marc lémann,* jean–yves mary,‡ bernard duclos,§ michel - IG-IBD

1056 LEMANN ET AL GASTROENTEROLOGY Vol. 130, No. 4
Data Collection
A complete medical history and current medications
were recorded at study inclusion. Physical examination and
laboratory tests (C-reactive protein, erythrocyte sedimentation
rate, blood counts, liver tests) were performed at screening and
at each visit (weeks 0, 2, 6, 12, 24, and 52). The CDAI, 10 a
steroid side-effect score, and the cumulative doses of steroids
also were calculated at each visit. A chest radiograph and
tuberculin test were performed at inclusion and at week 24. A
colonoscopy was performed, if the patient agreed, at baseline
and at week 24, and the Crohn’s Disease Endoscopic Index of
Severity (CDEIS) was calculated. 11 Adverse events were recorded
at each visit and were classified as mild, moderate, or
severe; the relationship to study medications also was evaluated.
The CDAI10 was calculated by using patient reports of
symptoms on diary cards within the week preceding each visit.
The CDEIS was assessed according to the presence and the
extent of lesions and ulcerations (deep or superficial), and
according to the presence of ulcerated and nonulcerated strictures
on the 5 following segments: rectum, sigmoid and left
colon, transverse colon, right colon, and ileum. 11 The steroid
side-effects score was calculated as follows: 1 point was attributed
for each minor to moderate side effect including acne,
swelling of the face, buffalo hump, striae, moderate increase in
abdominal fat, insomnia or minor psychic disturbances, and
other minor side effects; and 2 points for each severe side effect
including amyotrophy and/or muscular weakness, pronounced
cushingoid obesity, severe acne, diabetes mellitus, cataract,
symptomatic bone complications, severe psychic disturbances,
high blood pressure, or other severe side effects; the score could
vary from 0 to 16.
End Points
All primary and secondary end points were prespecified.
The primary efficacy end point was the rate of success,
defined as a clinical remission (CDAI 150) 12 off steroids at
week 24. Secondary efficacy end points were as follows: (1)
success rate at week 12, (2) rate of steroid resistance, (3)
cumulative dose of prednisone at week 24, (4) steroids sideeffect
score at weeks 6, 12, and 24, (5) endoscopic improvement
between inclusion and week 24, and (6) adverse events.
A follow-up evaluation also was planned at week 52, with
assessment of the success rate. During the follow-up period
(weeks 24–52), all treatments could be given as necessary;
patients who had a relapse or received additional infusions of
infliximab were classified as treatment failures.
Statistical Analysis
The sample size calculation was based on the assumption
that infliximab would be better than placebo (1-sided
basis). We estimated that 128 patients were needed to detect
a crude difference of 20% for the primary end point between
placebo and infliximab, assuming a remission rate of 60% with
the placebo, with a power of 80%. The analysis of efficacy was
performed according to the intent-to-treat principle. All pa-
tients enrolled and not lost to follow-up evaluation were
included in the efficacy analysis, except if the CDAI was
missing. The analysis of safety was conducted including all
patients who had received at least 1 infusion of study medication.
Categoric variables were described using frequencies and
percentages and their distributions were compared between
treatment groups, globally, and per stratum by using the 2
test or the Fisher exact test. Continuous variables were summarized
using the frequency, median, and interquartile range
and their distributions were compared between treatment
groups using the Mann–Whitney test.
Success rates (the primary end point) were compared using
the 2 test (globally and per stratum); the multiple logistic
regression method also was used to estimate the odds ratio
(OR) of success with 95% confidence intervals (CIs) and to test
if the efficacy of infliximab compared with placebo was different
across strata (interaction between treatment and stratum).
Success at 12 or 52 weeks and steroid resistance were analyzed
similar to the primary end point. The cumulative dose of
prednisone, steroid side-effect score, and decrease in the CDEIS
were analyzed using the Mann–Whitney test.
Multivariate logistic regression analysis, adjusted on treatment
and stratum, with backward selection using the likelihood
ratio test, was used to look for factors measured at
baseline that were independently predictive of success at week
24. Variables were proposed to this analysis if the P value was
less than .30 in the univariate analysis. Continuous factors
were categorized as follows: each variable first was divided into
4 categories at approximately the 25th, 50th, and 75th percentiles.
If the ORs of adjacent categories were not statistically
different, these categories were grouped. If no clear pattern was
observed, the median was taken as a cut-off point. Usual
limits, such as 150 for the CDAI, also were tested. The
treatment effect and treatment-strata interaction were tested
after adjustment on independent prognostic factors. Results
were expressed as ORs with 95% CIs.
Results were considered significant when the P value was
less than .05. Data were analyzed with SPSS Software for
Windows, release 6.1 (SPSS Inc, Chicago, IL).
Results
Baseline Characteristics of Patients
The trial profile is shown in Figure 1. A total of
115 patients were randomized (56 in the failure stratum/59
in the naive stratum); 57 patients (26 in the
failure stratum) were assigned randomly to receive infliximab
and 58 patients (30 in the failure stratum) to
receive placebo. Two patients allocated to placebo treatment
(1 in each stratum) were not enrolled and did not
receive the first infusion, 1 patient because his CDAI was
less than 150 at inclusion and the other patient because
he withdrew his consent before the inclusion visit.