Top‑down mirikizumab versus azathioprine standard of care in newly diagnosed moderate‑to‑severe Crohn’s disease: 52‑week randomised open‑label trial

The primary objective is to assess whether induction and maintenance therapy with mirikizumab results in a higher proportion of patients with newly diagnosed moderate-to-severe Crohn’s disease achieving deep remission at Week 52 compared with standard care comprising azathioprine plus glucocorticoids, using a step‑up rule that classifies any transition from azathioprine to mirikizumab as non‑response; confirming superiority would provide evidence for a top‑down treatment approach aimed at early, sustained disease control.

The trial enrolled adult individuals aged 18–75 years of both sexes who had a diagnosis of Crohn’s disease meeting criteria for moderate-to-severe activity, including a CDAI of 220–500, elevated CRP and/or fecal calprotectin, and endoscopic lesions (SES‑CD ≥4 or ≥6 depending on disease location). Participants were required to be naïve to thiopurines, methotrexate, and advanced biologic or small‑molecule therapies, and to have disease onset within 12 months prior to randomization. Selection was based on documented active disease, absence of actively draining fistulas, no prior CD‑related surgery, and compliance with medication washout periods (e.g., oral budesonide and mesalamine discontinued ≥2 weeks before screening). Lifestyle considerations were limited to adherence to study‑specified medication restrictions; no additional diet or physical‑activity requirements were imposed. The sponsor did not provide information on the total number of participants enrolled.

The study is a 52‑week, multicenter, open‑label, randomized controlled trial evaluating top‑down therapy with Crohn’s disease patients receiving mirikizumab versus standard‑of‑care azathioprine. Participants are randomized in a 1:1 ratio to receive either subcutaneous mirikizumab (200 mg induction followed by 100 mg maintenance) or oral azathioprine (2.5 mg/kg) throughout the study period. The trial consists of a screening visit, a baseline (Week 0) visit, scheduled follow‑up assessments at Weeks 4, 12, 24, 36, and 52, and an end‑of‑study visit at Week 52. Screening includes eligibility verification, laboratory tests, and ileocolonoscopy; baseline confirms randomization and initiates study medication. Follow‑up visits assess clinical status (CDAI), laboratory markers, safety, and endoscopic activity (SES‑CD) as required for the primary endpoint of deep remission at Week 52. Participants remain in the trial for the full 52 weeks unless discontinuation criteria specified in the protocol are met.

The investigational agent mirikizumab is administered in three formulations: a subcutaneous injection of 200 mg, a subcutaneous injection of 100 mg, and an intravenous infusion of 900 mg. Each dose is given according to the study‑specified induction and maintenance schedule, with administration intervals defined in the protocol. The pharmaceutical form for the subcutaneous doses is a sterile solution for injection; the intravenous dose is supplied as a sterile infusion solution. Dosing compliance is monitored by study personnel through documented administration records and verification of returned dosing devices.

The comparator arm includes oral azathioprine at a dose of 2.5 mg/kg body weight per day, provided in tablet form (PHF00170MIG). Azathioprine is administered once daily and continued throughout the 52‑week treatment period. Adherence is assessed by pill counts and patient diaries reviewed at each study visit.

A concomitant oral glucocorticoid is provided as part of standard‑of‑care therapy, dosed at 60 mg per day in tablet form (PHF00170MIG). The glucocorticoid is taken orally once daily during the induction phase, with tapering instructions outlined in the protocol. Compliance with the glucocorticoid regimen is tracked similarly to azathioprine, using returned medication counts and dosing logs.

Efficacy will be evaluated by determining the proportion of participants who achieve deep remission at Week 52. Deep remission is defined as the simultaneous fulfillment of several disease‑specific criteria: clinical remission assessed by a CDAI score < 150, endoscopic remission defined by a SES‑CD ≤ 2 with no deep ulcers as confirmed by central reading, absence of systemic glucocorticoid use for at least 8 weeks prior to Week 52, no IBD‑related surgical interventions through Week 52, no actively draining or newly formed fistulas, and no new clinically relevant stenoses. The primary efficacy analysis will calculate the proportion of patients meeting all these conditions in the modified intent‑to‑treat population at the Week 52 timepoint.