Phase III, Double-Blind, Placebo-Controlled, Multicenter Study of the Efficacy and Safety of Etrolizumab During Induction and Maintenance in Patients With Moderate to Severe Active Ulcerative Colitis Who Have Been Previously Exposed to TNF Inhibitors
Overview
- Phase
- Phase 3
- Intervention
- Etrozulimab
- Conditions
- Ulcerative Colitis
- Sponsor
- Hoffmann-La Roche
- Enrollment
- 609
- Locations
- 184
- Primary Endpoint
- Induction Phase: Percentage of Participants With Remission at Week 14, as Determined by the Mayo Clinic Score (MCS)
- Status
- Completed
- Last Updated
- 4 years ago
Overview
Brief Summary
This Phase III, double-blind, placebo-controlled, multicenter study will investigate the efficacy and safety of etrolizumab during induction and maintenance of remission compared with placebo in the treatment of participants with moderately to severely active ulcerative colitis (UC) who have been previously exposed to TNF inhibitors.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Diagnosis of UC established at least 3 months prior to Day 1
- •Moderately to severely active UC as determined by the Mayo Clinic Score (MCS) assessment
- •Treatment within 5 years prior to screening with one or two induction regimens that contain TNF inhibitors (including TNF inhibitor biosimilars)
- •Washout of anti-TNF therapy for at least 8 weeks preceding Day 1
- •Background regimen for UC may include oral 5-aminosalicylic acid (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 as defined by the protocol
- •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)
- •Any prior treatment with anti-adhesion molecules (e.g. anti-MAdCAM-1)
- •Any prior treatment with rituximab
- •Any treatment with tofacitinib during screening
- •Congenital 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 or clinically significant cytomegalovirus (CMV) colitis within 60 days prior to Day 1
- •Evidence of or treatment for other intestinal pathogens within 30 days prior to Day 1
Arms & Interventions
Cohort 1: Etrolizumab (Open-Label Induction (OLI) Phase)
Participants assigned to this arm will receive treatment with open-label etrolizumab 105 milligrams (mg) subcutaneous (SC) injection once every 4 weeks (Q4W) for 14 weeks during the induction phase.
Intervention: Etrozulimab
Cohort 2: Placebo (Double-Blind Induction Phase)
Participants randomized to this arm will receive treatment with double-blind placebo SC injection Q4W for 14 weeks during the induction phase.
Intervention: Placebo
Cohort 2: Etrolizumab (Double-Blind Induction Phase)
Participants randomized to this arm will receive treatment with double-blind etrolizumab 105 mg SC injection Q4W for 14 weeks during the induction phase.
Intervention: Etrozulimab
Placebo Responders: Placebo (Maintenance Phase)
Participants who received placebo during the induction phase, Cohort 2: Placebo (Double-Blind Induction Phase), and achieve a clinical response with placebo at Week 14 will continue to receive blinded placebo from Week 16 up to Week 66 during the maintenance phase.
Intervention: Placebo
Etrolizumab Responders: Placebo (Maintenance Phase)
Participants who received etrolizumab during the induction phase, Cohort 1: Etrolizumab (Open-Label Induction Phase) and Cohort 2: Etrolizumab (Double-Blind Induction Phase), and achieved a clinical response at Week 14 will be re-randomized by Week 16 for the double-blind maintenance phase. Clinical responders re-randomized to this arm will receive placebo SC injection Q4W from Week 16 up to Week 66.
Intervention: Placebo
Etrolizumab Responders: Etrolizumab (Maintenance Phase)
Participants who received etrolizumab during the induction phase, Cohort 1: Etrolizumab (Open-Label Induction Phase) and Cohort 2: Etrolizumab (Double-Blind Induction Phase), and achieved a clinical response at Week 14 will be re-randomized by Week 16 for the double-blind maintenance phase. Clinical responders re-randomized to this arm will receive etrolizumab 105 mg SC injection Q4W from Week 16 up to Week 66.
Intervention: Etrozulimab
Outcomes
Primary Outcomes
Induction Phase: Percentage of Participants With Remission at Week 14, as Determined by the Mayo Clinic Score (MCS)
Time Frame: Week 14
The Mayo Clinic Score (MCS) ranges from 0 to 12 and is a composite of 4 assessments (each rated from 0-3): stool frequency, rectal bleeding, endoscopy, and physician's global assessment. Higher scores represent greater disease severity. Remission was defined as MCS less than or equal to (≤)2 with individual subscores ≤1 and a rectal bleeding subscore of 0.
Maintenance Phase: Percentage of Participants With Remission at Week 66 Among Participants Who Had Achieved a Clinical Response at Week 14, as Determined by the MCS
Time Frame: Week 66
The MCS ranges from 0 to 12 and is a composite of 4 assessments (each rated from 0-3): stool frequency, rectal bleeding, endoscopy, and physician's global assessment. Higher scores represent greater disease severity. Remission was defined as MCS less than or equal to (≤)2 with individual subscores ≤1 and a rectal bleeding subscore of 0. 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.
Secondary Outcomes
- Induction Phase: Percentage of Participants With Clinical Remission at Week 14, as Determined by the MCS(Week 14)
- Induction Phase: Percentage of Participants With Clinical Response at Week 14, as Determined by the MCS(Week 14)
- Induction Phase: Percentage of Participants With Improvement From Baseline in Endoscopic Appearance of the Mucosa at Week 14, as Determined by the MCS Endoscopic Subscore(Baseline and Week 14)
- Induction Phase: Percentage of Participants With Endoscopic Remission at Week 14, as Determined by the MCS Endoscopic Subscore(Week 14)
- Induction Phase: Percentage of Participants With Histologic Remission at Week 14, as Determined by the Nancy Histological Index(Week 14)
- Induction Phase: Change From Baseline to Week 6 in MCS Rectal Bleed Subscore(Baseline and Week 6)
- Induction Phase: Change From Baseline to Week 6 in MCS Stool Frequency Subscore(Baseline and Week 6)
- Induction Phase: Change From Baseline to Week 14 in UC Bowel Movement Signs and Symptoms, as Assessed by the Ulcerative Colitis Patient-Reported Outcome Signs and Symptoms (UC-PRO/SS) Questionnaire(Baseline and Week 14)
- Induction Phase: Change From Baseline to Week 14 in UC Functional Symptoms, as Assessed by the UC-PRO/SS Questionnaire(Baseline and Week 14)
- Induction Phase: Change From Baseline to Week 14 in Health-Related Quality of Life, as Assessed by the Overall Score of the Inflammatory Bowel Disease Questionnaire (IBDQ)(Baseline and Week 14)
- Maintenance Phase: Change From Baseline to Week 66 in Health-Related Quality of Life, as Assessed by the Overall Score of the IBDQ(Baseline and Week 66)
- 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)(From Baseline up to Week 78)
- Number of Participants With Adverse Events Leading to Study Drug Discontinuation(From Baseline up to Week 78)
- Number of Participants With Serious Infection-Related Adverse Events(From Baseline up to Week 78)
- Maintenance Phase: Percentage of Participants With Clinical Remission at Week 66 Among Participants Who Had Achieved Clinical Remission at Week 14, as Determined by the MCS(Week 66)
- Maintenance Phase: Percentage of Participants With Clinical Remission at Week 66, as Determined by the MCS(Week 66)
- Maintenance Phase: Percentage of Participants With Remission at Week 66 Among Participants Who Had Achieved Remission at Week 14, as Determined by the MCS(Week 66)
- Maintenance Phase: Percentage of Participants With Improvement From Baseline in Endoscopic Appearance of the Mucosa at Week 66, as Determined by the MCS Endoscopic Subscore(Baseline and Week 66)
- Maintenance Phase: Percentage of Participants With Histologic Remission at Week 66, as Determined by the Nancy Histological Index(Week 66)
- Maintenance Phase: Percentage of Participants With Endoscopic Remission at Week 66, as Determined by the MCS Endoscopic Subscore(Week 66)
- Maintenance Phase: Percentage of Participants With Corticosteroid-Free Clinical Remission at Week 66 Among Participants Who Were Receiving Corticosteroids at Baseline, as Determined by the MCS(Week 66)
- Maintenance Phase: Percentage of Participants With Corticosteroid-Free Remission at Week 66 Among Participants Who Were Receiving Corticosteroids at Baseline, as Determined by the MCS(Week 66)
- Maintenance Phase: Change From Baseline to Week 66 in UC Bowel Movement Signs and Symptoms, as Assessed by the UC-PRO/SS Questionnaire(Baseline and Week 66)
- Maintenance Phase: Change From Baseline to Week 66 in UC Functional Symptoms, as Assessed by the UC-PRO/SS Questionnaire(Baseline and Week 66)
- Number of Participants With Infection-Related Adverse Events(From Baseline up to Week 78)
- Number of Participants With Injection-Site Reaction-Related Adverse Events(From Baseline up to Week 78)
- Number of Participants With Hypersensitivity Reaction-Related Adverse Events(From Baseline up to Week 78)
- Number of Participants With Malignancies(From Baseline up to Week 78)
- Number of Participants With Anti-Therapeutic Antibodies to Etrolizumab at Baseline and During the Study(Pre-dose at Baseline, Weeks 4, 14, 24, 44, and 66, and Early Termination/End of Safety Follow-Up (up to Week 78))
- Etrolizumab Serum Trough Concentration (for Arms/Timepoints Above LLOQ)(Pre-dose (0 hour) at Baseline and Weeks 14, 24, 44 and 66)
- Etrolizumab Serum Trough Concentration (for Arms/Timepoints Below LLOQ)(Weeks 44 and 66)