Lancet Gastroenterol Hepatol. 2024 Feb 21:S2468-1253(24)00034-7.doi: 10.1016/S2468-1253(24)00034-7. Online ahead of print.

Nurulamin M Noor ¹, James C Lee ², Simon Bond ³, Francis Dowling ⁴, Biljana Brezina ⁵, Kamal V Patel ⁶, Tariq Ahmad ⁷, Paul J Banim ⁸, James W Berrill ⁹, Rachel Cooney ¹⁰, Juan De La Revilla Negro ⁵, Shanika de Silva ¹¹, Shahida Din ¹², Dharmaraj Durai ¹³, John N Gordon ¹⁴, Peter M Irving ¹⁵, Matthew Johnson ¹⁶, Alexandra J Kent ¹⁷, Klaartje B Kok ¹⁸, Gordon W Moran ¹⁹, Craig Mowat ²⁰, Pritash Patel ²¹, Chris S Probert ²², Tim Raine ⁵, Rebecca Saich ²³, Abigail Seward ⁶, Dan Sharpstone ²⁴, Melissa A Smith ²⁵, Sreedhar Subramanian ⁵, Sara S Upponi ²⁶, Alan Wiles ²⁷, Horace R T Williams ²⁸, Gijs R van den Brink ²⁹, Séverine Vermeire ³⁰, Vipul Jairath ³¹, Geert R D'Haens ³², Eoin F McKinney ³³, Paul A Lyons ³³, James O Lindsay ¹⁸, Nicholas A Kennedy ⁷, Kenneth G C Smith ³³, Miles Parkes ³⁴; PROFILE Study Group

Author information

¹Department of Gastroenterology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK; Department of Medicine, University of Cambridge School of Clinical Medicine, Cambridge, UK.

²Genetic Mechanisms of Disease Laboratory, The Francis Crick Institute, London, UK; Department of Gastroenterology, UCL Institute of Liver and Digestive Diseases, Royal Free Hospital, London, UK.

³Cambridge Clinical Trials Unit, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK; Medical Research Council Biostatistics Unit, University of Cambridge, Cambridge, UK.

⁴Cambridge Clinical Trials Unit, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.

⁵Department of Gastroenterology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.

⁶Department of Gastroenterology, St George's University Hospitals NHS Foundation Trust, London, UK.

⁷Department of Gastroenterology, Royal Devon University Healthcare NHS Foundation Trust, Exeter, UK; Exeter Inflammatory Bowel Disease and Pharmacogenetics Research Group, University of Exeter, Exeter, UK.

⁸Department of Gastroenterology, James Paget University Hospital, Great Yarmouth, UK.

⁹Department of Gastroenterology, Royal Glamorgan Hospital, Llantrisant, UK.

¹⁰GI Unit, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK.

¹¹Department of Gastroenterology, The Dudley Group NHS Foundation Trust, Dudley, UK.

¹²Edinburgh IBD Unit, Western General Hospital, Edinburgh, UK.

¹³Department of Gastroenterology, Cardiff and Vale University Health Board, University Hospital of Wales, Cardiff, UK.

¹⁴Department of Gastroenterology, Royal Hampshire County Hospital, Winchester, UK.

¹⁵Department of Gastroenterology, Guy's and St Thomas' NHS Foundation Trust, London, UK.

¹⁶Gastroenterology Department, Luton and Dunstable University Hospital, Luton, UK.

¹⁷Department of Gastroenterology, King's College Hospital NHS Foundation Trust, London, UK.

¹⁸Department of Gastroenterology, Royal London Hospital, Barts Health NHS Trust, London, UK.

¹⁹National Institute of Health Research Nottingham Biomedical Research Centre, University of Nottingham and Nottingham University Hospitals, Nottingham, UK.

²⁰Department of Gastroenterology, Ninewells Hospital, Dundee, Scotland, UK.

²¹Department of Gastroenterology, Epsom and St Helier University Hospitals, Carshalton, UK.

²²Department of Gastroenterology, Liverpool University Hospitals NHS Foundation Trust, Liverpool, UK; Department of Molecular and Clinical Cancer Medicine, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, UK.

²³Department of Gastroenterology, Basingstoke and North Hampshire Hospital, Basingstoke, UK.

²⁴Department of Gastroenterology, West Suffolk NHS Foundation Trust, Bury St Edmunds, UK.

²⁵Department of Gastroenterology, University Hospitals Sussex NHS Foundation Trust, Brighton, UK.

²⁶Department of Radiology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.

²⁷Department of Gastroenterology, The Queen Elizabeth Hospital King's Lynn NHS Trust, King's Lynn, UK.

²⁸Department of Gastroenterology, Imperial College Healthcare NHS Trust, St Mary's Hospital, London, UK.

²⁹Roche Innovation Center Basel, Roche, Basel, Basel-Stadt, Switzerland.

³⁰Department of Gastroenterology and Hepatology, Department of Chronic Diseases and Metabolism, University Hospitals Leuven, KU Leuven, Leuven, Belgium.

³¹Division of Gastroenterology, Department of Medicine, Western University, London, Ontario, Canada.

³²Department of Gastroenterology, Amsterdam University Medical Center, Amsterdam, Netherlands.

³³Department of Medicine, University of Cambridge School of Clinical Medicine, Cambridge, UK; PredictImmune Ltd, Babraham Research Campus, Cambridge, UK; Cambridge Institute of Therapeutic Immunology and Infectious Disease, Jeffrey Cheah Biomedical Centre, Cambridge, UK.

³⁴Department of Gastroenterology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK; Department of Medicine, University of Cambridge School of Clinical Medicine, Cambridge, UK. Electronic address: mp372@cam.ac.uk.

Abstract

Background: Management 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.

Methods: PROFILE (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).

Findings: Between 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).

Interpretation: Top-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.

Funding: Wellcome and PredictImmune Ltd.