Title: Small bowel motility quantified by cine MRI as a predictor of long term response in patients with Crohn’s disease commencing biological therapy
Funder: Department of Health and Social Care

Abstract: RESEARCH QUESTION: Do segmental small bowel (SB) motility measurements using MRI (mMRI) better predict one year therapeutic outcome in patients commencing anti-TNF therapy for SB Crohn’s disease (CD) than C-reactive protein (CRP)? STUDY DESIGN & SETTING: Multicentre prospective cohort study; 10 British Society of Gastroenterology (BSG) & British Society of GI & Abdominal Radiology (BSGAR)-affiliated NHS hospitals with extensive radiological & clinical IBD experience. PATIENTS: Patients with CD, aged 16+ years with active luminal SB disease, commencing anti-TNFs (including biosimilar agents) as part of standard clinical care. INTERVENTION: mMRI at 0 weeks, 20-28 weeks & after one year. COMPARATOR: Existing predictors of response to anti-TNFs: C-reactive protein (CRP; primary) & faecal calprotectin (fC; secondary). PRIMARY ENDPOINT: Remission or response (RoR) to anti-TNFs at one year, judged by either (a) endoscopic criteria for patients with endoscopically-accessible SB disease and where it is performed as part of routine care or (b) validated morphological MRI activity scores (where disease is not endoscopically accessible, or where endoscopy is not performed as part of routine clinical care). In both cases (endoscopic or MRI assessment), RoR also implies no need for any of (i) steroid rescue for objectively active CD, (ii) switch to different anti-TNF due to loss of efficacy or (iii) small bowel surgery. PRIMARY OUTCOME: Difference in sensitivity between stable or improved MRI-measured segmental small bowel motility versus normalisation of C-reactive protein at week 20-28 to predict response or remission (RoR) to anti-TNFa therapy at one year. Pre-specified subgroup analyses will be conducted for: (i) stricturing disease (>50% reduction in luminal calibre) vs. non-stricturing disease, (ii) previous surgery vs. no previous surgery, (iii) endoscopic standard of reference to define therapeutic response vs. non-endoscopic standard of reference. SECONDARY OUTCOMES: 1. Difference in specificity between stable or improved MRI-measured small bowel motility versus normalisation of C-reactive protein at week 20-28 to predict RoR. 2. Difference in area under the receiver operating characteristic curve (ROC AUC) between changes from baseline to the week 20-28 in continuous small bowel motility MR score and in C-reactive protein levels to predict RoR. 3. Difference in prognostic accuracy between changes in the continuous small bowel motility MR score versus changes in C-reactive protein levels at week 20-28 to predict clinically significant improvements from baseline to one year in each quality of life measure (EQ-5D-5L, CUCQ-8 and IBD-Control 8). 4. Difference in (i) sensitivity and (ii) specificity between stable or improved MRI-measured small bowel motility and normalisation of faecal calprotectin at week 20-28 for predicting RoR. Difference in (iii) ROC AUC between changes from baseline to week 20-28 in small bowel motility and in faecal calprotectin for predicting RoR. 5. Difference in prognostic accuracy between changes in the continuous MRI-measured small bowel motility score versus changes in faecal calprotectin levels at week 20-28 to predict clinically significant improvements from baseline to one year in each quality of life measure. 6. Difference in prognostic accuracy and incremental prognostic value of multivariate prognostic models including MRI-measured small bowel motility versus those including (i) C-reactive protein and (ii) faecal calprotectin for response to anti-TNFa therapy at one year. 7. Interobserver variability of MRI-measured small bowel motility for (a) experts in mMRI and (b) experienced radiologists without prior mMRI experience. Intraobserver variability of MRI-measured small bowel motility for experts in mMRI. 8. Difference in (a) plasma levels of (i) gut peptides and (ii) inflammatory cytokines and (b) small bowel motility variance between patients with and without RoR. 9. Difference in small bowel motility variance between patients with normal and elevated levels of (a) gut peptides (b) inflammatory cytokines and (c) between patients with and without abdominal symptoms at each time point. 10. Difference in response rates to anti-TNFa therapy at one year for (a) patients with and without skeletal muscle myopenia and (b) patients with and without low skeletal muscle:fat ratios. ANALYSIS: McNemar’s test for paired proportions. Non-parametric ROC analysis. Logistic regression for prognostic models using known clinical predictors & study interventions SAMPLE SIZE & POWER: 156 patients with active SB disease. Effect size 20% (intervention 0.60, comparator 0.40), type 1 error=0.05, power=90%, correlation between tests=0.5, prevalence of RoR=0.5, two-tailed test, 10% drop-out rate RECRUITMENT & DURATION: 6month setup, 24month recruitment, 12month follow-up, 6month analysis/write-up=48 months. Recruitment rate (0.86patients/month/site) informed by 12month audit of eligible patient pool & sham recruitment period CHECKPOINT: At 12 months; recruitment >0.8 patients/site/month & 3+ sites open. SUBSTUDIES: 1. Mechanistic: Are global mMRI changes in morphologically normal bowel (i) due to gut peptide and cytokine upregulation and (ii) associated with patient symptom burden? 2. Observer variability: Both within- & between-readers 3. Body composition: Do patients with MRI-measured myopenia have differing rates of RoR to anti-TNFs vs. those without myopenia? DISSEMINATION: Our links with the BSG, BSGAR & European Crohn’s & Colitis Organisation ensure that our results will reach key opinion leaders rapidly BENEFITS & EXPECTED IMPACTS: If effective, the novel technology will allow timely triage of patients to appropriate therapy, improving outcomes, decreasing anxiety, & simultaneously reducing overall healthcare costs.

Lay abstract: Treatment of Crohn’s disease (CD), a painful, debilitating inflammatory bowel condition, has been revolutionised by the introduction of powerful medicines called anti-TNFs which can often be successful when other treatments have failed. Although a major therapeutic advance, occasionally they have side effects that can be very serious or even life-threatening. Furthermore, they are expensive (approximately £10,000 per patient/year). Unfortunately, approximately 50% of patients who start anti-TNF treatment ultimately do not improve, and so continue the medication with no benefit, sometimes causing harm. Because of this, there is an urgent clinical need for a test that would, at an early stage, identify patients in whom anti-TNF medication is destined to fail – allowing an early switch in therapy. This would avoid exposing patients who would not benefit from treatment to unnecessary risk, while simultaneously reducing cost to the NHS. This topic has been highlighted by NICE as a research priority and our patient representatives also judge it fundamentally important. Our research group has developed a novel test using MRI scanning and computer software to monitor and quantify bowel motility (mMRI), which is reduced in CD. In essence, the more inflamed the bowel, the less it moves. However, motility improves quite quickly after successful treatment. We hypothesize that these mMRI improvements early after starting treatment are better than current alternatives (blood and stool tests) at predicting whether or not a patient will respond to anti-TNFs in the longer term. To investigate this, we will perform mMRI on 156 patients with CD from 10 NHS hospitals who are about to start anti-TNFs because of small bowel inflammation, and repeat it after 20-28 weeks of treatment. Patients will also have the blood and stool tests and, by recording what happens to patients, we will compare all three tests to see which best predicts treatment response at one year. We will estimate to what extent mMRI could help patients avoid unnecessary treatment. Simultaneously, we will investigate if patient symptoms are related to disrupted patterns of bowel motion, and if this is caused by higher levels of chemicals in the blood that control the immune system (called cytokines) or hormones released by the inflamed bowel. Finally, we will investigate if body shape changes (loss of muscle) are associated with poorer response rates. In preparation for this research we have assembled a team who are experts in MRI, managing Crohn’s disease, running clinical trials, and statistics. Our research team includes a patient representative who is advising on all aspects of the study design and conduct. The research will take 4 years; after this, we will present our findings to the NIHR, to the medical community via conferences and in journal articles, and to patients and the public via patient associations and our patient advisory group. We hope mMRI will ultimately allow us to direct patients sooner to appropriate treatment, thereby (a) improving outcomes (b) reducing patients’ uncertainty and (c) reducing overall healthcare costs.

Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: ORAL AND GASTROINTESTINAL