There are currently three classes of biologic treatments approved in Canada for the management of moderate-to-severe Crohn's disease: anti-tumor necrosis factor [TNF] alpha, anti-integrin, and anti-interleukin [IL]-23 targeted agents. The purpose of this trial is to determine which of these three classes of biologics results in the highest percentage of patients with small bowel (ileal) Crohn's disease entering into endoscopic remission without needing corticosteroids at 1 year. Endoscopic remission means that the ulcers in the small bowel from Crohn's disease have healed. All treatments in this trial are approved by Health Canada. No experimental drugs will be included.

This is a pragmatic, real-world trial of patients with moderate-to-severe, ileal-dominant Crohn's disease. At week 0, participants who meet the eligibility criteria will be randomized in a 1:1:1 ratio to a TNF antagonist; anti-integrin; or anti-IL23 targeted treatment. All interventions will be offered according to standard of care.

The dosing will be as follows:

TNFα antagonist

• Infliximab 5 mg/kg intravenously [IV] at weeks 0, 2, 6, then 5 mg/kg every 8 weeks; OR
• Adalimumab subcutaneously [SC] 160 mg at week 0, 80 mg at week 2, then 40 mg every 2 weeks

Anti-integrin

• Vedolizumab 300 mg IV at weeks 0, 2, and 6, then every 8 weeks; OR
• Vedolizumab 300 mg IV at weeks 0 and 2, then 108 mg SC every 2 weeks

Anti-IL23 targeted agents

• Ustekinumab ~6 mg/kg IV x1, then 90 mg SC every 8 weeks; OR
• Risankizumab 600 mg IV at weeks 0, 4, and 8, then 360 mg SC every 8 weeks

All treatments will be administered as part of the participant's routine care. All participants will be monitored per standard of care. Participants on corticosteroids at baseline will begin a steroid taper within 6 weeks of starting their biologic. At months 4, 8 and 12 participants will be evaluated for the Harvey Bradshaw Index (HBI), EuroQOL 5-domain questionnaire (EQ-5D), and be tested for C-reactive protein and fecal calprotectin concentrations. At month 12 patients will undergo a video-recorded ileocolonoscopy to determine if they have achieved endoscopic remission.

Inclusion Criteria:

1. Male or nonpregnant, nonlactating females, 18 years of age or older. Females of childbearing potential must have a negative serum or urine pregnancy test prior to randomization
2. Established CD diagnosis by conventional criteria
3. Baseline colonoscopy within 3 months of the first day of the screening period, with photo or video documentation of at least one large ileal ulcer >5 mm and ileal segment SES-CD ≥4 (eligibility will be determined by local endoscopist, with subsequent confirmation by a CR at a later time, post enrolment)
4. HBI ≥5
5. Biologic-treatment naïve for CD-related therapies
6. Would otherwise have been eligible to start a biologic for moderate-to-severely active CD as part of their routine clinical care and for whom there is equipoise around which biologic class to start
7. Willing and able to participate fully in all aspects of this clinical trial, including adherence to study protocol and treatment algorithm
8. Written informed consent must be obtained and documented

Exclusion Criteria:

1. Condition(s) for which the biologics included in this study is contraindicated
2. CD-related complications such as symptomatic, endoscopically impassable strictures or abscesses that require imminent surgery (at investigator's discretion)
3. Participants with current or history of colonic dysplasia or neoplasia, toxic megacolon, or fulminant colitis
4. Recent bowel resection <3 months before screening
5. Active enteric infection (positive stool culture), including but not limited to bacterial (including C. difficile), viral, or parasitic enteric infections
6. Known active hepatitis B, hepatitis C, or human immunodeficiency virus infection
7. Active COVID-19 infection during the screening period
8. Tested positive as part of SOC for tuberculosis (TB) at screening by QuantiFERON® TB Gold Test, tuberculin skin test, or history of untreated latent or active TB
9. History of malignancy within 5 years of screening, except fully treated carcinoma in-situ of the cervix, fully treated and resolved nonmetastatic squamous or basal cell carcinoma of the skin
10. Active chronic or acute infections requiring treatment with systemic antibiotics, antivirals, antifungals, antiparasitics, or antiprotozoals during the screening period
11. Serious underlying disease other than CD that, in the opinion of the investigator, may interfere with the participant's ability to participate fully in the study
12. Not willing to withhold protocol-prohibited medications during the trial, or planned or anticipated use of any prohibited medications during screening
13. Received previously or currently receiving a TNF antagonist, anti-integrin, monoclonal antibody targeting IL-12/23 or IL-23, Janus kinase (JAK) inhibitors, or sphingosine 1 phosphate (S1P) receptor modulators (irrespective of indication)
14. History of alcohol or drug abuse that, in the opinion of the investigator, may interfere with the participant's ability to comply with the study procedures

De-identified patient information may be shared at the discretion the the trial steering committee and upon written request.

Data will be available after completion of the trial and publication of results. Data will be retained for 15 years.