OP01 PROFILE: a multi-centre, randomised, open-label, biomarker-stratified clinical trial of treatment strategies for patients with newly-diagnosed Crohn’s disease
Authors: Noor N , Lee J , Bond S , Dowling F , Brezina B , Patel K , Ahmad T , Banim P , Cooney R , De La Revilla Negro J , de Silva S , Din S , Durai D , Gordon J , Irving P , Johnson M , Kent A , Kok K B , Moran G , Patel P , Probert C , Raine T , Saich R , Seward A , Sharpstone D , Smith M , Subramanian S , Upponi S , Wiles A , van den Brink G , Vermeire S , Jairath V , D'Haens G , McKinney E , Lyons P , Lindsay J , Kennedy N , Smith K , Parkes M 
Published: January 2024

Abstract

Background
Clinical outcomes differ substantially between patients with Crohn’s disease and there is variability in how newly-diagnosed patients are managed. Recent interest has focused on developing biomarkers to predict outcomes and guide therapy. PROFILE was designed to evaluate the clinical utility of a blood-based prognostic biomarker in patients randomised to "top-down" or "accelerated step-up" treatment strategies for newly-diagnosed Crohn’s disease.

Methods
PROFILE (PRedicting Outcomes For Crohn's dIsease using a moLecular biomarker, ISRCTN 11808228) was an open-label, biomarker-stratified, randomised controlled trial. It enrolled adults with newly-diagnosed active Crohn’s disease (Harvey Bradshaw Index ≥7 and C-reactive protein &gt; upper limit of normal or faecal calprotectin ≥200 ug/g, plus endoscopic evidence of active inflammation) in 40 UK hospitals. Following biomarker testing patients were randomised to "top-down" (infliximab/immunomodulator) or "accelerated step-up" (conventional) treatment stratified by: biomarker subgroup (termed IBDhi/IBDlo), endoscopic inflammation (mild/mod/severe) and extent (colonic/other). The primary endpoint was sustained steroid and surgery-free remission to week 48. The key secondary endpoint was endoscopic remission (absence of ulcers). The full analysis population (equivalent to ‘intention-to-treat’) was analysed.

Results
386 patients were randomised from 29 December 2017 to 5 January 2022. Median time from diagnosis to trial enrollment was 12 days (0-191). Primary outcome data were available for 379 eligible participants. Sustained steroid and surgery-free remission was significantly more frequent in "top-down" (79% of 189 patients) compared to the "accelerated step-up" arm (15% of 190 patients), with an absolute difference of 64% (95% CI=57-72%, p&lt;0.001). There was no biomarker-treatment interaction effect (absolute difference 1%, 95% CI=-14 - +14%, p=0.944). Endoscopic remission at week 48 was greater in "top-down" vs "accelerated step-up" (67% vs 44%, 95% CI=11-36%, p&lt;0.001), with no biomarker-treatment interaction. Incidence of adverse events (including disease flares) and serious adverse events was lower in "top-down" vs "accelerated step-up" (168 vs 315; 16 vs 25 respectively), with fewer complications requiring abdominal surgery (1 vs 10, odds ratio=0.095, 95% CI=0.001-0.505) and no increase in infections.

Conclusion
"Top-down" treatment with combination infliximab/immunomodulator achieved substantially higher sustained steroid and surgery-free remission compared to "accelerated step-up". The biomarker did not show clinical utility in PROFILE. "Top-down" should now be considered standard-of-care for patients with newly-diagnosed active Crohn’s disease.