Defining predictors of responsiveness to advanced therapies in Crohn's disease and ulcerative colitis: protocol for the IBD-RESPONSE and nested CD-metaRESPONSE prospective, multicentre, observational cohort study in precision medicine

Abstract

Introduction: Characterised by chronic inflammation of the gastrointestinal tract, inflammatory bowel disease (IBD) symptoms including diarrhoea, abdominal pain and fatigue can significantly impact patient's quality of life. Therapeutic developments in the last 20 years have revolutionised treatment. However, clinical trials and real-world data show primary non-response rates up to 40%. A significant challenge is an inability to predict which treatment will benefit individual patients.Current understanding of IBD pathogenesis implicates complex interactions between host genetics and the gut microbiome. Most cohorts studying the gut microbiota to date have been underpowered, examined single treatments and produced heterogeneous results. Lack of cross-treatment comparisons and well-powered independent replication cohorts hampers the ability to infer real-world utility of predictive signatures.IBD-RESPONSE will use multi-omic data to create a predictive tool for treatment response. Future patient benefit may include development of biomarker-based treatment stratification or manipulation of intestinal microbial targets. IBD-RESPONSE and downstream studies have the potential to improve quality of life, reduce patient risk and reduce expenditure on ineffective treatments.

Methods and analysis: This prospective, multicentre, observational study will identify and validate a predictive model for response to advanced IBD therapies, incorporating gut microbiome, metabolome, single-cell transcriptome, human genome, dietary and clinical data. 1325 participants commencing advanced therapies will be recruited from ~40 UK sites. Data will be collected at baseline, week 14 and week 54. The primary outcome is week 14 clinical response. Secondary outcomes include clinical remission, loss of response in week 14 responders, corticosteroid-free response/remission, time to treatment escalation and change in patient-reported outcome measures.

Ethics and dissemination: Ethical approval was obtained from the Wales Research Ethics Committee 5 (ref: 21/WA/0228). Recruitment is ongoing. Following study completion, results will be submitted for publication in peer-reviewed journals and presented at scientific meetings. Publications will be summarised at www.ibd-response.co.uk.

Trial registration number: ISRCTN96296121.

Keywords: gastroenterology; inflammatory bowel disease; microbiology; patient reported outcome measures; patient-centered care.

Figure 1

Schematic illustrating the evolving approach to treatment of inflammatory bowel disease, with the aim of improving treatment outcomes through individualised precision medicine. Current treatment selection is stratified and modified based on diagnosis, disease phenotype, imaging (radiological and endoscopic) and limited clinical biomarkers, such as blood and stool markers of inflammation, drug metabolising enzyme activity, drug levels and antidrug antibodies. Precision medicine approaches integrating additional complex multi-omic data with information about environmental factors such as dietary intake, smoking and physical activity levels (the exogenous ‘exposome’), may enable individualised treatment selection through predictive modelling. Precision medicine may also help to identify at-risk populations, predict disease course, reduce unnecessary patient risk and health service costs associated with ineffective pharmacological therapies and guide non-pharmacological interventions such as dietary modification (figure created with BioRender.com). CRP, C reactive protein; TPMT, thiopurine methyltransferase.

Figure 2

Study overview schematic. 1325 participants with IBD planned to commence an advanced therapy will be recruited, including a nested subcohort of 300 patients with CD (CD-metaRESPONSE). All participants will collect two stool sample tubes at each study assessment timepoint (baseline, week 14 and week 54). CD-metaRESPONSE participants will be required to collect a third stool sample tube at baseline and week 14. If a participant attends hospital for a face-to-face appointment within the baseline and/or week 14 study assessment window, blood samples will be collected. If a participant attends hospital for a lower gastrointestinal endoscopy at any time during the study period (pre-treatment or post-treatment), biopsy samples will be collected. Participants will complete several questionnaires at each assessment timepoint. For CD-metaRESPONSE participants, additional detailed analyses will be undertaken of metabolic profiles (metabolome) in stool and matched blood plus in-depth dietary assessment (additional elements highlighted in blue boxes). Data generated will be used to perform predictive modelling. Any remaining participant samples will form a large biorepository for use in future research (figure created with BioRender.com). Anti-TNFα, antiumour necrosis factor alpha; anti-IL, anti-interleukin; BSFS, Bristol Stool Form Scale; CD, Crohn’s disease; FFPE, formalin-fixed paraffin embedded; IBD, inflammatory bowel disease; IPAQ, International Physical Activity Questionnaire; JAKi, Janus kinase inhibitor; JPSS, Joint Pain and Stiffness Score; PRO-2, patient-reported outcome-2; PROMIS, Patient-Reported Outcomes Measurement Information System; S1PR, sphingosine-1-phosphate receptor; UC, ulcerative colitis.

Figure 3

Flow chart providing overview of study events. Crohn’s disease (CD), inflammatory bowel disease (IBD), Janus kinase inhibitor (JAKi), Mayo Clinic Score (MCS), multidisciplinary team (MDT), patient-reported outcome-2 (PRO-2),Research Electronic Data Capture (REDCap), simple endoscopic score for Crohn’s disease (SES-CD), sphingosine-1-phosphate receptor (S1PR), ulcerative colitis (UC).