A Study of the Efficacy and Safety of Etrolizumab Treatment in Maintenance of Disease Remission in Ulcerative Colitis (UC) Participants Who Are Naive to Tumor Necrosis Factor (TNF) Inhibitors

Study Overview
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Brief Summary
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This Phase III, randomized, double-blind, parallel-grouped, placebo-controlled, multicenter study will investigate the efficacy and safety of etrolizumab in maintenance of remission in participants with moderately to severely active UC who are naive to TNF inhibitors and refractory to or intolerant of prior immunosuppressant and/or corticosteroid treatment.

Official Title
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Phase III, Randomized, Double-Blind, Placebo-Controlled, Multicenter Study to Evaluate the Efficacy (Maintenance of Remission) and Safety of Etrolizumab Compared With Placebo in Patients With Moderate to Severe Active Ulcerative Colitis Who Are Naive to TNF Inhibitors

Conditions
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Colitis, Ulcerative

Intervention / Treatment
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* Drug: Etrolizumab
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of ulcerative colitis (UC) established at least 3 months prior to Day 1 by clinical and endoscopic evidence Moderately to severely active UC as determined by an MCS of 6-12 with an endoscopic subscore greater than or equal to (≥)2 as determined by the central reading procedure (endoscopy to be performed 4-16 days prior to Day 1), a rectal bleeding subscore ≥1, and a stool frequency subscore ≥1 during the screening period (prior to Day 1) Evidence of UC extending a minimum of 20 centimeters (cm) from the anal verge as determined by baseline endoscopy (flexible sigmoidoscopy or colonoscopy) performed during screening, 4-16 days prior to Day 1 Naive to treatment with any anti-TNF therapy Participants must have had an inadequate response, loss of response, or intolerance to prior corticosteroid and/or immunosuppressant treatment Background regimen for UC may include oral 5-aminosalicylate (5-ASA), oral corticosteroids, budesonide, probiotics, azathioprine (AZA), 6-mercaptopurine (6-MP), or methotrexate (MTX) if doses have been stable during the screening period Use of highly effective contraception Must have received a colonoscopy within the past year or be willing to undergo a colonoscopy in lieu of a flexible sigmoidoscopy at screening Exclusion Criteria: A history of or current conditions and diseases affecting the digestive tract, such as indeterminate colitis, suspicion of ischemic colitis, radiation colitis, or microscopic colitis, Crohn's disease, fistulas or abdominal abscesses, colonic mucosal dysplasia, intestinal obstruction, toxic megacolon, or unremoved adenomatous colonic polyps Prior or planned surgery for UC Past or present ileostomy or colostomy Any prior treatment with etrolizumab or other anti-integrin agents (including natalizumab, vedolizumab, and efalizumab) as stated in the protocol Any prior treatment with anti-adhesion molecules (such as mucosal addressin cell adhesion molecule [MAdCAM-1]) Any prior treatment with rituximab Any treatment with tofacitinib during screening Cogenital or acquired immune deficiency, chronic hepatitis B or C infection, human immunodeficiency virus (HIV) positive, or history of tuberculosis (active or latent) Evidence of or treatment for Clostridium difficile within 60 days prior to Day 1 or other intestinal pathogens within 30 days prior to Day 1 History of recurrent opportunistic infections and/or severe disseminated viral infections History of organ transplant Any major episode of infection requiring treatment with intravenous (IV) antibiotics within 8 weeks prior to screening or oral antibiotics within 4 weeks prior to screening Received a live attenuated vaccine within 4 weeks prior to Day 1

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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Open-Label Induction Phase: Etrolizumab<br>All participants will receive treatment with open-label etrolizumab 105 milligrams (mg) subcutaneous (SC) injection once every 4 weeks (Q4W) up to Week 10. | Drug: Etrolizumab<br>* Participants will receive 105 mg etrolizumab SC injection Q4W.<br>* Other names: rhuMAb Beta7;|
| Experimental: Double-Blind Maintenance Phase: Etrolizumab<br>Participants who achieved a clinical response at Week 10 during the induction phase and randomized to this arm for the double-blind maintenance phase will receive etrolizumab 105 mg SC injection Q4W from Week 12 up to Week 62. | Drug: Etrolizumab<br>* Participants will receive 105 mg etrolizumab SC injection Q4W.<br>* Other names: rhuMAb Beta7;|
| Placebo Comparator: Double-Blind Maintenance Phase: Placebo<br>Participants who achieved a clinical response at Week 10 during the induction phase and randomized to this arm for the double-blind maintenance phase will receive placebo (matched to etrolizumab) SC injection Q4W from Week 12 up to Week 62. | Drug: Placebo<br>* Participants will receive placebo (matched to etrolizumab) SC injection Q4W.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maintenance Phase: Percentage of Participants in Remission at Week 62 Among Randomized Participants With a Clinical Response at Week 10, as Determined by the Mayo Clinic Score (MCS) | MCS is a composite of 4 assessments, each rated from 0-3: stool frequency, rectal bleeding, endoscopy, and physician's global assessment. Clinical Response is MCS with ≥3-point decrease and 30% reduction from baseline as well as ≥1-point decrease in rectal bleeding subscore or an absolute rectal bleeding score of 0 or 1. Remission is MCS ≤2 with individual subscores ≤1 and a rectal bleeding subscore of 0. | Week 62 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maintenance Phase: Percentage of Participants Who Maintained Clinical Remission at Week 62 Among Randomized Participants in Clinical Remission at Week 10, as Determined by the MCS | MCS is a composite of 4 assessments, each rated from 0-3: stool frequency, rectal bleeding, endoscopy, and physician's global assessment. Clinical Remission is MCS ≤2 with individual subscores ≤1. | Week 62 | 
| Maintenance Phase: Percentage of Participants in Clinical Remission at Week 62, as Determined by the MCS | MCS is a composite of 4 assessments, each rated from 0-3: stool frequency, rectal bleeding, endoscopy, and physician's global assessment. Clinical Remission is MCS ≤2 with individual subscores ≤1. | Week 62 | 
| Maintenance Phase: Percentage of Participants in Remission at Week 62 Among Randomized Participants in Remission at Week 10, as Determined by the MCS | MCS is a composite of 4 assessments, each rated from 0-3: stool frequency, rectal bleeding, endoscopy, and physician's global assessment. Remission is MCS ≤2 with individual subscores ≤1 and a rectal bleeding subscore of 0. | Week 62 | 
| Maintenance Phase: Percentage of Participants With Improvement From Baseline in Endoscopic Appearance of the Mucosa at Week 62, as Determined by the MCS Endoscopic Subscore | MCS is a composite of 4 assessments, each rated from 0-3: stool frequency, rectal bleeding, endoscopy, and physician's global assessment. Improvement in endoscopic appearance of the mucosa is Endoscopy subscore ≤1. | Baseline, Week 62 | 
| Maintenance Phase: Percentage of Participants With Endoscopic Remission at Week 62, as Determined by the MCS Endoscopic Subscore | MCS is a composite of 4 assessments, each rated from 0-3: stool frequency, rectal bleeding, endoscopy, and physician's global assessment. Endoscopic Remission is Endoscopy subscore = 0. | Week 62 | 
| Maintenance Phase: Percentage of Participants With Histologic Remission at Week 62, as Determined by the Nancy Histological Index | Nancy Histological Index (NHI) is a 5-level classification ranging from grade 0 (No histologically significant disease) to grade 4 (severely active disease). Histologic remission is defined as a Nancy histological index of 0 or 1. | Week 62 | 
| Maintenance Phase: Percentage of Participants With Corticosteroid-Free Clinical Remission at Week 62 Among Participants Who Were Receiving Corticosteroids at Baseline, as Determined by the MCS | MCS is a composite of 4 assessments, each rated from 0-3: stool frequency, rectal bleeding, endoscopy, and physician's global assessment. Clinical Remission is MCS ≤2 with individual subscores ≤1. | Baseline, Week 62 | 
| Maintenance Phase: Percentage of Participants With Corticosteroid-Free Remission at Week 62 Among Participants Who Were Receiving Corticosteroids at Baseline, as Determined by the MCS | MCS is a composite of 4 assessments, each rated from 0-3: stool frequency, rectal bleeding, endoscopy, and physician's global assessment. Remission is MCS ≤2 with individual subscores ≤1 and a rectal bleeding subscore of 0. | Baseline, Week 62 | 
| Maintenance Phase: Change From Baseline to Week 62 in UC Bowel Movement Signs and Symptoms, as Assessed by the Ulcerative Colitis Patient-Reported Outcome Signs and Symptoms (UC-PRO/SS) Questionnaire | The UC-PRO questionnaire is collected in the e-diary and completed by participants for at least 9-12 consecutive days prior to a study visit. The UC-PRO is being reported in three domains; two domains are key endpoints and reported as UC-PRO Signs and Symptoms (UC-PRO/SS). The bowel domain score ranges from 0-27, with a higher score indicating a worse disease state. | Baseline, Week 62 | 
| Maintenance Phase: Change From Baseline to Week 62 in UC Functional Symptoms, as Assessed by the UC-PRO/SS Questionnaire | The UC-PRO questionnaire is collected in the e-diary and completed by participants for at least 9-12 consecutive days prior to a study visit. The UC-PRO is being reported in three domains; two domains are key endpoints and reported as UC-PRO Signs and Symptoms (UC-PRO/SS). The functional domain score ranges from 0-12, with a higher score indicating a worse disease state. | Baseline, Week 62 | 
| Maintenance Phase: Change From Baseline to Week 62 in Health-Related Quality of Life, as Assessed by the Overall Score of the Inflammatory Bowel Disease Questionnaire (IBDQ) | The IBDQ is used to assess participant's health-related quality of life (QOL). The 32-item questionnaire contains four domains: bowel symptoms (10 items), systemic symptoms (5 items), emotional function (12 items), and social function (5 items). The items are scored on a 7-point Likert scale with a higher score indicating better health-related QOL. IBDQ score is a total score summed up from across all 32 questions on the questionnaire. The score can range from 32-224 and the higher score indicates a better quality of life. | Baseline, Week 62 | 
| Number of Participants With at Least One Adverse Event by Severity, According to National Cancer Institute Common Terminology Criteria for Adverse Events, Version 4.0 (NCI-CTCAE v4.0) | All adverse events (AEs) were graded for severity using the NCI-CTCAE v4.0. Any AE not specifically listed was assessed per the following 5 grades: Grade 1 = mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; or intervention not indicated. Grade 2 = moderate; minimal, local, or non-invasive intervention indicated; or limiting age-appropriate instrumental activities of daily living. Grade 3 = severe or medically significant, but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; or limiting self-care activities of daily living. Grade 4 = life-threatening consequences or urgent intervention indicated. Grade 5 = death related to AE. Not all grades are appropriate for all AEs; some AEs have fewer than 5 options. The terms severe and serious are not synonymous and are independently assessed for each AE. Multiple occurrences of AEs were counted only once per participant at the highest (worst) grade. | From Baseline up to Week 74 | 
| Number of Participants With Adverse Events Leading to Study Drug Discontinuation |  | From Baseline up to Week 74 | 
| Number of Participants With Serious Infection-Related Adverse Events |  | From Baseline up to Week 74 | 
| Number of Participants With Infection-Related Adverse Events by Severity, According to NCI-CTCAE v4.0 | All adverse events (AEs) were graded for severity using the NCI-CTCAE v4.0. Any AE not specifically listed was assessed per the following 5 grades: Grade 1 = mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; or intervention not indicated. Grade 2 = moderate; minimal, local, or non-invasive intervention indicated; or limiting age-appropriate instrumental activities of daily living. Grade 3 = severe or medically significant, but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; or limiting self-care activities of daily living. Grade 4 = life-threatening consequences or urgent intervention indicated. Grade 5 = death related to AE. Not all grades are appropriate for all AEs; some AEs have fewer than 5 options. The terms severe and serious are not synonymous and are independently assessed for each AE. Multiple occurrences of AEs were counted only once per participant at the highest (worst) grade. | From Baseline up to Week 74 | 
| Number of Participants With Injection-Site Reactions by Severity, According to NCI-CTCAE v4.0 | All adverse events (AEs) were graded for severity using the NCI-CTCAE v4.0. Any AE not specifically listed was assessed per the following 5 grades: Grade 1 = mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; or intervention not indicated. Grade 2 = moderate; minimal, local, or non-invasive intervention indicated; or limiting age-appropriate instrumental activities of daily living. Grade 3 = severe or medically significant, but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; or limiting self-care activities of daily living. Grade 4 = life-threatening consequences or urgent intervention indicated. Grade 5 = death related to AE. Not all grades are appropriate for all AEs; some AEs have fewer than 5 options. The terms severe and serious are not synonymous and are independently assessed for each AE. Multiple occurrences of AEs were counted only once per participant at the highest (worst) grade. | From Baseline up to Week 74 | 
| Number of Participants With Hypersensitivity Reaction Events by Severity, According to NCI-CTCAE v4.0 | All adverse events (AEs) were graded for severity using the NCI-CTCAE v4.0. Any AE not specifically listed was assessed per the following 5 grades: Grade 1 = mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; or intervention not indicated. Grade 2 = moderate; minimal, local, or non-invasive intervention indicated; or limiting age-appropriate instrumental activities of daily living. Grade 3 = severe or medically significant, but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; or limiting self-care activities of daily living. Grade 4 = life-threatening consequences or urgent intervention indicated. Grade 5 = death related to AE. Not all grades are appropriate for all AEs; some AEs have fewer than 5 options. The terms severe and serious are not synonymous and are independently assessed for each AE. Multiple occurrences of AEs were counted only once per participant at the highest (worst) grade. | From Baseline up to Week 74 | 
| Number of Participants With Malignancies |  | From Baseline up to Week 74 | 
| Number of Participants With Anti-Therapeutic Antibodies (ATAs) to Etrolizumab |  | Baseline, Weeks 4, 12, 24, 44, and 62, and and Early Termination/End of Safety Follow-Up (up to Week 74) | 
| Maintenance Phase: Etrolizumab Serum Trough Concentration (for Arms/Timepoints Above LLOQ) | As per protocol, the timepoints for each arm where more than a third of the samples were above the lower limit of quantitation (LLOQ), full summary statistics (Mean and Standard Deviation) were reported. For timepoints below the LLOQ, only the Median and Max were reported as a separate outcome measure below. | Pre-dose (0 hour) at Baseline and Weeks 12, 24, 44, and 62 | 
| Maintenance Phase: Etrolizumab Serum Trough Concentration (for Arms/Timepoints Below LLOQ) | As per protocol, the timepoints for each arm where more than a third of the samples were below the LLOQ only the Median and Max were reported. | Pre-dose (0 hour) at Baseline and Weeks 12, 24, 44, and 62 |