Maarten Cozijnsen

Abstract Rationale: Crohn’s disease (CD) is a chronic inflammatory disease predominantly affecting the gastrointestinal tract. CD usually requires lifelong medication and is accompanied by severe complications, such as fistulae and strictures resulting in surgery. Infliximab (IFX) is very effective for treating pediatric CD patients, but is currently only registered for therapy refractory patients – the so-called step-up strategy. We hypothesize that using IFX first-line, i.e. top-down, will give more mucosal healing, fewer relapses, less complications, need for surgery and hospitalization. Objectives : Compare efficacy and safety of top-down IFX versus conventional step-up treatment in pediatric CD patients. Methods and analysis: This international multicenter open-label randomized controlled trial includes children, aged 3-17 years, with new-onset, untreated, CD with moderate-to- severe disease activity (weighted Pediatric Crohn’s Disease Activity Index (wPCDAI)>40). Eligible patients will be randomized to top-down or step-up treatment. Top-down will consist of 5 IFX infusions combined with azathioprine (AZA). After these 5 infusions, patients will continue AZA. Patients randomized to step-up will receive standard induction treatment, either oral prednisolone or exclusive enteral nutrition, combined with AZA as maintenance treatment. Primary outcome is clinical remission (wPCDAI<12.5) at 52 weeks without need for additional CD related therapy or surgery. Total follow-up is 5 years. Secondary outcomes include clinical disease activity, mucosal healing by endoscopy (at week 10 and optionally week 52), faecal calprotectin, growth, quality of life, medication use, and adverse events. Ethics: Conducted according to the Declaration of Helsinki and Good Clinical Practice. Medical-ethical approval will be obtained for each site. Trial registration number: NCT02517684