Heterogeneity in Definitions of Efficacy and Safety Endpoints for Clinical Trials of Crohn's Disease: A Systematic Review for Development of a Core Outcome Set.

BACKGROUND & AIMS:

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

METHODS:

MEDLINE, EMBASE, and the Cochrane Library were searched to 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:

116 RCTs (81 induction, 44 maintenance, 7 postoperative prevention trials, enrolling 27,263 patients) were included. Clinical efficacy endpoints were reported in all trials, most commonly measured using the Crohn's Disease Activity Index. Thirty-eight unique definitions of clinical response or remission and 32 definitions of loss of response were identified. Definitions of endoscopic response, remission, and endoscopic healing were also heterogeneous, evaluated using the Crohn's Disease Endoscopic Index of Severity, Simple Endoscopic Score for Crohn's Disease, ulcer resolution, and Rutgeerts' Score for post-operative endoscopic appearance. Histologic outcomes were reported in 11.1%, 2.3%, and 14.3% of induction, maintenance, and postoperative prevention trials, respectively. Biomarker outcomes were reported in 81.5%, 68.2%, and 42.9% of induction, maintenance, and postoperative prevention trials, respectively. Safety outcomes were reported in 93.8%, 97.7%, and 85.7% of induction, maintenance, and postoperative prevention trials, respectively.

CONCLUSIONS:

In this systematic review, we highlight the heterogeneity in definitions of response and remission and the evolution of outcomes reported in placebo-controlled CD RCTs. Establishing a core outcome set to standardize efficacy and safety endpoint definitions is a research priority in this field.