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

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ClinicalTrials.gov Identifier: NCT02394028
Recruitment Status : Recruiting
First Posted : March 20, 2015
Last Update Posted : November 16, 2020
Sponsor:
Information provided by (Responsible Party):
Hoffmann-La Roche

Tracking Information
First Submitted Date  ICMJE February 27, 2015
First Posted Date  ICMJE March 20, 2015
Last Update Posted Date November 16, 2020
Actual Study Start Date  ICMJE March 20, 2015
Estimated Primary Completion Date July 31, 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: November 25, 2019)
  • Induction Phase: Percentage of Participants with Clinical Remission at Week 14 [ Time Frame: Baseline and 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: Percentage of Participants with Endoscopic Improvement at Week 14 [ Time Frame: Baseline and 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: Percentage of Participants with Endoscopic Improvement at Week 66 [ Time Frame: Baseline and Week 66 ]
    Endoscopic improvement is defined as 50% reduction from baseline in SES-CD score.
Original Primary Outcome Measures  ICMJE
 (submitted: March 16, 2015)
  • Maintenance of clinical remission (as determined by PRO2 score) at Week 66 (US) [ Time Frame: At Week 66 ]
  • Induction Phase: Clinical remission as determined by the Crohn's Disease Activity Index (CDAI) score (ex-US) [ Time Frame: At Week 14 ]
  • Maintenance of clinical remission (as determined by CDAI score) after at least 52 weeks and corticosteroid-free for at least 52 weeks (ex-US) [ Time Frame: 52 weeks ]
  • Induction Phase: Clinical remission as determined by the 2 Item Patient Reported Outcome (PRO2) score (US) [ Time Frame: At Week 14 ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: November 25, 2019)
  • Induction Phase: Percentage of Participants with Clinical Remission at Week 6 [ Time Frame: Baseline and 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.
  • Induction Phase: 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 [ Time Frame: Week 14 ]
  • Induction Phase: Change from Baseline in Crohn's Disease-Patient-Reported Outcome Signs and Symptoms (CD-PRO/SS) Score at Week 14 [ Time Frame: Baseline and Week 14 ]
  • Maintenance Phase: Percentage of Participants with Clinical Remission at Week 66, Among Those who Achieved Clinical Remission at Week 14 [ Time Frame: Baseline, Weeks 14 and 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: Percentage of Participants with Corticosteroid-Free Clinical Remission at Week 66, Among Those who Were Receiving Corticosteroids at Baseline [ 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: Percentage of Participants with Endoscopic Improvement at Week 66 Among Participants who Achieved Endoscopic Improvement at Week 14 [ Time Frame: Baseline, Weeks 14 and 66 ]
    Endoscopic improvement is defined as 50% reduction from baseline in SES-CD score.
  • 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 [ Time Frame: Week 66 ]
  • Maintenance Phase: Percentage of Participants with Durable Clinical Remission [ Time Frame: Week 14 up to Week 66 (assessed at Weeks 24, 28, 32, 44, 56, and 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. 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.
  • 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 [ Time Frame: Baseline and from Week 14 up to 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. Percentage of participants with clinical remission who will be off corticosteroids for at least 24 weeks prior to Week 66 will be reported.
  • Maintenance Phase: Change from Baseline in CD-PRO/SS Score at Week 66 [ Time Frame: 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) [ Time Frame: From Baseline up to Week 78 ]
  • Overall Number of Participants with Adverse Events Leading to Study Drug Discontinuation [ Time Frame: 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 [ Time Frame: From Baseline up to Week 78 ]
  • Overall Number of Participants who Experienced at Least One Infection-Related Serious Adverse Event [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: From Baseline up to Week 78 ]
  • Overall Number of Participants who Develop Malignancies [ Time Frame: From Baseline up to Week 78 ]
  • Percentage of Participants With Anti-Therapeutic Antibodies (ATAs) to Etrolizumab [ Time Frame: 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 (Cmin) of Etrolizumab [ Time Frame: Pre-dose (Hour 0) at Baseline and Weeks 0, 10, 14, 16, 24, 28, 32, 44, and 66 or early termination (up to Week 66) ]
Original Secondary Outcome Measures  ICMJE
 (submitted: March 16, 2015)
  • Safety (composite outcome measure): Incidence and severity of adverse events; incidence of anti-therapeutic antibodies to etrolizumab [ Time Frame: Up to 90 weeks ]
  • Proportion of patients who achieve 100 points reduction in their CDAI score (CDAI-100 response) [ Time Frame: At Week 14 ]
  • Maintenance Phase: Proportion of patients who achieve CDAI-100 response [ Time Frame: At Week 66 ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE A Study to Assess Whether Etrolizumab is a Safe and Efficacious Treatment for Participants With Moderately to Severely Active Crohn's Disease
Official Title  ICMJE 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
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.

Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Condition  ICMJE Crohn Disease
Intervention  ICMJE
  • Drug: Etrolizumab
    Etrolizumab will be administered as per regimen specified in individual arms.
    Other Names:
    • RO5490261
    • RG7413
  • Drug: Placebo
    Etrolizumab-matching placebo will be administered as per regimen specified in individual arms.
Study Arms  ICMJE
  • Experimental: 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.
    Interventions:
    • Drug: Etrolizumab
    • Drug: Placebo
  • Experimental: 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.
    Interventions:
    • Drug: Etrolizumab
    • Drug: Placebo
  • Placebo Comparator: 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: Drug: Placebo
  • Experimental: 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.
    Interventions:
    • Drug: Etrolizumab
    • Drug: Placebo
  • Experimental: 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.
    Interventions:
    • Drug: Etrolizumab
    • Drug: Placebo
  • Experimental: 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.
    Interventions:
    • Drug: Etrolizumab
    • Drug: Placebo
  • Experimental: 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.
    Interventions:
    • Drug: Etrolizumab
    • Drug: Placebo
  • Placebo Comparator: 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: Drug: Placebo
  • Placebo Comparator: 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: Drug: Placebo
  • Placebo Comparator: 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: Drug: Placebo
  • Experimental: 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: Drug: Etrolizumab
  • No Intervention: Maintenance Phase - Non-Responders: Safety Follow-Up/GA29145
    All participants from Cohorts 1-3 who are considered non-responders after the Induction Phase at Week 14 may be eligible to enter the open-label extension study GA29145 (NCT02403323) and/or undergo a 12-week safety follow-up.
Publications * Sandborn WJ, Vermeire S, Tyrrell H, Hassanali A, Lacey S, Tole S, Tatro AR; Etrolizumab Global Steering Committee. Etrolizumab for the Treatment of Ulcerative Colitis and Crohn's Disease: An Overview of the Phase 3 Clinical Program. Adv Ther. 2020 Jul;37(7):3417-3431. doi: 10.1007/s12325-020-01366-2. Epub 2020 May 22.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: November 29, 2017)
1150
Original Estimated Enrollment  ICMJE
 (submitted: March 16, 2015)
1250
Estimated Study Completion Date  ICMJE June 25, 2022
Estimated Primary Completion Date July 31, 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 80 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Reference Study ID Number: GA29144 www.roche.com/about_roche/roche_worldwide.htm 888-662-6728 (U.S. and Canada) global-roche-genentech-trials@gene.com
Listed Location Countries  ICMJE Argentina,   Australia,   Austria,   Belgium,   Brazil,   Bulgaria,   Canada,   Croatia,   Czechia,   Estonia,   France,   Germany,   Hungary,   Israel,   Italy,   Korea, Republic of,   Latvia,   Lithuania,   Luxembourg,   Mexico,   Netherlands,   New Zealand,   Poland,   Romania,   Russian Federation,   Serbia,   Slovakia,   South Africa,   Spain,   Sweden,   Switzerland,   Turkey,   Ukraine,   United Kingdom,   United States
Removed Location Countries Czech Republic
 
Administrative Information
NCT Number  ICMJE NCT02394028
Other Study ID Numbers  ICMJE GA29144
2014-003824-36 ( EudraCT Number )
Has Data Monitoring Committee Not Provided
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Hoffmann-La Roche
Study Sponsor  ICMJE Hoffmann-La Roche
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Clinical Trials Hoffmann-La Roche
PRS Account Hoffmann-La Roche
Verification Date November 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP