Clinical trial NCT02171429: 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
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Ulcerative Colitis
Lead sponsor: Hoffmann-La Roche
Sponsor class: INDUSTRY
First posted: 2014-06-24
Enrollment: 358
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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 ulcerative colitis (UC) who are naIve to tumor necrosis factor (TNF) inhibitors and refractory to or intolerant of prior immunosuppressant and/or corticosteroid treatment. In addition to this study, a second Phase III trial with identical study design (GA28948; NCT02163759) was independently conducted.


Eligibility criteria: Inclusion Criteria:

* Diagnosis of ulcerative colitis (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 intravenous (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

Primary outcomes:
measure: Percentage of Participants in Remission at Week 10 With Etrolizumab Compared With Placebo, as Determined by the Mayo Clinic Score (MCS), GA28949 Population
timeFrame: Week 10
Secondary outcomes:
measure: Percentage of Participants in Remission at Week 10 With Etrolizumab Compared With Adalimumab, as Determined by the MCS, GA28949 Population
timeFrame: Week 10
measure: Percentage of Participants in Remission at Week 10 With Etrolizumab as Compared With Adalimumab, as Determined by the MCS, GA28948 & GA28949 Pooled Population
timeFrame: Week 10
measure: Percentage of Participants With Clinical Response at Week 10, as Determined by the MCS, GA28949 Population
timeFrame: Week 10
measure: Percentage of Participants With Clinical Response at Week 10 With Etrolizumab as Compared With Adalimumab, as Determined by the MCS, GA28948 & GA28949 Pooled Population
timeFrame: Week 10
measure: Percentage of Participants With Improvement in Endoscopic Appearance of the Mucosa at Week 10, as Determined by the Mayo Endoscopy Subscore, GA28949 Population
timeFrame: Week 10
measure: Percentage of Participants With Improvement in Endoscopic Appearance of the Mucosa at Week 10 With Etrolizumab as Compared With Adalimumab, as Determined by the MCS Endoscopy Subscore, GA28948 & GA28949 Pooled Population
timeFrame: Week 10
measure: Percentage of Participants in Endoscopic Remission at Week 10, as Determined by the MCS Endoscopy Subscore, GA28949 Population
timeFrame: Week 10
measure: Percentage of Participants in Endoscopic Remission at Week 10 With Etrolizumab as Compared With Adalimumab, as Determined by the MCS Endoscopy Subscore, GA28948 & GA28949 Pooled Population
timeFrame: Week 10
measure: Percentage of Participants With Histologic Remission at Week 10, as Determined by the Nancy Histological Index, GA28949 Population
timeFrame: Week 10
measure: Percentage of Participants With Histologic Remission at Week 10 With Etrolizumab as Compared With Adalimumab, as Determined by the Nancy Histological Index, GA28948 & GA28949 Pooled Population
timeFrame: Week 10
measure: Change From Baseline in the MCS Rectal Bleeding Subscore at Week 6, GA28949 Population
timeFrame: Baseline, Week 6
measure: Change From Baseline in the MCS Rectal Bleeding Subscore at Week 6 With Etrolizumab as Compared With Adalimumab, GA28948 & GA28949 Pooled Population
timeFrame: Baseline, Week 6
measure: Change From Baseline in the MCS Stool Frequency Subscore at Week 6, GA28949 Population
timeFrame: Baseline, Week 6
measure: Change From Baseline in the MCS Stool Frequency Subscore at Week 6 With Etrolizumab as Compared With Adalimumab, GA28948 & GA28949 Pooled Population
timeFrame: Baseline, Week 6
measure: Change From Baseline in Ulcerative Colitis (UC) Bowel Movement Signs and Symptoms at Week 10, as Assessed by the UC Patient-Reported Outcome Signs and Symptoms (UC-PRO/SS), GA28949 Population
timeFrame: Baseline, Week 10
measure: Change From Baseline in Ulcerative Colitis Bowel Movement Signs and Symptoms at Week 10, as Assessed by the UC-PRO/SS, GA28948 & GA28949 Pooled Population
timeFrame: Baseline, Week 10
measure: Change From Baseline in Ulcerative Colitis Functional Symptoms at Week 10, as Assessed by the UC-PRO/SS, GA28949 Population
timeFrame: Baseline, Week 10
measure: Change From Baseline in Ulcerative Colitis Functional Symptoms at Week 10, as Assessed by the UC-PRO/SS, GA28948 & GA28949 Pooled Population
timeFrame: Baseline, Week 10
measure: Percentage of Participants in Clinical Remission at Week 10, as Determined by the MCS, GA28949 Population
timeFrame: Week 10
measure: Percentage of Participants in Remission at Week 10 and Week 14, as Determined by the MCS, GA28949 Population
timeFrame: Weeks 10 and 14
measure: Change From Baseline in Health-Related Quality of Life at Week 10, as Assessed by the Total Inflammatory Bowel Disease Questionnaire (IBDQ) Score, GA28949 Population
timeFrame: Baseline, Week 10
measure: Pharmacokinetics of Etrolizumab: Serum Concentration, GA28949 Population
timeFrame: Weeks 10 and 14
measure: Number and 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), GA28949 Population
timeFrame: From Baseline until the end of study (up to 26 weeks)
measure: Number and Percentage of Participants by Marked Laboratory Abnormality Status for Hematology Parameters as a Shift Table From Baseline to Week 10, GA28949 Population
timeFrame: From Baseline up to Week 10
measure: Number and Percentage of Participants by Marked Laboratory Abnormality Status for Chemistry Parameters as a Shift Table From Baseline to Week 10, GA28949 Population
timeFrame: From Baseline up to Week 10
measure: Number and Percentage of Participants With Anti-Drug Antibodies (ADAs) to Etrolizumab at Baseline and Anytime Post-Baseline, GA28949 Population
timeFrame: Pre-dose (0 hour) on Day 1 and Week 4, Week 10, Week 14, and early termination/end of safety follow-up (up to 26 weeks)
Other outcomes:
Locations:
city: Orlando
country: United States
facility: Center For Digestive Health
state: Florida
city: Orlando
country: United States
facility: Internal Medicine Specialists
state: Florida
city: Topeka
country: United States
facility: Cotton-O'Neil Clinical Research Center, Digestive Health
state: Kansas
city: Mentor
country: United States
facility: Great Lakes Gastroenterology Research, LLC
state: Ohio
city: Mar del Plata
country: Argentina
facility: Centro de Investigaciones Medicas Mar Del Plata
city: Concord
country: Australia
facility: Concord Repatriation General Hospital
state: New South Wales
city: Adelaide
country: Australia
facility: Royal Adelaide Hospital
state: South Australia
city: Bedford Park
country: Australia
facility: Flinders Medical Centre
state: South Australia
city: Fitzroy
country: Australia
facility: St Vincent's Hospital Melbourne
state: Victoria
city: Footscray
country: Australia
facility: Footscray Hospital; Gastroenterology
state: Victoria
city: Salvador
country: Brazil
facility: Hospital Universitario Prof Edgar Santos-Ufba; Ambulatorio Magalhaes Neto 3Andar- Dermatologia
state: BA
city: Fortaleza
country: Brazil
facility: Hospital Universitario Walter Cantidio - UFC
state: CE
city: Curitiba
country: Brazil
facility: Centro Digestivo de Curitiba
state: PR
city: Porto Alegre
country: Brazil
facility: Hospital Ernesto Dornelles
state: RS
city: Santo Andre
country: Brazil
facility: Pesquisare Saúde Sociedade Simples
state: SP
city: Dupnitsa
country: Bulgaria
facility: Medical Centre "Asklepii", OOD
city: Pleven
country: Bulgaria
facility: DCC Sv. Pantaleymon OOD
city: Pleven
country: Bulgaria
facility: Medical center Medconsult Pleven OOD
city: Ruse
country: Bulgaria
facility: MHAT - Ruse, AD
city: Sliven
country: Bulgaria
facility: MHAT "Hadzhi Dimitar", OOD
city: Sofia
country: Bulgaria
facility: "City Clinic UMHAC" EOOD
city: Sofia
country: Bulgaria
facility: Medical center CONVEX EOOD
city: Stara Zagora
country: Bulgaria
facility: Medical Center "Nov Rehabilitatsionen Tsentar", EOOD
city: Varna
country: Bulgaria
facility: MHAT 'Sv. Marina', EAD
city: Cali
country: Colombia
facility: RTS - Fundación Valle de Lili
city: Medellin
country: Colombia
facility: Instituto de Coloproctologia ICO S.A.S.
city: Osijek
country: Croatia
facility: Clinical Hospital Centre Osijek
city: Zagreb
country: Croatia
facility: Clinical Hospital Sveti Duh
city: Hradec Kralove
country: Czechia
facility: Fakultni nemocnice Hradec Kralove
city: Hradec Kralove
country: Czechia
facility: Hepato-Gastroenterologie HK, s.r.o.
city: Olomouc
country: Czechia
facility: PreventaMed, s.r.o.
city: Pardubice
country: Czechia
facility: Pardubicka krajska nemocnice, a.s.
city: Praha 7
country: Czechia
facility: ISCARE a.s.
city: Pierre Benite
country: France
facility: Centre Hospitalier Lyon Sud
city: Herakleion
country: Greece
facility: University General Hospital of Heraklion
city: Gyor
country: Hungary
facility: Petz Aladar Megyei Oktato Korhaz
city: Daugavpils
country: Latvia
facility: Central Outpatient Clinic
city: Rīga
country: Latvia
facility: Pauls Stradins Clinical University Hospital
city: Rīga
country: Latvia
facility: Digestive Diseases Center "Gastro"
city: Kaunas
country: Lithuania
facility: Hospital of Lithuanian University of Health. Sciences Kaunas Clinics
city: Klaipeda
country: Lithuania
facility: Klaipeda Seamen's Hospital, Public Institution
city: Vilnius
country: Lithuania
facility: Vilnius University Hospital Santariskiu Clinic, Public Institution; Cardiology
city: Kota Bahru
country: Malaysia
facility: Hospital Raja Perempuan Zainab II; Department of Medicine
city: Kuala Lumpur
country: Malaysia
facility: Pusat Perubatan Universiti Kebangsaan Malaysia
city: Kuala Lumpur
country: Malaysia
facility: University Malaya Medical Centre
city: Pahang
country: Malaysia
facility: Hospital Tengku Ampuan Afzan
city: Auckland
country: New Zealand
facility: North Shore Hospital
city: Dunedin
country: New Zealand
facility: Dunedin Hospital
city: Hamilton
country: New Zealand
facility: Waikato Hospital
city: Takapuna
country: New Zealand
facility: Shakespeare Specialist Group
city: Tauranga
country: New Zealand
facility: Tauranga Hospital
city: Katowice
country: Poland
facility: Pro Familia Altera Sp z o.o.
city: Katowice
country: Poland
facility: Nzoz All-Medicus
city: Katowice
country: Poland
facility: Uniwersyteckie Centrum Kliniczne im. prof. K. Gibinskiego SUM
city: Ksawerow
country: Poland
facility: Centrum Opieki Zdrowotnej Orkan-Med
city: Nowy Targ
country: Poland
facility: Allmedica Badania Kliniczne Sp z o.o. Sp K.
city: Rzeszow
country: Poland
facility: Centrum Medyczne Medyk
city: Rzeszów
country: Poland
facility: Gabinet Lekarski, Bartosz Korczowski
city: Szczecin
country: Poland
facility: Niepubliczny Zaklad Opieki Zdrowotnej SONOMED
city: Warszawa
country: Poland
facility: Endoterapia PFG Sp. z o.o.
city: Wroclaw
country: Poland
facility: LexMedica Osrodek Badan Klinicznych
city: Łódź
country: Poland
facility: AppleTreeClinics Sp. z o.o.
city: Sankt-peterburg
country: Russian Federation
facility: SBIH City Clinical Hospital #31
state: Sankt Petersburg
city: Barnaul
country: Russian Federation
facility: SBEI HPE Altai State Medical University of MoH and SD; Out-patient Department
city: Irkutsk
country: Russian Federation
facility: Irkutsk State Medical Academy of Continuing Education
city: Novosibirsk
country: Russian Federation
facility: FSBI "Scientific Research Institute of Physyology and Basic Medicine" under the SB of RAMS
city: Omsk
country: Russian Federation
facility: BHI of Omsk region Clinical Oncology Dispensary
city: St. Petersburg
country: Russian Federation
facility: Center of Emergency and Radiation Medicine; Pulmonology
city: St. Petersburg
country: Russian Federation
facility: Pavlov First Saint Petersburg State Medical University
city: St. Petersburg
country: Russian Federation
facility: SPb SHI "City Hospital #9"
city: Stavropol
country: Russian Federation
facility: FSBEI HE "Stavropol State Medical University" of Ministry of Healthcare of Russian Federation
city: Voronezh
country: Russian Federation
facility: Voronezh Regional Clinical Hospital #1
city: Ankara
country: Turkey
facility: Ankara Diskapi Yildirim Beyazit Training and Research Hospital; Gastroenterology
city: Gaziantep
country: Turkey
facility: Gaziantep University Medical Faculty Sahinbey Educational Research Hospital; Medical Oncology
city: Istanbul
country: Turkey
facility: Haydarpasa Numune Training and Research Hospital; Gastroenterology
city: Kocaeli
country: Turkey
facility: Kocaeli Universitesi Tip Fakultesi
city: Sumy
country: Ukraine
facility: CI of SRC Sumy RCH Dept of Gasroenterology Sumy SU MI
state: Kharkiv Governorate
city: Kyiv
country: Ukraine
facility: CNE Kyiv CCH #18
state: KIEV Governorate
city: Kyiv
country: Ukraine
facility: CI of Kyiv RC Kyiv Regional Clinical Hospital
state: KIEV Governorate
city: Kyiv
country: Ukraine
facility: Med Center of International Institute of Clinical Trials LLC; Medical Center "OK!Clinic+"
state: KIEV Governorate
city: Uzhgorod
country: Ukraine
facility: A.Novak Transcarpathian Regional Clinical Hospital
state: KIEV Governorate
city: Chernivtsi
country: Ukraine
facility: RCNECRCH Dept of Surgery, SHEI Ukr BSMU
state: Podolia Governorate
city: Dnipropetrovsk
country: Ukraine
facility: SI inst. of Gastroenterology of NAMSU Dept of Stomach & Duodenum Diseases, D&ThN SI DMA of MoHU
city: Kharkiv
country: Ukraine
facility: GI L.T.Malaya Therapy National Institute of the NAMS of Ukraine
city: Kherson
country: Ukraine
facility: CI Kherson Afanasii and Olha Tropiny City Clinical Hospital
city: Poltava
country: Ukraine
facility: M.V. Sklifosovskyi Poltava RCH Dept of Gastroenterology HSEIU UMSA
city: Vinnytsia
country: Ukraine
facility: Private Small Enterprise Medical Center Pulse
city: Vinnytsia
country: Ukraine
facility: MCIC MC LLC Health Clinic
city: Zaporizhzhia
country: Ukraine
facility: Zaporizhzhia SMU
city: Zaporizhzhia
country: Ukraine
facility: LLC Diaservis
Study officials:
affiliation: Hoffmann-La Roche
name: Clinical Trials
role: STUDY_DIRECTOR
References:
citation: Rubin DT, Dotan I, DuVall A, Bouhnik Y, Radford-Smith G, Higgins PDR, Mishkin DS, Arrisi P, Scalori A, Oh YS, Tole S, Chai A, Chamberlain-James K, Lacey S, McBride J, Panes J; HIBISCUS Study Group. Etrolizumab versus adalimumab or placebo as induction therapy for moderately to severely active ulcerative colitis (HIBISCUS): two phase 3 randomised, controlled trials. Lancet Gastroenterol Hepatol. 2022 Jan;7(1):17-27. doi: 10.1016/S2468-1253(21)00338-1. Epub 2021 Nov 17.
citation: 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.