Nurulamin M Noor*[1] Miles Parkes*[1] Francis Dowling[2] Leisha O’Brien[2] Biljana Brezina[1] Juan De La Revilla Negro[1] Simon Bond[2,3] Lynne Whitehead[4] Sara Upponi[5] Kamal Patel[6] Abigail Seward[6] Klaartje Kok[7] Dominic Studdart[7] John Gordon[8] Emma Levell[8] Paul A Lyons[1,9] Eoin F McKinney[1,9] Kenneth GC Smith[1,9] James C Lee[1] PROFILE Trial Investigators.

Affiliates

Department of Medicine, University of Cambridge School of Clinical Medicine, Addenbrooke's Hospital, Cambridge, UK.[1] Cambridge Clinical Trials Unit, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.[2] Medical Research Council Biostatistics Unit, University of Cambridge, Cambridge, UK.[3] Clinical Trials Pharmacy, Addenbrooke's Hospital, Cambridge, UK.[4] Department of Radiology, Addenbrooke's Hospital, Cambridge, UK.[5] Department of Gastroenterology, St George’s Hospital, London, UK.[6] Department of Gastroenterology, Barts and the Royal London Hospital, London, UK.[7] Department of Gastroenterology, Royal Hampshire County Hospital, UK.[8] PredictImmune Ltd, Babraham Research Campus, Cambridge, UK.[9]

Abstract

Background:

The course of Crohn’s disease (CD) and ulcerative colitis (UC) varies substantially between individuals, but reliable prognostic markers do not exist. This hinders disease management because patients with aggressive disease are undertreated by conventional ’step-up’ therapy while those with more indolent disease would be exposed to unnecessary treatment-related toxicity if a more aggressive ’top-down’ approach was indiscriminately used. We have previously developed and validated a prognostic transcriptional biomarker, which is a 17-gene qPCR assay that is reliably able to predict clinical outcomes for patients with both CD and UC. The PROFILE trial will assess whether this biomarker can improve clinical outcomes by appropriately matching therapy for patients with their predicted disease course.

Methods:

This biomarker-stratified trial will compare the relative efficacy of ’top-down’ and ’accelerated step-up’ therapy between biomarker-defined subgroups of patients with newly diagnosed CD. 400 participants from ~50 UK centres will be recruited. Subjects within each biomarker subgroup (IBDhi or IBDlo) will be randomised (1:1) to receive one of the treatment strategies until trial completion (48 weeks). The primary outcome is the incidence of sustained surgery and steroid-free remission from the completion of induction treatment through to week 48. Secondary outcomes include mucosal healing, quality-of-life assessments and surrogate measures of disease burden including number of flares, cumulative steroid exposure, number of hospital admissions and number of Crohn’s-related surgeries. Analyses will compare the relative benefit of the treatment strategies in each biomarker-defined subgroup, powered as an interaction analysis.

Results:

At the time of writing, 44 sites have been opened around the UK and 183 participants randomised. Recruitment is ongoing and the most up-to-date recruitment data will be available for presentation at the IBD Nordic meeting.

Conclusions:

We have developed, optimised and validated a whole-blood qPCR classifier that is able to predict disease course from diagnosis in patients with IBD. This classifier is currently under investigation in the PROFILE trial. If clinical utility of a stratified treatment approach is demonstrated, this would represent a major step towards personalised therapy in Inflammatory Bowel Disease.