Vedolizumab Intravenous (IV) Dose Optimization in Ulcerative Colitis
Condition: Colitis, Ulcerative
MeSH terms: Colitis; Colitis, Ulcerative; Ulcer
Intervention: Vedolizumab IV
Intervention description: Vedolizumab intravenous infusion.
Intervention MeSH terms: Vedolizumab
Phase: Phase 4
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 278.0
Sex: All
Minimum age: 18 Years
Maximum age: 85 Years
Healthy volunteers: No
Keywords: Drug Therapy

Summary:

      The purpose of this study is to investigate the efficacy and safety of vedolizumab
      intravenous (IV) dose optimization on mucosal healing compared with the standard vedolizumab
      IV dosing regimen over a 30 week treatment period in participants with moderately to severely
      active ulcerative colitis (UC) and high vedolizumab clearance, based on a Week 5 predefined
      serum vedolizumab concentration threshold less than (<) 50 microgram per milliliter
      (microg/mL) and who are Week 6 non-responders based on partial Mayo score.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Has a diagnosis of UC established at least 1 month prior to Screening by clinical and
             endoscopic evidence and corroborated by a histopathology report.

          2. Has moderately to severely active UC as determined by a complete Mayo score of 6 to 12
             with an endoscopic subscore ≥2 within 28 days prior to enrollment.

          3. Has evidence of UC proximal to the rectum (≥15 cm of involved colon) prior to start of
             vedolizumab IV dosing.

          4. Has been determined to be suitable for vedolizumab IV for routine management of UC by
             their physician.

          5. Has a family history of colorectal cancer, personal history of increased colorectal
             cancer risk, age >50 years, or other known risk factor must be up-to-date on
             colorectal cancer surveillance (may be performed during screening).

          6. Has demonstrated an inadequate response with, lost response to, or intolerance of at
             least 1 of the following agents: immunomodulators, corticosteroids, or tumor necrosis
             factor-alpha (TNF-α) antagonists. Subject who are naive to TNF-α antagonist therapy or
             who have previously failed TNF-α antagonist therapy (including primary and secondary
             non-responders or intolerant) may be included.

             Week 6 Randomized Treatment Period Inclusion Criteria

          7. Following Lead-in Period, the subject is assessed as having high vedolizumab drug
             clearance based on a predefined Week 5 serum vedolizumab concentration threshold (<50
             microg/mL).

          8. Following Lead-in Period, the subject is a non-responder based on partial Mayo score
             at Week 6.

        Exclusion Criteria:

          1. Has clinical evidence of abdominal abscess or toxic megacolon at the Screening Visit.

          2. Has had an extensive colonic resection, subtotal or total colectomy.

          3. Has had ileostomy, colostomy, or known fixed symptomatic stenosis of the intestine.

          4. Has a diagnosis of Crohn's colitis or indeterminate colitis, ischemic colitis,
             radiation colitis, diverticular disease associated with colitis, or microscopic
             colitis.

          5. Has received any of the following for the treatment of underlying disease within 30
             days of screening:

               1. Non-biologic therapies (eg. cyclosporine, tacrolimus, thalidomide)

               2. An approved non-biologic therapy in an investigational protocol.

          6. Has received any investigational or approved biologic or biosimilar agent within 60
             days or 5 half-lives prior to screening (whichever is longer).

          7. Has previously had prior exposure to approved or investigational anti-integrin
             antibodies (e.g. natalizumab, efalizumab, etrolizumab, AMG-181, anti-MAdCAM-1
             antibodies or rituximab).

          8. Has previously received approved or investigational vedolizumab.

          9. The subject currently requires or is anticipated to require surgical intervention for
             UC during the study.

         10. Has history or evidence of adenomatous colonic polyps that have not been removed, or
             colonic mucosal dysplasia.

         11. Has any evidence of an active infection during Screening (eg, sepsis, cytomegalovirus,
             or listeriosis).

         12. Has a clinically significant infection (eg, pneumonia, pyelonephritis) within 30 days
             prior to screening, or ongoing chronic infection.

         13. Has evidence of active C. difficile as evidenced by positive C. difficile toxin or is
             having treatment for C. difficile infection or other intestinal pathogens during
             Screening.

         14. Has a known history of infection with human immunodeficiency virus (HIV), hepatitis B
             (HBV), or chronic HBV (HBV immune subjects (ie, being hepatitis B surface antigen
             [HBsAg] negative and hepatitis B antibody positive) may, however, be included), or
             hepatitis C virus (HCV) infection. Subjects with documented successful treatment of
             HCV with sustained virological response (SVR) at 26 weeks can be enrolled.

         15. Has active or latent tuberculosis (TB), as evidenced by the following:

             a. A diagnostic TB test performed within 30 days of screening or during the Screening
             Period that is positive, defined as: i. Positive QuantiFERON test or 2 successive
             indeterminate QuantiFERON tests, OR ii. A TB skin test reaction ≥ 5 mm OR, b. Chest
             X-ray within 3 months of screening that is suspicious for pulmonary TB, and a positive
             or 2 successive indeterminate QuantiFERON tests within 30 days prior to Screening or
             during the Screening Period.

         16. Has any identified congenital or acquired immunodeficiency (eg, common variable
             immunodeficiency, HIV infection, organ transplantation).

         17. Has any live vaccination within 30 days prior to Screening or is planning to receive
             any live vaccination during participation in the study.

         18. Has used a topical (rectal) treatment with (5-ASA) or corticosteroid
             enemas/suppositories within 2 weeks prior to Screening.

         19. Has a history of hypersensitivity or allergies to vedolizumab IV or its components.

         20. Has received total parenteral nutrition (TPN) or albumin in the last 30 days prior to
             screening.

         21. Has any unstable or uncontrolled cardiovascular disorder, heart failure moderate to
             severe (New York Class Association III or IV), any pulmonary, hepatic, renal, 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 subject safety.

         22. Has 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
             non-metastatic 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. Subjects with 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 Screening.

         24. Has a history of any major neurological disorders, including stroke, multiple
             sclerosis, brain tumor, demyelinating, or neurodegenerative disease.

         25. Has a positive progressive multifocal leukoencephalopathy (PML) subjective symptom
             checklist during Screening or prior to the administration of the first dose of study
             drug on Day 1.

         26. Has a history of drug abuse (defined as any illicit drug use) or a history of alcohol
             abuse within 1 year prior to the Screening Visit.