Efficacy of Top-down Therapy With Mirikizumab Versus Standard of Care With Azathioprine in Patients With Newly Diagnosed Moderate-to-severe Ulcerative Colitis: A 52-week, Multicenter, Open-label, Randomized Controlled Trial
The MIRACLE trial is for patients who have been newly diagnosed with moderate to severe ulcerative colitis in the last 12 months and who have not responded adequately to treatment with mesalazine and prednisolone alone. The standard drug therapy for ulcerative colitis begins with mesalazine (+cortisone) and, if the response is insufficient, continues with azathioprine (+cortisone). Only in the next step are biologics (biotechnologically produced protein substances such as antibodies) such as mirikizumab used as needed. Recent studies have now shown that earlier treatment with mirikizumab without prior treatment with azathioprine may be more effective in the long term, and there are indications that this may result in fewer side effects. This study aims to investigate whether direct, early treatment with mirikizumab is more effective than the usual initiation of standard therapy with azathioprine, whereby these patients can then switch to mirikizumab at predetermined times during the course of the study from week 24 onwards if they have a defined disease activity despite the previous azathioprine treatment. The study consists of an initial treatment period of 12 weeks (induction therapy) and a maintenance therapy period of 40 weeks. Patients in the mirikizumab arm receive 12 doses of mirikizumab. This includes initially 300 mg intravenously every 4 weeks at the trial site, followed by 200 mg subcutaneously via two subcutaneous injections of 100 mg each, administered independently at home. In the azathioprine arm patients receive daily administration of azathioprine tablets in combination with a steroid. Assignment to one of the two treatment options is randomised with equal probability for each of the treatment options.
• Have given written informed consent prior to any study-specific procedures being completed.
• Are willing and able to complete the scheduled study assessments, including endoscopy and daily diary entry.
• Are willing to comply with contraception requirements (as specified in section 7.7)
• Age between 18 and 75 years.
• Naïve to azathioprine and its metabolite 6-MP
• Naïve to advanced therapies.
• Early disease (duration \< 12 months since first diagnosis).
• Patients with active ulcerative colitis (UC) for whom a previous therapy with 5-aminosalicylic acid (5-ASA) or steroids have not worked well enough, have stopped working, or have caused unacceptable side effects.
• The steroid oral therapy must have been stable for at least two weeks before baseline and may consist of prednisone ≤20 mg/day (or equivalent) per os.
⁃ The oral 5-ASA therapy must have been ongoing for at least 8 weeks and dose must be stable for at least 2 weeks before baseline.
⁃ Modified Mayo score (mMS) 5-9.
⁃ Endoscopic Mayo (eMayo) score ≥2 (local).
⁃ Robarts Histopathology Index (RHI) \>4 (central)
⁃ Elevated CRP (above the upper limit of normal) or Fcal (above 250 ug/g stool).
⁃ Disease localization involving at least the rectum and sigmoid colon (\>15 cm).