A biomarker-stratified comparison of top-down versus accelerated step-up treatment strategies for patients with newly diagnosed Crohn's disease (PROFILE): a multicentre, open-label randomised controlled trial
Authors: Nurulamin M Noor, James C Lee, Simon Bond, Francis Dowling, Biljana Brezina, Kamal V Patel, Tariq Ahmad, Paul J Banim, James W Berrill, Rachel Cooney, Juan De La Revilla Negro, Shanika de Silva, Shahida Din, Dharmaraj Durai, John N Gordon, Peter M Irving, Matthew Johnson, Alexandra J Kent, Klaartje B Kok, Gordon W Moran, Craig Mowat, Pritash Patel, Chris S Probert, Tim Raine, Rebecca Saich, Abigail Seward, Dan Sharpstone, Melissa A Smith, Sreedhar Subramanian, Sara S Upponi, Alan Wiles, Horace R T Williams, Gijs R van den Brink, Séverine Vermeire, Vipul Jairath, Geert R D'Haens, Eoin F McKinney, Paul A Lyons, James O Lindsay, Nicholas A Kennedy, Kenneth G C Smith, Miles Parkes, Nurulamin Noor, James Lee, Simon Bond, Francis Dowling, Biljana Brezina, Kamal Patel, Tariq Ahmad, Paul Banim, James Berrill, Rachel Cooney, Juan De La Revilla Negro, Shanika de Silva, Shahida Din, Dharmaraj Durai, John Gordon, Peter Irving, Matthew Johnson, Alexandra Kent, Klaartje Bel Kok, Gordon Moran, Craig Mowat, Pritash Patel, Chris Probert, Tim Raine, Rebecca Saich, Abigail Seward, Dan Sharpstone, Melissa Smith, Sreedhar Subramanian, Sara Upponi, Alan Wiles, Horace Williams, Gijs van Den Brink, Severine Vermeire, Vipul Jairath, Geert D'Haens, Eoin McKinney, Paul Lyons, James Lindsay, Nicholas Kennedy, Kenneth Smith, Miles Parkes, Clare Allcock, Suhaylah Bhatti, Jonathan Blackwell, Robert Boulton-Jones, Matthew Brookes, Rhys Butcher, Jeffrey Butterworth, Karlena Champion, Rakesh Chaudhary, Andy Cole, Lauranne Derikx, Anjan Dhar, Mary Flowerdew, Rishi Goel, Ailsa Hart, Rory Hughes, Babur Javaid, Paul Knight, Jacinta Lee, Charlie Lees, Emma Levell, Andy Li, Charles Murray, Leisha O'Brien, Gareth Parkes, Richard Pollok, Sam Powles, Arvind Ramdas, Philip Smith, Richard Ally Speight, Simon Travis, Sean Weaver, Emma Wesley
Journal: The Lancet. Gastroenterology & hepatology (2024)

BackgroundManagement strategies and clinical outcomes vary substantially in patients newly diagnosed with Crohn's disease. We evaluated the use of a putative prognostic biomarker to guide therapy by assessing outcomes in patients randomised to either top-down (ie, early combined immunosuppression with infliximab and immunomodulator) or accelerated step-up (conventional) treatment strategies.MethodsPROFILE (PRedicting Outcomes For Crohn's disease using a moLecular biomarker) was a multicentre, open-label, biomarker-stratified, randomised controlled trial that enrolled adults with newly diagnosed active Crohn's disease (Harvey-Bradshaw Index ≥7, either elevated C-reactive protein or faecal calprotectin or both, and endoscopic evidence of active inflammation). Potential participants had blood drawn to be tested for a prognostic biomarker derived from T-cell transcriptional signatures (PredictSURE-IBD assay). Following testing, patients were randomly assigned, via a secure online platform, to top-down or accelerated step-up treatment stratified by biomarker subgroup (IBDhi or IBDlo), endoscopic inflammation (mild, moderate, or severe), and extent (colonic or other). Blinding to biomarker status was maintained throughout the trial. The primary endpoint was sustained steroid-free and surgery-free remission to week 48. Remission was defined by a composite of symptoms and inflammatory markers at all visits. Flare required active symptoms (HBI ≥5) plus raised inflammatory markers (CRP >upper limit of normal or faecal calprotectin ≥200 μg/g, or both), while remission was the converse—ie, quiescent symptoms (HBI <5) or resolved inflammatory markers (both CRP ≤ the upper limit of normal and calprotectin <200 μg/g) or both. Analyses were done in the full analysis (intention-to-treat) population. The trial has completed and is registered (ISRCTN11808228).FindingsBetween Dec 29, 2017, and Jan 5, 2022, 386 patients (mean age 33·6 years [SD 13·2]; 179 [46%] female, 207 [54%] male) were randomised: 193 to the top-down group and 193 to the accelerated step-up group. Median time from diagnosis to trial enrolment was 12 days (range 0–191). Primary outcome data were available for 379 participants (189 in the top-down group; 190 in the accelerated step-up group). There was no biomarker–treatment interaction effect (absolute difference 1 percentage points, 95% CI –15 to 15; p=0·944). Sustained steroid-free and surgery-free remission was significantly more frequent in the top-down group than in the accelerated step-up group (149 [79%] of 189 patients vs 29 [15%] of 190 patients, absolute difference 64 percentage points, 95% CI 57 to 72; p<0·0001). There were fewer adverse events (including disease flares) and serious adverse events in the top-down group than in the accelerated step-up group (adverse events: 168 vs 315; serious adverse events: 15 vs 42), with fewer complications requiring abdominal surgery (one vs ten) and no difference in serious infections (three vs eight).InterpretationTop-down treatment with combination infliximab plus immunomodulator achieved substantially better outcomes at 1 year than accelerated step-up treatment. The biomarker did not show clinical utility. Top-down treatment should be considered standard of care for patients with newly diagnosed active Crohn's disease.FundingWellcome and PredictImmune Ltd.