A Phase III, Randomized, Double-Blind, Placebo-Controlled, Multicenter Study to Evaluate the Efficacy and Safety of Etrolizumab as an Induction And Maintenance Treatment For Patients With Moderately to Severely Active Crohn's Disease
Overview
- Phase
- Phase 3
- Intervention
- Etrolizumab
- Conditions
- Crohn Disease
- Sponsor
- Hoffmann-La Roche
- Enrollment
- 1035
- Locations
- 327
- Primary Endpoint
- Induction Phase: Cohort 1: Percentage of Participants With Endoscopic Improvement at Week 14
- Status
- Completed
- Last Updated
- 3 years ago
Overview
Brief Summary
This is a multicenter, Phase 3, double-blind, placebo-controlled study evaluating the efficacy, safety, and tolerability of etrolizumab compared with placebo during induction and maintenance treatment of moderately to severely active Crohn's Disease (CD). The target population includes participants with CD who are refractory or intolerant to corticosteroids (CS) and/or immunosuppressant (IS) therapy and who have either not received prior anti-tumor necrosis factor (anti-TNF) therapy (TNF-naive) or who have had prior exposure to anti-TNF therapies and demonstrated inadequate responses or intolerance to anti-TNFs.
The study period will consist of a Screening Phase (up to 35 days) plus (+) a 14-week Induction Phase + a 52-week Maintenance Phase + a 12-week Safety Follow-up Phase. At Week 14 (end of Induction Phase), participants achieving a decrease from baseline of at least 70 points in the Crohn's Disease Activity Index (CDAI) score (CDAI-70 response) without the use of rescue therapy will continue to the Maintenance Phase.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Moderately to severely active Crohn's Disease (CD) as determined by the CDAI, patient reported outcomes and endoscopically defined disease activity in the ileum and/or colon
- •Intolerance, refractory disease, or no response to corticosteroids (CS), immunosuppressants (IS), or anti-TNF therapy within 5 years from screening. Participants who have not previously demonstrated inadequate response or intolerance to one or more anti-TNF therapies are eligible to participate in the study provided they are intolerant or refractory to CS or IS therapy
- •Use of effective contraception as defined by the protocol
Exclusion Criteria
- •A history of, or current conditions affecting the digestive tract, such as ulcerative colitis, indeterminate colitis, fistulizing disease, abdominal or perianal abscess, adenomatous colonic polyps not excised, colonic mucosal dysplasia, and short bowel syndrome
- •Planned surgery for CD
- •Ileostomy or colostomy
- •Has received non-permitted inflammatory bowel disease (IBD) therapies (including natalizumab, vedolizumab, and efalizumab, as stated in the protocol)
- •Any prior treatment with ustekinumab within 14 weeks prior to randomization
- •Chronic hepatitis B or C infection, human immunodeficiency virus (HIV), active or latent tuberculosis (participants with prior history of Bacillus Calmette-Guérin \[BCG\] vaccination must pass protocol-defined screening criteria)
- •Sinus tract with evidence for infection (e.g., purulent discharge) in the clinical judgment of the investigator. Fistulas related to CD are not exclusionary
- •Any prior treatment with anti-adhesion molecules (e.g., anti-mucosal addressin cell adhesion molecule \[anti-MAdCAM-1\])
- •Any major episode of infection requiring treatment with intravenous antibiotics ≤8 weeks prior to screening or oral antibiotics ≤4 weeks prior to screening. Treatment with antibiotics as adjunctive therapy for CD in the absence of documented infection is not exclusionary
- •Hospitalization (other than for elective reasons) within 4 weeks prior to randomization
Arms & Interventions
Induction Phase - Cohort 1 (Exploratory): Etrolizumab 210 mg
Cohort 1 enrolled participants first before Cohorts 2 and 3 in order to conduct an exploratory analysis on induction data. Participants randomized to this arm will receive one subcutaneous (SC) injection of etrolizumab (210 mg) at Weeks 0, 2, 4, 8, and 12 during the 14-week Induction Phase. In order to preserve the masking, participants will also receive one SC injection of etrolizumab-matching placebo at Weeks 0, 4, 8, and 12.
Intervention: Etrolizumab
Induction Phase - Cohort 1 (Exploratory): Etrolizumab 210 mg
Cohort 1 enrolled participants first before Cohorts 2 and 3 in order to conduct an exploratory analysis on induction data. Participants randomized to this arm will receive one subcutaneous (SC) injection of etrolizumab (210 mg) at Weeks 0, 2, 4, 8, and 12 during the 14-week Induction Phase. In order to preserve the masking, participants will also receive one SC injection of etrolizumab-matching placebo at Weeks 0, 4, 8, and 12.
Intervention: Placebo
Induction Phase - Cohort 1 (Exploratory): Etrolizumab 105 mg
Cohort 1 enrolled participants first before Cohorts 2 and 3 in order to conduct an exploratory analysis on induction data. Participants randomized to this arm will receive one SC injection of etrolizumab (105 mg) at Weeks 0, 4, 8, 12 and one SC injection of etrolizumab-matching placebo at Week 2 during the 14-week Induction Phase. In order to preserve the masking, participants will also receive one SC injection of etrolizumab-matching placebo at Weeks 0, 4, 8, and 12.
Intervention: Etrolizumab
Induction Phase - Cohort 1 (Exploratory): Etrolizumab 105 mg
Cohort 1 enrolled participants first before Cohorts 2 and 3 in order to conduct an exploratory analysis on induction data. Participants randomized to this arm will receive one SC injection of etrolizumab (105 mg) at Weeks 0, 4, 8, 12 and one SC injection of etrolizumab-matching placebo at Week 2 during the 14-week Induction Phase. In order to preserve the masking, participants will also receive one SC injection of etrolizumab-matching placebo at Weeks 0, 4, 8, and 12.
Intervention: Placebo
Induction Phase - Cohort 1 (Exploratory): Placebo
Cohort 1 enrolled participants first before Cohorts 2 and 3 in order to conduct an exploratory analysis on induction data. Participants randomized to this arm will receive two SC injections of etrolizumab-matching placebo at Weeks 0, 4, 8, and 12 (and one SC injection of etrolizumab-matching placebo at Week 2) during the 14-week Induction Phase, in order to preserve the masking.
Intervention: Placebo
Induction Phase - Cohort 2 (Open-Label): Etrolizumab 210 mg
Cohort 2 is enrolling participants after Cohort 1 and is considered a "feeder" cohort to help achieve the necessary sample size for the Maintenance Phase. Participants randomized to this arm will receive one SC injection of open-label etrolizumab (210 mg) at Weeks 0, 2, 4, 8, and 12 during the 14-week Induction Phase. In order to preserve the masking for the dose of etrolizumab, participants will also receive one SC injection of etrolizumab-matching placebo at Weeks 0, 4, 8, and 12.
Intervention: Etrolizumab
Induction Phase - Cohort 2 (Open-Label): Etrolizumab 210 mg
Cohort 2 is enrolling participants after Cohort 1 and is considered a "feeder" cohort to help achieve the necessary sample size for the Maintenance Phase. Participants randomized to this arm will receive one SC injection of open-label etrolizumab (210 mg) at Weeks 0, 2, 4, 8, and 12 during the 14-week Induction Phase. In order to preserve the masking for the dose of etrolizumab, participants will also receive one SC injection of etrolizumab-matching placebo at Weeks 0, 4, 8, and 12.
Intervention: Placebo
Induction Phase - Cohort 2 (Open-Label): Etrolizumab 105 mg
Cohort 2 is enrolling participants after Cohort 1 and is considered a "feeder" cohort to help achieve the necessary sample size for the Maintenance Phase. Participants randomized to this arm will receive one SC injection of open-label etrolizumab (105 mg) at Weeks 0, 4, 8, 12 and one SC injection of etrolizumab-matching placebo at Week 2 during the 14-week Induction Phase. In order to preserve the masking of the dose of etrolizumab, participants will also receive one SC injection of etrolizumab-matching placebo at Weeks 0, 4, 8, and 12.
Intervention: Etrolizumab
Induction Phase - Cohort 2 (Open-Label): Etrolizumab 105 mg
Cohort 2 is enrolling participants after Cohort 1 and is considered a "feeder" cohort to help achieve the necessary sample size for the Maintenance Phase. Participants randomized to this arm will receive one SC injection of open-label etrolizumab (105 mg) at Weeks 0, 4, 8, 12 and one SC injection of etrolizumab-matching placebo at Week 2 during the 14-week Induction Phase. In order to preserve the masking of the dose of etrolizumab, participants will also receive one SC injection of etrolizumab-matching placebo at Weeks 0, 4, 8, and 12.
Intervention: Placebo
Induction Phase - Cohort 3 (Pivotal): Etrolizumab 210 mg
Cohort 3 is the last to enroll participants (after Cohort 2) and will be the pivotal cohort for the Induction Phase. Participants randomized to this arm will receive one SC injection of etrolizumab (210 mg) at Weeks 0, 2, 4, 8, and 12 during the 14-week Induction Phase. In order to preserve the masking, participants will also receive one SC injection of etrolizumab-matching placebo at Weeks 0, 4, 8, and 12.
Intervention: Etrolizumab
Induction Phase - Cohort 3 (Pivotal): Etrolizumab 210 mg
Cohort 3 is the last to enroll participants (after Cohort 2) and will be the pivotal cohort for the Induction Phase. Participants randomized to this arm will receive one SC injection of etrolizumab (210 mg) at Weeks 0, 2, 4, 8, and 12 during the 14-week Induction Phase. In order to preserve the masking, participants will also receive one SC injection of etrolizumab-matching placebo at Weeks 0, 4, 8, and 12.
Intervention: Placebo
Induction Phase - Cohort 3 (Pivotal): Etrolizumab 105 mg
Cohort 3 is the last to enroll participants (after Cohort 2) and will be the pivotal cohort for the Induction Phase. Participants randomized to this arm will receive one SC injection of etrolizumab (105 mg) at Weeks 0, 4, 8, 12 and one SC injection of etrolizumab-matching placebo at Week 2 during the 14-week Induction Phase. In order to preserve the masking, participants will also receive one SC injection of etrolizumab-matching placebo at Weeks 0, 4, 8, and 12.
Intervention: Etrolizumab
Induction Phase - Cohort 3 (Pivotal): Etrolizumab 105 mg
Cohort 3 is the last to enroll participants (after Cohort 2) and will be the pivotal cohort for the Induction Phase. Participants randomized to this arm will receive one SC injection of etrolizumab (105 mg) at Weeks 0, 4, 8, 12 and one SC injection of etrolizumab-matching placebo at Week 2 during the 14-week Induction Phase. In order to preserve the masking, participants will also receive one SC injection of etrolizumab-matching placebo at Weeks 0, 4, 8, and 12.
Intervention: Placebo
Induction Phase - Cohort 3 (Pivotal): Placebo
Cohort 3 is the last to enroll participants (after Cohort 2) and will be the pivotal cohort for the Induction Phase. Participants randomized to this arm will receive two SC injections of etrolizumab-matching placebo at Weeks 0, 4, 8, and 12 (and one SC injection of etrolizumab-matching placebo at Week 2) during the 14-week Induction Phase, in order to preserve the masking.
Intervention: Placebo
Maintenance Phase - Placebo Responders: Placebo
Participants who received placebo during the Induction Phase (from Cohorts 1 and 3) and achieved a CDAI-70 response at Week 14 will undergo a sham randomization into the Maintenance Phase. Placebo responders from induction will receive blinded maintenance treatment with an SC injection of placebo once every 4 weeks (q4w) from Week 16 to Week 64.
Intervention: Placebo
Maintenance Phase - Etrolizumab Responders: Placebo
Participants who received etrolizumab during the Induction Phase (from Cohorts 1-3) and achieved a CDAI-70 response at Week 14 without the use of rescue therapy will be re-randomized into the Maintenance Phase. Etrolizumab responders from induction who are re-randomized to this arm will receive blinded maintenance treatment with an SC injection of placebo q4w from Week 16 to Week 64.
Intervention: Placebo
Maintenance Phase - Etrolizumab Responders: Etrolizumab 105 mg
Participants who received etrolizumab during the Induction Phase (from Cohorts 1-3) and achieved a CDAI-70 response at Week 14 without the use of rescue therapy will be re-randomized into the Maintenance Phase. Etrolizumab responders from induction who are re-randomized to this arm will receive blinded maintenance treatment with an SC injection of etrolizumab (105 mg) q4w from Week 16 to Week 64.
Intervention: Etrolizumab
Outcomes
Primary Outcomes
Induction Phase: Cohort 1: Percentage of Participants With Endoscopic Improvement at Week 14
Time Frame: Week 14
Endoscopic improvement is defined as 50 percent (%) reduction from baseline in Simplified Endoscopic Index for Crohn's Disease (SES-CD) score.
Induction Phase: Cohort 2 and 3: Percentage of Participants With Clinical Remission at Week 14
Time Frame: Week 14
Clinical remission is defined as liquid/soft stool frequency (SF) mean daily score less than or equal (≤)3 and abdominal pain mean daily score ≤1, with no worsening in either subscore compared to baseline, averaged over the 7 days prior to visit.
Maintenance Phase: Percentage of Participants With Endoscopic Improvement at Week 66
Time Frame: Week 66
Endoscopic improvement is defined as 50% reduction from baseline in SES-CD score. Maintenance phase participants were evaluated.
Induction Phase: Cohort 1: Percentage of Participants With Clinical Remission at Week 14
Time Frame: Week 14
Clinical remission is defined as liquid/soft stool frequency (SF) mean daily score less than or equal (≤)3 and abdominal pain mean daily score ≤1, with no worsening in either subscore compared to baseline, averaged over the 7 days prior to visit.
Induction Phase: Cohort 2 and 3: Percentage of Participants With Endoscopic Improvement at Week 14
Time Frame: Week 14
Endoscopic improvement is defined as 50 percent (%) reduction from baseline in Simplified Endoscopic Index for Crohn's Disease (SES-CD) score.
Maintenance Phase: Percentage of Participants With Clinical Remission at Week 66
Time Frame: Baseline and Week 66
Clinical remission is defined as SF mean daily score ≤3 and abdominal pain mean daily score ≤1, with no worsening in either subscore compared to baseline, averaged over the 7 days prior to visit. Maintenance phase participants were evaluated.
Secondary Outcomes
- Induction Phase: Cohort 1: Percentage of Participants With SES-CD Score ≤4 (≤2 for Ileal Participants), With No Segment Having a Subcategory Score Greater Than (>)1, at Week 14(Week 14)
- Induction Phase: Cohort 1: Percentage of Participants With Clinical Remission at Week 6(Week 6)
- Induction Phase: Cohort 2 and 3: Percentage of Participants With Clinical Remission at Week 6(Week 6)
- Maintenance Phase: Percentage of Participants With Clinical Remission at Week 66, Among Those Who Achieved Clinical Remission at Week 14(Baseline, Weeks 14 and 66)
- Maintenance Phase: Percentage of Participants With SES-CD Score ≤4 (≤2 for Ileal Participants), With No Segment Having a Subcategory Score >1, at Week 66(Week 66)
- Maintenance Phase: Percentage of Participants With Corticosteroid-Free Clinical Remission for at Least 24 Weeks at Week 66, Among Those Who Were Receiving Corticosteroids at Baseline(Baseline and from Week 14 up to Week 66)
- Induction Phase: Cohort 2 and 3: Percentage of Participants With SES-CD Score ≤4 (≤2 for Ileal Participants), With No Segment Having a Subcategory Score Greater Than (>)1, at Week 14(Week 14)
- Maintenance Phase: Change From Baseline in CD-PRO/SS Score at Week 66(Baseline and Week 66)
- Overall Number of Participants Who Experienced 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)
- Overall Number of Participants With Adverse Events Leading to Study Drug Discontinuation(From Baseline up to Week 78)
- Overall Number of Participants Who Experienced at Least One Injection-Site Reaction by Severity, According to NCI-CTCAE v4.0(From Baseline up to Week 78)
- Percentage of Participants With Anti-Therapeutic Antibodies (ATAs) to Etrolizumab(Baseline, Pre-dose (Hour 0) on Weeks 4, 14, 24, 32, 44, 66 or early termination, 12 weeks after last dose (up to Week 78))
- Induction Phase: Cohort 1: Change From Baseline in Crohn's Disease-Patient-Reported Outcome Signs and Symptoms (CD-PRO/SS) Score at Week 14(Baseline and Week 14)
- Induction Phase: Cohort 2 and 3: Change From Baseline in Crohn's Disease-Patient-Reported Outcome Signs and Symptoms (CD-PRO/SS) Score at Week 14(Baseline and Week 14)
- Maintenance Phase: Percentage of Participants With Durable Clinical Remission(Week 14 up to Week 66 (assessed at Weeks 24, 28, 32, 44, 56, and 66))
- Overall Number of Participants Who Experienced at Least One Infection-Related Serious Adverse Event(From Baseline up to Week 78)
- Overall Number of Participants Who Experienced at Least One Hypersensitivity Reaction by Severity, According to NCI-CTCAE v4.0(From Baseline up to Week 78)
- Observed Trough Serum Concentration (Ctrough) of Etrolizumab(Induction Phase at Weeks 10 and 14, Maintenance Phase at Weeks 16, 24, 28, 32, 44, and 66)
- Maintenance Phase: Percentage of Participants With Corticosteroid-Free Clinical Remission at Week 66, Among Those Who Were Receiving Corticosteroids at Baseline(Baseline and Week 66)
- Maintenance Phase: Percentage of Participants With Endoscopic Improvement at Week 66 Among Participants Who Achieved Endoscopic Improvement at Week 14(Baseline, Weeks 14 and 66)
- Overall Number of Participants Who Develop Malignancies(From Baseline up to Week 78)
- Overall Number of Participants Who Experienced at Least One Infection-Related Adverse Event by Severity, According to NCI-CTCAE v4.0(From Baseline up to Week 78)