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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 #1) (HIBISCUS I)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02163759
Recruitment Status : Completed
First Posted : June 16, 2014
Last Update Posted : March 30, 2020
Sponsor:
Information provided by (Responsible Party):
Hoffmann-La Roche

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.

Condition or disease Intervention/treatment Phase
Ulcerative Colitis Drug: Adalimumab Other: Adalimumab Placebo Drug: Etrolizumab Other: Etrolizumab Placebo Phase 3

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 358 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Official Title: 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
Actual Study Start Date : November 4, 2014
Actual Primary Completion Date : February 19, 2020
Actual Study Completion Date : March 19, 2020

Resource links provided by the National Library of Medicine

Drug Information available for: Adalimumab

Arm Intervention/treatment
Active Comparator: Adalimumab + Etrolizumab Placebo
Participants will receive adalimumab up to Week 8 and placebo matching to etrolizumab up to Week 12.
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: Etrolizumab Placebo
Placebo matching to etrolizumab will be administered SC Q4W.

Experimental: Etrolizumab + Adalimumab Placebo
Participants will receive etrolizumab up to Week 12 and placebo matching to adalimumab up to Week 8.
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

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.
Other: Adalimumab Placebo
Placebo matching to adalimumab will be administered SC at Weeks 0, 2, 4, 6 and 8.

Other: Etrolizumab Placebo
Placebo matching to etrolizumab will be administered SC Q4W.




Primary Outcome Measures :
  1. 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 ]

Secondary Outcome Measures :
  1. Percentage of Participants With Induction of Remission With Etrolizumab Compared With Adalimumab at Week 10, as Determined by the MCS [ Time Frame: Week 10 ]
  2. Percentage of Participants With Induction of Clinical Remission at Week 10, as Determined by the MCS [ Time Frame: Week 10 ]
  3. Percentage of Participants With Clinical Response at Week 10, as Determined by the MCS [ Time Frame: Week 10 ]
  4. 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 ]
  5. Percentage of Participants With Endoscopic Remission at Week 10, as Determined by the Mayo Endoscopic Subscore [ Time Frame: Week 10 ]
  6. 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 ]
  7. Percentage of Participants With Histological Remission at Week 10, as Determined by the Nancy Histological Subscore [ Time Frame: Week 10 ]
  8. Change from Baseline in MCS Rectal Bleeding Subscore at Week 6 [ Time Frame: Baseline, Week 6 ]
  9. Change from Baseline in MCS Stool Frequency Subscore at Week 6 [ Time Frame: Baseline, Week 6 ]
  10. 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 ]
  11. Change From Baseline in UC Abdominal Symptoms at Week 10, as Assessed by UC-PRO/SS [ Time Frame: Baseline, Week 10 ]
  12. 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 ]
  13. 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) ]
  14. 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) ]
  15. Percentage of Participants With at Least One Serious Adverse Event [ Time Frame: Baseline up to end of study (up to Week 26) ]
  16. Percentage of Participants With Adverse Events Leading To Study Drug Discontinuation [ Time Frame: Baseline up to end of study (up to Week 26) ]
  17. 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) ]
  18. Percentage of Participants With Serious Infection-Related Adverse Events [ Time Frame: Baseline up to end of study (up to Week 26) ]
  19. 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) ]
  20. 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) ]
  21. 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) ]
  22. 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.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 80 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02163759


Locations
Show Show 97 study locations
Sponsors and Collaborators
Hoffmann-La Roche
Investigators
Layout table for investigator information
Study Director: Clinical Trials Hoffmann-La Roche
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Hoffmann-La Roche
ClinicalTrials.gov Identifier: NCT02163759    
Other Study ID Numbers: GA28948
2013-004279-11 ( EudraCT Number )
First Posted: June 16, 2014    Key Record Dates
Last Update Posted: March 30, 2020
Last Verified: March 2020
Additional relevant MeSH terms:
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Colitis
Colitis, Ulcerative
Ulcer
Gastroenteritis
Gastrointestinal Diseases
Digestive System Diseases
Colonic Diseases
Intestinal Diseases
Pathologic Processes
Inflammatory Bowel Diseases
Adalimumab
rhuMAb Beta7
Anti-Inflammatory Agents
Antirheumatic Agents
Gastrointestinal Agents
Immunologic Factors
Physiological Effects of Drugs