Effect of Intravenous (IV) Vedolizumab on Mucosal Healing in Crohn's Disease

An Open-Label Phase 3b Study to Assess Mucosal Healing in Subjects With Moderately to Severely Active Crohn's Disease Treated With Vedolizumab IV

The purpose of this study is to evaluate endoscopic remission at Week 26 as assessed by ileocolonoscopy.

The drug being tested in this study is called vedolizumab. Vedolizumab is being tested to treat people who have Crohn's disease. This study will look at mucosal healing in people who take vedolizumab.

The study will enroll approximately 100 patients and will be conducted in 2 Parts. Part A will consist of a 26-week treatment period and all participants will receive vedolizumab 300 mg intravenously (IV) on Day 1 and at Weeks 2, 6, 14 and 22. Part B will consist of a 26-week extension treatment period and all participants will receive vedolizumab 300 mg IV at Weeks 30, 38, and 46.

This multi-center trial will be conducted worldwide. The overall time to participate in this study is approximately 70 weeks for Parts A, B and 18-Week Follow-up combined. Participants will make multiple visits to the clinic. All participants included in the study will also have a 6 month safety follow-up telephone call following his/her last dose of study drug.

Inclusion Criteria:

1. In the opinion of the investigator, the participant is capable of understanding and complying with protocol requirements.

2. Signs and dates a written, informed consent form and any required privacy authorization prior to the initiation of any study procedures.

3. Has a diagnosis of moderately to severely active Crohn's disease (CD) at least 3 months prior to enrollment, with a Crohn's Disease Activity Index (CDAI) score of 220-450 during the Screening Period, a simple endoscopic score for Crohn's Disease (SES-CD) score of ≥7 and presence of at least one mucosal ulceration documented by recorded ileocolonoscopy at Screening assessed by the central reader.

4. Has CD with involvement of the ileum and/or colon that can be assessed by ileocolonoscopy.

5. Is male or female and aged 18 to 80 years, inclusive.

6. A male participant who is nonsterilized and sexually active with a female partner of childbearing potential agrees to use adequate contraception from signing of informed consent throughout the duration of the study and for 18 weeks after last dose.

7. A female participant of childbearing potential who is sexually active with a nonsterilized male partner agrees to use routinely adequate contraception from signing of informed consent throughout the duration of the study and for 18 weeks after last dose.

8. Has demonstrated an inadequate response to, loss of response to, or intolerance of at least 1 of the following agents as defined below:

   • Immunomodulators:

     i. Has signs and symptoms of persistently active disease despite a history of at least one 12-week regimen of oral azathioprine (≥1.5 mg/kg) or 6-mercaptopurine (≥0.75 mg/kg), OR ii. Has a history of intolerance (including but not limited to nausea/vomiting, abdominal pain, pancreatitis, liver function test abnormalities, lymphopenia, thiopurine S-methyltransferase non wild type [where wild type is defined as thiopurine S-methyltransferase (TPMT)*1/*1], infection) to at least 1 immunomodulator.

   • Tumor necrosis factor- alpha (TNF-α) antagonists:

     i. Has signs and symptoms of persistently active disease despite a history of at least 1 induction with:

     1. Infliximab: 4-week regimen of 5 mg/kg, 2 doses at 2 weeks apart, OR
     2. Adalimumab: 2-week regimen of 160 mg on Day 1 and 80 mg on Day 15, OR
     3. Certolizumab: 4-week regimen of 400 mg initially at Weeks 0, 2, 4 OR ii. Has recurrence of symptoms during maintenance dosing following prior clinical benefit (discontinuation despite clinical benefit does not qualify), OR iii. Has a history of intolerance of infliximab, adalimumab, or certolizumab, including but not limited to, infusion-related reaction, demyelination, congestive heart failure, or infection.

   • Corticosteroids i. Signs and symptoms of persistently active disease despite a history of at least one 4-week induction regimen that included a dose equivalent to prednisone 30 mg daily orally for 2 weeks or intravenous(ly) (IV) for 1 week, OR ii. Signs and symptoms of persistently active disease despite treatment with budesonide 9 mg daily or 6 mg daily for maintenance, OR iii. At least one failed attempt to taper corticosteroids to below a dose equivalent to prednisone 10 mg daily orally, OR iv. History of intolerance to corticosteroids (including, but not limited to, Cushing's syndrome, osteopenia/osteoporosis, hyperglycemia, insomnia, and infection).

9. May be receiving a stable therapeutic dose of conventional therapies for CD (excluding other biologic agents 60 days before enrollment).

10. Has a family history of colorectal cancer, personal history of increased colorectal cancer risk, age >50 years, or other known risk factors must be up-to-date on colorectal cancer surveillance (may be performed during Screening).

Exclusion Criteria:

1. Has received a diagnosis of ulcerative colitis or indeterminate colitis.

2. Has clinical evidence of abdominal abscess.

3. Has a history of >3 small bowel resections or diagnosis of short bowel syndrome.

4. Has extensive colonic resection, ie, subtotal or total colectomy with <15 cm colon remaining.

5. Has ileostomy, colostomy, or known fixed symptomatic stenosis of the intestine.

6. Has a history or evidence of adenomatous colonic polyps that have not been removed.

7. Has a history or evidence of colonic mucosal dysplasia.

8. Has intolerance or contraindication to undergo ileocolonoscopy.

9. Has active or latent tuberculosis, regardless of treatment history, as evidenced by any of the following:

   a. History of tuberculosis (TB). b. A diagnostic TB test performed during screening that is positive, as defined by: i. A positive QuantiFERON® test or 2 successive indeterminate QuantiFERON tests OR ii. A tuberculin skin test reaction ≥10 mm (≥5 mm in participants receiving the equivalent of >15 mg/day prednisone).

10. Has chronic hepatitis B (HBV) or hepatitis C (HCV) infection.

11. Has any identified congenital or acquired immunodeficiency (eg, common variable immunodeficiency, human immunodeficiency virus [HIV] infection, organ transplantation).

12. Has evidence of active C. difficile infection or is having treatment for C. difficile infection or other intestinal pathogens during Screening.

13. Has evidence of an active infection during Screening.

14. Currently requires or has a planned surgical intervention for CD during the study.

15. Has received any investigational compound within 60 days of enrollment.

16. Has received any biologics within 60 days of enrollment.

17. Has received any live vaccinations within 30 days prior to enrollment.

18. Has conditions which, in the opinion of the investigator, may interfere with the participant's ability to comply with the study procedures.

19. Has any unstable or uncontrolled cardiovascular, pulmonary, hepatic, renal, gastrointestinal (GI), genitourinary, hematological, coagulation, immunological, endocrine/metabolic, or other medical disorder that, in the opinion of the investigator, would confound the study results or compromise participant safety.

20. Has a history of hypersensitivity or allergies to vedolizumab or its components.

21. Has had prior exposure to vedolizumab, natalizumab, efalizumab, or rituximab.

22. Had a surgical procedure requiring general anesthesia within 30 days prior to screening or is planning to undergo major surgery during the study period.

23. Has a 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 and must be discussed with the sponsor on a case-by-case basis prior to enrollment.

24. Has a history of any major neurological disorders, including stroke, multiple sclerosis, brain tumor, or neurodegenerative disease.

25. Has a positive progressive multifocal leukoencephalopathy (PML) subjective symptom checklist during Screening or prior to the administration of study drug.

26. Has any of the following laboratory abnormalities during the Screening Period:

    i. Hemoglobin level <8 g/dL. ii. White blood cell (WBC) count <3*10^9/L. iii. Lymphocyte count <0.5*10^9/L. iv. Platelet count <100*10^9/L or >1200*10^9/L. v. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >3*the upper limit of normal (ULN).

    vi. Alkaline phosphatase >3*ULN. vii. Serum creatinine >2*ULN.

27. Has a history of drug abuse (defined as any illicit drug use) or a history of alcohol abuse within 1 year prior to enrollment.

28. Has an active psychiatric problem that, in the investigator's opinion, may interfere with compliance with study procedures.

29. Is unable to attend all the study visits or comply with study procedures.

30. If female, the participant is pregnant or lactating or intending to become pregnant before, during, or within 18 weeks after participating in this study; or intending to donate ova during such time period.

31. If male, the participant intends to donate sperm during the course of this study or for 18 weeks thereafter.

32. Is an immediate family member, study site employee, or is in a dependent relationship with a study site employee who is involved in conduct of this study (eg, spouse, parent, child, sibling) or may consent under duress.

33. Participants who are at sites participating in the magnetic resonance enterography (MREn) substudy may not participate if they have intolerance or contraindication to the procedure or if any of the following exclusions apply:

    1. Has certain implanted medical devices, such as pacemakers or implantable cardioverter defibrillators (ICDs), or ferromagnetic metallic foreign bodies, such as shrapnel or certain tattoos.
    2. Has allergy to gadolinium-based magnetic resonance (MR) IV contrast agents.
    3. Has known claustrophobia.
    4. Has estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m^2 at Screening.