Efficacy of Top-down Therapy With Mirikizumab Versus Standard of Care With Azathioprine in Patients With Newly Diagnosed, Moderate-to-severe Crohn's Disease

Efficacy of Top-down Therapy With Mirikizumab Versus Standard of Care With Azathioprine in Patients With Newly Diagnosed, Moderate-to-severe Crohn's Disease: A 52-week, Multicenter, Open-label, Randomized Controlled Trial

The choice of drug therapy for Crohn's disease depends on several factors, such as the severity of the condition, the sections of the bowel affected, or the patient's previous treatment history. Conventional therapy consists of a short course of corticosteroid treatment followed by azathioprine therapy. Alternatively, there are so-called advanced therapies using biologics (biotechnologically produced protein substances such as antibodies), for example mirikizumab. This study aims to investigate whether direct, early treatment with mirikizumab is more effective than the standard therapy of azathioprine in combination with corticosteroids. Following an inclusion phase, patients will be randomly assigned to either treatment with mirikizumab or azathioprine + corticosteroids. Patients in the azathioprine arm may switch to mirikizumab therapy at three time points from week 24 onwards if they do not respond adequately to azathioprine therapy. 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 13 doses of mirikizumab. This includes initially 900 mg intravenously every 4 weeks followed by 300 mg subcutaneously. 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.

Inclusion Criteria:

1. Given written informed consent prior to any study-specific procedures.

2. Willing and able to complete the scheduled study assessments, including ileocolonoscopy and daily Diary entry.

3. Willing to comply with contraception requirements (as specified in Section 7.7 Contraception requirements).

4. Age 18-75 years.

5. Naïve to thiopurines (azathioprine or 6-mercaptopurine) and methotrexate.

6. Naïve to advanced therapies (targeted biologic or small-molecule therapies) for Crohn's disease or any other disease.

7. Early disease: Crohn's disease diagnosed per DGVS/ECCO criteria ≤12 months and ≥4 weeks before Week 0 (randomization).

8. Prior 5-aminosalicylate (5-ASA) and/or oral glucocorticoid therapy with inadequate response, loss of response, or intolerance to the agent(s) received.

9. If receiving systemic GC at screening start: cumulative systemic GC exposure prior to screening start should be ≤8 weeks, and prednisolone ≤20 mg/day (or equivalent) should be stable for ≥2 weeks before screening colonoscopy.

10. Oral budesonide must be discontinued ≥2 weeks before screening colonoscopy. A switch to prednisolone is permitted. Oral mesalamine must be discontinued ≥2 weeks before screening colonoscopy.

11. Evidence of active Crohn's disease at enrollment, defined as all of the following:

    1. CDAI 220-500 at screening and Week 0; and
    2. CRP > ULN and/or fecal calprotectin >250 μg/g measured during screening (Week -8 to Week 0); and
    3. Endoscopic activity on screening ileocolonoscopy (Week -8 to Week 0)

12. No actively draining fistula at screening and baseline.

13. No prior CD-related surgery

Exclusion Criteria:

1. Acute severe/fulminant Crohn's disease requiring immediate inpatient management or urgent surgery at screening (e.g., obstructive complication with imminent surgery, perforation, draining fistula, uncontrolled sepsis/abscess, toxic megacolon).
2. Oral and rectal 5-ASA or rectal steroids treatment within 2 weeks prior to screening colonoscopy.
3. History of malignancy, except for non-melanoma skin cancer that has been successfully treated and considered cured at screening.
4. Planned or foreseeable surgery at or before randomization (Week 0).
5. Known thiopurine methyltransferase deficiency or known inherited mutated nudix hydrolase 15 (NUDT15) gene.
6. Known hereditary problems of galactose intolerance, total lactase deficiency, or glucose-galactose malabsorption.
7. Diagnosis inconsistent with Crohn's disease, including ulcerative colitis, indeterminate colitis, microscopic colitis, or other non-CD inflammatory enteropathies.
8. Clinically important active infection, including but not limited to hepatitis B, hepatitis C, HIV/AIDS, or active tuberculosis (TB).
9. Detectable hepatitis B virus (HBV) DNA or hepatitis C virus (HCV) RNA at screening.
10. Latent TB.
11. Planned receipt of live or live-attenuated vaccines (including Bacillus Calmette-Guerin, BCG) during screening or the study.
12. Systemic mycoses or parasitosis.
13. Unstable or uncontrolled illness that could increase risk or confound efficacy assessment, including but not limited to cerebro-cardiovascular, respiratory, gastrointestinal (other than CD), hepatic, renal, endocrine, hematologic, neurological disorders, or active malignancy.
14. Known systemic hypersensitivity to any study drug or any excipient, or prior acute systemic hypersensitivity to monoclonal antibodies that, in the investigator's judgment, precludes mirikizumab therapy.
15. Women who are pregnant, lactating or planning pregnancy
16. Employee of Lilly or any of the organizations involved with this study or study site personnel directly affiliated with this study and/or their immediate families.
17. Participation in another interventional clinical trial involving an investigational product or nonapproved use of a drug within the 12 weeks before screening, or concurrent enrollment in any other clinical study or any other type of medical research judged not to be scientifically or medically compatible with this trial.
18. Unwilling or unable to comply with eDiary/data-capture requirements or other study procedures for the duration of the study.
19. Committed to an institution by judicial or administrative order.