of remission interspersed with exacerbations. The aim of therapy is to
keep the condition of the patient stable, maintaining
remission whenever possible.
Sulfasalazine (salicylazosulfapyridine) has been
shown to be effective in treating acute attacks of De
(1,2) and also in maintaining remission (3-5). However, tolerance to the drug is often pOOl' (6). Sulfasalazine consists of sulfapyridine and 5-aminosalicylic
acid (5-ASA) joined by an azo-bond, which is split
by bacteria in the colon, releasing the constituents.
The sulfapyridine moiety is now known to cause the
majority of the adverse reactions of sulfasalazine,
including allergy, whereas the 5-ASA moiety has
been shown to be the active component in inflammatory bowel disease (7-11). The latter drug has
been investigated in oral, enema, and suppository
forms in active colitis and in refractory proctitis
(7-14). 5-Aminosalicylic acid cannot be given by
mouth as it is unstable in acid and is rapidly absorbed by the small intestine. Delivery systems have
been developed to bypass this problem.
The Pentasa tablets used in this study have been
designed to releas e 5-ASA slowly and in a pHdependent way. Part of the active substance is released and about a third absorbed in the small
intestine; therefore, the majority is available for
activity in the distal ileum and colon (15,16). 5Aminosalicylic acid coated with an acrylic-based
resin has been tested for maintenance therapy in De
(17,18).
1450 MULDER ET AL.
Until now clinical experience with Pentasa tablets
has been limited to small groups of patients. This
study was designed to compare the efficacy and,
safety of p-ASA acid microgranules cOélted with a
semipermeable membrane of ethyl ~ellulose (Pentasal with sulfasalazine for maintenance of remission
in Ue.
'
Materials aml Methods
Study Design
This study was designed as a double-blind, doubledummy, randomized multicenter study. The aim was to
compare the efficacy of 12 nio of treatment with slowrelease 5-ASA tablets (Pentasa) and sulfasalazine entericcoated tablets (Salazopyrin RC) in preventing relapse in
patients with ue in remission and to compare the inddence of si de effects and the tolerance' to these two
treatments. Ulcerative colitis was diagnosed by assessing
the usual clinical, endoscopic, and histologic criteria (1921).
The study was conducted under the provisions of the
Declaration of Helsinki.
Patients
Male and female outpatients, aged 218 yr, with ue
in remission for between 1 mo and 5 yr who had not taken
steroids (either orally or as an enema) or azathioprine
during at least 1 mo before entry were included. Excluded
were aIl pregnant and lactating women, women of
childbearing potential not taking adequate contraceptive
measures, patiep.ts who were likely to be unreliable to
follow the instructions properly, patients allergic to aspirin, other salicylates, or sulfcinainides, patients with malignant disease, and patients with renal disease, especially
those with analgesic nephritis.
Randomization
According to a double-blind randomization code,
patients' were either allocated to treatment with active
Pentasa tablets + placebo Salazopyrin Re tablets or to
placebo Pentasa tablets + active Salazopyrin Re tablets.
Medication
Patients received either 6 tablets (1500 mg) of
Pentasa plus 6 pla~ebo tablets of Salazopyrin Re or 6
placebo tablets of Pentasa plus 6 tablets (3 g) of Salazopyrin Re daily. The patients were instructed to take their
daily dosage in thre8 doses before or after the II1ain meals.
The duration of treatment was 12 ruo.
The placebo tablets were identical in appearance,
weight, and taste.
Assessments
Before the start of the study, all relevant medical
and family history data were noted, including symptoms,
duration of disl'lase, previous therapy, response to previ-
GASTROENTEROLOGY VoL 95, No, 6
ous therapy, allergy, aud all other (concomitant) therapy
previously taken by the patient. Patients were assessed
clinically, endoscopically (recto/sigmoidoscopy) (20), and
histologically (21) before and 3, 6, 9, and 12 mo after the
start of treatII1ent. At endoscopy the mucosal color, vessel
pattern, granularity, presence oí valves, distention, polyp_
oid structures, ulcers, spontaneous hemorrhage, and
mucopurulent covering were studied and a wipe-test Was
performed to determine friability. Overall, endoscopy Was
scored from normal through mild, moderate, and severe
abnormality to very severe abnormality.
As for histology, the biopsy specimens were examined
for edema and hemorrhage in the mucosa and submucosa,
for quality and quantity of mucosal cellular infiltrate, and
for epithelial architecture of the crypts. They were finally
scored as normal, little inflammation, medium inflammation, severe inflammation, or ue in remission. Patients
were assessed immediately if symptoms developed or if
side effects occurred.
After the completion of the study it was to be determined whether a patient had remained in remission Dr not.
The following criteria were used to assess this:
If all the data obtained at each visit were assessed as
"normal" or "in remission," the patient was considered to have remained in remission.
If at any time during the study all the data obtained were
not considered to be "normal" or "in remission" or
if the investigator had given a prescription for
additional treatment (e.g., enemas), then the patient was considered to have experienced relapse.
In case of abnormalities in only one or two of the assessment groups (clinical, endoscopic, histologic), the
patient's data were discussed by the monitor with a
blinded investigator. In this way a final judgment
as to whether the patient had remained in remission or not was given.
Relevant laboratory data were obtained during every visit
[erythtocyte sedimentation rate, hemoglobin, hematocrit,
leukocytes, thrombocytes, albumin, alkaline phosphatase,
total protein, y-glutamyl transaminase, urea, creatinine,
lactic dehydrogenase, serum glutamic oxaloacetic transaminase, serum glutamic pyruvic transaminase, and urine
(protein, glucose, and sediment)]. During each visit the
patients were asked whether any unusual event had occurred during the preceding periodo The patients were not
aske9. for specific signs or symptoms. Side effects were
recorded Dn special forms.
Statistics
Before eyaluating the results of therapy, it was
checked whether the groups .vere comparable per treatment and per center. This was' done using analysis of
variance, Student's t-test, y tests, Fisher's test (tWQ-sided),
and Mantel-Haenszel y tests where appropriate. The data
concerning the remission rates were statistically evaluated
using life-table analysis with the SAS statistical package
and the log-rank test was applied fo detect significant
differences.
5-AMINOSALICYLIC Acm IN UC
December 1988
rabIe 1. InitiaI Patient Data
n
Sex (M/F)
Age
Mean ± SD (yr)
Range (yr)
Duration of disease
Mean ± SD (yr)
Range (yr)
Duration of remission
befare the trial
Mean ± SD (mo)
Range (mo)
Median (mo)
Extent of disease
Proctitis
Proctosigmoiditis
Left -sided colitis
Pancolitis
Salazopyrin therapy during
month befare entry (n)
Pentasa
Salazopyrin
p
41
29/12
34
20/14
NS
43.3 ± 15.6
18-79
42.0 ± 11.5
22-63
NS
9.7 ± 10.2
0.5 ± 42
9.5 ± 8.4
0.4 ± 40
NS
13.6 ± 13.8
1-48
7
10.6 ± 10.1
2-39
7.5
11
12
10
8
40
7
11
12
4
33
healthy baby was born), but she continued open
Salazopyrin therapy.
Patient Characteristics
Both groups were comparable for aH parameters per treatment and per center. AH except 2
patients had been on sulfasalazine before the study
(Table 1).
Evaluation of Efficacy in Maintaining
Remission
NS
NS
NS
NS
NS, not significant.
Results
Dropouts
Three patients dropped out of the study before
the first follow-up visit. Dne patient (Salazopyrin)
considered the tablets unpalatable and 2 patients
stopped the therapy because of lack of motivation
(Pentasa 1, Salazopyrin 1). Dropouts were not included in the analysis.
Protocol Violations
Six patients on Pentasa and 6 patients on
Salazopyrin did not fulfil the inclusion criteria: they
had not been in complete remission at least 1 mo
before entry into the study. These patients were only
included in the safety analysis.
Patients
Seventy-five patients, 49 men and 26 women,
with ages ranging from 18 to 79 yr were available for
analysis. Forty-one were treated with Pentasa and 34
with Salazopyrin. Eight of the 41 patients in the
Pentasa group stopped the trial medication after they
had experienced a relapse, despite the investigator's
request to continue. Four patients in the Salazopyrin
group did the same. Another 3 patients in the
Salazopyrin group were withdrawn: one developed
severe erythrodermia 5 wk after the start of treatment, another complained of anxiety and backache 6
wk after the start of treatment, and the third left the
study after 3 mo of therapy because of pregnancy (a
1451
The data of 41 patients treated with Pentasa
and 34 patients treated with Salazopyrin in four
centers were included in the life-table analysis for
calculating the remission rates. The results are
shown in Figure 1. No significant differences between the two treatments were revealed (~ = 0.14,
df = 1, P > 0.70). The final remission rates were 54%
for Pentasa and 46% for Salazopyrin, with 95%
confidence intervals of 38%-69% for Pentasa and
29%-64% for Salazopyrin. The difference is 8% in
favor of Pentasa, with a 95% confidence interval of
~16% to +31%.
Safety Analysis
Laboratory findings. Dne patient on Pentasa
had transient slight abnormalities in the urinary
sediment (bacteria, leukocytes, and erythrocytes) at
3 and 9 mo. Dne patient on Salazopyrin had a
transient rise in serum urea, creatinine, and lactic
dehydrogenase after 3 mo of therapy. Eighteen days
later the values were normalized. The possibility of a
laboratory error was considered.
Tolerance. Dne patient on Salazopyrin
dropped out almost immediately because she
thought the tablets were unpalatable. Two patients
receiving Salazopyrin, one developing severe erythrodermia and another anxiety/backache, were dis% remission
(100
80
1__ -
1
----------1----------
60
1
I
'-
Therapy
40
- - Pentasa
------ Salazopyrin
20
o
2
3
4
5
6
_
7
8
9
10
11
12
months alter star! 01 therapy
Figure 1. Remission rates.
1452
MULDER ET AL.
cussed aboye as withdrawals. Another patient on
Salazopyrin reported slight los s of hair during the
treatment, which seemed to recover after treatment
was stopped.
Discussion
No statistically significant differences were
revealed between Pentasa and Salazopyrin with respect to their ability to maintain remission in De.
There was a slight trend in favor of Pentasa as it
maintained remission in 54% of patients over the
year whereas the figure for Salazopyrin was 46%.
Several studies have been published showing that
5-ASA, when delivered to the colon in a suitable
form, is effective in DC (16). This study not only
provides additional evidence of 5-ASA being the
active moiety of sulfasalazine but also demonstrates
that, when given in the Pentasa slow-release preparation, it is at least as effective as the "parent drug."
It has already been argued that Pentasa, on theoretical grounds, should constitute an advance with
regard to tolerance. Should adverse reactions be
observed they will in all likelihood be limited to
those ascribed to the salicylates in general. The rate
at which the patient is able to acetylate absorbed
5-ASA may playa major part in the frequency and
severity of si de effects. In this study Pentasa lived up
to expectations as no adverse reactions were recorded. In contrast, 3 patients in the Salazopyrin
group suffered side effects. Hair loss during Salazopyrin therapy was recently reported by others too
(22). Qne patient in our study had to be withdrawn
because of severe erythrodermia. It is well known
that sulfasalazine can cause reactions necessitating
discontinuation of therapy (6).
In this study we did not monitor plasma levels or
urinary excretion of 5-ASA or its main metabolite
acetyl-5-ASA. However, a Danish group recently
published the results of Pentasa and Salazopyrin
urine and plasma level determinations in patients
with DC and Crohn's disease (23,24). Although these
studies do not involve a direct comparison of similar
patient groups, we believe that it can be concluded
that 1.5 g/day Pentasa is probably as safe as Salazopyrin as far as the 5-ASA moiety is concerned.
This study shows that Pentasa is another promising slow-release 5-ASA preparation, equally effective in maintaining remission in colitis and therefore
especially useful in patients unable to take sulfasalazine (25).
References
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GASTROENTEROLOGY Vol. 95, No. B
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5-AMINOSALICYLlC ACm IN DC
1453
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Received June 24,1987. Accepted April 21, 1988.
Address requests for reprints to: Dr. C.J.J. Mulder, Department
of Gastroenterology-Hepatology, Academic Medical Center,
Meibergdreef 9,1105 AZ, Amsterdam, the Netherlands.
The authars thank Jenny Peeters and Janke Turksema far
secretarial assistance.