Phase III Study of MLN0002 (300 mg) in the Treatment of Ulcerative Colitis
Condition: Ulcerative Colitis
MeSH terms: Colitis; Colitis, Ulcerative; Ulcer
Intervention: Vedolizumab; Vedolizumab placebo
Intervention description: Vedolizumab intravenous infusion; Vedolizumab placebo
Intervention MeSH terms: Vedolizumab
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 292.0
Sex: All
Minimum age: 15 Years
Maximum age: 80 Years
Healthy volunteers: No
Keywords: Drug therapy

Summary:

      The purpose of this study is to evaluate efficacy, safety and pharmacokinetics of the
      vedolizumab (MLN0002) induction and maintenance therapy in Japanese participants with
      moderate or severe ulcerative colitis (UC).
    

Eligibility criteria:

        Inclusion Criteria:

          1. In the opinion of the investigator, a participant is capable of understanding and
             complying with protocol requirements.

          2. A participant who is capable of entering the signature and the date on the informed
             consent by himself/herself or by the participant's legally acceptable representative,
             if applicable, prior to initiation of study procedures.

          3. A participant aged 15 to 80 (inclusive) at the time of signing the informed consent
             (regardless of sexes).

          4. A male participant, who has no sterilization history and whose female partner has
             child-bearing potential, who agreed with taking proper contraception during the period
             from the time of signing the informed consent form through 6 months after the last
             dose of study drug.

          5. A female participant with child-bearing potential (having no history of sterilization
             or whose last menstruation was within 2 years) whose male partner is not receiving
             contraceptive treatment, and agreed to take proper contraception during the period
             from the time of signing on the informed consent form through 6 months after the last
             dose of the study drug.

          6. Participants with diagnosis of total or left-sided ulcerative colitis (UC) based on
             the Revised Diagnostic Criteria for UC issued by "Research Group for Intractable
             Inflammatory Bowel Disease Designated as Specified Disease" by the Ministry of Health,
             Labor and Welfare (MHLW) of Japan (2012) at least 6 months before the start of
             administration of the study drug.

          7. A participant with moderately or severely active UC as determined by baseline complete
             Mayo score of 6 to 12 (inclusive) with an endoscopic subscore of ≥2.

          8. Participants whose complication of colon cancer or dysplasia had to be ruled out by
             total colonoscopy at the start of the study drug administration (or the results from
             total colonoscopy performed within 1 year before giving consent are available), if
             participants met any of the following criteria; participants with ≥8-year history of
             total or left-sided colitis, participants aged ≥50 years, or participants with a
             first-degree family history of colon cancer.

          9. Participants meeting the following treatment failure criteria with at least one of the
             following agents within 5 years before signing on the informed consent:

               1. Corticosteroids

                    -  Resistance: Participants whose response was inadequate after treatment of
                       ≥40 mg/day for ≥1 week (oral or IV) or 30 to 40 mg/day for ≥2 weeks (oral or
                       IV).

                    -  Dependence: Participants for which it is difficult to reduce the dosage to
                       <10 mg/day due to recurrence during gradual dose reduction (oral or IV).

                    -  Intolerance: Participants who were unable to receive continuous treatment
                       due to adverse reactions (e.g., Cushing's syndrome, osteopenia/osteoporosis,
                       hyperglycaemia, insomnia, infection).

               2. Immunomodulators (azathioprine [AZA] or 6- mercaptopurine [6-MP])

                    -  Refractory: Participants whose response was inadequate after treatment for
                       ≥12 weeks.

                    -  Intolerance: Participants who were unable to receive continuous treatment
                       due to adverse reactions (e.g., nausea/vomiting, abdominal pain,
                       pancreatitis, liver function test abnormalities, lymphopenia, thiopurine
                       S-methyltransferase genetic mutation, infection).

               3. Tumor necrosis factor-alpha (TNFα) antagonist

                    -  Inadequate response: Participants whose response was inadequate after the
                       induction therapy in the dosage described in the package insert.

                    -  Loss of response: Participants who had recurrence during the scheduled
                       maintenance therapy after achievement of clinical response (those who
                       withdrew for other reasons than relapse are not applicable here).

                    -  Intolerance: Participants who were unable to receive continuous treatment
                       due to adverse reactions (eg, infusion-related reaction, demyelination,
                       congestive heart failure, infection).

        Exclusion Criteria:

          1. Participants whose partial Mayo score decrease by 3 points or more between screening
             and the start of study drug administration.

          2. Participants having or suspected to have abdominal abscess or toxic megacolon.

          3. Participants with a history of subtotal or total colectomy.

          4. Participants with ileostomy, colostomy, fistula or severe intestinal stenosis.

          5. Participants having a treatment history with natalizumab, efalizumab or rituximab.

          6. Participants who started oral 5-ASA, probiotics, or oral corticosteroids (≤30 mg/day)
             within 13 days before the first dose of the study drug. Participants who have used
             these drugs for at least 14 days before the first dose of the study drug, and who
             changed dosage of or discontinued these drugs within 13 days before the first dose of
             the study drug.

          7. Participants who have received 5-ASA, corticosteroid enemas/suppositories,
             corticosteroid IV infusion, oral corticosteroid at >30 mg/day, drugs for
             diarrhea-predominant irritable bowel syndrome, or Chinese herbal medicine for the UC
             treatment (eg, Daikenchuto) within 13 days before the first dose of the study drug.

          8. Participants who have used an antidiarrheal drug for 4 or more consecutive days within
             13 days before the first dose of the study drug or within 7 days before the first dose
             of the study drug.

          9. Participants who have received AZA or 6-MP within 27 days before the first dose of the
             study drug However, this will not apply to participants who have used these drugs for
             83 or more days before the first dose of the study drug and continued the steady dose
             administration of the drugs for 27 or more days before the first dose of the study
             drug.

         10. Participants who have received cyclosporine, tacrolimus, methotrexate, tofacitinib or
             any study drugs of low-molecular compound for UC treatment within 27 days before the
             first dose of the study drug.

         11. Participants who have received adalimumab within 27 days before the first dose of the
             study drug or any biologic agents other than adalimumab within 55 days before the
             first dose of the study drug. However, this will not apply to participants who have
             topically received these drugs (eg., intraocular injection for treatment of
             age-related macular degeneration).

         12. Participants who have received any live-vaccinations within 27 days before the first
             dose of the study drug.

         13. Participants who underwent the enterectomy within 27 days before the first dose of the
             study drug or those anticipated to require an enterectomy during the study.

         14. Participants who have received leukocytapheresis or granulocyte apheresis within 27
             days before the first dose of the study drug.

         15. Participants who have been infected with an intestinal pathogen including clostridium
             difficile or cytomegalovirus within 27 days before the first dose of the study drug.

         16. Participants with evidence of adenomatous colonic polyps that need to be removed at
             the start of study drug administration.

         17. Participants with a history or a complication of colonic mucosal dysplasia.

         18. Participants suspected to have enteritis other than UC.

         19. Participants indicated in the screening test as hepatitis B surface (HBs)
             antigen-positive or hepatitis C virus (HCV) antibody-positive. Participants indicated
             as hepatitis B core (HBc) antibody-positive or HBs antibody positive even though HBs
             antigen-negative However, the criteria will not apply to those with only HBs
             antibody-positive due to hepatitis B virus (HBV) vaccination, HBV-DNA-negative, HCV
             antigen-negative or HCV-RNA-negative.

         20. Participants who have or are suspected to have a history of tuberculosis (including
             those whose findings in the chest imaging procedure at screening showing anamnesis of
             tuberculosis). However, the criteria will not apply to those who had completed
             prophylactic treatment with isoniazid, and who have been receiving prophylactic
             isoniazid for 21 days or longer before the first dose of the study drug (the latter
             may initiate study drug administration with screening phase extended to 28 days at
             maximum for prophylactic treatment to become 21 days or more).

         21. Participants indicated as positive in T-SPOT or QuantiFERON at screening test.

         22. Participants who have a history or complication of identified congenital or acquired
             immunodeficiency syndrome (eg, not-classifiable immunodeficiency, human
             immunodeficiency virus [HIV] infection or organ transplantation).

         23. Participants who were affected by extra-intestinal infection (eg, pneumonia, sepsis,
             active hepatitis or pyelonephritis) within 27 days before the first dose of the study
             drug.

         24. Participants who have treatment history with MLN0002.

         25. Nursing mothers during the screening phase, or female participants indicated positive
             in urine pregnancy test either at the screening or baseline.

         26. Participants having serious complications in the heart, lung, liver, kidney,
             metabolism, gastrointestinal system, urinary system, endocrine system or blood.

         27. Participants with a history of an operation requiring general anesthesia within 27
             days before the first dose of the study drug, or with a schedule of an operation
             requiring hospitalization during the study period.

         28. Participants having a complication or a history of malignancy However, it will not
             apply to the following participants;

               -  Participants who had a curative resection of localized skin basal cell carcinoma
                  or had completed curative radiotherapy.

               -  Participants who have not experienced recurrence for 1 year or longer since
                  completion of curative resection or curative radiotherapy for skin squamous cell
                  carcinoma.

               -  Participants who have not experienced recurrence for 3 year or longer since
                  completion of curative resection or curative radiotherapy for intraepithelial
                  carcinoma of uterine cervix.

             For participants having a substantially distant history of malignancy (eg, 10 years or
             longer without recurrence since treatment completion), the Investigator and the
             sponsor will discuss to decide eligibility on the basis of type of malignancy and
             treatment applied.

         29. Participants having a history or a complication of the central nervous disorder,
             including stroke, multiple sclerosis, brain tumor, or neurodegenerative disease.

         30. Participants for which any subjective symptoms in the Subjective PML checklist were
             found at the screening or baseline.

         31. Participants for which any of the following laboratory abnormalities were found at the
             screening;

               -  Hemoglobin ≤8 g/dL

               -  White blood cells ≤3,000/μL

               -  Lymphocytes ≤500/μL

               -  Platelets ≤100,000/μL, or ≥1,200,000/μL

               -  Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≥3×upper limit
                  of normal (ULN)

               -  Alkaline phosphatase (ALP) ≥3×ULN

               -  Creatinine ≥2×ULN

         32. Participants having a history or a complication of alcohol dependence or illicit drug
             use within one year before the first dose of the study drug.

         33. Participants having a history or a complication of psychotic disorder that may
             obstruct compliance with the study procedures.