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Evaluating Study Withdrawal Among Biologics and Immunomodulators in Treating Ulcerative Colitis: A Meta-analysis of Controlled Clinical Trials

Shah, Eric D. MD, MBA; Siegel, Corey A. MD, MS; Chong, Kelly PhD; Melmed, Gil Y. MD, MS

doi: 10.1097/MIB.0000000000000680
Original Clinical Articles

Background: We conducted a systematic review and meta-analysis to evaluate the efficacy and adverse event (AE)-associated tolerability of treatment with immunomodulators and biologics in ulcerative colitis clinical trials.

Methods: We performed a literature search of PubMed and the Cochrane databases to identify randomized placebo-controlled trials of immunomodulators and biologics. Tolerability was defined through study withdrawal due to AEs and efficacy through clinical response in induction trials and clinical remission in maintenance trials. We performed meta-analyses using a random-effects model to determine relative risks (RRs) of efficacy and study withdrawal. Number needed to treat (NNT) and number needed to stop (NNS) were determined. The ratio of NNS/NNT was calculated, with a higher ratio indicating a greater number of patients in remission for every AE study discontinuation.

Results: We examined 13 single-agent trials representing biologics (infliximab, adalimumab, golimumab, and vedolizumab) and immunomodulators (tacrolimus and azathioprine). Induction therapy did not result in excess study withdrawal with immunomodulators (RR = 0.9, 95% CI 0.1–12.0) or biologics (RR = 0.7, 95% CI 0.3–1.8), therefore the NNS/NNT ratio could not be assessed because of high tolerability. Maintenance immunomodulator therapy resulted in a NNS of 14 (RR = 2.8, 95% CI 0.7–10.5) and NNS/NNT ratio of 2.4 in 2 trials. Biologics did not result in excess study withdrawal in maintenance (RR = 0.7, 95% CI 0.3–1.7) or combined induction-and-maintenance (RR = 0.6, 95% CI 0.4–1.0) trials.

Conclusions: Biologics were not associated with a higher RR of study withdrawal due to AE than placebo. There were insufficient data to compare these results with immunomodulators.

Article first published online 28 January 2016.

*Division of Gastroenterology, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California;

Section of Gastroenterology, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire; and

Department of Veterans Affairs, Los Angeles, California.

Reprints: Gil Y. Melmed, MD, 8730 Alden Drive #203B, Cedars-Sinai Medical Center, Los Angeles, CA 90048 (e-mail:

C.A. Siegel has served as a consultant and on the advisory board for Abbvie, Given Imaging, Jannsen, Prometheus, and Takeda; has delivered CME talks for Abbvie and Jannsen; and has received grant support from Abbvie, Janssen, Salix, UCB and Warner-Chilcott. G.Y. Melmed has served as a consultant and on the advisory board for Abbvie, Celgene, Given Imaging, Jannsen, and Luitpold and has conducted research on behalf of Pfizer. The other authors have no conflict of interest to disclose.

Received August 26, 2015

Accepted November 9, 2015

© Crohn's & Colitis Foundation of America, Inc.
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