An Open-Label, Phase 4 Study to Evaluate the Efficacy and Safety of Dual Targeted Therapy with Vedolizumab Intravenous (IV) and Adalimumab Subcutaneous (SC) or Vedolizumab IV and Ustekinumab IV/SC in Moderate to Severe Crohn’s Disease (CD)

Inclusion Criteria

1. Is an adult 18 to 65 years of age, inclusive, at screening.
2. Has provided informed consent (that is, in writing, documented via a signed and dated ICF) and any required privacy authorization before the initiation of any study procedures.
3. Has a confirmed diagnosis of CD at least 3 months before baseline, based on endoscopy results.
4. Has moderately to severely active CD at screening, defined as both of the following:
   1. a CDAI score ≥220 and <450, and
   2. a SES-CD ≥6 (≥4 if isolated ileal disease).
5. Has demonstrated at least 1 of the following (a, b, or c) to at least 1 IL antagonist (ustekinumab or risankizumab) or at least 1 TNF antagonist (infliximab or biosimilar, adalimumab, or certolizumab pegol), at doses approved for the treatment of CD:
   1. Inadequate response after completing the full induction regimen;
   2. Loss of response (recurrence of symptoms during scheduled maintenance dosing after prior clinical benefit); or
   3. Intolerance (a significant AE that precluded further use, including but not limited to serious infection including opportunistic infections, malignancy, infusion—related and hypersensitivity reactions including anaphylaxis, and liver injury).
6. If taking oral corticosteroids, has been taking a stable dose up to a maximum dose of 20 mg/day, for ≥4 weeks before Baseline and must be willing to follow a mandatory taper of corticosteroids.
7. If taking methotrexate, azathioprine, 6-mercaptopurine, 5-aminosalicylic acid, antibiotics, or probiotics; must be willing to stop that treatment ≥2 weeks prior to Screening. Note: Intermittent use of antidiarrheals is permitted.
8. Participants at increased risk for colorectal cancer (eg, family history, personal history, age >50 years) must be up to date on colorectal cancer surveillance (may be performed during screening as standard of care).
9. A male participant who is nonsterilized, capable of producing viable sperm, and sexually active with a female partner of childbearing potential must agree to use highly effective contraception (ie, dual contraception) and to avoid donating sperm from signing of the ICF, throughout the duration of the study and for 18 weeks after last dose of any study treatment.
10. A female participant of childbearing potential must:
    1. Have a negative serum pregnancy test at Screening.
    2. Not be breastfeeding.
    3. Agree to use highly effective contraception (as defined in Section 10.4) and to avoid
    4. donating ova from signing of the ICF throughout the duration of the study and for
    5. 18 weeks after last dose of any study treatment.
11. Willing and able to understand and fully comply with study procedures and requirements (including digital tools and applications), in the opinion of the investigator.

Inclusion Criteria – Part B:

12. Participant is in clinical remission at Week 26. Note: Participants exhibiting a clinical response (defined as a ≥100-point decrease in CDAI) at Week 26 may enter Part B at the Investigator’s discretion.

Exclusion Criteria

Participants will be excluded from the study if any of the following exclusion criteria are met:

GI Exclusion Criteria

1. A current diagnosis of ulcerative colitis or indeterminate colitis.
2. Clinical evidence of a current abdominal abscess or a history of prior abdominal abscess.
3. Known fistula (other than perianal fistula) or phlegmon.
4. Known perianal fistula with abscess (perianal fistula without abscess is permitted).
5. Ileostomy, colostomy, or severe, or symptomatic stenosis of the intestine.
6. Previous extensive colon resection with ≥2 colonic segments remaining, performed ≥6 months prior to screening.
7. Other intra-abdominal surgery or a hospital admission for bowel obstruction ≤3 months prior to screening.
8. Short bowel syndrome.
9. Any planned surgical intervention for CD, except for seton placement for perianal fistula without abscess.
10. History or evidence of adenomatous colonic polyps that have not been removed.
11. History or evidence of colonic mucosal dysplasia.
12. Intolerance or contraindication to ileocolonoscopy.

Infectious Disease Exclusion Criteria

13. Any identified congenital or acquired immunodeficiency (eg, common variable immunodeficiency, human immunodeficiency virus [HIV] infection).
14. Previous organ transplantation.
15. Evidence of an active infection during screening.
16. Infections requiring treatment with oral or IV antibiotics, antivirals, or antifungals within 4 weeks prior to screening.
17. Active or latent tuberculosis (TB), regardless of treatment history, as evidenced by any of the following:
    1. History of TB.
    2. A diagnostic TB test performed during screening that is positive, as defined by:
       1. A positive QuantiFERON test or 2 successive indeterminate QuantiFERON tests, OR
       2. A tuberculin skin test reaction ≥10 mm (≥5 mm in participants receiving the equivalent of >15 mg/day prednisone).
18. History of opportunistic infections including, but not limited to listeria, histoplasmosis, coccidioidomycosis, blastomycosis, candidiasis, aspergillosis, legionella, or pneumocystosis.
19. A positive test for hepatitis B virus (HBV), as defined by the presence of hepatitis B surface antigen (HBsAg) or hepatitis B core antibody (HBcAb) test. If a participant tests negative for HBsAg, but positive for HBcAb, the participant would be considered eligible if no HBV DNA is present, confirmed by HBV DNA polymerase chain reaction reflex testing performed by the central laboratory.
20. A positive test for hepatitis C virus (HCV), as defined by a positive HCV antibody test and detectable HCV RNA. Participants who are HCV antibody positive without evidence of HCV RNA may be considered eligible (spontaneous viral clearance or previously treated and cured [defined as no evidence of HCV RNA at least 12 weeks prior to Screening]).
21. Has evidence of active C. difficile infection or is receiving treatment for C difficile or other intestinal pathogens during Screening.

Medication Exclusion Criteria

22. Primary nonresponse to ≥2 IL antagonists (Cohort 1) or ≥2 TNF antagonists (Cohort 2) for the treatment of CD.
23. Received approved or investigational anti-integrin antibodies (ie, vedolizumab, natalizumab, efalizumab, etrolizumab, abrilumab [AMG 181], anti-mucosal addressin cell adhesion molecule-1 [MAdCAM-1] antibodies), or rituximab.
24. Received any approved or investigational biologic therapy ≤6 months prior to screening or any other investigational agent ≤4 weeks or 5 half-lives prior to screening, except for IL antagonists or TNF antagonists.
25. Received any live vaccine ≤4 weeks (28 days) prior to screening.
26. Received corticosteroid enema / suppository ≤2 weeks prior to screening.
27. Received stem cell therapy for fistula ≤8 weeks prior to screening.
28. Receiving >20 mg/day of prednisone or equivalent at screening.
29. Requires treatment with any excluded medication during study participation: trimethoprim/sulfamethoxazole, leflunomide, theophylline, tizanidine, phenytoin, phenylbutazone, probenecid, and chronic nonsteroidal anti-inflammatory drug (NSAID) or salicylates (Note: occasional use of NSAIDs and acetaminophen, and daily use of baby or low-dose aspirin, are permitted).
30. Medical history or known allergy, hypersensitivity, or intolerance to vedolizumab (all participants), adalimumab (Cohort 1), ustekinumab (Cohort 2), or their excipients.

General Exclusion Criteria

31. Body mass index >37 kg/m2.
32. Other systemic inflammatory or rheumatic diseases (eg, psoriasis, rheumatoid arthritis, ankylosing spondylitis).
33. History of any lymphoma or lymphoproliferative disease.
34. Concomitant diagnosis or any history of congestive heart failure (New York Heart Association class III/IV) or unstable angina.
35. Any unstable or uncontrolled cardiovascular, pulmonary, hepatic, renal, GI, genitourinary, hematological, coagulation, immunological, endocrine/metabolic, neurologic, or other medical disorder that could, in the opinion of the investigator, confound the study results or compromise participant safety.
36. History of malignancy, except for the following: adequately treated nonmetastatic basal cell skin cancer; squamous cell skin cancer that has been adequately treated and that has not recurred for at least 1 year prior to Screening; and history of cervical carcinoma in situ that has been adequately treated and that has not recurred for at least 3 years prior to screening. Participants with a remote history of malignancy (eg, >10 years since completion of curative therapy without recurrence) will be considered based on the nature of the malignancy and the therapy received; this must be discussed with the sponsor on a case by-case basis prior to enrollment.
37. History of any major neurological disorders, including stroke, central nervous system demyelinating disease, brain tumor, or neurodegenerative disease.
38. History of or symptoms of progressive multifocal leukoencephalopathy (PML) in the Investigator’s opinion.
39. History of pre-existing blood dyscrasias, such as bone marrow hypoplasia, leukopenia (white blood cell [WBC] count <3 × 109/L), thrombocytopenia (platelet count <100 × 109/L), or significant anemia (hemoglobin level <8 g/dL). This does not include transient leukopenia, thrombocytopenia, or anemia.
40. Hereditary problems of galactose intolerance, or Lapp lactase deficiency.
41. Has any of the following laboratory abnormalities during the screening period:
    1. Hemoglobin level <8 g/dL.
    2. WBC count <3.0 × 109/L.
    3. Lymphocyte count <0.5 × 109/L.
    4. Platelet count <100 × 109/L or >1200 × 109/L.
    5. Alanine aminotransferase (ALT) or aspartate aminotransferase >1.5 the upper limit of normal (ULN).
    6. Alkaline phosphatase (ALP) >1.5 × ULN.
42. A surgical procedure requiring general anesthesia within 3 months prior to screening or is planning to undergo major surgery during the study period.
43. Any investigational procedure ≤4 weeks prior to screening.
44. Prior gastric bypass surgery.
45. Prior enrolment in this study and received study intervention.
46. Unwilling to withhold protocol-restricted medications during the study.
47. History of excessive alcohol or drug abuse that, in the opinion of the investigator, may interfere with the participant’s ability to comply with the study procedures.
48. Participant is an immediate family member, study site employee, or is in a dependent relationship with a study site employee who is involved in the conduct of this study (eg, spouse, parent, child, sibling).