Clinical trial NCT02163759: 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: 2014-06-16
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 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.


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 as Compared With Placebo, as Determined by the Mayo Clinic Score (MCS), GA28948 Population
timeFrame: Week 10
Secondary outcomes:
measure: Percentage of Participants in Remission at Week 10 With Etrolizumab as Compared With Adalimumab, as Determined by the MCS, GA28948 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, GA28948 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 MCS Endoscopy Subscore, GA28948 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, GA28948 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, GA28948 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, GA28948 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, GA28948 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), GA28948 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, GA28948 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, GA28948 Population
timeFrame: Week 10
measure: Percentage of Participants in Remission at Week 10 and Week 14, as Determined by the MCS, GA28948 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, GA28948 Population
timeFrame: Baseline, Week 10
measure: Pharmacokinetics of Etrolizumab: Serum Concentration, GA28948 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), GA28948 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, GA28948 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, GA28948 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, GA28948 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: Lakewood
country: United States
facility: Rocky Mountain Gastroenterology Associates, P.L.L.C.; Gastroenterology
state: Colorado
city: Maitland
country: United States
facility: Center for Advanced Gastroenterology
state: Florida
city: Naples
country: United States
facility: Gastroenterology Group of Naples
state: Florida
city: Macon
country: United States
facility: Gastroenterology Associates of Central Georgia
state: Georgia
city: Chicago
country: United States
facility: University of Chicago Medical Center
state: Illinois
city: Troy
country: United States
facility: Center for Digestive Health
state: Michigan
city: Ypsilanti
country: United States
facility: Huron Gastroenterology Associates
state: Michigan
city: San Antonio
country: United States
facility: Wellness Clinical Research Center
state: Texas
city: Tyler
country: United States
facility: Tyler Research Institute, LLC
state: Texas
city: Cordoba
country: Argentina
facility: Instituto Medico DAMIC
city: Bankstown
country: Australia
facility: Bankstown-Lidcombe Hospital
state: New South Wales
city: Herston
country: Australia
facility: Royal Brisbane and Women's Hospital
state: Queensland
city: South Brisbane
country: Australia
facility: Mater Hospital Brisbane
state: Queensland
city: Woolloongabba
country: Australia
facility: Princess Alexandra Hospital
state: Queensland
city: Clayton
country: Australia
facility: Monash Medical Centre
state: Victoria
city: Murdoch
country: Australia
facility: Fiona Stanley Hospital
state: Western Australia
city: Brasilia
country: Brazil
facility: CCBR - Brasilia
state: DF
city: Goiânia
country: Brazil
facility: Instituto Goiano de Gastroenterologia e Endoscopia Digestiva Ltda
state: GO
city: Belo Horizonte
country: Brazil
facility: Hospital Felicio Rocho
state: MG
city: Rio de Janeiro
country: Brazil
facility: Hospital Universitario Clementino Fraga Filho - UFRJ
state: RJ
city: Porto Alegre
country: Brazil
facility: Hospital das Clinicas - UFRGS
state: RS
city: Botucatu
country: Brazil
facility: UNESP - Faculdade de Medicina da Universidade Estadual Paulista - Campus Botucatu
state: SP
city: Sofia
country: Bulgaria
facility: UMHAT "Sv. Ivan Rilski", EAD
city: Sofia
country: Bulgaria
facility: UMHAT Tsaritsa Yoanna - ISUL, EAD
city: Veliko Tarnovo
country: Bulgaria
facility: MC Medica Plus
city: Tallinn
country: Estonia
facility: OÜ Innomedica
city: Tallinn
country: Estonia
facility: East Tallinn Central Hospital
city: Tallinn
country: Estonia
facility: West Tallinn Central Hospital
city: Tallinn
country: Estonia
facility: North Estonia Medical Centre Foundation
city: Tartu
country: Estonia
facility: Tartu University Hospital
city: Clichy cedex
country: France
facility: Hôpital Beaujon
city: Nice
country: France
facility: CHU Nice - Hopital de l'Archet 2
city: Hong Kong
country: Hong Kong
facility: University of Hong Kong
city: Guadalajara
country: Mexico
facility: Centro Integral en Reumatología S.A. de C.V. (CIRSA)
state: Jalisco
city: Monterrey
country: Mexico
facility: Accelerium S. de R.L. de C.V.
city: Monterrey
country: Mexico
facility: Hospital Universitario Dr Jose Eleuterio Gonzalez; Universidad Autónoma de Nuevo León
city: Częstochowa
country: Poland
facility: Centrum Medyczne Sw. Lukasza
city: Gdansk
country: Poland
facility: 7 Szpital Marynarki Wojennej z Przychodnia SPZOZ im. W. Lasinskiego
city: Krakow
country: Poland
facility: NZOZ Centrum Medyczne ProMiMed
city: Lodz
country: Poland
facility: Med-Gastr Przychodnia Specjalistyczna
city: Lublin
country: Poland
facility: Indywidualna Specjalistyczna Praktyka Lekarska
city: Lublin
country: Poland
facility: GASTROMED Sp. z o.o.
city: Olsztyn
country: Poland
facility: Wojewodzki Specjalistyczny Szpital w Olsztynie
city: Poznań
country: Poland
facility: SOLUMED Centrum Medyczne
city: Sopot
country: Poland
facility: Specjalistyczna Praktyka Lekarska Dr med. Marek Horynski; endoskopia
city: Szczecin
country: Poland
facility: Twoja Przychodnia-Szczecinskie Centrum Medyczne
city: Warszawa
country: Poland
facility: Centrum Zdrowia MDM
city: Warszawa
country: Poland
facility: Narodowy Instytut Onkologii im. Marii Skłodowskiej-Curie - Państwowy Instytut Badawczy
city: Wrocław
country: Poland
facility: EMC Instytut Medyczny S.A.
city: Wrocław
country: Poland
facility: PlanetMed
city: Łódź
country: Poland
facility: AppleTreeClinics Sp. z o.o.
city: Moskva
country: Russian Federation
facility: Yusupov Hospital
state: Adygeja
city: St.Petersburg
country: Russian Federation
facility: Baltic Medicine
state: Leningrad
city: Sankt-peterburg
country: Russian Federation
facility: SPb SBIH "City Multy-field Hospital # 2"; Intensive Pulmonology and Thoracal Surgery
state: Sankt Petersburg
city: Cherepovets
country: Russian Federation
facility: Medical and Sanitary Division of Severstal
state: Vologda
city: Barnaul
country: Russian Federation
facility: SBEI HPE Altai State Medical University of MoH and SD; Out-patient Department
city: Moscow
country: Russian Federation
facility: FSBIH Central Clinical Hospital of RAS
city: Moscow
country: Russian Federation
facility: FSBI "State Scientific Centre of Coloproctology" of the MoH of RF; Gastroenterology
city: Nizhny Novgorod
country: Russian Federation
facility: SBHI of NN region "RCH of NN n.a. N.A.Semashko"
city: Omsk
country: Russian Federation
facility: SBEI of HPE "Omsk SMA" Ministry of healthcare of RF"
city: Rostov-on-Don
country: Russian Federation
facility: SEIHPE "Rostov SMU of MoH of RF"
city: St Petersburg
country: Russian Federation
facility: City Hospital #26
city: St-Petersburg
country: Russian Federation
facility: LLC International Medical Centre "SOGAZ"
city: St. Petersburg
country: Russian Federation
facility: FSMEI HPE "Military Medical Academy n.a. S.M.Kirov"of Minist
city: Stavropol
country: Russian Federation
facility: Stavropol Regional Clinical Diagnostic Consultative Center
city: Belgrade
country: Serbia
facility: Clinical Center Zvezdara
city: Belgrade
country: Serbia
facility: Military Medical Academy
city: Belgrade
country: Serbia
facility: Clinical Center Bezanijska Kosa
city: Belgrade
country: Serbia
facility: Clinical Center Zemun
city: Kragujevac
country: Serbia
facility: Clinical Center Kragujevac
city: Zrenjanin
country: Serbia
facility: General Hospital "Djordje Joanovic"; Gastroenterology
city: Banska Bystrica
country: Slovakia
facility: Fakultna nemocnica s poliklinikou F.D. Roosevelta
city: Humenné
country: Slovakia
facility: Nemocnica A.Lena Humenne, n.o.
city: Nitra
country: Slovakia
facility: KM Management spol. s r.o.
city: Prešov
country: Slovakia
facility: Gastro I, s.r.o.
city: Rimavská Sobota
country: Slovakia
facility: Svet zdravia a.s.
city: Šahy
country: Slovakia
facility: Accout Center s.r.o.
city: Kharkiv
country: Ukraine
facility: CNE Prof. O.O. Shalimov Kharkiv City Clinical Hospital #2 of KCC
state: Kharkiv Governorate
city: Kharkiv
country: Ukraine
facility: Communal Non-commercial Enterprise of Kharkiv Regional Council Regional Clinical Hospital
state: Kharkiv Governorate
city: Kyiv
country: Ukraine
facility: Communal Institution of Kyiv Regional Council Kyiv Regional Clinical Hospital
state: Kharkiv Governorate
city: Kyiv
country: Ukraine
facility: Medical Center of Limited Liability Company Medical Clinic Blagomed
state: KIEV Governorate
city: Kyiv
country: Ukraine
facility: CI of Kyiv RC Regional Clinical Hospital #2
state: KIEV Governorate
city: Zaporizhzhia
country: Ukraine
facility: CI City Hospital #1
state: Tavria Okruha
city: Chernivtsi
country: Ukraine
facility: RCI Chernivtsi RCH Gastroenterology Bukovinsky SMU
city: Kharkiv
country: Ukraine
facility: CHI Kharkiv City Clinical Hospital #13
city: Kyiv
country: Ukraine
facility: CNI Consultative and Diagnostic Center of Desnianskyi District of Kyiv
city: Poltava
country: Ukraine
facility: M.V. Sklifosovskyi Poltava RCH Outpatient UMSA HSEIU Ukrainian Medical Stomatological Academy
city: Zaporizhzhia
country: Ukraine
facility: CI City Hospital #7
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.