Title: Diagnostic accuracy for the extent and activity of newly diagnosed and relapsed Crohn’s disease: Multicentre prospective comparison of magnetic resonance imaging and small bowel ultrasound
Funder: Department of Health and Social Care

Abstract: DESIGN: Multicenter prospective cohort study. SETTING: 7 secondary care hospitals. TARGET POPULATION: 1) New patients with a confirmed diagnosis of Crohn’s disease. 2) Known diagnosis and clinically suspected relapse. HEALTH TECHNOLOGIES BEING ASSESSED: 1) enteric MRI (magnetic resonance imaging)- MR technique applied after bowel distension with luminal contrast 2) enteric US (Ultrasound)- technique utilising high resolution probes to visualise the bowel. Alternative technologies: endoscopy (ileo-colonoscopy-IC and capsule endoscopy-CE)-good diagnostic accuracy but invasive, relatively high cost/complexity and limited due to inaccessibility of the whole small bowel. Conventional barium fluoroscopic (BF) techniques and CT scanning are currently the mainstay of whole small bowel investigation in the NHS, but impart ionising radiation. MEASUREMENT OF COSTS AND OUTCOMES: A key early milestone will be the design of practicable MRI and US acquisition, quality assurance and analysis protocols generalisable to the NHS. PRIMARY OUTCOME MEASURE: comparative diagnostic accuracy of MRI and US for the extent (presence and segmental location) of crohn’s disease against a composite standard of reference considering IC, contemporaneous imaging, CE (if performed), clinical, and histopathological data after 6 months patient follow up. Recruited new patients will have undergone IC as part of routine clinical practice-IC has high diagnostic accuracy for colonic and terminal ileal (TI) disease and is the most robust standard of reference. Standards of reference for the proximal small bowel are less defined-BF and CT have finite accuracy and impart ionising radiation. Small bowel CE is sensitive but lower specificity, expensive with limited access, and not without complications including retention. CE use in established crohns is not yet fully defined. To strengthen the standard of reference, patients with discrepant small bowel imaging test results for the presence of proximal disease, or incomplete IC will undergo CE or additional small bowel imaging test(s). Secondary Outcomes: (i) Disease activity classification by MRI and US compared to a composite clinical reference (based on endoscopy, Harvey Bradshaw index, CRP, stool calprotectin and changes thereof in response to therapy). (ii) Comparative influence of MRI and US on clinician diagnostic confidence and patient management-a validated proforma will be completed by clinicians after each imaging test (iv) Cost and cost-effectiveness from the perspective of the NHS and personal social services using 6 month (within study) and lifetime time horizons, including analysis of the incremental cost per QALY gained of MRI and US vs. standard diagnostic investigations. SAMPLE SIZE: 334 (allowing for 10% loss to follow up); 167 patients with a newly confirmed diagnosis and 167 patients with clinically suspected disease relapse. Sample size gives 90% power to detect an 10% difference in diagnostic accuracy between MRI and USS for the presence and extent of disease. Secondary powered (80%) to detect a 13% difference in patient management (for each recruited cohort) and 10% difference in classification of per patient disease activity. PROJECT TIMETABLE: Month 1-6 : REC & R&D permissions. Staff recruitment, contract signing, imaging and QA protocol consensus meetings. Month 7 (official start date) to 36: patient recruitment. Reference standard consensus meetings (every 6 months). Recruitment rate informed by audit of activities at recruitment sites: each site recruits 9-10 new diagnosis and 9-10 relapse patients per year. Month 37 to 42-6 months follow up of last recruited cohort. Final reference standard consensus meeting. Month 43 to 48 Data analysis & write up. PROJECT TEAM: a multi-disciplinary team of radiologists (active members of the BSGAR including the current research officer), Gastroenterologists, surgeons (members of the IBD section of the British Society of Gastroenterologists), pathologists, trialist, health economist and medical statisticians (with extensive experience of studies of diagnostic imaging tests)

Lay abstract: BACKGROUND Crohn’s disease is a lifelong inflammatory bowel condition, predominately affecting the young. The colon (large bowel) and small bowel are commonly affected and radiological imaging is pivotal. Several small bowel imaging tests exist – conventional tests include barium follow through (BF) and computerised tomography (CT); newer technologies include Magnetic resonance imaging (MRI), ultrasound (US) and capsule endoscopy (CE). Both BF and CT impart significant x-ray radiation, which is concerning since patients often require repeated imaging. Our recent NHS audit shows that MRI and US are disseminating and the HTA wish to know how they compare. We will recruit patients just diagnosed (or are very likely to have Crohn,s disease based on colonoscopy) (167 patients), as well as those with suspected relapse (167 patients), invite them to undergo MRI and US (performed by two independent radiologists) and compare the diagnostic accuracy for the presence and extent of crohn’s disease. Unfortunately there is no single reference standard against which we can judge accuracy. The best way to assess the large bowel and last section of the small bowel (terminal ileum) is ileo-colonoscopy (IC) (endoscopic camera inserted via the back passage). All new diagnosis patients and some of the relapse patients will undergo IC as part of their usual clinical care. The reference standard for the remaining proximal bowel is less clear cut-it simply cannot be reached by IC. Radiological tests are the most widely used reference but we must be very careful not to bias our results by using MR and US alone to “judge” themselves. BF and CT are widely used and useful, but they are not perfect and exposure patients to additional tests using X-Rays. Another way to look at the proximal bowel is using a swallowed pill camera (CE). This is quite complicated and expensive, and can get stuck, precipitating an operation and so we don’t want to use it in all patients. However we will invite patients to have another test of their small bowel such as BF, CT or CE (which ever their doctor prefers) as a check if MRI and US disagree whether there is proximal disease present. The HTA is also interested in how good the tests are at assessing disease activity (how inflamed the bowel is). Again, there is no one single reference test for this-doctors use a combination of patient questionnaires, blood tests and chemicals in stool samples. We will combine these existing standards but include how patients respond to treatment to assign disease activity. Our final reference standard will be derived by multi disciplinary committee who will consider all endoscopic, imaging, clinical and pathological data after 6 months of patient follow up. This is standard methodology in Crohn’s disease trials. We will also ask doctors looking after the patients to mark their management based on the US and the MRI findings independent of each other. This data, along with the 6 month patient follow up will allow our health economist to model the cost effectiveness of MRI, US and conventional tests in each patient cohort. HOW AND WHERE THE RESEARCH WILL BE CARRIED OUT. We will use a network of 7 UK recruitment sites affiliated to the British Society of Gastrointestinal and Abdominal Radiology. Such an approach ensures we will have access to relevant expertise amongst radiologists, and by using a number of sites we can assess how generalisable the tests are across the NHS. We have calculated that each site will need to recruit 10 new diagnosis and 10 relapse patients a year, which based on audited activity data is highly achievable. Because it is important that those interpreting MR and US are not aware of the results of other tests, we will store the images away from the hospital, control the information available and ensure both tests are performed by separate radiologists. If MRI or US was done prior to recruitment, the images will be reviewed (MRI) or the test repeated (US) by radiologists unaware of any clinical data. We will favour recruitment sites who still use BF and CT as their first line small bowel investigations to enrich the final reference standard (by having available another whole small bowel test other than MRI or US), and to provide comparative data on “conventional” imaging for our later analysis. OUTCOMES :1) diagnostic accuracy of MRI and US for the presence, extent and activity of crohn’s disease against our composite reference standard; 2) the impact of the tests on patient management in comparison to each other and to conventional imaging; 3) cost-effectiveness of the tests; 4) how MRI and US can most effectively be implemented. In addition we plan to look at novel imaging sequences and the affect of radiologist confidence on their diagnostic performance. ETHICAL ISSUES: Only in the small number of patients in whom MR and US disagree about the presence of proximal disease will we perform additional tests such as BF, CT or CE.

Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES;6.3 MEDICAL DEVICES
Health categories: ORAL AND GASTROINTESTINAL