Efficacy of biological drugs in short-duration versus long-duration inflammatory bowel disease: a protocol for a systematic review and an individual-patient level meta-analysis of randomised controlled trials

Introduction: Crohn's disease (CD) and ulcerative colitis (UC) are remitting-relapsing inflammatory diseases often culminating in disease complications and/or need for surgery. Biologic monoclonal antibody drugs ('Biologics') are efficacious for both diseases, but there are no systematic assessments of their efficacy if administered early after disease onset ('top-down' strategy) vis-à-vis later in the course of disease ('step-up' approach).

Methods and analysis: Electronic databases (MEDLINE, EMBASE/EMBASE classic Cochrane CENTRAL register of controlled trials, the Cochrane IBD Group Specialised Trials Register and Clinicaltrials.gov registry) will be searched to identify all randomised placebo-controlled clinical trials of food and drug administration (FDA)-approved biologics for CD and UC (by March 2016). Two independent reviewers will screen identified papers, extract data and assess the risk of bias according to the Cochrane Handbook for Systematic Reviews of Interventions. Individual-patient-level data (IPD) will be extracted from the identified trials through data-sharing platforms for pharmaceutical companies' sponsored trials and by contacting principal investigators of independent investigator-initiated trials. We will analyse induction of remission in patients with early-disease (<18 months since disease onset) versus patients with longer disease duration, using a generalised linear mixed effect model and by a two-stage approach using coefficient for the treatment-by-subgroup interaction within each trial. We will perform receiver operator curve analysis of optimal disease duration for response. Analyses will be separate for CD and UC. This first-of-its-kind meta-analysis at IPD level of interaction of disease duration with the response to biologics in UC and CD may elucidate the impact of early initiation of biologics, which is of paramount importance for clinical practice and management strategies of inflammatory bowel disease.

Ethics and dissemination: This meta-analysis was approved by the Ethics Committee of the First Affiliated Hospital of Sun Yat-sen University. Findings will be published in peer-reviewed journal and disseminated via scientific meetings and links with organisations.

Prospero registration number: CRD42018041961.