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Noor NM, Lee JC, Bond S, Dowling F, Brezina B, Patel KV, Ahmad T, Banim PJ, Berrill JW, Cooney R, De La Revilla Negro J, de Silva S, Din S, Durai D, Gordon JN, Irving PM, Johnson M, Kent AJ, Kok KB, Moran GW, Mowat C, Patel P, Probert CS, Raine T, Saich R, Seward A, Sharpstone D, Smith MA, Subramanian S, Upponi SS, Wiles A, Williams HRT, van den Brink GR, Vermeire S, Jairath V, D’Haens GR, McKinney EF, Lyons PA, Lindsay JO, Kennedy NA, Smith KGC, Parkes M; PROFILE Study Group

A biomarker-stratified comparison of top-down versus accelerated step-up treatment strategies for patients with newly diagnosed Crohn’s disease (PROFILE): A multicenter, open-label randomized controlled trial

Background: Management strategies and clinical outcomes vary substantially in patients newly diagnosed with Crohn’s disease. The authors evaluated the use of a putative prognostic biomarker to guide therapy by assessing outcomes in patients randomized to either top-down (i.e., 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 multicenter, open-label, biomarker-stratified, randomized controlled trial that enrolled adults with newly diagnosed active Crohn’s disease (Harvey-Bradshaw Index [HBI] ≥ 7, either elevated C-reactive protein [CRP] or fecal 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 end point 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 > the upper limit of normal or fecal calprotectin ≥ 200 μg/g, or both), while remission was the converse – i.e., quiescent symptoms (HBI < 5) or resolved inflammatory markers (both CRP ≤ the upper limit of normal and fecal calprotectin < 200 μg/g) or both. Analyses were done in the full analysis (intention-to-treat) population.
Findings: Between December 29, 2017, and January 5, 2022, 386 patients (mean age 33.6 years [standard deviation 13.2]; 179 [46%] female, 207 [54%] male) were randomized: 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 point, 95% confidence interval [CI]: -15–15; 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 (149/189 patients [79%] vs. 29/190 patients [15%], absolute difference, 64 percentage points, 95% CI: 57–72; 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 (1 vs. 10) and no difference in serious infections (3 vs. 8).

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.

Prof. Dr. M. Parkes, Department of Medicine, University of Cambridge School of Clinical Medicine and Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK, E-Mail:

DOI: 10.1016/s2468-1253(24)00034-7

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