A Study to Assess Whether Etrolizumab is a Safe and Efficacious Treatment for Participants With Moderately to Severely Active Crohn's Disease

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Crohn Disease

Intervention / Treatment
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* Drug: Etrolizumab
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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

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: Induction Phase - Cohort 1 (Exploratory): Etrolizumab 210 mg<br>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. | Drug: Etrolizumab<br>* Etrolizumab will be administered as per regimen specified in individual arms.<br>* Other names: RG7413;Drug: Placebo<br>* Etrolizumab-matching placebo will be administered as per regimen specified in individual arms.<br>|
| Experimental: Induction Phase - Cohort 1 (Exploratory): Etrolizumab 105 mg<br>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. | Drug: Etrolizumab<br>* Etrolizumab will be administered as per regimen specified in individual arms.<br>* Other names: RG7413;Drug: Placebo<br>* Etrolizumab-matching placebo will be administered as per regimen specified in individual arms.<br>|
| Placebo Comparator: Induction Phase - Cohort 1 (Exploratory): Placebo<br>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. | Drug: Placebo<br>* Etrolizumab-matching placebo will be administered as per regimen specified in individual arms.<br>|
| Experimental: Induction Phase - Cohort 2 (Open-Label): Etrolizumab 210 mg<br>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. | Drug: Etrolizumab<br>* Etrolizumab will be administered as per regimen specified in individual arms.<br>* Other names: RG7413;Drug: Placebo<br>* Etrolizumab-matching placebo will be administered as per regimen specified in individual arms.<br>|
| Experimental: Induction Phase - Cohort 2 (Open-Label): Etrolizumab 105 mg<br>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. | Drug: Etrolizumab<br>* Etrolizumab will be administered as per regimen specified in individual arms.<br>* Other names: RG7413;Drug: Placebo<br>* Etrolizumab-matching placebo will be administered as per regimen specified in individual arms.<br>|
| Experimental: Induction Phase - Cohort 3 (Pivotal): Etrolizumab 210 mg<br>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. | Drug: Etrolizumab<br>* Etrolizumab will be administered as per regimen specified in individual arms.<br>* Other names: RG7413;Drug: Placebo<br>* Etrolizumab-matching placebo will be administered as per regimen specified in individual arms.<br>|
| Experimental: Induction Phase - Cohort 3 (Pivotal): Etrolizumab 105 mg<br>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. | Drug: Etrolizumab<br>* Etrolizumab will be administered as per regimen specified in individual arms.<br>* Other names: RG7413;Drug: Placebo<br>* Etrolizumab-matching placebo will be administered as per regimen specified in individual arms.<br>|
| Placebo Comparator: Induction Phase - Cohort 3 (Pivotal): Placebo<br>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. | Drug: Placebo<br>* Etrolizumab-matching placebo will be administered as per regimen specified in individual arms.<br>|
| Placebo Comparator: Maintenance Phase - Placebo Responders: Placebo<br>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. | Drug: Placebo<br>* Etrolizumab-matching placebo will be administered as per regimen specified in individual arms.<br>|
| Placebo Comparator: Maintenance Phase - Etrolizumab Responders: Placebo<br>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. | Drug: Placebo<br>* Etrolizumab-matching placebo will be administered as per regimen specified in individual arms.<br>|
| Experimental: Maintenance Phase - Etrolizumab Responders: Etrolizumab 105 mg<br>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. | Drug: Etrolizumab<br>* Etrolizumab will be administered as per regimen specified in individual arms.<br>* Other names: RG7413;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Induction Phase: Cohort 1: Percentage of Participants With Clinical Remission at 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. | Week 14 | 
| Induction Phase: Cohort 2 and 3: Percentage of Participants With Clinical Remission at 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. | Week 14 | 
| Induction Phase: Cohort 1: Percentage of Participants With Endoscopic Improvement at Week 14 | Endoscopic improvement is defined as 50 percent (%) reduction from baseline in Simplified Endoscopic Index for Crohn's Disease (SES-CD) score. | Week 14 | 
| Induction Phase: Cohort 2 and 3: Percentage of Participants With Endoscopic Improvement at Week 14 | Endoscopic improvement is defined as 50 percent (%) reduction from baseline in Simplified Endoscopic Index for Crohn's Disease (SES-CD) score. | Week 14 | 
| Maintenance Phase: Percentage of Participants With Clinical Remission at 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. | Baseline and Week 66 | 
| Maintenance Phase: Percentage of Participants With Endoscopic Improvement at Week 66 | Endoscopic improvement is defined as 50% reduction from baseline in SES-CD score. Maintenance phase participants were evaluated. | Week 66 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Induction Phase: Cohort 1: Percentage of Participants With Clinical Remission at Week 6 | 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. | Week 6 | 
| Induction Phase: Cohort 2 and 3: Percentage of Participants With Clinical Remission at Week 6 | 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. | Week 6 | 
| 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 | Endoscopic Remission is defined as SES-CD total score <=4 (<=2 for ileal only patients), with no segment having a subcategory score >1. SES-CD = Simple Endoscopic Score for Crohn's Disease. A composite of four assessments, each rated from 0 to 3: size of ulcers, proportion of the surface covered by ulcers, proportion of the surface with any other lesions, and presence of narrowings (stenosis). The SES-CD total score ranges from 0 to 60, a higher score indicates worse disease activity. | Week 14 | 
| 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 | Endoscopic Remission is defined as SES-CD total score <=4 (<=2 for ileal only patients), with no segment having a subcategory score >1. SES-CD = Simple Endoscopic Score for Crohn's Disease. A composite of four assessments, each rated from 0 to 3: size of ulcers, proportion of the surface covered by ulcers, proportion of the surface with any other lesions, and presence of narrowings (stenosis). The SES-CD total score ranges from 0 to 60, a higher score indicates worse disease activity. | Week 14 | 
| Induction Phase: Cohort 1: Change From Baseline in Crohn's Disease-Patient-Reported Outcome Signs and Symptoms (CD-PRO/SS) Score at Week 14 | CD-PRO/SS: Crohn's Disease Patient Reported Outcomes Signs and Symptoms. For each item, the score is taken as the average across 4-7 days eDiary data within a 9 day window from visit, else the score is considered missing. The CD-PRO/SS Bowel domain is a total score summed across 3 items and ranges from 0 - 16. The Functional domain score is a total score summed across 3 items and ranges from 0 - 12. A higher CD-PRO/SS score indicates worse quality of life. Participants are included in the analysis if they have both Baseline and at least one post-baseline score available. | 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 | CD-PRO/SS: Crohn's Disease Patient Reported Outcomes Signs and Symptoms. For each item, the score is taken as the average across 4-7 days eDiary data within a 9 day window from visit, else the score is considered missing. The CD-PRO/SS Bowel domain is a total score summed across 3 items and ranges from 0 - 16. The Functional domain score is a total score summed across 3 items and ranges from 0 - 12. A higher CD-PRO/SS score indicates worse quality of life. Participants are included in the analysis if they have both Baseline and at least one post-baseline score available. | Baseline and Week 14 | 
| Maintenance Phase: Percentage of Participants With Clinical Remission at Week 66, Among Those Who Achieved Clinical Remission at Week 14 | 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. Induction Phase Cohorts are not included | Baseline, Weeks 14 and 66 | 
| Maintenance Phase: Percentage of Participants With Corticosteroid-Free Clinical Remission at Week 66, Among Those Who Were Receiving Corticosteroids at Baseline | 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. Induction Phase Cohorts are not included | Baseline and Week 66 | 
| Maintenance Phase: Percentage of Participants With Endoscopic Improvement at Week 66 Among Participants Who Achieved Endoscopic Improvement at Week 14 | Endoscopic improvement is defined as 50% reduction from baseline in SES-CD score. Induction Phase Cohorts are not included | 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 | Endoscopic Remission is defined as SES-CD total score <=4 (<=2 for ileal only patients), with no segment having a subcategory score >1. SES-CD = Simple Endoscopic Score for Crohn's Disease. A composite of four assessments, each rated from 0 to 3: size of ulcers, proportion of the surface covered by ulcers, proportion of the surface with any other lesions, and presence of narrowings (stenosis). The SES-CD total score ranges from 0 to 60, a higher score indicates worse disease activity. | Week 66 | 
| Maintenance Phase: Percentage of Participants With Durable Clinical Remission | 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. Durable clinical remission was defined as clinical remission at ≥4 of the 6 in-clinic assessment visits conducted during the Maintenance Phase at Weeks 24, 28, 32, 44, 56, and 66. Induction Phase Cohorts are not included | Week 14 up to Week 66 (assessed at Weeks 24, 28, 32, 44, 56, and 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 | 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. Percentage of participants with clinical remission who will be off corticosteroids for at least 24 weeks prior to Week 66 will be reported. Induction Phase Cohorts are not included | Baseline and from Week 14 up to Week 66 | 
| Maintenance Phase: Change From Baseline in CD-PRO/SS Score at Week 66 | CD-PRO/SS: Crohn's Disease Patient Reported Outcomes Signs and Symptoms. For each item, the score is taken as the average across 4-7 days eDiary data within a 9 day window from visit, else the score is considered missing. The CD-PRO/SS Bowel domain is a total score summed across 3 items and ranges from 0 - 16. The Functional domain score is a total score summed across 3 items and ranges from 0 - 12. A higher CD-PRO/SS score indicates worse quality of life. Participants are included in the analysis if they have both Baseline and at least one post-baseline score available. | 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) | Investigator text for AEs is coded using MedDRA version 24.0. For participants counts, multiple occurrences of AEs in the same category for an individual are counted only once. For event counts, multiple occurrences of AEs in the same category for an individual are counted separately. Severity Grades from 1 to 5. | From Baseline up to Week 78 | 
| Overall Number of Participants With Adverse Events Leading to Study Drug Discontinuation | Number of participants who discontinued the study due to the adverse events is reported. | 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 | Participants who Experienced at Least One Infection-Related Adverse Event by Severity, According to NCI-CTCAE v4.0 are reported. 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 indicated; disabling; or limiting self-care activities of daily living. Grade 4 = life-threatening consequences or urgent intervention indicated. Grade 5 = Death. The terms 'severe' and 'serious' are not synonymous and are independently assessed for each AE. Multiple occurrences of AEs are counted only once per participant at the highest (worst) grade. Infections are identified by Primary System Organ Class term 'Infections and Infestations' | From Baseline up to Week 78 | 
| Overall Number of Participants Who Experienced at Least One Infection-Related Serious Adverse Event | Investigator text for AEs is coded using MedDRA version 24.0. Infections are identified by primary System Organ Class term 'Infections and Infestations'. The terms 'severe' and 'serious' are not synonymous and are independently assessed for each AE. Multiple occurrences of AEs in the same category for an individual are counted only once | 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 | Investigator test for AEs is coding using MedDRA version 24.0. Injection-Site Reactions are identified by eCRF checkbox for local injection site reactions, and/or primary or secondary HLT Injection Site Reactions. Multiple occurrences of AEs for an individual are counted only once, under the worst grade reported. | 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 | Investigator text for AEs is coded using MedDRA version 24.0. Multiple occurrences of AEs for an individual are counted only once, under the worst grade reported. | From Baseline up to Week 78 | 
| Overall Number of Participants Who Develop Malignancies | Participants with malignancies are reported. 'Malignancies are identified by SMQ Malignant and unspecified tumors (narrow) | From Baseline up to Week 78 | 
| Percentage of Participants With Anti-Therapeutic Antibodies (ATAs) to Etrolizumab | Participants who received at least one dose of study treatment and had at least one baseline or post-baseline ATA result. Induction: treatment groups were pooled across cohorts 1-3. Maintenance: treatment group is stratified by induction dose | 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) | 
| Observed Trough Serum Concentration (Ctrough) of Etrolizumab | Serum Etrolizumab Trough Concentration | Induction Phase at Weeks 10 and 14, Maintenance Phase at Weeks 16, 24, 28, 32, 44, and 66 |