Phase III Study of MLN0002 (300 mg) in Treatment of Crohn's Disease
Condition: Crohn's Disease
MeSH terms: Crohn Disease
Intervention: Vedolizumab; Vedolizumab placebo
Intervention description: Vedolizumab IV injection; Vedolizumab placebo-matching IV infusion
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: 157.0
Sex: All
Minimum age: 15 Years
Maximum age: 80 Years
Healthy volunteers: No
Keywords: Drug Therapy

Summary:

      This study is a phase 3, multicenter, randomized, double-blinded, placebo-controlled,
      parallel-group study to examine the efficacy, safety, and pharmacokinetics of vedolizumab
      (MLN0002) in induction and maintenance therapy in Japanese participants with moderately or
      severely active Crohn's disease.
    

Eligibility criteria:

        Inclusion Criteria:

          1. In the opinion of the investigator, participants were capable of understanding and
             complying with protocol requirements

          2. Participants or, when applicable, participants legally acceptable representative sign
             and date the informed consent form prior to initiation of any study procedures

          3. Participants aged 15 to 80 years (inclusive) at the time of consent

          4. A nonsterilized male participant who has a female partner of child-bearing potential
             has to agree to use adequate contraception during the period from the signing of
             informed consent to 6 months after the last dose of the study drug

          5. A female participant of child-bearing potential (i.e., nonsterilized or whose last
             regular menses was within previous 2 years) who has a nonsterilized male partner has
             to agree to use adequate contraception during the period from the signing of informed
             consent to 6 months after the last dose of the study drug

          6. Participants with a diagnosis of small-intestinal, large-intestinal, or
             small-/large-intestinal Crohn's disease (CD) established based on the Revised
             Diagnostic Criteria for Crohn's disease issued by Research Group for Intractable
             Inflammatory Bowel Disease Designated as Specified Disease by the Ministry of Health,
             Labor and Welfare of Japan (2012) at least 3 months before the start of administration
             of study drug

          7. Participants with baseline CDAI score of 220 to 450(inclusive) and meeting at least
             one of the followings:

               -  C-reactive protein (CRP) at screening test is above 0.30 mg/dL

               -  Participants with irregular or semicircular ulcers or multiple aphthae (10 or
                  more) observed over an extensive area of the small or large intestine on
                  endoscopy or imaging test within the 4 months before the start of administration
                  of study drugs

               -  Participants with longitudinal ulcers or a cobblestone appearance observed in the
                  small or large intestine on endoscopy or imaging test within 4 months before the
                  start of administration of study drugs

          8. In case of the participants who meet any of the following criteria; participants with
             ≥ 8-year history of extensive or limited colitis, participants aged ≥ 50 years, or
             participants with a first-degree family history of colon cancer, those whom the
             complication of colon cancer or dysplasia was ruled out by total colonoscopy at the
             start of study drug administration (or the results from total colonoscopy performed
             within 1 year before giving consent are available)

          9. Participants meeting the criteria for treatment failure below with at least one of the
             following agents received within previous 5 year period before giving consent

               1. Corticosteroids

                    -  Resistance

                    -  Dependence

                    -  Intolerance

               2. Immunomodulators (azathioprine, 6-mercaptopurine or methotrexate)

                    -  Refractory

                    -  Intolerance

               3. Anti-tumor necrosis factor alpha (TNFα) antibodies

                    -  Inadequate response

                    -  Loss of response

                    -  Intolerance

        Exclusion Criteria:

          1. Participants with an evidence of or suspected abdominal abscess

          2. Participants with a history of subtotal or total colectomy

          3. Participants who have had a resection of the small intestine in at least 3 locations
             or have a diagnosis of short bowel syndrome

          4. Participants with ileostomy, colostomy, or internal fistula, or severe intestinal
             stenosis

          5. Participants who have a treatment history with natalizumab, efalizumab or rituximab

          6. Participants who started 5-aminosalicylic acid oral drug or probiotics treatment,
             antimicrobials to treat Crohn's disease, or 30 mg/day or less of oral corticosteroids
             within 13 days before initiation of study drug administration. If these drugs were
             used within 14 days before initiation of study drug administration, the dosage must
             have been changed or their use discontinued within 13 days before the initiation of
             study drug administration

          7. Participants who had received 5-aminosalicylic acid or corticosteroid
             enemas/suppositories, intravenous corticosteroid injections, or more than 30 mg/day of
             oral corticosteroids, medications for diarrhea-predominant irritable bowel syndrome,
             or Chinese herbal medicine for the treatment of Crohn's disease (e.g., Daikenchuto)
             within 13 days before initiation of study drug administration

          8. Participants who had received azathioprine, 6-mercaptopurine, or methotrexate within
             27 days before initiation of study drug administration. However, this shall not apply
             to participants who have received these drugs for 83 or more days before initiation of
             the study drug administration and continued the steady dose administration of the
             drugs for 27 or more days before initiation of the study drug administration

          9. Participants who had received cyclosporin, tacrolimus, tofacitinib or any study drugs
             for treatment of ulcerative colitis within 27 days before initiation of the study drug
             administration

         10. Participants who had received adalimumab within 27 days before initiation of study
             drug administration or any biological drugs other than adalimumab within 55 days
             before initiation of study drug administration. Topical administration (such as
             intraocular implantation for treatment of age-related maculopacy) is allowed

         11. Participants who had received any live vaccinations within 27 days before initiation
             of study drug administration

         12. Participants who had undergone intestinal resection within 27 days before initiation
             of study drug administration or those anticipated to require intestinal resection
             during the study

         13. Participants who had received leukocytapheresis or granulocyte apheresis within 27
             days before initiation of the study drug administration

         14. Participants who had received intravenous hyperalimentation or total enteral nutrition
             within the 20 days before initiation of the study drug administration or participants
             who are fasted

         15. Participants who had received enteral nutrition at > 900 kcal/day or started enteral
             nutrition at <= 900 kcal/day within the 20 days before initiation of the study drug
             administration. Participants receiving 900 kcal/day or less of enteral nutrition for
             at least 21 days before initiation of the study drug administration whom these dosage
             was changed or the medications were discontinued within 20 days before initiation of
             the study drug administration

         16. Participants who had been infected with Clostridium difficile, cytomegalovirus, or any
             other intestinal pathogen within 27 days before the first dose of the study drug

         17. Participants with evidence of adenomatous colonic polyps that need to be removed at
             the start of study drug administration

         18. Participants with a history or an complication of dysplasia of the small or large
             intestine

         19. Participants who were suspected to have enteritis other than CD

         20. Participants who were hepatitis B surface (HBs) antigen-positive or hepatitis C virus
             (HCV) antibody-positive at the screening. Or participants who are hepatitis B core
             (HBc) antibodypositive or HBs antibody positive, even though HBs antigen-negative.
             However, this does not apply to participants who are only HBs antibody-positive due to
             hepatitis B virus (HBV) vaccination, HBV-DNA-negative, HCV antigen-negative, or
             HCV-RNA-negative

         21. Participants who had an evidence of history of tuberculosis or a suspected history of
             tuberculosis (including those who have findings suggesting previous tuberculosis on
             chest imaging procedure at the screening). However, this does not apply to
             participants who had completed prophylactic isoniazid, or participants who had been
             receiving prophylactic isoniazid for more than 21 days before the first dose of the
             study drug (in the latter case, the screening period are allowed to extend up to 28
             days to ensure at least 21-day prophylactic isoniazid and then the study treatment is
             allowed to start)

         22. Participants who had positive T-SPOT test or QuantiFERON test at the screening

         23. Participants who had a history or complication of identified congenital or acquire
             immunodeficiency syndrome (eg, not-classifiable immunodeficiency, human
             immunodeficiency virus [HIV] infection or organ transplantation)

         24. Participants who had been affected by extraintestinal infection (eg, pneumonia,
             sepsis, active hepatitis or pyelonephritis) within 27 days before the first dose of
             the study drug

         25. Participants who had a treatment history with MLN0002

         26. Female participants who are lactating at the screening, or have positive urine
             pregnancy test either at the screening or baseline

         27. Participants who had serious complications in the heart, lung, liver, kidney,
             metabolism, gastrointestinal system, urinary system, endocrine system or blood

         28. Participants who had a history of a surgery requiring general anesthesia within 27
             days before the first dose of the study drug, or with a schedule of a surgery
             requiring hospitalization during the study period

         29. Participants who had a complication or a history of malignancy. However, this does not
             apply to the following participants:

               -  Participants who had a curative resection of localized skin basal cell carcinoma
                  or have completed curative radiotherapy

               -  Participants who had not experienced recurrence for more than 1 year since
                  completion of a curative resection or curative radiotherapy for skin squamous
                  cell carcinoma

               -  Participants who had not experienced recurrence for more than 3 years since
                  completion of a curative resection or curative radiotherapy for intraepithelial
                  carcinoma of uterine cervix For participants who had a substantially distant
                  history of malignancy (eg, 10 years or longer without recurrence since treatment
                  completion), the investigator and the sponsor had a discussion to decide
                  eligibility on the basis of type of malignancy and treatment applied

         30. Participants who had a history or a complication of the central nervous disorder,
             including stroke, multiple sclerosis, brain tumor, or neurodegenerative disease.

         31. Participants who had any subjective symptoms in the subjective PML checklist at the
             screening or baseline

         32. Participants who had any of the following laboratory abnormalities 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

         33. Participants who had a history or a complication of alcohol dependence or illicit drug
             use within one year before the first dose of the study drug

         34. Participants who had a history or a complication of psychotic disorder that could
             obstruct compliance with the study procedures