BMJ Open Gastroenterology best clinical science abstract: endoscopic outcomes from PROFILE: a multi-centre, randomised, open-label, biomarker-stratified clinical trial of treatment strategies for patients with newly-diagnosed Crohn’s disease

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 randomised to either ‘top-down’ or ‘accelerated step-up’ therapy for newly-diagnosed, active Crohn’s disease. Here we focus on endoscopic outcomes.

Methods PROFILE (PRedicting Outcomes For Crohn’s dIsease using a moLecular biomarker, ISRCTN 11808228) was an open-label, biomarker-stratified, randomised controlled trial. It enrolled adults with newly-diagnosed active Crohn’s disease (Harvey Bradshaw Index ≥7 and elevated CRP or faecal calprotectin ≥200 ug/g, with active inflammation at endoscopy). Following biomarker testing patients were randomised to ‘top-down’ (infliximab/immunomodulator) or ‘accelerated step-up’ treatment stratified by: biomarker subgroup (termed IBDhi/IBDlo), endoscopic severity (mild/mod/severe) and extent (colonic/other). Ileo-colonoscopies were undertaken at baseline and week 48. Where possible they were video recorded, uploaded to Endoread® and centrally-read. The remainder were scored locally. The primary endpoint was sustained steroid and surgery-free remission to week 48 and the key secondary endpoint was endoscopic remission (absence of ulcers/SES-CD ulcer subscore=0) at week 48. Tertiary endoscopic endpoints included: endoscopic remission at week 48 using centrally-read videos only, endoscopic response at week 48 (≥50% improvement in SES-CD vs baseline), and deep endoscopic remission at week 48 (total SES-CD=0). The full analysis (‘intention-to-treat’) population was analysed.

Results 386 patients were randomised from Dec 2017 to Jan 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=57–72%, p<0.001). No biomarker-treatment interaction was observed. By week 48, of the 190 patients on ‘accelerated step-up’ 85% were on immunomodulators and 41% had escalated to infliximab. Endoscopic remission at week 48 was assessed in 253 patients and was significantly greater in ‘top-down’ compared to ‘accelerated step-up’ (67% vs 44%, absolute difference 23%, 95% CI=11–36%, p<0.001). Respective proportions in endoscopic remission were 60% vs 45% where only the 166 centrally-read colonoscopies were considered. Endoscopic response at week 48 was more frequent in ‘top-down’ compared to ‘accelerated step-up’ (82% vs 63%), as was deep endoscopic remission (52% vs 37%).

Conclusion ‘Top-down’ treatment with combination infliximab and immunomodulator achieved substantially better clinical and endoscopic outcomes at week 48 compared to ‘accelerated step-up’ therapy. The biomarker lacked clinical utility. ‘Top-down’ should now be considered standard-of-care for patients with newly-diagnosed active Crohn’s disease.