A Study of the Efficacy and Safety of Etrolizumab Treatment in Maintenance of Disease Remission in Ulcerative Colitis (UC) Participants Who Are Naive to Tumor Necrosis Factor (TNF) Inhibitors

Colitis, Ulcerative Clinical Trial

— LAUREL  

Official title:

Phase III, Randomized, Double-Blind, Placebo-Controlled, Multicenter Study to Evaluate the Efficacy (Maintenance of Remission) and Safety of Etrolizumab Compared With Placebo in Patients With Moderate to Severe Active Ulcerative Colitis Who Are Naive to TNF Inhibitors

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02165215
• Other study ID #: GA29102
• Secondary ID: 2013-004280-31
• Status: Completed
• Phase: Phase 3
• Start date: August 12, 2014
• Est. completion date: April 6, 2020

Study information

• Verified date: July 2021
• Source: Hoffmann-La Roche
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This Phase III, randomized, double-blind, parallel-grouped, placebo-controlled, multicenter study will investigate the efficacy and safety of etrolizumab in maintenance 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 359
• Est. completion date: April 6, 2020
• Est. primary completion date: April 6, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 80 Years

Eligibility

Inclusion Criteria:

• Diagnosis of ulcerative colitis (UC) established at least 3 months prior to Day 1 by clinical and endoscopic evidence

• Moderately to severely active UC as determined by an MCS of 6-12 with an endoscopic subscore greater than or equal to (=)2 as determined by the central reading procedure (endoscopy to be performed 4-16 days prior to Day 1), a rectal bleeding subscore =1, and a stool frequency subscore =1 during the screening period (prior to Day 1)

• Evidence of UC extending a minimum of 20 centimeters (cm) from the anal verge as determined by baseline endoscopy (flexible sigmoidoscopy or colonoscopy) performed during screening, 4-16 days prior to Day 1

• Naive to treatment with any anti-TNF therapy

• Participants must have had an inadequate response, loss of response, or intolerance to prior corticosteroid and/or immunosuppressant treatment

• Background regimen for UC may include oral 5-aminosalicylate (5-ASA), oral corticosteroids, budesonide, probiotics, azathioprine (AZA), 6-mercaptopurine (6-MP), or methotrexate (MTX) if doses have been stable during the screening period

• Use of highly effective contraception

• Must 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:

• A history of or current conditions and diseases affecting the digestive tract, such as indeterminate colitis, suspicion of ischemic colitis, radiation colitis, or microscopic colitis, Crohn's disease, fistulas or abdominal abscesses, colonic mucosal dysplasia, intestinal obstruction, toxic megacolon, or unremoved adenomatous colonic polyps

• Prior or planned surgery for UC

• Past or present ileostomy or colostomy

• Any prior treatment with etrolizumab or other anti-integrin agents (including natalizumab, vedolizumab, and efalizumab) as stated in the protocol

• Any prior treatment with anti-adhesion molecules (such as mucosal addressin cell adhesion molecule [MAdCAM-1])

• Any prior treatment with rituximab

• Any treatment with tofacitinib during screening

• Cogenital or acquired immune deficiency, chronic hepatitis B or C infection, human immunodeficiency virus (HIV) positive, or history of tuberculosis (active or latent)

• Evidence of or treatment for Clostridium difficile within 60 days prior to Day 1 or other intestinal pathogens within 30 days prior to Day 1

• History of recurrent opportunistic infections and/or severe disseminated viral infections

• History of organ transplant

• Any major episode of infection requiring treatment with intravenous (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 Day 1

Related Conditions & MeSH terms

• Colitis
• Colitis, Ulcerative
• Ulcer

Intervention

Drug:
• Etrolizumab
Participants will receive 105 mg etrolizumab SC injection Q4W.
• Placebo
Participants will receive placebo (matched to etrolizumab) SC injection Q4W.

Locations

Country	Name	City	State
Brazil	Centro Digestivo de Curitiba	Curitiba	PR
Brazil	Hospital Universitario Walter Cantidio - UFC	Fortaleza	CE
Brazil	CECIP - Centro de Estudos Clínicos do Interior Paulista	Jaú	SP
Brazil	Hospital Moinhos de Vento	Porto Alegre	RS
Brazil	Hospital Estadual Mario Covas	Santo Andre	SP
Brazil	Pesquisare Saúde Sociedade Simples	Santo Andre	SP
Brazil	Hospital Sírio-Libanês	Sao Paulo	SP
Brazil	Hospital do Servidor Público Estadual/HSPE-SP	São Paulo	SP
Canada	Queen Elizabeth II Health Sciences Centre; Gastroenterology Research	Halifax	Nova Scotia
Canada	LHSC - University Hospital; Movement Disorders Program	London	Ontario
Canada	London Health Sciences Centre Victoria Hospital; Research Pharmacy	London	Ontario
Canada	Mount Sinai Hospital	Toronto	Ontario
Canada	Pacific Gastroenterology Associates	Vancouver	British Columbia
Canada	Toronto Digestive Disease Associates	Vaughan	Ontario
Czechia	Fakultni nemocnice u sv. Anny v Brne; I.Interni kardioangiologicka klinika	Brno
Czechia	Hepato-Gastroenterologie HK, s.r.o.	Hradec Kralove
Czechia	Nemocnice Na Bulovce	Prague
Denmark	Alborg Universitets Hospital	Aalborg
Denmark	Herlev og Gentofte Hospital	Herlev
Germany	Charite Universitaetsmedizin Berlin - Campus Charite Mitte	Berlin
Germany	Berufsgenossenschaftliches Universitaetsklinikum Bergmannsheil GmbH	Bochum
Germany	Ärztezentrum Ellwangen; Gemeinschaftspraxis	Ellwangen
Germany	Klinik Johann Wolfgang von Goethe Uni	Frankfurt
Germany	Medizinische Hochschule Hannover; Klinik für Gastroenterologie, Hepatologie und Endokrinologie	Hannover
Germany	Universitaetsklinikum Jena; Apotheke des Uniersitätsklinikums Jena	Jena
Germany	Medizinisches Zentrum Klinikum Lueneburg	Lueneburg
Germany	Klinikum Mannheim GmbH Universitätsklinikum	Mannheim
Hungary	DRC Gyogyszervizsgalo Kozpont Kft	Balatonfured
Hungary	Pannónia Klinika Magánorvosi	Budapest
Hungary	Debreceni Egyetem Klinikai Kozpont	Debrecen
Hungary	Pest Megyei Flor Ferenc Korhaz	Kistarcsa
Hungary	Csongrad Megyei Dr. Bugyi Istvan Korhaz	Szentes
India	K.L.E. Society's Dr. Prabhakar Kore Hospital and Medical Research Centre	Belgaum	Karnataka
India	M. S. Ramaiah Medical College and Hospital	Bengaluru	Karnataka
India	Deccan College of Medical Sciences and Allied Hospitals	Hyderabad	Andhra Pradesh
India	Osmania General Hospital	Hyderabad	Andhra Pradesh
India	S. R. Kalla Memorial General Hospital	Jaipur
India	Dayanand Medical College and Hospital	Ludhiana	Punjab
India	Kasturba Medical College & Hospital	Mangalore
India	Midas institute of Gastroenterology	Nagpur	Maharashtra
India	Pushpawati Singhania Research Institute	New Delhi	Delhi
India	King Edward Memorial Hospital Research Centre	Pune
India	Ruby Hall Clinic	Pune
India	Shree Giriraj Multispeciality Hospital	Rajkot	Gujarat
India	Nirmal Hospital	Surat	Gujarat
Israel	Assaf Harofeh Medical Center	Beer Yaacov
Israel	Bnei Zion Medical Center; Department of Internal Medicine B	Haifa
Israel	Hadassah University Hospital - Ein Kerem	Jerusalem
Israel	Shaare Zedek Medical Center	Jerusalem
Israel	Holy Family Hospital	Nazareth
Italy	Fondazione Poliambulanza Istituto Ospedaliero	Brescia	Lombardia
Italy	Azienda Ospedaliera Universitaria Policlinico Paolo Giaccone	Palermo	Sicilia
Italy	Ospedale di Circolo; Neuropsichiatria Infantile	Rho	Lombardia
Italy	Ospedale Sandro Pertini	Roma	Lazio
Mexico	Instituto de Investigaciones Aplicadas a la Neurociencia A.C.	Durango
Mexico	Phylasis Clinicas Research S de RL de CV	Estado de México
Mexico	Centro Regiomontano de Estudios Clínicos Roma S.C.	Monterrey	Nuevo LEON
Poland	Zespó Przychodni Specjalistycznych PRIMA	Warszawa
Poland	LexMedica Osrodek Badan Klinicznych	Wroclaw
Slovakia	Fakultna nemocnica Nitra	Nitra
Slovakia	Endomed, s.r.o.	Vranov nad Toplou
South Africa	Dr JP Wright Practice	Cape Town
South Africa	Emmed Research	Pretoria
Ukraine	CI of Kyiv RC Kyiv Regional Clinical Hospital	Kyiv	KIEV Governorate
Ukraine	Lviv Regional Clinical Hospital	Lviv	KIEV Governorate
Ukraine	Odessa regional clinical Hospital	Odessa
Ukraine	M.V. Sklifosovskyi Poltava RCH Dept of Gastroenterology HSEIU UMSA	Poltava
Ukraine	CI of SRC Sumy RCH Dept of Rheumatology Sumy SU MI	Sumy	Kharkiv Governorate
Ukraine	A.Novak Transcarpathian Regional Clinical Hospital	Uzhgorod	KIEV Governorate
Ukraine	SI Divisional Clinical Hospital of Uzhgorod Station of ST&BA LZ Dep of Therapy SHEI Uzhgorod NU	Uzhgorod
Ukraine	M.I. Pyrogov VRCH Dept of Gastroenterology M.I. Pyrogov VNMU	Vinnytsia
United States	Asheville Gastroenterology Associates, P.A.	Asheville	North Carolina
United States	Northwest Gastroenterology Associates	Bellevue	Washington
United States	Ehrhardt Clinical Research, LLC	Belton	Missouri
United States	Commonwealth Clinical Studies	Brockton	Massachusetts
United States	UNC at Chapel Hill - Dpt of Family Medicine; Center for Functional GI and Motility Disorders	Chapel Hill	North Carolina
United States	Northwestern University-Feinberg School of Medicine; Division of Gastroenterology and Hepatology	Chicago	Illinois
United States	West Central Gastroenterology d/b/a Gastro Florida	Clearwater	Florida
United States	Ericksen Research and Development	Clinton	Utah
United States	Peak Gastroenterology Associates; Gastroenterology	Colorado Springs	Colorado
United States	Texas Digestive Disease Consultants - Dallas	Dallas	Texas
United States	Henry Ford Health System	Detroit	Michigan
United States	University of Mississippi Medical Center	Jackson	Mississippi
United States	Kinston Medical Specialists	Kinston	North Carolina
United States	Clinical Research of the Rockies	Lafayette	Colorado
United States	Regenerate Clinical Trials	Miami	Florida
United States	IMIC, Inc	Miami Beach	Florida
United States	University of Minnesota	Minneapolis	Minnesota
United States	Aquiant Research	New Albany	Indiana
United States	Manhattan Clinical Research	New York	New York
United States	Weill Cornell Medical College-New York Presbyterian Hospital	New York	New York
United States	Southwest Gastroenterology	Oak Lawn	Illinois
United States	University of California, Irvine Medical Center	Orange	California
United States	McGuire Research Institute; Gastroenterology	Richmond	Virginia
United States	University of Utah School of Medicine	Salt Lake City	Utah
United States	Clinical Applications Laboratories, Inc.	San Diego	California
United States	University of California at San Francisco	San Francisco	California
United States	Louisiana Research Center, LLC	Shreveport	Louisiana
United States	Texas Digestive Disease Consultants - Southlake	Southlake	Texas
United States	Advanced Research Institute, Inc.	Trinity	Florida
United States	Center for Digestive Health	Troy	Michigan
United States	Digestive Health Specialists of Tyler	Tyler	Texas
United States	Ventura Clinical Trials	Ventura	California
United States	Shafran Gastroenterology Center	Winter Park	Florida

Sponsors (1)

Lead Sponsor	Collaborator
Hoffmann-La Roche

Countries where clinical trial is conducted

United States,  Brazil,  Canada,  Czechia,  Denmark,  Germany,  Hungary,  India,  Israel,  Italy,  Mexico,  Poland,  Slovakia,  South Africa,  Ukraine, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Maintenance Phase: Percentage of Participants in Remission at Week 62 Among Randomized Participants With a Clinical Response at Week 10, as Determined by the Mayo Clinic Score (MCS)	MCS is a composite of 4 assessments, each rated from 0-3: stool frequency, rectal bleeding, endoscopy, and physician's global assessment.; Clinical Response is MCS with =3-point decrease and 30% reduction from baseline as well as =1-point decrease in rectal bleeding subscore or an absolute rectal bleeding score of 0 or 1.; Remission is MCS =2 with individual subscores =1 and a rectal bleeding subscore of 0.	Week 62
Secondary	Maintenance Phase: Percentage of Participants Who Maintained Clinical Remission at Week 62 Among Randomized Participants in Clinical Remission at Week 10, as Determined by the MCS	MCS is a composite of 4 assessments, each rated from 0-3: stool frequency, rectal bleeding, endoscopy, and physician's global assessment.; Clinical Remission is MCS =2 with individual subscores =1.	Week 62
Secondary	Maintenance Phase: Percentage of Participants in Clinical Remission at Week 62, as Determined by the MCS	MCS is a composite of 4 assessments, each rated from 0-3: stool frequency, rectal bleeding, endoscopy, and physician's global assessment.; Clinical Remission is MCS =2 with individual subscores =1.	Week 62
Secondary	Maintenance Phase: Percentage of Participants in Remission at Week 62 Among Randomized Participants in Remission at Week 10, as Determined by the MCS	MCS is a composite of 4 assessments, each rated from 0-3: stool frequency, rectal bleeding, endoscopy, and physician's global assessment.; Remission is MCS =2 with individual subscores =1 and a rectal bleeding subscore of 0.	Week 62
Secondary	Maintenance Phase: Percentage of Participants With Improvement From Baseline in Endoscopic Appearance of the Mucosa at Week 62, as Determined by the MCS Endoscopic Subscore	MCS is a composite of 4 assessments, each rated from 0-3: stool frequency, rectal bleeding, endoscopy, and physician's global assessment.; Improvement in endoscopic appearance of the mucosa is Endoscopy subscore =1.	Baseline, Week 62
Secondary	Maintenance Phase: Percentage of Participants With Endoscopic Remission at Week 62, as Determined by the MCS Endoscopic Subscore	MCS is a composite of 4 assessments, each rated from 0-3: stool frequency, rectal bleeding, endoscopy, and physician's global assessment.; Endoscopic Remission is Endoscopy subscore = 0.	Week 62
Secondary	Maintenance Phase: Percentage of Participants With Histologic Remission at Week 62, as Determined by the Nancy Histological Index	Nancy Histological Index (NHI) is a 5-level classification ranging from grade 0 (No histologically significant disease) to grade 4 (severely active disease). Histologic remission is defined as a Nancy histological index of 0 or 1.	Week 62
Secondary	Maintenance Phase: Percentage of Participants With Corticosteroid-Free Clinical Remission at Week 62 Among Participants Who Were Receiving Corticosteroids at Baseline, as Determined by the MCS	MCS is a composite of 4 assessments, each rated from 0-3: stool frequency, rectal bleeding, endoscopy, and physician's global assessment.; Clinical Remission is MCS =2 with individual subscores =1.	Baseline, Week 62
Secondary	Maintenance Phase: Percentage of Participants With Corticosteroid-Free Remission at Week 62 Among Participants Who Were Receiving Corticosteroids at Baseline, as Determined by the MCS	MCS is a composite of 4 assessments, each rated from 0-3: stool frequency, rectal bleeding, endoscopy, and physician's global assessment.; Remission is MCS =2 with individual subscores =1 and a rectal bleeding subscore of 0.	Baseline, Week 62
Secondary	Maintenance Phase: Change From Baseline to Week 62 in UC Bowel Movement Signs and Symptoms, as Assessed by the Ulcerative Colitis Patient-Reported Outcome Signs and Symptoms (UC-PRO/SS) Questionnaire	The UC-PRO questionnaire is collected in the e-diary and completed by participants for at least 9-12 consecutive days prior to a study visit. The UC-PRO is being reported in three domains; two domains are key endpoints and reported as UC-PRO Signs and Symptoms (UC-PRO/SS).; The bowel domain score ranges from 0-27, with a higher score indicating a worse disease state.	Baseline, Week 62
Secondary	Maintenance Phase: Change From Baseline to Week 62 in UC Functional Symptoms, as Assessed by the UC-PRO/SS Questionnaire	The UC-PRO questionnaire is collected in the e-diary and completed by participants for at least 9-12 consecutive days prior to a study visit. The UC-PRO is being reported in three domains; two domains are key endpoints and reported as UC-PRO Signs and Symptoms (UC-PRO/SS).; The functional domain score ranges from 0-12, with a higher score indicating a worse disease state.	Baseline, Week 62
Secondary	Maintenance Phase: Change From Baseline to Week 62 in Health-Related Quality of Life, as Assessed by the Overall Score of the Inflammatory Bowel Disease Questionnaire (IBDQ)	The IBDQ is used to assess participant's health-related quality of life (QOL). The 32-item questionnaire contains four domains: bowel symptoms (10 items), systemic symptoms (5 items), emotional function (12 items), and social function (5 items). The items are scored on a 7-point Likert scale with a higher score indicating better health-related QOL.; IBDQ score is a total score summed up from across all 32 questions on the questionnaire. The score can range from 32-224 and the higher score indicates a better quality of life.	Baseline, Week 62
Secondary	Number of Participants With at Least One Adverse Event by Severity, According to National Cancer Institute Common Terminology Criteria for Adverse Events, Version 4.0 (NCI-CTCAE v4.0)	All adverse events (AEs) were graded for severity using the NCI-CTCAE v4.0. Any AE not specifically listed was assessed per the following 5 grades: Grade 1 = mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; or intervention not indicated. Grade 2 = moderate; minimal, local, or non-invasive intervention indicated; or limiting age-appropriate instrumental activities of daily living. Grade 3 = severe or medically significant, but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; or limiting self-care activities of daily living. Grade 4 = life-threatening consequences or urgent intervention indicated. Grade 5 = death related to AE. Not all grades are appropriate for all AEs; some AEs have fewer than 5 options. The terms "severe" and "serious" are not synonymous and are independently assessed for each AE. Multiple occurrences of AEs were counted only once per participant at the highest (worst) grade.	From Baseline up to Week 74
Secondary	Number of Participants With Adverse Events Leading to Study Drug Discontinuation		From Baseline up to Week 74
Secondary	Number of Participants With Serious Infection-Related Adverse Events		From Baseline up to Week 74
Secondary	Number of Participants With Infection-Related Adverse Events by Severity, According to NCI-CTCAE v4.0	All adverse events (AEs) were graded for severity using the NCI-CTCAE v4.0. Any AE not specifically listed was assessed per the following 5 grades: Grade 1 = mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; or intervention not indicated. Grade 2 = moderate; minimal, local, or non-invasive intervention indicated; or limiting age-appropriate instrumental activities of daily living. Grade 3 = severe or medically significant, but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; or limiting self-care activities of daily living. Grade 4 = life-threatening consequences or urgent intervention indicated. Grade 5 = death related to AE. Not all grades are appropriate for all AEs; some AEs have fewer than 5 options. The terms "severe" and "serious" are not synonymous and are independently assessed for each AE. Multiple occurrences of AEs were counted only once per participant at the highest (worst) grade.	From Baseline up to Week 74
Secondary	Number of Participants With Injection-Site Reactions by Severity, According to NCI-CTCAE v4.0	All adverse events (AEs) were graded for severity using the NCI-CTCAE v4.0. Any AE not specifically listed was assessed per the following 5 grades: Grade 1 = mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; or intervention not indicated. Grade 2 = moderate; minimal, local, or non-invasive intervention indicated; or limiting age-appropriate instrumental activities of daily living. Grade 3 = severe or medically significant, but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; or limiting self-care activities of daily living. Grade 4 = life-threatening consequences or urgent intervention indicated. Grade 5 = death related to AE. Not all grades are appropriate for all AEs; some AEs have fewer than 5 options. The terms "severe" and "serious" are not synonymous and are independently assessed for each AE. Multiple occurrences of AEs were counted only once per participant at the highest (worst) grade.	From Baseline up to Week 74
Secondary	Number of Participants With Hypersensitivity Reaction Events by Severity, According to NCI-CTCAE v4.0	All adverse events (AEs) were graded for severity using the NCI-CTCAE v4.0. Any AE not specifically listed was assessed per the following 5 grades: Grade 1 = mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; or intervention not indicated. Grade 2 = moderate; minimal, local, or non-invasive intervention indicated; or limiting age-appropriate instrumental activities of daily living. Grade 3 = severe or medically significant, but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; or limiting self-care activities of daily living. Grade 4 = life-threatening consequences or urgent intervention indicated. Grade 5 = death related to AE. Not all grades are appropriate for all AEs; some AEs have fewer than 5 options. The terms "severe" and "serious" are not synonymous and are independently assessed for each AE. Multiple occurrences of AEs were counted only once per participant at the highest (worst) grade.	From Baseline up to Week 74
Secondary	Number of Participants With Malignancies		From Baseline up to Week 74
Secondary	Number of Participants With Anti-Therapeutic Antibodies (ATAs) to Etrolizumab		Baseline, Weeks 4, 12, 24, 44, and 62, and and Early Termination/End of Safety Follow-Up (up to Week 74)
Secondary	Maintenance Phase: Etrolizumab Serum Trough Concentration (for Arms/Timepoints Above LLOQ)	As per protocol, the timepoints for each arm where more than a third of the samples were above the lower limit of quantitation (LLOQ), full summary statistics (Mean and Standard Deviation) were reported. For timepoints below the LLOQ, only the Median and Max were reported as a separate outcome measure below.	Pre-dose (0 hour) at Baseline and Weeks 12, 24, 44, and 62
Secondary	Maintenance Phase: Etrolizumab Serum Trough Concentration (for Arms/Timepoints Below LLOQ)	As per protocol, the timepoints for each arm where more than a third of the samples were below the LLOQ only the Median and Max were reported.	Pre-dose (0 hour) at Baseline and Weeks 12, 24, 44, and 62