Efficacy of biologic drugs in short-duration versus long-duration inflammatory bowel disease: A systematic review and an individual-patient level meta-analysis of randomized controlled trials - revised

Crohn’s disease (CD) and ulcerative colitis (UC) are remitting-relapsing inflammatory diseases often culminating in disease complications and/or the need of 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) as opposed to later in the course of disease (‘Step-up’ approach).
Electronic databases (MEDLINE, EMBASE/EMBASE classic Cochrane CENTRAL register of controlled trials, the Cochrane Inflammatory Bowel Disease (IBD) Group Specialized Trials Register, and Clinicaltrials.gov registry) will be searched to identify all randomized 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 analyze induction of remission in patients with early-disease (<18months since disease onset) versus patients with longer disease duration, using a generalized linear mixed effect model as well as 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 to biologics. All 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 has been 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 presentations at scientific meetings and links with patients groups and organizations.
Study Registration number: PROSPERO: CRD42018041961
Benefits to science and public health:
• The meta-analysis, whose protocol is described, will be the first to evaluate by individual-patient level data the association between duration of inflammatory bowel disease (IBD) and response to biologic drugs, thereby accounting for multiple confounders that may impact the outcome of biologics treatment.
• The meta-analysis will only analyze data from randomized placebo controlled clinical trials thereby ensuring high-quality source data with standardized outcomes measures