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

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


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.

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