Placebo Rates in Randomized Controlled Trials of Pouchitis Therapy
- 112 Downloads
Approximately half of the patients with ulcerative colitis (UC) who undergo restorative proctocolectomy develop pouchitis within 10 years of surgery. Currently, there are no approved pouchitis treatments. It is important to quantify, and ultimately minimize, placebo rates to design and conduct efficient pouchitis trials.
To quantify the placebo rate observed in pouchitis randomized controlled trials (RCTs) in meta-analysis.
Embase, MEDLINE, and the Cochrane Library were searched from inception to November 3, 2017, for placebo-controlled RCTs enrolling adult UC patients with, or at risk for developing, pouchitis. A fixed-effect binomial-normal model was used to pool placebo rates on the log-odds (logit) scale. Proportions and 95% confidence intervals were reported. Outcomes of interest included development of pouchitis, induction of remission/response, and maintenance of remission/response. The Cochrane risk of bias tool was used to evaluate study quality.
Twelve trials (five prevention, five induction, and two maintenance) enrolling a total of 229 placebo patients were eligible for inclusion. The pooled placebo rates for development of pouchitis and induction of response were 47% (95% CI 39–56%) and 24% (95% CI 14–37%), respectively. An insufficient number of trials prevented additional data pooling and meta-regression analysis and no consistent definitions of outcome were identified.
No consistent methods for measuring pouchitis disease activity or defining response and remission were identified, highlighting the need for standardized definitions of outcomes for use in pouchitis trials. Additional high-quality trials are required to evaluate existing and novel therapies in this area.
KeywordsUlcerative colitis Pouchitis Placebo effect Trial design
CM is supported by a Clinician Fellowship from the Canadian Association of Gastroenterology and the Canadian Institutes of Health Research.
JA, SCD, and CEP performed the data screening and data collection; LG performed the statistical analysis; JA, SCD, CEP, LG, RK, BGF, and VJ performed data interpretation; JA, SCD, and CEP drafted the manuscript; LG, CM, RK, BGF, and VJ edited the manuscript for intellectual content; VJ supervised the project. All authors provided final approval of the submitted manuscript.
Compliance with ethical standards
Conflicts of interest
JA, SD, CEP, LG none known; CM is supported by a Clinician Fellowship from the Canadian Association of Gastroenterology and the Canadian Institutes for Health Research; RK has received consulting fees from AbbVie, Janssen, Pfizer, Shire, and Takeda; BGF has received grant/research support from Millennium Pharmaceuticals, Merck, Tillotts Pharma AG, AbbVie, Novartis Pharmaceuticals, Centocor Inc., Elan/Biogen, UCB Pharma, Bristol-Myers Squibb, Genentech, ActoGenix, and Wyeth Pharmaceuticals Inc.; consulting fees from Millennium Pharmaceuticals, Merck, Centocor Inc., Elan/Biogen, Janssen-Ortho, Teva Pharmaceuticals, Bristol-Myers Squibb, Celgene, UCB Pharma, AbbVie, Astra Zeneca, Serono, Genentech, Tillotts Pharma AG, Unity Pharmaceuticals, Albireo Pharma, Given Imaging Inc., Salix Pharmaceuticals, Novonordisk, GSK, Actogenix, Prometheus Therapeutics and Diagnostics, Athersys, Axcan, Gilead, Pfizer, Shire, Wyeth, Zealand Pharma, Zyngenia, GiCare Pharma Inc., and Sigmoid Pharma; and speakers bureaux fees from UCB, AbbVie, and J&J/Janssen; VJ has received scientific advisory board fees from AbbVie and Sandoz; and speakers bureaux fees from Takeda and Janssen.
- 9.Singh S, Stroud AM, Holubar SD, Sandborn WJ, Pardi DS. Treatment and prevention of pouchitis after ileal pouch-anal anastomosis for chronic ulcerative colitis. Cochrane Database Syst Rev. 2015;11:Cd001176.Google Scholar
- 12.Das P, Smith JJ, Tekkis PP, Heriot AG, Antropoli M, John Nicholls R. Quality of life after indefinite diversion/pouch excision in ileal pouch failure patients. Colorectal Dis Off J Assoc Coloproctol GB Irel. 2007;9:718–724.Google Scholar
- 20.Murad MHMV, Ioannidis JPA, et al. Fixed-effects and random-effects models. In: Guyatt G, Rennie D, Meade MO, Cook DJ, eds. Users’ guide to the medical literature. A manual for evidence-based clinical practice. 3rd ed. New York: McGraw-Hill; 2015.Google Scholar
- 25.Team RC. R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria. https://www.R-project.org/.2017.
- 26.Team R. RStudio: Integrated development for R. RStudio, Inc., Boston, MA. http://www.rstudio.com (2016).
- 28.Ha CY, Bauer JJ, Lazarev M, et al. Early institution of tinidazole may prevent pouchitis following ileal-pouch anal anastomosis (IPAA) surgery in ulcerative colitis (UC) patients. Gastroenterology. 2010;1:S69.Google Scholar
- 38.Hahnloser D, Pemberton JH, Wolff BG, Larson DR, Crownhart BS, Dozois RR. The effect of ageing on function and quality of life in ileal pouch patients: a single cohort experience of 409 patients with chronic ulcerative colitis. Ann Surg. 2004;240:615–621. (discussion 21-3).PubMedPubMedCentralGoogle Scholar
- 41.Abdelrazeq AS, Kandiyil N, Botterill ID, et al. Predictors for acute and chronic pouchitis following restorative proctocolectomy for ulcerative colitis. Colorectal Dis Off J Assoc Coloproctol GB Irel. 2008;10:805–813.Google Scholar
- 42.Hashavia E, Dotan I, Rabau M, Klausner JM, Halpern Z, Tulchinsky H. Risk factors for chronic pouchitis after ileal pouch-anal anastomosis: a prospective cohort study. Colorectal Dis Off J Assoc Coloproctol GB Irel. 2012;14:1365–1371.Google Scholar
- 46.Brook RH. The RAND/UCLA appropriateness method. In: McCormick KA, Moore SR, Siegel RA, eds. Clinical practice guideline development: Methodology practices (AHCPR Publication No 95-0009). Rockville, MD: Agency for Health Care Policy and Research, Public Health Service, U.S. Department of Health and Human Services; 1994.Google Scholar
- 47.Ma C, Panaccione R, Fedorak RN, et al. Development of a core outcome set for clinical trials in inflammatory bowel disease: study protocol for a systematic review of the literature and identification of a core outcome set using a Delphi survey. BMJ Open. 2017;7:e016146.CrossRefPubMedPubMedCentralGoogle Scholar