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

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April 2006 INFLIXIMAB AND AZATHIOPRINE 1055 The aim of the present study thus was to evaluate the usefulness of infliximab (3 infusions) combined with AZA/6-MP compared with AZA/6-MP alone for achieving clinical remission off steroids in steroid-dependent CD patients. Materials and Methods Patients Eligible patients were at least 18 years old and had luminal steroid-dependent CD. The diagnosis of CD was based on established clinical, endoscopic, radiologic, and histologic criteria. Steroid dependency was defined as follows: (1) prednisone had to be given for at least 6 months at a dosage 10 mg/day or more, with no interruption for more than 2 months within the past 6 months; (2) at least 2 clinical luminal relapses when tapering of steroids had been attempted, leading to an increase in the dose to more than 10 mg/day; and (3) the last attempt for steroid tapering had to be within the past 6 months. At baseline, patients had to be treated with prednisone 10 mg/day or more. Regarding AZA/6-MP status at baseline, 2 types of patients could be included: those in the naive stratum who did not receive AZA/6-MP in the past 2 years, and those in the failure stratum who still had clinically active disease (Crohn’s Disease Activity Index [CDAI] 150) despite receiving AZA/6-MP for more than 6 months at a stable and appropriate dose (2–3 mg/kg/day for AZA and 1–1.5 mg/kg/day for 6-MP). Men and women with reproductive potential were required to practice birth control throughout the study and for 6 months after the last infliximab infusion. The exclusion criteria were as follows: (1) contraindication to AZA/6-MP or to infliximab according to labeling recommendations; (2) treatment with an immunosuppressive drug other than AZA/6-MP in the past 6 months; (3) previous use of infliximab or other anti–tumor necrosis factor drugs including thalidomide; (4) concomitant treatment with aminosalicylates, budesonide, topical steroids, or artificial nutrition; or (5) presence of at least 1 of the following conditions: symptomatic stricture, intra-abdominal abscess or infection, severe sepsis within the past 3 months, tuberculosis (because the bacillus Calmette-Guérin vaccination still is recommended in France, patients with a tuberculin skin test 10 mm and a bacillus Calmette-Guérin vaccination performed 10 years before the tuberculin skin test were excluded), history of B or C hepatitis, human immunodeficiency virus infection, liver failure, pregnancy, breast-feeding, or participation in pharmaceutical research within the past 3 months. Study Design This randomized, multicenter, double-blind, placebocontrolled trial was performed at 22 sites in France; all physicians were members of the Groupe d’Etude Thérapeutique des Affections Inflammatoires du tube Digestif (GETAID). The recruitment of patients took place from June 2000 to May 2002. When the study was designed, we hypothesized that results could be different depending on whether or not patients received AZA/6-MP at inclusion. Patients thus were randomized per stratum (AZA/6-MP failure or naive) and per center to receive either infliximab or placebo in a 1:1 ratio. The randomization was performed centrally, using permutation tables of size 2 or 4 according to the number of patients that we anticipated would be enrolled at each center per stratum. The protocol was approved by the ethical committee (Comité Consultatif de Protection des Personnes dans La Recherche Biomédicale Paris Saint-Louis) for each participating center. Written informed consent was obtained from all patients before enrollment into the study. Treatments Infliximab/placebo. According to the randomization, patients received at 0, 2, and 6 weeks either a 2-hour infusion of infliximab (Remicade) administered at a dose of 5 mg/kg or an infusion of an identical placebo. Neither the patients nor the study investigators were aware of the treatment assigned. Azathioprine/6-MP. All patients were treated with AZA (2–3 mg/kg per day) or 6-MP (1–1.5 mg/kg per day). Patients previously treated with AZA or 6-MP (failure stratum) continued their treatment at the same dose; in the naive-stratum patients, AZA (2–2.5 mg/kg per day) was started 1 week after the first infliximab infusion (to differentiate side effects related to infliximab from those related to AZA). The AZA or 6-MP dose had to be maintained at a stable dose throughout the study, except for patients who experienced toxicity related to the drug. If leukopenia (1500 neutrophils/mL) or mild transaminase increases occurred (2 times the upper limit of normal value), the AZA/6-MP dose was decreased by 50%. Steroids. At baseline, all patients were treated with prednisone or prednisolone at a daily dose of 10 mg or more. In patients with active disease (CDAI, 150), the steroid daily dose was increased by 15 mg. After 2 weeks, in patients with a clinical remission (CDAI, 150), steroids were tapered according to a standardized scheme (10 mg/wk to a daily dose of 20 mg, and then 5 mg/wk). If the CDAI still was more than 150 after 2 weeks, the prednisone daily dose could be increased to 40 mg/day or 1 mg/kg of body weight/day. Throughout the study, in patients who experienced a relapse, steroids were reintroduced or increased until a new remission was achieved, and then tapered according to the same scheme. Patients who did not reach a clinical remission after 2 weeks with 40 mg/day or more were considered to be steroid resistant and were classified as treatment failures; they were offered infliximab infusion in an open-label fashion. Other treatments. Concomitant treatment that has been shown to facilitate steroid withdrawal in steroid-dependent patients such as mesalamine, budesonide, artificial nutrition, or other immunosuppressive drugs were not allowed during the study.
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 patients 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.
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marc lémann,* jean–yves mary,‡ bernard duclos,§ michel - IG-IBD

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