Efficacy and Safety of Vedolizumab Subcutaneously (SC) as Maintenance Therapy in Ulcerative Colitis

Study Overview
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Brief Summary
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The purpose of this study is to assess the effect of vedolizumab subcutaneous (vedolizumab SC) maintenance treatment on clinical remission at Week 52 in participants with moderately to severely active ulcerative colitis (UC) who achieved clinical response following administration of vedolizumab intravenous (vedolizumab IV) induction therapy.

Detailed Description
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The drug being tested in this study is called vedolizumab subcutaneous (vedolizumab SC). Vedolizumab SC is being tested to treat people who have moderate to severely active ulcerative colitis. This study will look at clinical remission as well as mucosal healing, durable clinical response, durable clinical remission, and corticosteroid free remission in participants with UC who receive vedolizumab SC maintenance therapy after having achieved a clinical response to vedolizumab IV induction therapy. The study enrolled 383 patients. All participants will enter into a 6-week Induction Phase where they will be administered open-label vedolizumab IV 300 mg via intravenous infusion (IV) at Week 0 (Day 1) and Week 2 (Day 15), and will then be assessed for a clinical response at Week 6. Participants who achieve a clinical response at Week 6 will be randomly assigned to one of the three treatment groups: Vedolizumab SC 108 mg Q2W and Placebo IV Q8W Vedolizumab IV 300 mg Q8W and Placebo SC Q2W Placebo SC Q2W and Placebo IV Q8W Participants who do not achieve a clinical response at Week 6 will not be randomized in to the Maintenance Period, and will receive a third infusion of vedolizumab IV 300 mg at Week 6. This multi-center trial will be conducted worldwide. The overall time to participate in this study is up to 71 weeks (up to 4 weeks of screening, 52 weeks of treatment and 18 weeks of safety follow-up). Participants will make multiple visits to the clinic, plus a final visit 18 weeks after last dose of study drug for a follow-up assessment. Participants will also participate in a long-term safety follow-up, by phone, at 6 months after the last dose of study drug. After the Week 52 assessments, participants meeting protocol-defined criteria were eligible to enroll in Study MLN0002SC-3030 (NCT02620046; Long-term Safety) 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 also have been eligible for Study MLN0002SC-3030. Participants who did not enroll into Study MLN0002SC-3030 were to complete a final on-study safety assessment at Week 68 (or final safety visit 18 weeks after the last dose) in the Maintenance Phase of Study MLN0002SC-3027.

Official Title
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A Phase 3 Randomized, Double-Blind, Placebo-Controlled Study, With a Vedolizumab IV Reference Arm, to Evaluate the Efficacy and Safety of Vedolizumab Subcutaneous as Maintenance Therapy in Subjects With Moderately to Severely Active Ulcerative Colitis Who Achieved Clinical Response Following Open-Label Vedolizumab Intravenous Therapy

Conditions
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Colitis, Ulcerative

Intervention / Treatment
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* Drug: Vedolizumab 300 mg IV
* Drug: Placebo IV
* Drug: Vedolizumab 108 mg SC
* Drug: Placebo SC


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of ulcerative colitis (UC) established at least 6 months prior to screening, by clinical and endoscopic evidence and corroborated by a histopathology report. Moderately to severely active UC as determined by a complete Mayo score of 6-12 (with an endoscopic subscore ≥2) Evidence of UC extending proximal to the rectum (≥15 cm of involved colon). Inadequate response with, loss of response to, or intolerance to corticosteroids, immunomodulators, or Tumor Necrosis Factor-alpha (TNF-α) antagonists Exclusion Criteria: Evidence of abdominal abscess or toxic megacolon at the initial Screening Visit. Extensive colonic resection, subtotal or total colectomy. Ileostomy, colostomy, or known fixed symptomatic stenosis of the intestine. Prior exposure to investigational or approved non-biologic therapies (eg, cyclosporine, tacrolimus, thalidomide, methotrexate or tofacitinib) for the treatment of underlying disease within 30 days or 5 half-lives of screening (whichever is longer). Prior exposure to any investigational or approved biologic or biosimilar agent within 60 days or 5 half-lives of screening (whichever is longer). Prior exposure to vedolizumab Surgical intervention for UC required at any time during the study. History or evidence of adenomatous colonic polyps that have not been removed or has a history or evidence of colonic mucosal dysplasia. Suspected or confirmed diagnosis of Crohn's entercolitis, indeterminate colitis, ischaemic colitis, radiation colitis, diverticular disease associated with colitis, or microscopic colitis. Active infections Chronic hepatitis B virus (HBV) infection or chronic hepatitis C virus (HCV) infection, HIV or tuberculosis (active or latent), identified congenital or acquired immunodeficiency. HBV immune participants (ie, being hepatitis B surface antigen [HBsAg] negative and hepatitis B antibody positive) may, however, be included. History of any major neurological disorders, including stroke, multiple sclerosis, brain tumor, demyelinating or neurodegenerative disease.

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: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Maintenance Phase: Induction IV + Vedolizumab 108 mg SC<br>Participants received vedolizumab 300 mg IV infusion in open-label induction phase and achieved clinical response at Week 6 were randomized to receive vedolizumab SC in maintenance phase. Vedolizumab SC, 108 mg, injection, Q2W and placebo-matching IV infusions, Q8W, starting at Week 6 up to approximately Week 50. | Drug: Vedolizumab 300 mg IV<br>* Vedolizumab intravenous infusion<br>Drug: Placebo IV<br>* Vedolizumab intravenous infusion placebo<br>Drug: Vedolizumab 108 mg SC<br>* Vedolizumab subcutaneous injection<br>|
| Experimental: Maintenance Phase: Induction IV + Vedolizumab 300 mg IV<br>Participants received vedolizumab 300 mg IV infusion in open-label induction phase and achieved clinical response at Week 6 were randomized to receive vedolizumab IV in maintenance phase. Vedolizumab 300 mg, IV infusion, Q8W and placebo-matching SC injection, Q2W starting at Week 6 up to approximately Week 50. | Drug: Vedolizumab 300 mg IV<br>* Vedolizumab intravenous infusion<br>Drug: Placebo SC<br>* Vedolizumab subcutaneous injection placebo<br>|
| Experimental: Maintenance Phase: Induction IV + Placebo<br>Participants received vedolizumab 300 mg IV infusion in open-label induction phase and achieved clinical response at Week 6 were randomized to receive placebo in maintenance phase. Placebo-matching subcutaneous (SC) injections, once every 2 weeks (Q2W) and placebo-matching IV infusions, once every 8 weeks (Q8W) starting at Week 6 up to approximately Week 50. | Drug: Vedolizumab 300 mg IV<br>* Vedolizumab intravenous infusion<br>Drug: Placebo IV<br>* Vedolizumab intravenous infusion placebo<br>Drug: Placebo SC<br>* Vedolizumab subcutaneous injection placebo<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Achieving Clinical Remission at Week 52 | Clinical remission is defined as a complete Mayo score ≤ 2 points and no individual subscore > 1 point. The Mayo score is a standard assessment tool to measure ulcerative colitis disease activity in clinical trials. The index consists of 4 subscores: rectal bleeding, stool frequency, findings on endoscopy, and physician's global assessment. Each subscore is scored on a scale from 0 to 3 and the complete Mayo score ranges from 0 to 12 (higher scores indicate greater disease activity). | Week 52 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Achieving Mucosal Healing at Week 52 | Mucosal healing is defined as Mayo endoscopic subscore ≤1 point. The findings on endoscopy scale ranges from 0 to 3, where 0=normal or inactive disease 1=mild disease (erythema, decreased vascular pattern, mild friability) 2=moderate disease (marked erythema, lack of vascular pattern, friability, erosions) 3=severe disease (spontaneous bleeding, ulceration). | Week 52 | 
| Percentage of Participants Achieving Durable Clinical Response at Week 6 and Week 52 | Durable clinical response is defined as clinical response at both Weeks 6 and 52, where clinical response is defined as a reduction in complete Mayo score of ≥3 points and ≥30% from Baseline (Week 0) with an accompanying decrease in rectal bleeding subscore of ≥1 point or absolute rectal bleeding subscore of ≤1 point. The Mayo score is a standard assessment tool to measure ulcerative colitis disease activity in clinical trials. The index consists of 4 subscores: rectal bleeding, stool frequency, findings on endoscopy, and physician's global assessment. Each subscore is scored on a scale from 0 to 3 and the complete Mayo score ranges from 0 to 12 (higher scores indicate greater disease activity). | Baseline, Weeks 6 and 52 | 
| Percentage of Participants Achieving Durable Clinical Remission at Week 6 and Week 52 | Durable clinical remission is defined as clinical remission at both Weeks 6 and 52. Clinical remission is defined as a complete Mayo score of less than or equal to (≤) 2 points and no individual subscore greater than (>) 1 point. The Mayo score is a standard assessment tool to measure ulcerative colitis disease activity in clinical trials. The index consists of 4 subscores: rectal bleeding, stool frequency, findings on endoscopy, and physician's global assessment. Each subscore is scored on a scale from 0 to 3 and the complete Mayo score ranges from 0 to 12 (higher scores indicate greater disease activity). | Weeks 6 and 52 | 
| Percentage of Participants Achieving Corticosteroid-free Remission at Week 52 | Corticosteroid-free remission is defined as participants using oral corticosteroids at Baseline (Week 0) who have discontinued oral corticosteroids and are in clinical remission at Week 52. Clinical remission is defined as a complete Mayo score of ≤ 2 points and no individual subscore > 1 point. The Mayo score is a standard assessment tool to measure ulcerative colitis disease activity in clinical trials. The index consists of 4 subscores: rectal bleeding, stool frequency, findings on endoscopy, and physician's global assessment. Each subscore is scored on a scale from 0 to 3 and the complete Mayo score ranges from 0 to 12 (higher scores indicate greater disease activity). | Week 52 | 

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