Phase III Study of MLN0002 (300 mg) in Treatment of Crohn's Disease

Study Overview
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Brief Summary
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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.

Detailed Description
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This is a phase 3, multicenter, randomized, double-blinded, placebo-controlled, parallel-group study to examine the efficacy, safety, and pharmacokinetics of intravenous vedolizumab (300 mg) infusion in induction and maintenance therapy in Japanese participants with moderately or severely active Crohn's disease.

Official Title
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Phase III, Multicenter, Randomized, Double-blinded, Placebo-controlled, Parallel-group Study to Evaluate the Efficacy, Safety, and Pharmacokinetics of Intravenous MLN0002 (300 mg) Infusion in Induction and Maintenance Therapy in Japanese Subjects With Moderate or Severe Crohn's Disease

Conditions
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Crohn's Disease

Intervention / Treatment
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* Drug: Vedolizumab
* Drug: Vedolizumab placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: In the opinion of the investigator, participants were capable of understanding and complying with protocol requirements Participants or, when applicable, participants legally acceptable representative sign and date the informed consent form prior to initiation of any study procedures Participants aged 15 to 80 years (inclusive) at the time of consent 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 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 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 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 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) 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 Corticosteroids Resistance Dependence Intolerance Immunomodulators (azathioprine, 6-mercaptopurine or methotrexate) Refractory Intolerance Anti-tumor necrosis factor alpha (TNFα) antibodies Inadequate response Loss of response Intolerance Exclusion Criteria: Participants with an evidence of or suspected abdominal abscess Participants with a history of subtotal or total colectomy Participants who have had a resection of the small intestine in at least 3 locations or have a diagnosis of short bowel syndrome Participants with ileostomy, colostomy, or internal fistula, or severe intestinal stenosis Participants who have a treatment history with natalizumab, efalizumab or rituximab 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 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 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 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 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 Participants who had received any live vaccinations within 27 days before initiation of study drug administration 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 Participants who had received leukocytapheresis or granulocyte apheresis within 27 days before initiation of the study drug administration 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 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 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 Participants with evidence of adenomatous colonic polyps that need to be removed at the start of study drug administration Participants with a history or an complication of dysplasia of the small or large intestine Participants who were suspected to have enteritis other than CD 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 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) Participants who had positive T-SPOT test or QuantiFERON test at the screening 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) 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 Participants who had a treatment history with MLN0002 Female participants who are lactating at the screening, or have positive urine pregnancy test either at the screening or baseline Participants who had serious complications in the heart, lung, liver, kidney, metabolism, gastrointestinal system, urinary system, endocrine system or blood 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 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 Participants who had a history or a complication of the central nervous disorder, including stroke, multiple sclerosis, brain tumor, or neurodegenerative disease. Participants who had any subjective symptoms in the subjective PML checklist at the screening or baseline 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 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 Participants who had a history or a complication of psychotic disorder that could obstruct compliance with the study procedures

Ages Eligible for Study
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Minimum Age: 15 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Induction Phase: Vedolizumab, 300 mg<br>Vedolizumab 300 mg, intravenous (IV) infusion, once at Weeks 0, 2 and 6 in the induction phase. | Drug: Vedolizumab<br>* Vedolizumab IV injection<br>* Other names: MLN0002;|
| Placebo Comparator: Induction Phase: Placebo<br>Vedolizumab placebo-matching IV infusion once at Weeks 0, 2 and 6 in the induction phase. | Drug: Vedolizumab placebo<br>* Vedolizumab placebo-matching IV infusion<br>|
| Experimental: Maintenance Phase: Vedolizumab 300 mg<br>Vedolizumab placebo-matching, IV infusion, once at Weeks 14, 22, 30, 38, 46 and 54 in maintenance phase. Participants received vedolizumab in induction phase and achieved Crohn's Disease Activity Index (CDAI)-70 response at Week 10 and were randomized to receive vedolizumab in maintenance phase. | Drug: Vedolizumab<br>* Vedolizumab IV injection<br>* Other names: MLN0002;|
| Placebo Comparator: Maintenance Phase: Placebo<br>Vedolizumab placebo-matching, IV infusion, once at Weeks 14, 22, 30, 38, 46 and 54 in maintenance phase. Participants received vedolizumab in induction phase and achieved CDAI-70 response at Week 10 and were randomized to receive placebo in maintenance phase. | Drug: Vedolizumab placebo<br>* Vedolizumab placebo-matching IV infusion<br>|
| Placebo Comparator: Maintenance Phase: Placebo Continuation<br>Vedolizumab placebo-matching, IV infusion, once at Weeks 14, 22, 30, 38, 46 and 54 in maintenance phase. Participants received vedolizumab placebo-matching in induction phase and achieved CDAI-70 response at Week 10 received placebo in maintenance phase without randomization. | Drug: Vedolizumab placebo<br>* Vedolizumab placebo-matching IV infusion<br>|
| Experimental: Open-Label: Vedolizumab 300 mg<br>Vedolizumab 300 mg, IV infusion, once at Weeks 0, 2 and 6 and then every 8 weeks thereafter up to Week 94 as a maximum duration in open-label phase. | Drug: Vedolizumab<br>* Vedolizumab IV injection<br>* Other names: MLN0002;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Markedly Abnormal Values of Laboratory Parameters Values | The laboratory values outside the range (Hemoglobin <=7 g/dL, Lymphocytes <500 /microL, White Blood Cell (WBC) <2000 /microL, Platelets <7.5 10^4/microL, Neutrophils <1000 /microL, Alanine Aminotransferase (ALT) (Glutamic Pyruvic Transaminase; GPT) >3.0 U/L x upper limit of normal (ULN), Aspartate Aminotransferase (AST) (Glutamic Oxaloacetic Transaminase; GOT) >3.0 U/L x ULN, Total Bilirubin >2.0 mg/dL x ULN, Amylase >2.0 (U/L) x ULN are considered markedly abnormal. | From Baseline up to 16 weeks after the last dose of study drug (Up to approximately 170 weeks) | 
| Induction Phase: Percentage of Participants With Crohn's Disease Activity Index (CDAI)-100 Response | A response to therapy is considered a decrease from baseline of at least 100 points in the CDAI score at Week 10. CDAI is scoring system for the assessment of Crohn's disease activity. The total CDAI score ranges from 0 to approximately 600, where higher scores indicate more severe disease. Index values of 150 and below are associated with quiescent disease; values above that indicate active disease. | Week 10 | 
| Maintenance Phase: Percentage of Participants With Clinical Remission | Clinical remission is defined as the CDAI score ≤150. CDAI is scoring system for the assessment of Crohn's disease activity. Index values of 150 and below are associated with quiescent disease; values above that indicate active disease. | Week 60 | 
| Number of Participants Who Experienced at Least One or More Treatment-Emergent Adverse Events (TEAEs) | An Adverse event (AE) is defined as any untoward medical occurrence in a study participant who received a drug (including a study drug); it does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (e.g., a clinically significant abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug whether or not it is considered related to the drug. A TEAE is defined as an adverse event with an onset that occurs after receiving study drug. | From Baseline up to 16 weeks after the last dose of study drug (Up to approximately 170 weeks) | 
| Number of Participants With TEAE Related to Body Weight (Weight Decreased) | Reported events on this outcome measure were Weight Decreased. | From Baseline up to 16 weeks after the last dose of study drug (Up to approximately 170 weeks) | 
| Number of Participants With TEAE Related to Vital Signs | Vital signs included body temperature (axilla), sitting blood pressure (after the participant has rested for at least 5 minutes), and pulse (bpm). Reported events on this outcome measure were Pyrexia, Body temperature increased, Hypertension, and Orthostatic hypotension. | From Baseline up to 16 weeks after the last dose of study drug (Up to approximately 170 weeks) | 
| Number of Participants With TEAE Related to Electrocardiogram (ECG) [Bundle Branch Block Right] | Reported events on this outcome measure were Bundle Branch Block Right. | From Baseline up to 16 weeks after the last dose of study drug (Up to approximately 170 weeks) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Induction Phase: Percentage of Participants With Clinical Remission | Clinical remission is defined as the CDAI score ≤150. CDAI is scoring system for the assessment of Crohn's disease activity. Index values of 150 and below are associated with quiescent disease; values above that indicate active disease. | Week 10 | 
| Induction Phase: Change From Baseline in C-reactive Protein (CRP) Values |  | Baseline to Week 10 | 
| Maintenance Phase: Percentage of Participants With Crohn's Disease Activity Index (CDAI)-100 Response | A response to therapy is considered a decrease from baseline of at least 100 points in the CDAI score at Week 10. CDAI is scoring system for the assessment of Crohn's disease activity. The total CDAI score ranges from 0 to approximately 600, where higher scores indicate more severe disease. Index values of 150 and below are associated with quiescent disease; values above that indicate active disease. | Week 60 | 
| Maintenance Phase: Percentage of Participants With Durable Clinical Remission | Durable clinical remission is defined as participants with CDAI score ≤ 150 at both Weeks 14 and 60. CDAI is scoring system for the assessment of Crohn's disease activity. The total CDAI score ranges from 0 to approximately 600, where higher scores indicate more severe disease. Index values of 150 and below are associated with quiescent disease; values above that indicate active disease. | From Week 14 and Week 60 | 
| Maintenance Phase: Percentage of Participants With Corticosteroid-free Clinical Remission | Corticosteroid-free clinical remission is defined as participants using oral corticosteroids at baseline (Week 0) who discontinued corticosteroids and were in clinical remission (CDAI score ≤ 150) at Week 60. CDAI is scoring system for the assessment of Crohn's disease activity. The total CDAI score ranges from 0 to approximately 600, where higher scores indicate more severe disease. Index values of 150 and below are associated with quiescent disease; values above that indicate active disease. | Week 60 | 
| Serum Vedolizumab Concentration in Induction Phase |  | Weeks 2, 6, 10 and 14 | 
| Serum Vedolizumab Concentration in Maintenance Phase |  | Weeks 2, 6, 10, 14, 22, 30 and 60 | 
| Number of Participants With Anti-vedolizumab Antibodies (AVA) in Induction Phase |  | Weeks 0, 10 and 16 weeks after the last dose of study drug in induction phase | 
| Number of Participants With Anti-vedolizumab Antibodies (AVA) in Maintenance Phase |  | Weeks 0, 10, 30, 60 and 16 weeks after the last dose of study drug in maintenance phase | 
| Number of Participants With Anti-vedolizumab Antibodies (AVA) in Open Label Cohort |  | Weeks 0, 10, 30, 62, 94 and 16 weeks after the last dose of study drug in open-label cohort | 
| Number of Participants With Neutralizing Anti-vedolizumab Antibodies (AVA) in Induction Phase |  | Weeks 0, 10 and 16 weeks after the last dose of study drug in induction phase | 
| Number of Participants With Neutralizing Anti-vedolizumab Antibodies (AVA) in Maintenance Phase |  | Weeks 0, 10, 30, 60 and 16 weeks after the last dose of study drug in maintenance phase | 
| Number of Participants With Neutralizing Anti-vedolizumab Antibodies (AVA) in Open Label Cohort |  | Weeks 0, 10, 30, 62, 94 and 16 weeks after the last dose of study drug in open-label cohort | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Drug Therapy