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

doi:10.1016/S2468-1253(24)00034-7

Randomized Controlled Trial

. 2024 May;9(5):415-427.

doi: 10.1016/S2468-1253(24)00034-7. Epub 2024 Feb 22.

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

Nurulamin M Noor¹, James C Lee², Simon Bond³, Francis Dowling⁴, Biljana Brezina⁵, Kamal V Patel⁶, Tariq Ahmad⁷, Paul J Banim⁸, James W Berrill⁹, Rachel Cooney¹⁰, Juan De La Revilla Negro⁵, Shanika de Silva¹¹, Shahida Din¹², Dharmaraj Durai¹³, John N Gordon¹⁴, Peter M Irving¹⁵, Matthew Johnson¹⁶, Alexandra J Kent¹⁷, Klaartje B Kok¹⁸, Gordon W Moran¹⁹, Craig Mowat²⁰, Pritash Patel²¹, Chris S Probert²², Tim Raine⁵, Rebecca Saich²³, Abigail Seward⁶, Dan Sharpstone²⁴, Melissa A Smith²⁵, Sreedhar Subramanian⁵, Sara S Upponi²⁶, Alan Wiles²⁷, Horace R T Williams²⁸, Gijs R van den Brink²⁹, Séverine Vermeire³⁰, Vipul Jairath³¹, Geert R D'Haens³², Eoin F McKinney³³, Paul A Lyons³³, James O Lindsay¹⁸, Nicholas A Kennedy⁷, Kenneth G C Smith³³, Miles Parkes³⁴; PROFILE Study Group

Collaborators, Affiliations

Collaborators

PROFILE Study Group:
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

Affiliations

¹ Department of Gastroenterology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK; Department of Medicine, University of Cambridge School of Clinical Medicine, Cambridge, UK.
² Genetic 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.
³ Cambridge Clinical Trials Unit, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK; Medical Research Council Biostatistics Unit, University of Cambridge, Cambridge, UK.
⁴ Cambridge Clinical Trials Unit, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.
⁵ Department of Gastroenterology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.
⁶ Department of Gastroenterology, St George's University Hospitals NHS Foundation Trust, London, UK.
⁷ Department of Gastroenterology, Royal Devon University Healthcare NHS Foundation Trust, Exeter, UK; Exeter Inflammatory Bowel Disease and Pharmacogenetics Research Group, University of Exeter, Exeter, UK.
⁸ Department of Gastroenterology, James Paget University Hospital, Great Yarmouth, UK.
⁹ Department of Gastroenterology, Royal Glamorgan Hospital, Llantrisant, UK.
¹⁰ GI Unit, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK.
¹¹ Department of Gastroenterology, The Dudley Group NHS Foundation Trust, Dudley, UK.
¹² Edinburgh IBD Unit, Western General Hospital, Edinburgh, UK.
¹³ Department of Gastroenterology, Cardiff and Vale University Health Board, University Hospital of Wales, Cardiff, UK.
¹⁴ Department of Gastroenterology, Royal Hampshire County Hospital, Winchester, UK.
¹⁵ Department of Gastroenterology, Guy's and St Thomas' NHS Foundation Trust, London, UK.
¹⁶ Gastroenterology Department, Luton and Dunstable University Hospital, Luton, UK.
¹⁷ Department of Gastroenterology, King's College Hospital NHS Foundation Trust, London, UK.
¹⁸ Department of Gastroenterology, Royal London Hospital, Barts Health NHS Trust, London, UK.
¹⁹ National Institute of Health Research Nottingham Biomedical Research Centre, University of Nottingham and Nottingham University Hospitals, Nottingham, UK.
²⁰ Department of Gastroenterology, Ninewells Hospital, Dundee, Scotland, UK.
²¹ Department of Gastroenterology, Epsom and St Helier University Hospitals, Carshalton, UK.
²² Department 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.
²³ Department of Gastroenterology, Basingstoke and North Hampshire Hospital, Basingstoke, UK.
²⁴ Department of Gastroenterology, West Suffolk NHS Foundation Trust, Bury St Edmunds, UK.
²⁵ Department of Gastroenterology, University Hospitals Sussex NHS Foundation Trust, Brighton, UK.
²⁶ Department of Radiology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.
²⁷ Department of Gastroenterology, The Queen Elizabeth Hospital King's Lynn NHS Trust, King's Lynn, UK.
²⁸ Department of Gastroenterology, Imperial College Healthcare NHS Trust, St Mary's Hospital, London, UK.
²⁹ Roche Innovation Center Basel, Roche, Basel, Basel-Stadt, Switzerland.
³⁰ Department of Gastroenterology and Hepatology, Department of Chronic Diseases and Metabolism, University Hospitals Leuven, KU Leuven, Leuven, Belgium.
³¹ Division of Gastroenterology, Department of Medicine, Western University, London, Ontario, Canada.
³² Department of Gastroenterology, Amsterdam University Medical Center, Amsterdam, Netherlands.
³³ Department 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.
³⁴ Department 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.

PMID: 38402895
PMCID: PMC11001594
DOI: 10.1016/S2468-1253(24)00034-7

Randomized Controlled Trial

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

Nurulamin M Noor et al. Lancet Gastroenterol Hepatol. 2024 May.

. 2024 May;9(5):415-427.

doi: 10.1016/S2468-1253(24)00034-7. Epub 2024 Feb 22.

Authors

Collaborators

PROFILE Study Group:
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

Affiliations

¹ Department of Gastroenterology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK; Department of Medicine, University of Cambridge School of Clinical Medicine, Cambridge, UK.
² Genetic 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.
³ Cambridge Clinical Trials Unit, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK; Medical Research Council Biostatistics Unit, University of Cambridge, Cambridge, UK.
⁴ Cambridge Clinical Trials Unit, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.
⁵ Department of Gastroenterology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.
⁶ Department of Gastroenterology, St George's University Hospitals NHS Foundation Trust, London, UK.
⁷ Department of Gastroenterology, Royal Devon University Healthcare NHS Foundation Trust, Exeter, UK; Exeter Inflammatory Bowel Disease and Pharmacogenetics Research Group, University of Exeter, Exeter, UK.
⁸ Department of Gastroenterology, James Paget University Hospital, Great Yarmouth, UK.
⁹ Department of Gastroenterology, Royal Glamorgan Hospital, Llantrisant, UK.
¹⁰ GI Unit, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK.
¹¹ Department of Gastroenterology, The Dudley Group NHS Foundation Trust, Dudley, UK.
¹² Edinburgh IBD Unit, Western General Hospital, Edinburgh, UK.
¹³ Department of Gastroenterology, Cardiff and Vale University Health Board, University Hospital of Wales, Cardiff, UK.
¹⁴ Department of Gastroenterology, Royal Hampshire County Hospital, Winchester, UK.
¹⁵ Department of Gastroenterology, Guy's and St Thomas' NHS Foundation Trust, London, UK.
¹⁶ Gastroenterology Department, Luton and Dunstable University Hospital, Luton, UK.
¹⁷ Department of Gastroenterology, King's College Hospital NHS Foundation Trust, London, UK.
¹⁸ Department of Gastroenterology, Royal London Hospital, Barts Health NHS Trust, London, UK.
¹⁹ National Institute of Health Research Nottingham Biomedical Research Centre, University of Nottingham and Nottingham University Hospitals, Nottingham, UK.
²⁰ Department of Gastroenterology, Ninewells Hospital, Dundee, Scotland, UK.
²¹ Department of Gastroenterology, Epsom and St Helier University Hospitals, Carshalton, UK.
²² Department 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.
²³ Department of Gastroenterology, Basingstoke and North Hampshire Hospital, Basingstoke, UK.
²⁴ Department of Gastroenterology, West Suffolk NHS Foundation Trust, Bury St Edmunds, UK.
²⁵ Department of Gastroenterology, University Hospitals Sussex NHS Foundation Trust, Brighton, UK.
²⁶ Department of Radiology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.
²⁷ Department of Gastroenterology, The Queen Elizabeth Hospital King's Lynn NHS Trust, King's Lynn, UK.
²⁸ Department of Gastroenterology, Imperial College Healthcare NHS Trust, St Mary's Hospital, London, UK.
²⁹ Roche Innovation Center Basel, Roche, Basel, Basel-Stadt, Switzerland.
³⁰ Department of Gastroenterology and Hepatology, Department of Chronic Diseases and Metabolism, University Hospitals Leuven, KU Leuven, Leuven, Belgium.
³¹ Division of Gastroenterology, Department of Medicine, Western University, London, Ontario, Canada.
³² Department of Gastroenterology, Amsterdam University Medical Center, Amsterdam, Netherlands.
³³ Department 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.
³⁴ Department 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.

PMID: 38402895
PMCID: PMC11001594
DOI: 10.1016/S2468-1253(24)00034-7

Erratum in

Correction to Lancet Gastroenterol Hepatol 2024; 9: 415-27.
[No authors listed] [No authors listed] Lancet Gastroenterol Hepatol. 2025 Aug;10(8):e10. doi: 10.1016/S2468-1253(25)00203-1. Lancet Gastroenterol Hepatol. 2025. PMID: 40651481 No abstract available.

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.

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Conflict of interest statement

Declaration of interests NMN reports personal fees from Galapagos, Janssen, Lilly, SBK Healthcare, and Takeda outside the submitted work; and grants from Dr Falk, Pfizer, Pharmacosmos, and Tillotts Pharma outside the submitted work. JCL reports consultancy fees from AbbVie, AgPlus Diagnostics, PredictImmune, and C4X Discover outside the submitted work; and grants from GSK outside the submitted work. KVP reports personal fees from AbbVie, DrFalk, Galapagos, Janssen, PredictImmune, Pfizer, and Takeda outside the submitted work; grants from AbbVie, Celltrion, Dr Falk, Ferring, Janssen, Takeda, and Tillotts Pharma outside the submitted work; and fees from advisory board membership of AbbVie, Galapagos, Janssen, and Pfizer outside the submitted work. TA reports personal fees from Amgen, Celltrion, Janssen, Lilly, Pfizer, and Tillotts Pharma; and grants from Biogen, Celltrion, Galapagos, Nova Pharmaceuticals, Pfizer, Roche, and Takeda outside the submitted work. JWB reports personal fees from Janssen outside the submitted work. RC reports personal fees from AbbVie, Galapagos, and Lilly outside the submitted work, grants from Celltrion, Ferring, and Tillotts Pharma outside the submitted work; and fees from advisory board membership of AbbVie and Bristol Myers Squibb outside the submitted work. SD reports personal fees from AbbVie, Ferring, Janssen, and Takeda outside the submitted work; grants from AbbVie, Dr Falk, and Janssen, outside the submitted work; and fees from advisory board membership of AbbVie outside the submitted work. DD reports personal fees from Takeda outside the submitted work; and grants from AbbVie and Janssen outside the submitted work. PMI reports personal fees from AbbVie, Arena, Boehringer-Ingelheim, BMS, Celgene, Celltrion, Dr Falk, Galapagos, Genentech, Gilead, Hospira, Janssen, Lilly, MSD, Pfizer, Prometheus, Sandoz, Samsung Bioepis, Sapphire Medical, Takeda, Topivert, VH2, Vifor Pharma, and Warner Chilcott outside the submitted work; and grants from AbbVie and Takeda outside the submitted work. AJK reports personal fees from AbbVie, Galapagos, and Takeda outside the submitted work; grants from AbbVie, Janssen, and Tillotts Pharma outside the submitted work; and fees from advisory board membership of AbbVie and Janssen outside the submitted work. CM reports grants from Janssen outside the submitted work. CSP reports personal fees from Dr Falk outside the submitted work. TR reports personal fees from AbbVie, Arena, Aslan, AstraZeneca, Boehringer-Ingelheim, BMS, Eli Lilly, Ferring, Galapagos, Gilead, GSK, Heptares, LabGenius, Novartis, Numab, Janssen, Pfizer, Roche, Takeda, UCB, and XAP therapeutics outside the submitted work; grants from AbbVie outside the submitted work; and fees from data monitoring board membership of UCB outside the submitted work. SS reports personal fees from AbbVie, Celltrion, Dr Falk, Ipsen, Janssen, and Takeda outside the submitted work. HRTW reports fees from advisory board membership of Pfizer outside the submitted work. SV reports personal fees from AbbVie, Abivax, AbolerISPharma, AgomAb, Alimentiv (formerly Robarts Clinical Trials), Arena Pharmaceuticals, AstraZeneca, BMS, Boehringer Ingelheim, Celgene, Cytoki Pharma, Dr Falk Pharma, Ferring, Galapagos, Genentech-Roche, Gilead, GSK, Hospira, Imidomics, Janssen, J&J, Lilly, Materia Prima, Mestag Therapeutics, MiroBio, Morphic, MrMHealth, MSD, Mundipharma, Pfizer, Prodigest, Progenity, Prometheus, Surrozen, Takeda, Theravance, Tillotts Pharma, VectivBio, Ventyx, and Zealand Pharma outside the submitted work; and grants from AbbVie, Galapagos, J&J, Pfizer, and Takeda outside the submitted work. VJ reports personal fees from AbbVie, Alimentiv (formerly Robarts Clinical Trials), Arena Pharmaceuticals, Asahi Kasei Pharma, Asieris, AstraZeneca, Avoro Capital, BMS, Celltrion, Endpoint Health, Enthera, Ferring, Flagship Pioneering, Fresenius Kabi, Galapagos, Gilde Healthcare, GSK, Genentech, Gilead, Innomar, JAMP, Janssen, Lilly, Merck, Metacrine, Mylan, Pandion, Pendopharm, Pfizer, Protagonist, Prometheus, Reistone Biopharma, Roche, Roivant, Sandoz, SCOPE, Second Genome, Sorriso Pharmaceuticals, Takeda, Teva, Topivert, Ventyx, and Vividion outside the submitted work; and fees from advisory board membership of AbbVie, Alimentiv (formerly Robarts Clinical Trials), Arena Pharmaceuticals, Asahi Kasei Pharma, Asieris, AstraZeneca, BMS, Celltrion, Ferring, Flagship Pioneering, Fresenius Kabi, Galapagos, Gilde Healthcare, GSK, Genentech, Gilead, Innomar, JAMP, Janssen, Lilly, Merck, Metacran, Mylan, Pandion, Pendopharm, Pfizer, Protagonist, Prometheus, Reistone Biopharma, Roche, Sandoz, SCOPE, Second Genome, Sorriso Pharmaceuticals, Takeda, Teva, Topivert, Ventyx, and Vividion outside the submitted work. GRDH reports personal fees from AbbVie, Alimentiv, AstraZeneca, Immunic, J&J, Lilly, Pfizer, Takeda, Tillotts, and Ventyx outside the submitted work; grants from AbbVie, BMS, Lilly, Pfizer, and Takeda outside the submitted work; and fees from advisory board membership of AstraZeneca, Galapagos, and Seres Health outside the submitted work. EFM reports being a co-founder and receiving consultancy fees from PredictImmune; and holds PredictImmune stock or stock options. PAL reports being a co-founder and receiving consultancy fees from PredictImmune; and holds PredictImmune stock or stock options. JOL reports personal fees from AbbVie, Atlantic Healthcare, Bristol Meyer Squibb, Celgene, Celltrion, Engytix, Eli Lilly, Ferring, Galapagos, Gilead, GSK, Janssen, MSD, Norgine, Pfizer, Shire, and Takeda outside the submitted work; and grants from AbbVie, Ferring, Gilead, Takeda, and Shire outside the submitted work. NAK reports personal fees from Amgen, Bristol Myers Squibb, Celltrion, Falk, Galapagos, Janssen, Pfizer, Pharmacosmos, Takeda, and Tillotts Pharma outside the submitted work; and reports data monitoring board membership for the BEACON study outside the submitted work. KGCS reports being a co-founder and receiving consultancy fees from Predictimmune; consultancy fees from GSK outside the submitted work; and holds PredictImmune stock or stock options. MP reports personal fees from Janssen and Takeda outside the submitted work; and grants from AstraZeneca, Galapagos, Gilead, and Pfizer outside the submitted work. All other authors declare no competing interests.

Figures

**Figure 1**
Trial design (A) Trial design. (B) Trial visits and escalation summary.

**Figure 3**
Primary endpoint and key secondary endpoint (A) Sustained steroid-free and surgery-free remission until week 48 for treatment groups. (B) Sustained steroid-free and surgery-free remission until week 48 for biomarker–treatment subgroups. (C) Endoscopic remission (absence of ulceration) at week 48 for treatment groups. (D) Endoscopic remission (absence of ulceration) at week 48 for biomarker-treatment subgroups.

**Figure 4**
Kaplan-Meier analysis of time to flare, surgery, or both (A) Time to first event by treatment group with data censored at 12 months. (B) Time to first event by biomarker–treatment group with data censored at 12 months. (C) Time to second event by treatment group with data censored at 12 months. (D) Time to second event by biomarker–treatment group with data censored at 12 months. Numbers of patients at risk at 0 months may not match the total number of patients randomised to each group due to missing data.

See this image and copyright information in PMC

Comment in

Has the time come for a systematic top-down approach in Crohn's disease?
Fumery M, Buisson A. Fumery M, et al. Lancet Gastroenterol Hepatol. 2024 May;9(5):394-395. doi: 10.1016/S2468-1253(24)00073-6. Lancet Gastroenterol Hepatol. 2024. PMID: 38604192 No abstract available.
Treatment strategies and biomarkers in Crohn's disease: the PROFILE trial.
Bourgonje AR, Visschedijk MC, Festen EAM, Weersma RK, Dijkstra G. Bourgonje AR, et al. Lancet Gastroenterol Hepatol. 2024 Jul;9(7):590-591. doi: 10.1016/S2468-1253(24)00120-1. Lancet Gastroenterol Hepatol. 2024. PMID: 38870963 No abstract available.
Treatment strategies and biomarkers in Crohn's disease: the PROFILE trial.
Satsangi J, Nowak J, Kalla R, Colombel JF. Satsangi J, et al. Lancet Gastroenterol Hepatol. 2024 Jul;9(7):591-592. doi: 10.1016/S2468-1253(24)00082-7. Lancet Gastroenterol Hepatol. 2024. PMID: 38870964 No abstract available.
Treatment strategies and biomarkers in Crohn's disease: the PROFILE trial.
Borkar V, Lunagariya Y, Chopra S, Sasikumar D, Ingle M. Borkar V, et al. Lancet Gastroenterol Hepatol. 2024 Jul;9(7):591. doi: 10.1016/S2468-1253(24)00112-2. Lancet Gastroenterol Hepatol. 2024. PMID: 38870965 No abstract available.
Treatment strategies and biomarkers in Crohn's disease: the PROFILE trial.
Chen R, Zhang S. Chen R, et al. Lancet Gastroenterol Hepatol. 2024 Jul;9(7):592. doi: 10.1016/S2468-1253(24)00077-3. Lancet Gastroenterol Hepatol. 2024. PMID: 38870967 No abstract available.
The need for affordable, pragmatic, investigator-led clinical trials of treatment strategies in inflammatory bowel disease.
Noor NM, Sebastian S, Parkes M, Raine T. Noor NM, et al. Lancet Gastroenterol Hepatol. 2024 Oct;9(10):900-903. doi: 10.1016/S2468-1253(24)00225-5. Epub 2024 Jul 31. Lancet Gastroenterol Hepatol. 2024. PMID: 39094586 No abstract available.

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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

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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

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