Adalimumab Is More Effective Than Azathioprine and Mesalamine at Preventing Postoperative Recurrence of Crohn's Disease

A Randomized Controlled Trial

Edoardo Savarino MD; PhD; Giorgia Bodini MD; Pietro Dulbecco MD; Lorenzo Assandri MD; Linda Bruzzone MD; Fabrizio Mazza MD; Anna Chiara Frigo MSc; Valentina Fazio MD; Elisa Marabotto MD; Vincenzo Savarino MD

Disclosures

Am J Gastroenterol. 2013;8(11):1731-1742. 

In This Article

Methods

Study Design

A randomized, prospective, three-armed, unblinded (not triple-dummy), controlled study with parallel group design was conducted at the Inflammatory Bowel Disease center of the University Hospital of Genoa, Italy. Eligible and consenting patients were assigned randomly using a computer-generated sequence (http://www.randomizer.org) to a regimen of either ADA 40 mg, every two weeks, or AZA (Azafor, Sofar S.P.A., Milan, Italy), at the dose of 2 mg/kg every day, or mesalamine (Pentasa, Ferring S.P.A., Milan, Italy), at the dose of 3 g/day. Patient allocation was concealed and performed by an independent nurse not involved with the trial. The study protocol was approved by the local independent Ethics Committee and performed according to the Declaration of Helsinki Principles. All patients gave written informed consent before the start of the study. The costs of the study were not supported by any pharmaceutical company, but by research funds of our institution.

Patients

Between May 2008 and October 2010, 58 adult patients with ileal or ileocolonic CD undergoing resection participated in the study. All patients were enrolled within 4 weeks of resection of macroscopically diseased bowel with anastomosis between normal ileum and colon. Before formation of the anastomosis, the surgeon everted the ileal and colonic limbs to ensure no mucosal apparent lesions. All anastomoses were side to side and stapled. Exclusion criteria included the following: (i) more than 10 years of CD requiring first resective surgery for short (10 cm) fibrostenotic stricture, (ii) macroscopically active disease not resected at the time of surgery, and (iii) presence of a stoma.

Treatment

Before surgery, patients were screened (purified protein derivative skin test or quantiferon test, chest radiography, and careful history taking) and were found negative for latent tuberculosis. Hepatitis B and C were excluded. They were also evaluated and found negative for past and present cardiac, neurologic, lymphoproliferative, and other neoplastic diseases. After completely removing the involved intestine, treatment was started shortly after the 2-week postoperative visit and in all patients within 4 weeks of surgery. Patients received for 2 years either subcutaneous injections of ADA 160/80 mg at 0 and 2 weeks, followed by 40 mg every 2 weeks, or AZA at the dose of 2 mg/kg every day or mesalamine at the dose of 3 g/day, divided in 3 doses. Patients on antibiotics or immunomodulators at entry into the study discontinued these medications 12 weeks before surgery. Continuous use of nonsteroidal anti-inflammatory drugs was not allowed during the study. No other medications were prescribed except for occasional tablets of paracetamol or tramadol.

Study Outcomes

The primary study outcome was the proportion of patients with endoscopic and clinical recurrence at 2 years after surgery. Total ileocolonoscopy was performed 2–4 weeks after the final period study. A previously developed endoscopic recurrence score developed by Rutgeerts et al.[1] was used. The scores were as follows: i0, no lesions; i1, 5 aphthous lesions; i2, >5 aphthous lesions with normal mucosa between the lesions or skip areas of larger lesions or lesions confined to the ileocolonic anastomosis; i3, diffuse aphthous ileitis with diffusely inflamed mucosa; and i4, diffuse inflammation with large ulcers, nodules, and/or narrowing.

Endoscopic recurrence was defined by a score of i2, i3, or i4 and endoscopic remission by a score of i0 or i1. In addition, the number of ulcers in the neoterminal ileum was counted and recorded as 0, 1–10, and >10. All ileocolonoscopies were video-recorded. A pill camera enteroscopy was performed if ileal inspection was not possible on colonoscopy; only 2 patients required a pill endoscopy. An initial endoscopic score was recorded by the endoscopist (E.S.) at the time of the ileocolonoscopy. A blinded investigator (P.D.) reviewed each patient's video-recorded procedure and provided a separate endoscopic score. The colonoscopic video-recordings were placed on compact discs that were devoid of patient identifiers. At the conclusion of the study, the principal investigator (E.S.) rescored each patient by re-reviewing the video recordings in a random and blinded manner. Thus, three separate scores were collected for each patient. For those patients with scores that were not the same in the three readings, the investigators chose the score that matched in two readings and came to consensus agreement. This occurred in only one patient.

Clinical recurrence was defined as a score of 2 on the clinical recurrence grading scale (where 1 indicates absent; 2, mild; 3, moderate; and 4, severe symptoms) proposed by Hanauer et al..[9] In addition, clinical recurrence based on CD activity index (CDAI) was calculated for each patient and recurrence was set in case of a score >200, whereas clinical remission was defined by a CDAI score of <150. The C-reactive protein (CRP) concentration and erythrocyte sedimentation rate (ESR) were measured. The ESR and CRP were obtained at each study visit as surrogate markers of inflammation. The ESR was recorded as mm/h and the CRP level as mg/dl. A normal ESR was 0–20 mm/h; levels >20 indicated inflammation. A normal CRP was 0–0.8 mg/dl; levels >0.8 mg/dl indicated inflammation.

Radiological relapse was defined as a score of 2 on the radiographic recurrence grading scale (where 1 indicates normal; 2, mucosal edema/aphthoid ulcers; 3, linear ulcers/cobblestoning; and 4, strictures/fistulas/inflammatory mass).[4,9]

Secondary outcome of interest included assessment of quality of life by means of a previously validated structured questionnaire (Inflammatory Bowel Disease–Questionnaire (IBD-Q)) at 12 and 24 months.[22] The IBD-Q is a 32-item questionnaire consisting of four dimensions: bowel-related symptoms (loose stools, abdominal pain), systemic function (fatigue, sleep pattern), social function (ability to attend work and social events), and emotional status (anger, depression, irritability). The response for each question ranges from one to seven, with one corresponding to significant impairment and seven corresponding to no impairment. The overall IBD-Q score is the sum of the responses to each of the IBD-Q questions. Total IBD-Q score can range from 32 (very poor health-related quality of life) to 224 (perfect health-related quality of life). Patients in symptomatic remission usually have a score of 170.[22]

Schedule of Study Events

Patients were subjected to endoscopy at 12 and 24 months; small-bowel enteroclysis or magnetic resonance imaging at 12 and 24 months; physical examination with interviews, together with an extensive battery of blood tests (complete blood cell count; erythrocyte sedimentation rate; CRP, albumin, glucose, electrolyte, autoantibody, and thyroid hormone levels; liver, pancreatic, and renal function tests), weekly for the first 4 weeks and then every 2 months, and completed an IBD-Q at 1 month before surgery and at 12 and 24 months after surgery. The CDAI was determined at each study visit. In addition, adverse events were ascertained at each visit. Any evidence of abnormal blood cells count, elevated liver enzyme levels, or an increase in amylase or lipase levels >2 times the normal values were indications for withdrawal from the trial.

Statistical Analysis

Sample Size Sample size was calculated a priori at the design stage of the study with the numbers of patients needed to treat estimated from the only article available that compares IFX vs. placebo for the prevention of postoperative recurrence of CD.[15] However, given that the latter article provided data on endoscopic (IFX 9.1% vs. placebo 84.6%) and clinical recurrence (defined by a CDAI score >200: IFX 0% vs. placebo 38.5%) only at 1 year of follow-up, and based on previous studies showing that the endoscopic recurrence correlates with the likelihood of future clinical recurrence, we considered reasonable to hypothesize an endoscopic recurrence rate of ~80% and 15% and a clinical recurrence rate of ~65% and 5% for the mesalamine and ADA groups, respectively, at 2 years of follow-up. This estimation has been supported by the results shown in previous trials on postoperative CD relapse.[9,13,14] Thus, based on these data, 13 patients per treatment group resulted to be sufficient to detect a difference of at least 65% for endoscopic recurrence and 60% for clinical recurrence in favor of the ADA group with a power of 80% (global type I error of 5%). The number of patients in each group was increased to 16 to compensate for an anticipated dropout rate of 15%. A closed test procedure has been used in order to control the maximum overall type I error rate. Fixing the α-level at 5%, once the hypothesis of no difference in the global comparison mesalamine vs. ADA vs. AZA was rejected, each of the pairwise comparisons (mesalamine vs. ADA, mesalamine vs. AZA, and ADA vs. AZA) was performed at the same 5% level.

Analysis of Data Statistical analysis was conducted according to the intention-to-treat principle. Categorical variables were analyzed using the χ2 or Fisher's exact test followed by pairwise comparisons in case of a statistically significant result and continuous variables with Kruskall–Wallis test followed by Dunn's test for pairwise comparisons in case of a statistically significant result. The dichotomous variables at 2-year follow-up were analyzed with a univariate logistic regression model including in the model the treatment group factor, and the results are presented as P values and odds ratios (ORs) with the 95% confidence interval (CI). The nondichotomous variables at 2-year follow-up were analyzed with the Kruskall–Wallis test followed by Dunn's test for pairwise comparisons in case of a statistically significant result. The significance level was set at 5%. The analyses were conducted with SAS for Windows (SAS Institute, Cary, NC).

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