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: NCT02163759

Last Updated: 2021-07-23

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 358 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2014-11-04
• Study Completion Date: 2020-03-19

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 naÏve 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 (GA28949; NCT02171429) 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

Rocky Mountain Gastroenterology Associates, P.L.L.C.; Gastroenterology

Lakewood, Colorado, United States

Center for Advanced Gastroenterology

Maitland, Florida, United States

Gastroenterology Group of Naples

Naples, Florida, United States

Gastroenterology Associates of Central Georgia

Macon, Georgia, United States

University of Chicago Medical Center

Chicago, Illinois, United States

Center for Digestive Health

Troy, Michigan, United States

Huron Gastroenterology Associates

Ypsilanti, Michigan, United States

Wellness Clinical Research Center

San Antonio, Texas, United States

Tyler Research Institute, LLC

Tyler, Texas, United States

Instituto Medico DAMIC

Córdoba, , Argentina

Bankstown-Lidcombe Hospital

Bankstown, New South Wales, Australia

Royal Brisbane and Women's Hospital

Herston, Queensland, Australia

Mater Hospital Brisbane

South Brisbane, Queensland, Australia

Princess Alexandra Hospital

Woolloongabba, Queensland, Australia

Monash Medical Centre

Clayton, Victoria, Australia

Fiona Stanley Hospital

Murdoch, Western Australia, Australia

CCBR - Brasilia

Brasília, Federal District, Brazil

Instituto Goiano de Gastroenterologia e Endoscopia Digestiva Ltda

Goiânia, Goiás, Brazil

Hospital Felicio Rocho

Belo Horizonte, Minas Gerais, Brazil

Hospital Universitario Clementino Fraga Filho - UFRJ

Rio de Janeiro, Rio de Janeiro, Brazil

Hospital das Clinicas - UFRGS

Porto Alegre, Rio Grande do Sul, Brazil

UNESP - Faculdade de Medicina da Universidade Estadual Paulista - Campus Botucatu

Botucatu, São Paulo, Brazil

UMHAT "Sv. Ivan Rilski", EAD

Sofia, , Bulgaria

UMHAT Tsaritsa Yoanna - ISUL, EAD

Sofia, , Bulgaria

MC Medica Plus

Veliko Tarnovo, , Bulgaria

OÜ Innomedica

Tallinn, , Estonia

East Tallinn Central Hospital

Tallinn, , Estonia

West Tallinn Central Hospital

Tallinn, , Estonia

North Estonia Medical Centre Foundation

Tallinn, , Estonia

Tartu University Hospital

Tartu, , Estonia

Hôpital Beaujon

Clichy, , France

CHU Nice - Hopital de l'Archet 2

Nice, , France

University of Hong Kong

Hong Kong, , Hong Kong

Centro Integral en Reumatología S.A. de C.V. (CIRSA)

Guadalajara, Jalisco, Mexico

Accelerium S. de R.L. de C.V.

Monterrey, , Mexico

Hospital Universitario Dr Jose Eleuterio Gonzalez; Universidad Autónoma de Nuevo León

Monterrey, , Mexico

Centrum Medyczne Sw. Lukasza

Częstochowa, , Poland

7 Szpital Marynarki Wojennej z Przychodnia SPZOZ im. W. Lasinskiego

Gdansk, , Poland

NZOZ Centrum Medyczne ProMiMed

Krakow, , Poland

AppleTreeClinics Sp. z o.o.

Lodz, , Poland

Med-Gastr Przychodnia Specjalistyczna

Lodz, , Poland

Indywidualna Specjalistyczna Praktyka Lekarska

Lublin, , Poland

GASTROMED Sp. z o.o.

Lublin, , Poland

Wojewodzki Specjalistyczny Szpital w Olsztynie

Olsztyn, , Poland

SOLUMED Centrum Medyczne

Poznan, , Poland

Specjalistyczna Praktyka Lekarska Dr med. Marek Horynski; endoskopia

Sopot, , Poland

Twoja Przychodnia-Szczecinskie Centrum Medyczne

Szczecin, , Poland

Centrum Zdrowia MDM

Warsaw, , Poland

Narodowy Instytut Onkologii im. Marii Skłodowskiej-Curie - Państwowy Instytut Badawczy

Warsaw, , Poland

EMC Instytut Medyczny S.A.

Wroclaw, , Poland

PlanetMed

Wroclaw, , Poland

Yusupov Hospital

Moskva, Adygeya Republic, Russia

SPb SBIH "City Multy-field Hospital # 2"; Intensive Pulmonology and Thoracal Surgery

Saint Petersburg, Sankt-Peterburg, Russia

Baltic Medicine

Saint Petersburg, Sankt-Peterburg, Russia

Medical and Sanitary Division of Severstal

Cherepovets, Vologda Oblast, Russia

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

Barnaul, , Russia

FSBIH Central Clinical Hospital of RAS

Moscow, , Russia

FSBI "State Scientific Centre of Coloproctology" of the MoH of RF; Gastroenterology

Moscow, , Russia

SBHI of NN region "RCH of NN n.a. N.A.Semashko"

Nizhny Novgorod, , Russia

SBEI of HPE "Omsk SMA" Ministry of healthcare of RF"

Omsk, , Russia

SEIHPE "Rostov SMU of MoH of RF"

Rostov-on-Don, , Russia

FSMEI HPE "Military Medical Academy n.a. S.M.Kirov"of Minist

Saint Petersburg, , Russia

City Hospital #26

Saint Petersburg, , Russia

LLC International Medical Centre "SOGAZ"

Saint Petersburg, , Russia

Stavropol Regional Clinical Diagnostic Consultative Center

Stavropol, , Russia

Clinical Center Zvezdara

Belgrade, , Serbia

Military Medical Academy

Belgrade, , Serbia

Clinical Center Bezanijska Kosa

Belgrade, , Serbia

Clinical Center Zemun

Belgrade, , Serbia

Clinical Center Kragujevac

Kragujevac, , Serbia

General Hospital "Djordje Joanovic"; Gastroenterology

Zrenjanin, , Serbia

Fakultna nemocnica s poliklinikou F.D. Roosevelta

Banská Bystrica, , Slovakia

Nemocnica A.Lena Humenne, n.o.

Humenné, , Slovakia

KM Management spol. s r.o.

Nitra, , Slovakia

Gastro I, s.r.o.

Prešov, , Slovakia

Svet zdravia a.s.

Rimavská Sobota, , Slovakia

Accout Center s.r.o.

Šahy, , Slovakia

CNE Prof. O.O. Shalimov Kharkiv City Clinical Hospital #2 of KCC

Kharkiv, Kharkiv Governorate, Ukraine

Communal Non-commercial Enterprise of Kharkiv Regional Council Regional Clinical Hospital

Kharkiv, Kharkiv Governorate, Ukraine

Communal Institution of Kyiv Regional Council Kyiv Regional Clinical Hospital

Kyiv, Kharkiv Governorate, Ukraine

Medical Center of Limited Liability Company Medical Clinic Blagomed

Kyiv, KIEV Governorate, Ukraine

CI of Kyiv RC Regional Clinical Hospital #2

Kyiv, KIEV Governorate, Ukraine

CI City Hospital #1

Zaporizhzhia, Tavria Okruha, Ukraine

RCI Chernivtsi RCH Gastroenterology Bukovinsky SMU

Chernivtsi, , Ukraine

CHI Kharkiv City Clinical Hospital #13

Kharkiv, , Ukraine

CNI Consultative and Diagnostic Center of Desnianskyi District of Kyiv

Kyiv, , Ukraine

M.V. Sklifosovskyi Poltava RCH Outpatient UMSA HSEIU Ukrainian Medical Stomatological Academy

Poltava, , Ukraine

CI City Hospital #7

Zaporizhzhia, , Ukraine

Countries

United States; Argentina; Australia; Brazil; Bulgaria; Estonia; France; Hong Kong; Mexico; Poland; Russia; Serbia; Slovakia; 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

2013-004279-11

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

GA28948

Identifier Type: -

Identifier Source: org_study_id