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A Study Comparing the Efficacy and Safety of Etrolizumab With Adalimumab and Placebo in Participants With Moderate to Severe Ulcerative Colitis (UC) in Participants Naive to Tumor Necrosis Factor (TNF) Inhibitors (Study #2) (HIBISCUS II)

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ClinicalTrials.gov Identifier: NCT02171429
Recruitment Status : Completed
First Posted : June 24, 2014
Last Update Posted : June 4, 2020
Sponsor:
Information provided by (Responsible Party):
Hoffmann-La Roche

Tracking Information
First Submitted Date  ICMJE June 20, 2014
First Posted Date  ICMJE June 24, 2014
Last Update Posted Date June 4, 2020
Actual Study Start Date  ICMJE November 14, 2014
Actual Primary Completion Date March 2, 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: November 4, 2019)
Percentage of Participants With Induction of Remission With Etrolizumab Compared With Placebo at Week 10, as Determined by the Mayo Clinic Score (MCS) [ Time Frame: Week 10 ]
Original Primary Outcome Measures  ICMJE
 (submitted: June 23, 2014)
Induction of remission compared with placebo as determined by the Mayo Clinic Score (MCS) [ Time Frame: Week 10 ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: November 4, 2019)
  • Percentage of Participants With Induction of Remission With Etrolizumab Compared With Adalimumab at Week 10, as Determined by the MCS [ Time Frame: Week 10 ]
  • Percentage of Participants With Induction of Clinical Remission at Week 10, as Determined by the MCS [ Time Frame: Week 10 ]
  • Percentage of Participants With Clinical Response at Week 10, as Determined by the MCS [ Time Frame: Week 10 ]
  • Percentage of Participants With Improvement in Endoscopic Appearance of the Mucosa at Week 10, as Determined by the Mayo Endoscopic Subscore [ Time Frame: Week 10 ]
  • Percentage of Participants With Endoscopic Remission at Week 10, as Determined by the Mayo Endoscopic Subscore [ Time Frame: Week 10 ]
  • Percentage of Participants who Achieve Remission at Week 10 and who Maintained Remission to Week 14, as Determined by the MCS [ Time Frame: Week 10 and 14 ]
  • Percentage of Participants With Histological Remission at Week 10, as Determined by the Nancy Histological Subscore [ Time Frame: Week 10 ]
  • Change From Baseline in MCS Rectal Bleeding Subscore at Week 6 [ Time Frame: Baseline, Week 6 ]
  • Change From Baseline in MCS Stool Frequency Subscore at Week 6 [ Time Frame: Baseline, Week 6 ]
  • Change From Baseline in Ulcerative Colitis (UC) Bowel Movement Signs and Symptoms at Week 10, as Assessed by UC-Participant-Reported Outcome Signs and Symptoms (PRO/SS) [ Time Frame: Baseline, Week 10 ]
  • Change From Baseline in UC Abdominal Symptoms at Week 10, as Assessed by UC-PRO/SS [ Time Frame: Baseline, Week 10 ]
  • Change From Baseline in Health-Related Quality of Life (QOL) at Week 10, as Assessed by Overall Inflammatory Bowel Disease Questionnaire (IBDQ) [ Time Frame: Baseline, Week 10 ]
  • Pharmacokinetics of Etrolizumab: Serum Concentration [ Time Frame: Pre-dose (0 hour) on Day 1, Week 10, Week 14, early termination/end of safety follow-up (up to Week 26) ]
  • Percentage of Participants With at Least One Adverse Event by Severity, According to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0 (NCI CTCAE v4.0) [ Time Frame: Baseline up to end of study (up to Week 26) ]
  • Percentage of Participants With at Least One Serious Adverse Event [ Time Frame: Baseline up to end of study (up to Week 26) ]
  • Percentage of Participants With Adverse Events Leading To Study Drug Discontinuation [ Time Frame: Baseline up to end of study (up to Week 26) ]
  • Percentage of Participants With Infection-Related Adverse Events by Severity, According to NCI CTCAE v4.0 [ Time Frame: Baseline up to end of study (up to Week 26) ]
  • Percentage of Participants With Serious Infection-Related Adverse Events [ Time Frame: Baseline up to end of study (up to Week 26) ]
  • Percentage of Participants With Injection-Site Reactions by Severity, According to NCI CTCAE v4.0 [ Time Frame: Baseline up to end of study (up to Week 26) ]
  • Percentage of Participants With Hypersensitivity Reaction Events by Severity, According to NCI CTCAE v4.0 [ Time Frame: Baseline up to end of study (up to Week 26) ]
  • Percentage of Participants With Anti-Therapeutic Antibodies (ATA) to Etrolizumab [ Time Frame: Pre-dose (0 hour) on Day 1, Week 4, Week 10, Week 14, early termination/end of safety follow-up (up to Week 26) ]
  • Percentage of Participants With Laboratory Abnormalities [ Time Frame: Baseline (Day 1), Week 10, and any unscheduled visits or early withdrawal from treatment, up to end of study (up to Week 26) ]
    Laboratory parameters for hematology, blood chemistry, and urinalysis will be measured compared with a standard reference range. Values outside the standard reference range are considered abnormalities. Not every laboratory abnormality qualifies as an adverse event. A laboratory test result must be reported as an adverse event if it meets any of the following criteria: is accompanied by clinical symptoms; results in a change in study treatment or a medical intervention; or is clinically significant in the investigator's judgment.
Original Secondary Outcome Measures  ICMJE
 (submitted: June 23, 2014)
Induction of remission compared with adalimumab as determined by the Mayo Clinic Score (MCS) [ Time Frame: Week 10 ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE A Study Comparing the Efficacy and Safety of Etrolizumab With Adalimumab and Placebo in Participants With Moderate to Severe Ulcerative Colitis (UC) in Participants Naive to Tumor Necrosis Factor (TNF) Inhibitors (Study #2)
Official Title  ICMJE Phase III, Randomized, Double-Blind, Double-Dummy, Placebo-Controlled, Multicenter Study to Evaluate the Efficacy (Induction of Remission) and Safety of Etrolizumab Compared With Adalimumab and Placebo in Patients With Moderate to Severe Ulcerative Colitis Who Are Naive to TNF Inhibitors
Brief Summary This Phase III, double-blind, placebo and active comparator controlled, multicenter study will investigate the efficacy and safety of etrolizumab in induction 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.
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 Ulcerative Colitis
Intervention  ICMJE
  • Drug: Adalimumab
    Adalimumab 160 milligrams (mg) will be administered subcutaneously (SC) at Week 0; 80 mg SC at Week 2; 40 mg SC at Weeks 4, 6 and 8.
    Other Name: Humira
  • Other: Adalimumab Placebo
    Placebo matching to adalimumab will be administered SC at Weeks 0, 2, 4, 6 and 8.
  • Drug: Etrolizumab
    Etrolizumab 105 mg will be administered SC every 4 weeks (Q4W).
    Other Names:
    • PRO145223
    • RO5490261
    • RG7413
  • Other: Etrolizumab Placebo
    Placebo matching to etrolizumab will be administered SC Q4W.
Study Arms  ICMJE
  • Active Comparator: Adalimumab + Etrolizumab Placebo
    Participants will receive adalimumab up to Week 8 and placebo matching to etrolizumab up to Week 12.
    Interventions:
    • Drug: Adalimumab
    • Other: Etrolizumab Placebo
  • Experimental: Etrolizumab + Adalimumab Placebo
    Participants will receive etrolizumab up to Week 12 and placebo matching to adalimumab up to Week 8.
    Interventions:
    • Other: Adalimumab Placebo
    • Drug: Etrolizumab
  • Placebo Comparator: Etrolizumab Placebo + Adalimumab Placebo
    Participants will receive placebo matching to etrolizumab up to Week 12 and placebo matching to adalimumab up to Week 8.
    Interventions:
    • Other: Adalimumab Placebo
    • Other: Etrolizumab Placebo
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 May 22. doi: 10.1007/s12325-020-01366-2. [Epub ahead of print]

*   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 Completed
Actual Enrollment  ICMJE
 (submitted: March 4, 2020)
358
Original Estimated Enrollment  ICMJE
 (submitted: June 23, 2014)
350
Actual Study Completion Date  ICMJE May 25, 2020
Actual Primary Completion Date March 2, 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Diagnosis of UC established at least 3 months prior to randomization (Day 1)
  • Moderately to severely active UC as determined by the MCS
  • Naive to treatment with TNF inhibitor therapy
  • An inadequate response, loss of response, or intolerance to prior corticosteroid and/or immunosuppressant treatment
  • Background UC therapy may include oral 5-aminosalisylate (5-ASA), budesonide, oral corticosteroids, probiotics, azathioprine (AZA), 6-mercaptopurine (6MP), or methotrexate (MTX) if doses have been stable for:
  • AZA, 6-MP, MTX: 8 weeks immediately prior to randomization
  • 5-ASA: 4 weeks immediately prior to randomization
  • Corticosteroids: 4 weeks immediately prior to randomization; if corticosteroids are being tapered, dose has to be stable for at least 2 weeks prior to randomization
  • Use of highly effective contraception method as defined by the protocol
  • 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:

Exclusion Criteria Related to Inflammatory Bowel Disease:

  • Prior extensive colonic resection, subtotal or total colectomy, or planned surgery for UC
  • Past or present ileostomy or colostomy
  • Diagnosis of indeterminate colitis
  • Suspicion of ischemic colitis, radiation colitis, or microscopic colitis
  • Diagnosis of toxic megacolon within 12 months of initial screening visit
  • Any diagnosis of Crohn's disease
  • Past or present fistula or abdominal abscess
  • A history or current evidence of colonic mucosal dysplasia
  • Patients with any stricture (stenosis) of the colon
  • Patients with history or evidence of adenomatous colonic polyps that have not been removed

Exclusion Criteria Related to Prior or Concomitant Therapy:

  • Prior treatment with TNF-alpha antagonists
  • Any prior treatment with etrolizumab or other anti integrin agents
  • Any prior treatment with rituximab
  • Any treatment with tofacitinib during screening
  • Any prior treatment with anti-adhesion molecules
  • Use of IV steroids within 30 days prior to screening with the exception of a single administration of IV steroid
  • Use of agents that deplete B or T cells
  • Use of anakinra, abatacept, cyclosporine, sirolimus, or mycophenolate mofetil (MMF) within 4 weeks prior to randomization
  • Chronic nonsteroidal anti inflammatory drug (NSAID) use
  • Patients who are currently using anticoagulants including, but not limited to, warfarin, heparin, enoxaparin, dabigatran, apixaban, rivaroxaban
  • Patients who have received treatment with corticosteroid enemas/suppositories and/or topical (rectal) 5 ASA preparations within 2 weeks prior to randomization
  • Apheresis (i.e., Adacolumn apheresis) within 2 weeks prior to randomization
  • Received any investigational treatment including investigational vaccines within 5 half lives of the investigational product or 28 days after the last dose, whichever is greater, prior to randomization
  • History of moderate or severe allergic or anaphylactic/anaphylactoid reactions to chimeric, human, or humanized antibodies, fusion proteins, or murine proteins or hypersensitivity to etrolizumab (active drug substance) or any of the excipients (L histidine, L-arginine, succinic acid, polysorbate 20)
  • Patients administered tube feeding, defined formula diets, or parenteral alimentation/nutrition who have not discontinued these treatments within 3 weeks prior to randomization

Exclusion Criteria Related to General Safety:

  • Pregnant or lactating
  • Lack of peripheral venous access
  • Hospitalization (other than for elective reasons) during the screening period
  • Significant uncontrolled comorbidity, such as cardiac (e.g., moderate to severe heart failure New York Heart Association Class III/IV), pulmonary, renal, hepatic, endocrine, or gastrointestinal disorders
  • Neurological conditions or diseases that may interfere with monitoring for PML
  • History of demyelinating disease
  • Clinically significant abnormalities on screening neurologic examination (PML Objective Checklist)
  • Clinically significant abnormalities on the screening PML Subjective Checklist
  • History of alcohol, drug, or chemical abuse less than 6 months prior to screening
  • Conditions other than UC that could require treatment with > 10 mg/day of prednisone (or equivalent) during the course of the study
  • History of cancer, including hematologic malignancy, solid tumors, and carcinoma in situ, within 5 years before screening

Exclusion Criteria Related to Infection Risk

  • Congenital or acquired immune deficiency
  • Patients must undergo screening for HIV and test positive for preliminary and confirmatory tests
  • Positive hepatitis C virus (HCV) antibody test result
  • Positive hepatitis B virus (HBV) antibody test result
  • Evidence of or treatment for Clostridium difficile (as assessed by C. difficile toxin testing) within 60 days prior to randomization or other intestinal pathogens (as assessed by stool culture and ova and parasite evaluation) within 30 days prior to randomization
  • Evidence of or treatment for clinically significant cytomegalovirus (CMV) colitis (based on the investigator's judgment) within 60 days prior to randomization
  • History of active or latent TB
  • History of recurrent opportunistic infections and/or history of severe disseminated viral infections
  • Any serious opportunistic infection within the last 6 months prior to screening
  • Any current or recent signs or symptoms (within 4 weeks before screening and during screening) of infection
  • Any major episode of infection requiring treatment with 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 randomization
  • History of organ transplant

Exclusion Criteria Related to Laboratory Abnormalities (at Screening)

  • Serum creatinine >2 x upper limit of normal (ULN)
  • ALT or AST > 3 x ULN or alkaline phosphatase > 3 x ULN or total bilirubin > 2.5 x ULN
  • Platelet count < 100,000/uL
  • Hemoglobin < 8 g/dL
  • Absolute neutrophil count < 1500/uL
  • Absolute lymphocyte count < 500/uL
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 information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Argentina,   Australia,   Brazil,   Bulgaria,   Colombia,   Croatia,   Czechia,   Greece,   Hungary,   Latvia,   Lithuania,   Malaysia,   New Zealand,   Poland,   Russian Federation,   Turkey,   Ukraine,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02171429
Other Study ID Numbers  ICMJE GA28949
2013-004277-27 ( EudraCT Number )
Has Data Monitoring Committee Not Provided
U.S. FDA-regulated Product Not Provided
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 June 2020

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