Title: METRIC-EF: Magnetic Resonance Enterography and Small Bowel Ultrasound as predictors of disabling disease in newly-diagnosed Crohn’s disease
Funder: Department of Health and Social Care

Abstract: DESIGN: Extended follow-up of METRIC (HTA 11/23) prospective cohort study. Additional 40 patient retrospective cohort. Average 5yr f/u (min=4yrs). Development & internal validation of a multivariable model to improve prediction of disabling CD by incorporating MRE features with existing clinical predictors SETTING: 8 NHS hospitals LITERATURE: #1 MRE: MRE has high accuracy for diagnosis & activity assessment[26]. Bowel damage measured by MRE may be associated with poorer outcomes[45]. #2 Predicting severe CD: Subject of current HTA call 14/210. Recent meta-analysis[37], narrative review & applicant scoping review do not identify any primary evidence using MRE to predict long-term CD outcome. TARGET POPULATION: Newly diagnosed CD INCLUSIONS: Patients aged 16+years & newly diagnosed CD. All undergo MRE within 3 months of diagnosis. Prospective group recruited via METRIC. Retrospective cohort from sites using MRE as routine for new CD diagnosis. HEALTH TECHNOLOGIES: MRE as part of a multivariable model to predict disabling CD. ENDPOINT DEFINITION: Consensus panel categorisation of patient outcome (disabling vs non disabling) after mean 5yr f/u (range: 4 to 6.8 yrs). Definition of disabling CD based on Beaugerie[7]). Other definitions of severe disease (Liege criteria, Montreal classification) collected[13,19]. PRIMARY OUTCOME: Comparative predictive ability of prognostic models incorporating current predictors with & without MRE to predict disabling CD. COSTS: MRE health economic analysis is incorporated into METRIC. Additional estimation of healthcare usage & associated costs during mean 5yr f/u. Analysis of factors driving higher healthcare costs. SAMPLE SIZE/ANALYSIS: 167 patient METRIC cohort with additional 40 patient retrospective cohort. Sample size conserved by pre-specifying existing clinical predictors using the outputs of the HTA systematic review 14/210/07. We will add MRE via 1) severity scores (MEGS, MaRIA & Lemann indices) and 2) using principal components analysis to condense MRI characteristics. 5yr event rate (accounting for attrition as per HTA feedback) = 45-56% i.e. 98-116 events; an acceptable sample size[14] for models including pre-specified known predictors[10]. Separate prognostic models (i.e. with and without MRE) compared for statistical significance of MRE as a predictor. Time-to-event survival analysis increases power. Additional descriptive analysis using other definitions of severe CD. CARE PATHWAYS: Standard care pathways kept intact. Ethical permission to access healthcare records for 4yr min, 6.8yrs max. No additional interventions. MRE acquired as part of METRIC or standard care (retrospective group) TIMETABLES: METRIC recruitment started 1.12.13 & completes 30.9.16. New proposal extends follow-up to min. 4 yrs; completion=30.9.20. 6 months data analysis, model development & internal validation, report preparation/submission. End date 31.3.21. TEAM EXPERTISE: ST, SH are NIHR senior investigators. Proven track-record in trials of high technology imaging platforms (e.g. METRIC HTA 11/23/01, SIGGAR HTA 02/02/01) and prognostic modelling with imaging (e.g. PROSPeCT, HTA 09/29/49). SM is member of PROBAST[58]. Clinical content experts include president of ECCO & research-active local IBD leads. Continuity of trial management & patient involvement assured via METRIC collaborations DISSEMINATION: Peer-reviewed publications; conferences; to patients via PPI links

Lay abstract: Crohn’s disease (CD) is a painful, debilitating bowel condition that usually affects young adults. The cause is unknown, but it leads to symptoms because of bowel inflammation (painful ulcers & swelling). It can be mild and require little treatment, or very severe ("disabling"), requiring powerful drugs or surgery. It is important to treat patients with disabling disease as early as possible, because this improves long term health. It is not possible to give the most powerful drugs to all patients, because they have side-effects & risks that can be serious. Patients and doctors need a reliable way to predict who will develop disabling CD. This way, treatment can be given to those who need it, and patients who do not need such powerful drugs can avoid their side-effects. This may also save money for the NHS. We are currently running a HTA-funded study (called METRIC) to test the accuracy of a scan of the bowel called magnetic resonance enterography (MRE) when diagnosing CD. METRIC will include 167 patients just diagnosed with CD and determine if MRE or a different kind of scan (ultrasound) are better for diagnosis. We want to extend this work and determine if MRE scans can be used not only to diagnose CD, but also to predict who will get disabling disease in the future. We believe this is possible, because MRE is very accurate in CD, and other researchers have done a small study suggesting that it can predict who will need surgery. However, to date there are no long-term studies comparing MRE findings at the time of diagnosis with long term health in patients, so the idea is unproven. Because METRIC has already identified patients & arranged for them to have MRE scans, there is an excellent opportunity to investigate if MRE abnormalities can predict health 5 years later. The patients have already been scanned, so there is little additional patient inconvenience - all we need to do is look at their medical records. To make sure we have enough patients in the study to give meaningful answers, we will also study 40 more patients who have had MRE scans as part of normal clinical care when they were diagnosed. To do this, we will monitor patients for a longer period than originally planned in our METRIC study; currently, it is only 6 months but we will ask for ethical & patient permission to extend this to an average of 5 years. We will use medical records to find out how many patients develop severe (disabling) CD during this time. There are already some patient factors (e.g. young age, cigarette smoking) that we know are associated with more serious CD, so we need to know what the MRE scan can add. To test this, we will develop a statistical model that combines all of the known factors, and then tests if the addition of MRE helps make better predictions about future health. If the prediction model has promise, then we will recommend that it is tested in a separate group of patients, to prove that it works reliably for most patients with CD. We have gathered experts in Crohn’s disease, MRI, statistics, trial & data management, and patient representatives from Crohn’s & Colitis UK. We intend to use existing teams from the METRIC study, because they are already working effectively. The whole research project will take an additional 4 years; after this, we will report results to the HTA, present our findings at conferences, explain them to patients via the Crohn’s and Colitis UK charity, and publish in medical journals.

Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: ORAL AND GASTROINTESTINAL