Heterogeneity in Definitions of Efficacy and Safety Endpoints for Clinical Trials of Crohn's Disease: A Systematic Review

Christopher Ma; Isra M Hussein; Yousef J Al-Abbar; Remo Panaccione; Richard N Fedorak; Claire E Parker; Tran M Nguyen; Reena Khanna; Corey A Siegel; Laurent Peyrin-Biroulet; Rish K Pai; Niels Vande Casteele; Geert R D'Haens; William J Sandborn; Brian G Feagan; Vipul Jairath

doi:10.1016/j.cgh.2018.02.051

Heterogeneity in Definitions of Efficacy and Safety Endpoints for Clinical Trials of Crohn's Disease: A Systematic Review

Clin Gastroenterol Hepatol. 2018 Sep;16(9):1407-1419.e22. doi: 10.1016/j.cgh.2018.02.051. Epub 2018 Mar 27.

Authors

Christopher Ma¹, Isra M Hussein², Yousef J Al-Abbar³, Remo Panaccione⁴, Richard N Fedorak⁵, Claire E Parker⁶, Tran M Nguyen⁶, Reena Khanna⁷, Corey A Siegel⁸, Laurent Peyrin-Biroulet⁹, Rish K Pai¹⁰, Niels Vande Casteele¹¹, Geert R D'Haens¹², William J Sandborn¹¹, Brian G Feagan¹³, Vipul Jairath¹⁴

Affiliations

¹ Division of Gastroenterology and Hepatology, University of Calgary, Calgary, Alberta, Canada; Robarts Clinical Trials, Western University, London, Ontario, Canada.
² University of Guelph, Guelph, Ontario, Canada.
³ St James School of Medicine, Park Ridge, Illinois.
⁴ Division of Gastroenterology and Hepatology, University of Calgary, Calgary, Alberta, Canada.
⁵ Division of Gastroenterology, University of Alberta, Edmonton, Alberta, Canada.
⁶ Robarts Clinical Trials, Western University, London, Ontario, Canada.
⁷ Robarts Clinical Trials, Western University, London, Ontario, Canada; Department of Medicine, Western University, London, Ontario, Canada.
⁸ Section of Gastroenterology and Hepatology, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire.
⁹ Department of Gastroenterology and Inserm U954, Nancy University Hospital, Lorraine University, Vandoeuvre-lès-Nancy, France.
¹⁰ Robarts Clinical Trials, Western University, London, Ontario, Canada; Department of Pathology and Laboratory Medicine, Mayo Clinic Arizona, Scottsdale, Arizona.
¹¹ Robarts Clinical Trials, Western University, London, Ontario, Canada; Division of Gastroenterology, University of California San Diego, La Jolla, California.
¹² Robarts Clinical Trials, Western University, London, Ontario, Canada; Inflammatory Bowel Disease Centre, Academic Medical Centre, Amsterdam, Netherlands.
¹³ Robarts Clinical Trials, Western University, London, Ontario, Canada; Department of Medicine, Western University, London, Ontario, Canada; Department of Epidemiology and Biostatistics, Western University, London, Ontario, Canada.
¹⁴ Robarts Clinical Trials, Western University, London, Ontario, Canada; Department of Medicine, Western University, London, Ontario, Canada; Department of Epidemiology and Biostatistics, Western University, London, Ontario, Canada. Electronic address: vjairath@uwo.ca.

PMID: 29596987
DOI: 10.1016/j.cgh.2018.02.051

Abstract

Background & aims: Endpoints in randomized controlled trials (RCTs) of Crohn's disease (CD) are changing. We performed a systematic review of efficacy and safety outcomes reported in placebo-controlled RCTs of patients with CD.

Methods: We searched the MEDLINE, EMBASE, and the Cochrane Library through March 1, 2017 for placebo-controlled RCTs of adult patients with CD treated with aminosalicylates, immunomodulators, corticosteroids, biologics, and oral small molecules. Efficacy and safety outcomes, definitions, and measurement tools were collected and stratified by decade of publication.

Results: Our final analysis included 116 RCTs (81 induction, 44 maintenance, 7 postoperative prevention trials, comprising 27,263 patients). Clinical efficacy endpoints were reported in all trials; the most common endpoint was CD activity index score. We identified 38 unique definitions of clinical response or remission and 32 definitions of loss of response. Definitions of endoscopic response, remission, and endoscopic healing were also heterogeneous, evaluated using the CD endoscopic index of severity, the simple endoscopic score for CD, ulcer resolution, and Rutgeerts' Score for postoperative endoscopic appearance. Histologic outcomes were reported in 11.1% of induction trials, 2.3% of maintenance trials, and 14.3% of postoperative prevention trials. Biomarker outcomes were reported in 81.5% induction trials, 68.2% of maintenance trials, and 42.9% of postoperative prevention trials. Safety outcomes were reported in 93.8% of induction trials, 97.7% of maintenance trials, and 85.7% of postoperative prevention trials.

Conclusions: In this systematic review, we demonstrate heterogeneity in definitions of response and remission, and changes in outcomes reported in RCTs of CD. It is a priority to select a core set of outcomes to standardize efficacy and safety evaluation in trials of patients with CD.

Keywords: Effects; IBD; Inflammatory Bowel Disease; RCT; Treatment.

Publication types

Research Support, Non-U.S. Gov't
Systematic Review

MeSH terms

Adult
Aged
Aged, 80 and over
Anti-Inflammatory Agents / adverse effects*
Anti-Inflammatory Agents / therapeutic use*
Crohn Disease / diagnosis*
Crohn Disease / therapy*
Drug-Related Side Effects and Adverse Reactions / diagnosis*
Female
Humans
Male
Middle Aged
Randomized Controlled Trials as Topic / standards*
Treatment Outcome*
Young Adult

Substances

Anti-Inflammatory Agents

Grants and funding

CIHR/Canada