Study of Vedolizumab (MLN0002) in Patients With Moderate to Severe Crohn's Disease

Study Overview
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Brief Summary
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The primary purpose of this study was to determine the effect of vedolizumab induction treatment on clinical response and remission at 6 weeks and to determine the effect of vedolizumab maintenance treatment on clinical remission at 52 weeks.

Detailed Description
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Study C13007 comprised 2 randomized, double-blind, placebo-controlled studies conducted under 1 protocol which, operationally, consisted of 2 phases. The Induction Phase, designed to establish the efficacy and safety of vedolizumab for the induction of clinical response and clinical remission, and The Maintenance Phase, designed to establish the efficacy and safety of vedolizumab for the maintenance of clinical response and clinical remission. The 6-week Induction Phase contained 2 cohorts of participants: Cohort 1 participants were randomized and treated with double-blind study drug, and Cohort 2 participants were treated with open-label vedolizumab. The second cohort was enrolled to ensure that the sample size of Induction Phase responders randomized into the Maintenance Study provided sufficient power for the Maintenance Study primary efficacy analysis. These participants did not contribute to the efficacy analyses performed for the Induction Study. Participants in both cohorts were assessed for treatment response at Week 6. In the Maintenance Phase vedolizumab-treated participants from both Cohort 1 and Cohort 2 who demonstrated a clinical response were randomized in a 1:1:1 ratio to double-blind treatment with vedolizumab administered every 4 weeks (Q4W), vedolizumab administered every 8 weeks (Q8W), or placebo. Vedolizumab-treated participants who did not demonstrate response at Week 6 continued treatment with open-label vedolizumab, administered Q4W. Participants treated with double-blind placebo in the Induction Phase continued on double-blind placebo during the Maintenance Phase, regardless of treatment response during induction. The Maintenance Phase began at Week 6 and concluded with Week 52 assessments. After the Week 52 assessments, participants may have been eligible to enroll in Study C13008 (NCT00790933; Long-term Safety Study) to receive open-label vedolizumab treatment. Participants who withdrew early (prior to Week 52) due to sustained nonresponse, disease worsening, or the need for rescue medications may have been eligible to enroll in Study C13008. Participants who did not enroll into Study C13008 were to complete a final on-study safety assessment at Week 66 (or Final Safety visit 16 weeks after the last dose) in the Maintenance Phase of Study C13007.

Official Title
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A Phase 3, Randomized, Placebo-Controlled, Blinded, Multicenter Study of the Induction and Maintenance of Clinical Response and Remission by Vedolizumab (MLN0002) in Patients With Moderate to Severe Crohn's Disease

Conditions
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Crohn's Disease

Intervention / Treatment
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* Drug: vedolizumab
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 18 to 80 Diagnosis of moderately to severely active Crohn's disease (CD) CD involvement of the ileum and/or colon Demonstrated, over the previous 5 year period, an inadequate response to, loss of response to, or intolerance of at least 1 of the following agents, within protocol-specified parameters: Immunomodulators Tumor necrosis factor-alpha (TNFα) antagonists Corticosteroids May be receiving a therapeutic dose of conventional therapies for irritable bowel disease (IBD) defined by the protocol Exclusion Criteria Evidence of abdominal abscess at the initial screening visit, other than a minimum of 10 aphthous ulcerations involving a minimum of 10 contiguous cm of intestine Extensive colonic resection, subtotal or total colectomy History of >3 small bowel resections or diagnosis of short bowel syndrome Ileostomy, colostomy, or known fixed symptomatic stenosis of the intestine Have received non permitted IBD therapies within either 30 or 60 days, depending on the medication, as stated in the protocol Chronic hepatitis B or C infection Active or latent tuberculosis

Ages Eligible for Study
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Minimum Age: 18 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: Factorial Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Vedolizumab<br>In the Induction Phase participants received vedolizumab 300 mg, administered by intravenous infusion at Week 0 and Week 2 (Days 1 and 15). In the Maintenance Phase, participants who demonstrated a clinical response at Week 6 according to protocol-specified criteria were randomized in a 1:1:1 ratio to double-blind treatment with vedolizumab administered every 4 weeks, vedolizumab administered every 8 weeks, or placebo for up to Week 50. Participants who did not demonstrate response at Week 6 of the Induction Phase continued treatment with vedolizumab, administered every 4 weeks during the Maintenance Phase. | Drug: vedolizumab<br>* Vedolizumab for intravenous infusion<br>* Other names: LDP-02;|
| Placebo Comparator: Placebo<br>In the Induction Phase participants received placebo intravenous infusion at Week 0 and Week 2 (Days 1 and 15). Participants continued to receive placebo during the Maintenance Phase, regardless of treatment response during Induction. | Other: Placebo<br>* Placebo intravenous infusion<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Induction Phase: Percentage of Participants Achieving Clinical Remission at Week 6 | Clinical remission is defined as a Crohn's Disease Activity Index (CDAI) score ≤ 150 points. The CDAI is used to quantify the symptoms of patients with Crohn's disease and consists of eight factors, each summed after adjustment with a weighting factor. The components of the CDAI are: Number of liquid or soft stools each day for 7 days; Abdominal pain (graded from 0-3 on severity) each day for 7 days; General well-being, subjectively assessed from 0 (well) to 4 (terrible) each day for 7 days; Presence of complications; Taking Lomotil or opiates for diarrhea; Presence of an abdominal mass (0 as none, 2 as questionable, 5 as definite); Hematocrit of < 0.47 in men and < 0.42 in women; Percentage deviation from standard weight. The total score ranges from 0 to approximately 600 and with higher scores indicating greater disease activity. All participants who prematurely discontinued for any reason were considered as not achieving clinical remission. | Week 6 | 
| Induction Phase: Percentage of Participants With Enhanced Clinical Response at Week 6 | Enhanced clinical response is defined as a CDAI score at least 100 points lower than Baseline. The CDAI is used to quantify the symptoms of patients with Crohn's disease and consists of eight factors, each summed after adjustment with a weighting factor. The components of the CDAI are: Number of liquid or soft stools each day for 7 days; Abdominal pain (graded from 0-3 on severity) each day for 7 days; General well-being, subjectively assessed from 0 (well) to 4 (terrible) each day for 7 days; Presence of complications; Taking Lomotil or opiates for diarrhea; Presence of an abdominal mass (0 as none, 2 as questionable, 5 as definite); Hematocrit of < 0.47 in men and < 0.42 in women; Percentage deviation from standard weight. The total score ranges from 0 to 600 with higher scores indicating greater disease activity. All participants who prematurely discontinued for any reason were considered as not achieving enhanced clinical response. | Baseline and Week 6 | 
| Maintenance Phase: Percentage of Participants Achieving Clinical Remission at Week 52 | Clinical remission is defined as a CDAI score ≤ 150. The CDAI is used to quantify the symptoms of patients with Crohn's disease and consists of eight factors, each summed after adjustment with a weighting factor. The components of the CDAI are: Number of liquid or soft stools each day for 7 days; Abdominal pain (graded from 0-3 on severity) each day for 7 days; General well-being, subjectively assessed from 0 (well) to 4 (terrible) each day for 7 days; Presence of complications; Taking Lomotil or opiates for diarrhea; Presence of an abdominal mass (0 as none, 2 as questionable, 5 as definite); Hematocrit of < 0.47 in men and < 0.42 in women; Percentage deviation from standard weight. The total score ranges from 0 to 600 with higher scores indicating greater disease activity. All participants who prematurely discontinued for any reason were considered as not achieving clinical remission. | Week 52 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Induction Phase: Change From Baseline in C-Reactive Protein (CRP) Levels at Week 6 | C-reactive protein (CRP) is a protein found in the blood, the levels of which rise in response to inflammation. Normal concentration in healthy human serum is usually lower than 10 mg/L, slightly increasing with age. Higher levels indicate mild inflammation (10-40 mg/L) and active inflammation (40-200 mg/L). | Baseline and Week 6 | 
| Maintenance Phase: Percentage of Participants With Enhanced Clinical Response at Week 52 | Enhanced clinical response is defined as a CDAI score at least 100 points lower than the Baseline value. The CDAI is used to quantify the symptoms of patients with Crohn's disease and consists of eight factors, each summed after adjustment with a weighting factor. The components of the CDAI are: Number of liquid or soft stools each day for 7 days; Abdominal pain (graded from 0-3 on severity) each day for 7 days; General well-being, subjectively assessed from 0 (well) to 4 (terrible) each day for 7 days; Presence of complications; Taking Lomotil or opiates for diarrhea; Presence of an abdominal mass (0 as none, 2 as questionable, 5 as definite); Hematocrit of < 0.47 in men and < 0.42 in women; Percentage deviation from standard weight. The total score ranges from 0 to 600 with higher scores indicating greater disease activity. All participants who prematurely discontinued for any reason were considered as not achieving enhanced clinical response. | Baseline and Week 52 | 
| Maintenance Phase: Percentage of Participants in Corticosteroid-free Clinical Remission at Week 52 | Participants using oral corticosteroids at Baseline, who discontinued corticosteroids and were in clinical remission (CDAI score ≤ 150) at Week 52 achieved corticosteroid-free clinical remission. The CDAI quantifies the symptoms of patients with Crohn's disease and consists of eight factors, summed after adjustment with a weighting factor. The total score ranges from 0 to 600 with higher scores indicating greater disease activity. All participants who prematurely discontinued for any reason were considered as not achieving corticosteroid-free clinical remission. | Week 52 | 
| Maintenance Phase: Percentage of Participants With Durable Clinical Remission | Durable clinical remission is defined as CDAI score ≤ 150 points at 80% or more of study visits during the Maintenance Phase, including the Week 52 visit (11 of 13 study visits). The CDAI quantifies the symptoms of patients with Crohn's disease and consists of eight factors, summed after adjustment with a weighting factor. The total score ranges from 0 to 600 with higher scores indicating greater disease activity. All participants who prematurely discontinued for any reason were considered as not achieving durable clinical remission | Assessed every 4 weeks from Week 6 to Week 50, and at Week 52 |