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OP004. Early combined immunosuppression for the management of Crohn's disease: A community-based cluster randomized trial

R. Khanna1, B.G. Levesque1,2, B. Bressler3, G. Zou1,4, L. Stitt1, G.R. Greenberg5, R. Panaccione6, A. Bitton7, P. Pare8, S. Vermeire9, G. D'Haens1,10, D. MacIntosh11, W.J. Sandborn1,2, M.K. Vandervoort1, J.C. Morris1, B.G. Feagan1,12, 1Robarts Clinical Trials Inc., Robarts Research Institute, Western University, London, Ontario, Canada, 2University of California, San Diego, Division of Gastroenterology, La Jolla, United States, 3St. Paul's Hospital, Department of Gastroenterology, Vancouver, British Columbia, Canada, 4Western University, Department of Epidemiology and Biostatistics, London Ontario, Canada, 5Mount Sinai Hospital, Division of Gastroenterology, Toronto Ontario, Canada, 6University of Calgary, Division of Gastroenterology & Hepatology, Calgary Alberta, Canada, 7McGill University, Division of Gastroenterology, Montreal Quebec, Canada, 8Laval University, Hopital du St-Sacrement, Quebec City, Quebec, Canada, 9Department of Clinical and Experimental Medicine, KU Leuven, Translational Research in GastroIntestinal Disorders, Leuven, Belgium, 10University of Amsterdam, Academic Medical Center, Amsterdam, Netherlands, 11Dalhousie University, Division of Gastroenterology, Halifax, Canada, 12Western University, Department of Epidemiology and Biostatistics, Department of Medicine, London Ontario, Canada

Background

Conventional management (CM) of Crohn's disease (CD) consists of sequential use of corticosteroids, antimetabolites, and tumor necrosis factor (TNF)-antagonists. Recent evidence indicates that early combined immunosuppression (ECI) with a TNF-antagonist and an antimetabolite may be more effective than CM. We compared the effectiveness of ECI (Figure 1) to CM in community gastroenterology practices.

Methods

In this cluster randomization trial (Randomized Evaluation of an Algorithm for Crohn's Treatment or REACT; Clinicaltrials.gov NCT01030809; partial support AbbVie), practices in Canada (n = 34) or Belgium (n = 5) were randomly assigned in a 1:1 ratio to ECI or CM. Up to 60 consecutive adult patients (≥18 years of age) with a documented diagnosis of CD in each practice were evaluated for 24 months. The primary outcome was the proportion of patients in remission (Harvey–Bradshaw Score (HBS) ≤4 in the absence of steroids) at 12 months, evaluated at the practice level. Secondary measures were the rates of complications, hospitalizations, and surgeries over the entire follow-up period, based on patient-level analyses.

Results

Twenty-one centers (1084 patients) were assigned to ECI and 18 (898 patients) to CM. The mean age of the patients was 44.2 in the ECI group and 44.1 in the CM group. Mean HBS scores were 4.1 in both groups. The proportion of patients in the ECI and CM groups who received combination of antimetabolite/TNF-antagonist by 12 months was 15.1% and 6.5% P < 0.001) and 19.7% and 9.6% by 24 months (P < 0.001). Mean % (SD) remission rates in the ECI and CM groups were 66 (14) and 62 (17) at 12 months (P = 0.65) and 73 (8) and 65 (17) at 24 months (P = 0.35). However, highly significant and clinically important differences in the rates of complications, surgeries, and the combined outcome of hospitalizations, complications, and surgeries were observed in favor of ECI over 24 months (Figure 2). The 24 month actuarial estimates for the combined outcome were 27.7% and 35.1% in the ECI and CM groups, respectively (hazard ratio adjusted for CD caseload and country: 0.74 [0.62, 0.87, P < 0.001]).

Figure 1. Therapeutic algorithm utilized for patients in the ECI group.

Figure 2. Hospitalizations, complications*, and surgeries for patients in the ECI and CM groups over 24 months. *Abscess, new fistula, extra-intestinal manifestations of CD and serious AEs.

Conclusion

Community-based data indicate that (1) a symptom based conventional approach to CD management may not be optimal and (2) ECI may be more effective in preventing CD-related complications.