Background
Management strategies and clinical outcomes vary substantially in patients newly-diagnosed with Crohn’s disease. We evaluated the clinical utility of a biomarker in patients receiving either “top-down” or “accelerated step-up” therapy in newly-diagnosed, active Crohn’s disease, with a focus on endoscopic endpoints.

Methods
PROFILE (PRedicting Outcomes For Crohn's dIsease using a moLecular biomarker, ISRCTN 11808228) was an open-label, biomarker-stratified, randomized controlled trial. It enrolled adults with newly-diagnosed active Crohn’s disease (Harvey Bradshaw Index >7 and C-reactive protein > upper limit of normal or fecal calprotectin >200 ug/g, with active inflammation at endoscopy). Following biomarker testing patients were randomized to “top-down” (infliximab/immunomodulator) or “accelerated step-up” treatment stratified by: biomarker subgroup (termed IBDhi/IBDlo), endoscopic inflammation (mild/mod/severe) and extent (colonic/other). The primary endpoint was sustained steroid and surgery-free remission to week 48 and the key secondary endpoint was endoscopic remission (absence of ulcers) at week 48. Endoscopic imaging was predominantly video-captured and centrally-read using Endoread® software, with local-reading for the remainder. Several tertiary endoscopic endpoints included: endoscopic response at week 48 (>50% improvement in SES-CD), endoscopic remission at week 48 (absence of ulcers) using centrally-read videos only, and deep endoscopic remission at week 48 (total SES-CD score =0). The full analysis population (equivalent to ‘intention-to-treat’) was analyzed.

Results
386 patients were randomized from December 2017 to January 2022. Median time from diagnosis to trial enrollment was 12 days (0-191). Primary outcome data were available for 379 eligible participants, with sustained steroid and surgery-free remission being more frequent in “top-down” compared to “accelerated step-up” (79% vs 15%, absolute difference 64%, 95% CI=57 to 72%, p<0.001), and no biomarker-treatment interaction effect. Endoscopic remission at week 48 was significantly greater in “top-down” compared to “accelerated step-up” (67% vs 44%, absolute difference 23%, 95% CI=11 to 36%, p-value <0.001), with no biomarker-treatment interaction effect. Similar results were seen for endoscopic remission at week 48 when only centrally-read videos (166/253) were considered (60% vs 45%). Endoscopic response at week 48 was more frequent in “top-down” compared to “accelerated step-up” (82% vs 63%), as was deep endoscopic remission at week 48 (52% vs 37%).

Conclusion
“Top-down” treatment with combination infliximab/immunomodulator achieved substantially better outcomes compared to “accelerated step-up” therapy. The biomarker did not show clinical utility in PROFILE. “Top-down” should now be considered standard-of-care for patients with newly-diagnosed active Crohn’s disease.

Paul Lyons

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