An Open-Label, Phase 4, Single-Arm, Multicenter Study to Evaluate the Induction of Response and Remission of Vedolizumab Dual Targeted Therapy with Tofacitinib in Adult Patients with Moderately to Severely Active Ulcerative Colitis

1. Is an adult, aged 18 to 65 years, inclusive, at screening.
2. Has provided informed consent (that is, in writing, documented via a signed and dated informed consent form) and any required privacy authorization before the initiation of any study procedures.
3. Has a confirmed diagnosis of UC established at least 3 months prior to screening, by clinical and endoscopic evidence and corroborated by a histopathology report.
4. Has moderately to severely active UC at screening as determined by a complete Mayo score (including PGA) of 6 to 12 with a rectal bleeding subscore ≥1 and a centrally assessed endoscopic subscore ≥2.
5. Has evidence of UC extending proximally to the rectum (≥15 cm of involved colon).
6. Participants with extensive colitis or pancolitis of >8 years duration or left‑sided colitis >12 years duration must have documented evidence that a surveillance colonoscopy was performed within 12 months of the initial Screening Visit (if not performed in previous 12 months, may be performed during screening).
7. Participants with 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).
8. Has demonstrated an inadequate response to, loss of response to, or intolerance to no more than 2 TNF‑α antagonists.
9. If taking oral corticosteroids, must be on a stable dose up to a maximum of 40 mg/dayd of prednisone or equivalent for at least 2 weeks prior to first dose and must be willing to follow a mandatory taper of corticosteroids.
10. A male participant who is non‑sterilized, capable of producing viable sperm, and sexually active with a female partner of childbearing potential agree to use highly effective contraception (i.e.ie, dual contraception) and to avoid donating sperm from signing of informed consent throughout the duration of the study and for 18 weeks after last dose of any study intervention.
11. A female participant of childbearing potential must:
    1. Have a negative serum pregnancy test at screening.
    2. Agree to use highly effective contraception (as defined in this protocol) and to avoid donating ova from signing of the informed consent form (ICF) throughout the duration of the study and for 18 weeks after last dose of any study intervention.
    3. If capable of breastfeeding, must agree to forego breastfeeding for the period from signing of the ICF until 18 weeks after last dose of any study intervention.
12. The participant is willing and able to understand and fully comply with study procedures and requirements (including digital tools and applications), in the opinion of the investigator.

Exclusion Criteria:

Gastrointestinal Exclusion Criteria

1. Has any of the following UC-related complications:
   1. Acute severe UC, defined by ≥6 bloody diarrhea/dayd and any signs of systemic toxicity (pulse >90 beats/min, temperature >37.8°C, hemoglobin <10.5 g/dL, erythrocyte sedimentation rate [ESR] >30 mm/h, or CRP >30 mg/L), or in the investigator’s opinion, hospitalization for the treatment of UC may be imminent.
   2. The participant has had extensive colonic resection, subtotal or total colectomy.
   3. The participant has clinical evidence of abdominal abscess or toxic megacolon.
   4. The participant has had ileostomy, colostomy, or known fixed symptomatic stenosis of the intestine.
   5. Short bowel syndrome.
2. Has Crohn’s, colitis, indeterminate colitis, ischemic colitis, nonsteroidal anti-inflammatory drug (NSAID) induced colitis, idiopathic colitis (ie, colitis not consistent with UC), radiation colitis, microscopic colitis, colonic mucosal dysplasia, or untreated bile acid malabsorption.
3. Has uncontrolled primary sclerosing cholangitis.

Infectious Disease Exclusion Criteria

4. Has evidence of an active infection during screening.
5. Has 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/dayd prednisone).
6. Personal history of congenital or acquired immunodeficiency (eg, common variable immunodeficiency, human immunodeficiency virus [HIV]  infection, organ transplantation) excluding pharmacologic immunosuppressant.
7. 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.
8. 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]).
9. Has evidence of active C. difficile infection or is receiving treatment for C. difficile or other intestinal pathogens during screening.
10. Evidence of active Cytomegalovirus (CMV) infection at screening.

Medication Exclusion Criteria

11. Has received any approved or investigational biologic therapy, other than a TNF‑α antagonist.
12. Has had previous exposure to approved or investigational anti-integrins (eg, vedolizumabVDZ, natalizumab), or Janus kinase inhibitors (eg, tofacitinibTOF, upadacitinib), or anti-interleukins (ustekinumab), or S1P receptor agonists (eg, ozanimod).
13. Has received any investigational product within 60 days or 5 half-lives prior to screening, whichever is longer.
14. Has received any live vaccine within 4 weeks prior to first dose.
15. Has received any medicinal product, herbal medication, or natural health product that might interfere with cytochrome P450 (CYP) 3A4P4503A4 within 2 weeks prior to first dose.
16. Has received the following medical therapies for UC:
    1. Immunomodulators (eg, 6-MPmercaptopurine, azathioprine, and methotrexate) within 4 weeks prior to first dose
    2. Immunosuppressants (eg, cyclosporine, tacrolimus) within 8 weeks prior to first dose.
    3. IV antibiotics within 8 weeks prior to first dose.
    4. Any rectal therapy within 2 weeks prior to screening endoscopy.
    5. Chronic nonsteroidal anti-inflammatory drug (NSAID)  use defined as daily use for >2 consecutive weeks (Note: occasional use of NSAIDs and acetaminophen for headache, arthritis, myalgias, or menstrual cramps are permitted).
17. Medical history or known allergy, hypersensitivity, or intolerance to vedolizumab, tofacitinibVDZ, TOF, or their excipients. 

General Exclusion Criteria

18. Has any of the following cardiovascular or thrombotic conditions:
    1. Recent (within past 6 months) cerebrovascular accident, myocardial infarction, or coronary stenting.
    2. Recent (within past 6 months) moderate to severe congestive heart failure (New York Heart Association class III or IV).
    3. Prior history of thrombotic events, including deep vein thrombosis and pulmonary embolism.
    4. Known inherited conditions that predispose to hypercoagulability.
19. History of lymphoproliferative disease, including lymphoma, or signs and symptoms suggestive of possible lymphoproliferative disease, such as lymphadenopathy and/or splenomegaly.
20. 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.
21. History of any major neurological disorders, including stroke, multiple sclerosis, epilepsy, or demyelinating or neurodegenerative disease.
22. History or symptoms of progressive multifocal leukoencephalopathy (PML) at screening or prior to first dose, in the investigator’s discretion.
23. Any of the following laboratory abnormalities during the screening period:
    1. Hemoglobin level <9 g/dL.
    2. WBCWhite blood cell count <3 × 109/L.
    3. Lymphocyte count <0.5 × 109/L.
    4. Platelet count <100 × 109/L or >1200 × 109/L.
    5. ALT or ASTAlanine aminotransferase or aspartate aminotransferase >3 × the upper limit of normal (ULN).
    6. Alkaline phosphatase >3 × ULN.
    7. Serum creatinine >2 × ULN.
    8. Serum albumin <2.5 g/dL.
24. Participant has other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation, study treatment administration, study participation, or may interfere with the interpretation of study results, as determined by the investigator.
25. A surgical procedure requiring general anesthesia within 3 months prior to screening or is planning to undergo major surgery during the study period.
26. Any investigational procedure ≤4 weeks prior to screening.
27. Prior enrollment in this study and had received study intervention. 
28. Unwilling to withhold protocol-restricted interventions during the study.
29. 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. 
30. 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, or sibling).