Systematic review: Outcomes and adverse events from randomised trials in Crohn’s disease

Abstract

Background: The suitability of disease activity indices has been challenged, with growing interest in objective measures of inflammation. Aim: To undertake a systematic review of efficacy and safety outcomes in placebo-controlled randomised controlled trials (RCTs) of patients with Crohn's disease. Methods: MEDLINE, EMBASE, CINAHL and Cochrane Library were searched until November 2015, for RCTs of adult Crohn's disease patients treated with medical or surgical therapies. Data on efficacy and safety outcomes, end-point definitions, and measurement instruments were extracted and stratified by publication date (pre-2009 and 2009 onwards). Results: One hundred and eighty-one RCTs (110 induction and 71 maintenance) were identified, including 23 850 patients. About 92.3% reported clinical efficacy endpoints. The Crohn's Disease Activity Index (CDAI) dominated, defining clinical response or remission in 63.5% of trials (35 definitions of response or remission). CDAI < 150 was the commonest endpoint, but reporting reduced between periods (46.4%-41.1%), whilst use of CDAI100 increased (16.8%-30.4%). Fistula studies most commonly reported fistula closure (9, 90.0%). Reporting of biomarker, endoscopy and histology endpoints increased overall (33.3%-40.6%, 14.4%-30.4% and 3.2%-12.5%, respectively), but were heterogeneous and rarely reported in fistula trials. Patient-reported outcome measures were reported in 41.4% of trials and safety endpoints in 35.4%. Many of the common adverse events relate to disease exacerbation or treatment failure. Conclusions: Trial endpoints vary across studies, over time and are distinct in fistula studies. Despite growth in reporting of objective measures of inflammation and in patient-reported outcome measures, there is a lack of standardisation. This confirms the need for a core outcome set for comparative effectiveness research in Crohn's disease.