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

NCT ID: NCT02171429

Last Updated: 2021-07-23

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 358 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2014-11-14
• Study Completion Date: 2020-05-25

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.

Conditions

Ulcerative Colitis

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: DOUBLE

Study Groups

Placebo

Participants will receive placebo matching to etrolizumab up to Week 12 and placebo matching to adalimumab up to Week 8.

Group Type: PLACEBO_COMPARATOR

Adalimumab Placebo

Intervention Type: OTHER

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

Etrolizumab Placebo

Intervention Type: OTHER

Placebo matching to etrolizumab will be administered SC once every 4 weeks (Q4W) up to Week 12 (at Weeks 0 \[Day 1\], 4, 8, and 12 \[clinical remitters only\]).

Adalimumab

Participants will receive adalimumab up to Week 8 and placebo matching to etrolizumab up to Week 12.

Group Type: ACTIVE_COMPARATOR

Adalimumab

Intervention Type: DRUG

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.

Etrolizumab Placebo

Intervention Type: OTHER

Placebo matching to etrolizumab will be administered SC once every 4 weeks (Q4W) up to Week 12 (at Weeks 0 \[Day 1\], 4, 8, and 12 \[clinical remitters only\]).

Etrolizumab

Participants will receive etrolizumab up to Week 12 and placebo matching to adalimumab up to Week 8.

Group Type: EXPERIMENTAL

Adalimumab Placebo

Intervention Type: OTHER

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

Etrolizumab

Intervention Type: DRUG

Etrolizumab 105 mg will be administered SC every 4 weeks (Q4W) up to Week 12 (at Weeks 0 \[Day 1\], 4, 8, and 12 \[clinical remitters only\]).

Interventions

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.

Intervention Type: DRUG

Adalimumab Placebo

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

Intervention Type: OTHER

Etrolizumab

Etrolizumab 105 mg will be administered SC every 4 weeks (Q4W) up to Week 12 (at Weeks 0 \[Day 1\], 4, 8, and 12 \[clinical remitters only\]).

Intervention Type: DRUG

Etrolizumab Placebo

Placebo matching to etrolizumab will be administered SC once every 4 weeks (Q4W) up to Week 12 (at Weeks 0 \[Day 1\], 4, 8, and 12 \[clinical remitters only\]).

Intervention Type: OTHER

Other Intervention Names

Humira; PRO145223; RO5490261; RG7413

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

• 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

• 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

• 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

• 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

• 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

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 80 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Hoffmann-La Roche

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Clinical Trials

Role: STUDY_DIRECTOR

Hoffmann-La Roche

Locations

Center For Digestive Health

Orlando, Florida, United States

Internal Medicine Specialists

Orlando, Florida, United States

Cotton-O'Neil Clinical Research Center, Digestive Health

Topeka, Kansas, United States

Great Lakes Gastroenterology Research, LLC

Mentor, Ohio, United States

Centro de Investigaciones Medicas Mar Del Plata

Mar del Plata, , Argentina

Concord Repatriation General Hospital

Concord, New South Wales, Australia

Royal Adelaide Hospital

Adelaide, South Australia, Australia

Flinders Medical Centre

Bedford Park, South Australia, Australia

St Vincent's Hospital Melbourne

Fitzroy, Victoria, Australia

Footscray Hospital; Gastroenterology

Footscray, Victoria, Australia

Hospital Universitario Walter Cantidio - UFC

Fortaleza, Ceará, Brazil

Hospital Universitario Prof Edgar Santos-Ufba; Ambulatorio Magalhaes Neto 3Andar- Dermatologia

Salvador, Estado de Bahia, Brazil

Centro Digestivo de Curitiba

Curitiba, Paraná, Brazil

Hospital Ernesto Dornelles

Porto Alegre, Rio Grande do Sul, Brazil

Pesquisare Saúde Sociedade Simples

Santo André, São Paulo, Brazil

Medical Centre "Asklepii", OOD

Dupnitsa, , Bulgaria

DCC Sv. Pantaleymon OOD

Pleven, , Bulgaria

Medical center Medconsult Pleven OOD

Pleven, , Bulgaria

MHAT - Ruse, AD

Rousse, , Bulgaria

MHAT "Hadzhi Dimitar", OOD

Sliven, , Bulgaria

"City Clinic UMHAC" EOOD

Sofia, , Bulgaria

Medical center CONVEX EOOD

Sofia, , Bulgaria

Medical Center "Nov Rehabilitatsionen Tsentar", EOOD

Stara Zagora, , Bulgaria

MHAT 'Sv. Marina', EAD

Varna, , Bulgaria

RTS - Fundación Valle de Lili

Cali, , Colombia

Instituto de Coloproctologia ICO S.A.S.

Medellín, , Colombia

Clinical Hospital Centre Osijek

Osijek, , Croatia

Clinical Hospital Sveti Duh

Zagreb, , Croatia

Fakultni nemocnice Hradec Kralove

Hradec Králové, , Czechia

Hepato-Gastroenterologie HK, s.r.o.

Hradec Králové, , Czechia

PreventaMed, s.r.o.

Olomouc, , Czechia

Pardubicka krajska nemocnice, a.s.

Pardubice, , Czechia

ISCARE a.s.

Prague, , Czechia

Centre Hospitalier Lyon Sud

Pierre-Bénite, , France

University General Hospital of Heraklion

Heraklion, , Greece

Petz Aladar Megyei Oktato Korhaz

Győr, , Hungary

Central Outpatient Clinic

Daugavpils, , Latvia

Pauls Stradins Clinical University Hospital

Riga, , Latvia

Digestive Diseases Center "Gastro"

Riga, , Latvia

Hospital of Lithuanian University of Health. Sciences Kaunas Clinics

Kaunas, , Lithuania

Klaipeda Seamen's Hospital, Public Institution

Klaipėda, , Lithuania

Vilnius University Hospital Santariskiu Clinic, Public Institution; Cardiology

Vilnius, , Lithuania

Hospital Raja Perempuan Zainab II; Department of Medicine

Kota Bharu, , Malaysia

Pusat Perubatan Universiti Kebangsaan Malaysia

Kuala Lumpur, , Malaysia

University Malaya Medical Centre

Kuala Lumpur, , Malaysia

Hospital Tengku Ampuan Afzan

Kuala Pahang, , Malaysia

North Shore Hospital

Auckland, , New Zealand

Dunedin Hospital

Dunedin, , New Zealand

Waikato Hospital

Hamilton, , New Zealand

Shakespeare Specialist Group

Takapuna, , New Zealand

Tauranga Hospital

Tauranga, , New Zealand

Pro Familia Altera Sp z o.o.

Katowice, , Poland

Nzoz All-Medicus

Katowice, , Poland

Uniwersyteckie Centrum Kliniczne im. prof. K. Gibinskiego SUM

Katowice, , Poland

Centrum Opieki Zdrowotnej Orkan-Med

Ksawerów, , Poland

AppleTreeClinics Sp. z o.o.

Lodz, , Poland

Allmedica Badania Kliniczne Sp z o.o. Sp K.

Nowy Targ, , Poland

Centrum Medyczne Medyk

Rzeszów, , Poland

Gabinet Lekarski, Bartosz Korczowski

Rzeszów, , Poland

Niepubliczny Zaklad Opieki Zdrowotnej SONOMED

Szczecin, , Poland

Endoterapia PFG Sp. z o.o.

Warsaw, , Poland

LexMedica Osrodek Badan Klinicznych

Wroclaw, , Poland

SBIH City Clinical Hospital #31

Saint Petersburg, Sankt-Peterburg, Russia

SBEI HPE Altai State Medical University of MoH and SD; Out-patient Department

Barnaul, , Russia

Irkutsk State Medical Academy of Continuing Education

Irkutsk, , Russia

FSBI "Scientific Research Institute of Physyology and Basic Medicine" under the SB of RAMS

Novosibirsk, , Russia

BHI of Omsk region Clinical Oncology Dispensary

Omsk, , Russia

Center of Emergency and Radiation Medicine; Pulmonology

Saint Petersburg, , Russia

Pavlov First Saint Petersburg State Medical University

Saint Petersburg, , Russia

SPb SHI "City Hospital #9"

Saint Petersburg, , Russia

FSBEI HE "Stavropol State Medical University" of Ministry of Healthcare of Russian Federation

Stavropol, , Russia

Voronezh Regional Clinical Hospital #1

Voronezh, , Russia

Ankara Diskapi Yildirim Beyazit Training and Research Hospital; Gastroenterology

Ankara, , Turkey (Türkiye)

Gaziantep University Medical Faculty Sahinbey Educational Research Hospital; Medical Oncology

Gaziantep, , Turkey (Türkiye)

Haydarpasa Numune Training and Research Hospital; Gastroenterology

Istanbul, , Turkey (Türkiye)

Kocaeli Universitesi Tip Fakultesi

Kocaeli, , Turkey (Türkiye)

CI of SRC Sumy RCH Dept of Gasroenterology Sumy SU MI

Sumy, Kharkiv Governorate, Ukraine

CNE Kyiv CCH #18

Kyiv, KIEV Governorate, Ukraine

CI of Kyiv RC Kyiv Regional Clinical Hospital

Kyiv, KIEV Governorate, Ukraine

Med Center of International Institute of Clinical Trials LLC; Medical Center "OK!Clinic+"

Kyiv, KIEV Governorate, Ukraine

A.Novak Transcarpathian Regional Clinical Hospital

Uzhhorod, KIEV Governorate, Ukraine

RCNECRCH Dept of Surgery, SHEI Ukr BSMU

Chernivtsi, Podolia Governorate, Ukraine

SI inst. of Gastroenterology of NAMSU Dept of Stomach & Duodenum Diseases, D&ThN SI DMA of MoHU

Dnipropetrovsk, , Ukraine

GI L.T.Malaya Therapy National Institute of the NAMS of Ukraine

Kharkiv, , Ukraine

CI Kherson Afanasii and Olha Tropiny City Clinical Hospital

Kherson, , Ukraine

M.V. Sklifosovskyi Poltava RCH Dept of Gastroenterology HSEIU UMSA

Poltava, , Ukraine

Private Small Enterprise Medical Center Pulse

Vinnytsia, , Ukraine

MCIC MC LLC Health Clinic

Vinnytsia, , Ukraine

Zaporizhzhia SMU

Zaporizhzhia, , Ukraine

LLC Diaservis

Zaporizhzhia, , Ukraine

Countries

United States; Argentina; Australia; Brazil; Bulgaria; Colombia; Croatia; Czechia; France; Greece; Hungary; Latvia; Lithuania; Malaysia; New Zealand; Poland; Russia; Turkey (Türkiye); Ukraine

References

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.

Reference Type: DERIVED

PMID: 34798036 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 32445184 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Other Identifiers

2013-004277-27

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

GA28949

Identifier Type: -

Identifier Source: org_study_id