Clinical trial NCT01672853: Simtuzumab (GS-6624) in the Prevention of Progression of Liver Fibrosis in Adults With Primary Sclerosing Cholangitis (PSC)
Official title: A Phase 2b, Dose-Ranging, Randomized, Double-Blind, Placebo-Controlled Trial Evaluating the Safety and Efficacy of GS-6624, a Monoclonal Antibody Against Lysyl Oxidase Like 2 (LOXL2) in Subjects With Primary Sclerosing Cholangitis (PSC)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Primary Sclerosing Cholangitis (PSC)
Keywords: PSC
Sclerosis
Monoclonal antibody
LOXL2
Simtuzumab
Primary sclerosing cholangitis
Liver fibrosis
Liver disease
MRCP
MRE
Liver biopsy
Lead sponsor: Gilead Sciences
Sponsor class: INDUSTRY
First posted: 2012-08-27
Enrollment: 235
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: The purpose of this study is to evaluate whether simtuzumab (GS-6624) is effective at preventing the progression of liver fibrosis in adults with primary sclerosing cholangitis (PSC).


Eligibility criteria: Key Inclusion Criteria:

* Adult Individuals (aged 18-70) with chronic cholestatic liver disease of at least 6 months.
* Liver biopsy consistent with PSC: If a liver biopsy has been performed within 3 months of the screening visit, tissue from that biopsy may be used as the screening biopsy. Slides would be re-cut from the existing tissue block and submitted for central reader assessment. Some individuals with PSC may have a normal liver biopsy, in the event of a normal liver biopsy, the individual must have an abnormal magnetic resonance cholangiopancreatography (MRCP).
* MRCP consistent with PSC: Some individuals with PSC may have a normal MRCP; in the event of a normal MRCP, the individual must have an abnormal liver biopsy.
* Exclusion of other causes of liver disease including viral hepatitis ,alcoholic liver disease,primary biliary cirrhosis and secondary sclerosing cholangitis
* Must have aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 10 x the Central Laboratory Upper Limit of Normal (clULN)
* Must have serum creatinine \< 2.0 mg/dL
* A negative serum pregnancy test is required for female individuals of childbearing potential
* All sexually active female individuals of childbearing potential must agree to use a protocol recommended method of contraception during heterosexual intercourse throughout the study and for 90 days following the last dose of study medication
* Lactating females must agree to discontinue nursing before starting study treatment
* Males if not vasectomized, are required to use barrier contraception (condom plus spermicide) during intercourse from the screening through the study completion and for 90 days following the last dose of study drug

Key Exclusion Criteria:

* Pregnant or breast feeding
* Evidence of hepatic decompensation present, including ascites, episodes of hepatic encephalopathy, variceal bleeding or a prolonged prothrombin time/international normalized ratio (PT/INR)
* Positive for hepatitis C virus (HCV) RNA
* Positive for HBsAg
* Positive for anti-mitochondrial antibody
* Alcohol consumption greater than 21oz/week for males or 14oz/week for females
* Moderately active ulcerative colitis (UC) defined as either a partial Mayo score of \> 4, bleeding score of \>1, or current use of oral corticosteroid therapy and/or any inhibitor of Tumor necrosis factor-α (TNF-α) or α4β7 integrin antagonist
* Positive urine screen for amphetamines, cocaine or opiates (i.e. heroin, morphine) at screening. Individuals on stable methadone or buprenorphine maintenance treatment for at least 6 months prior to screening may be included in the study. Individuals with a positive urine drug screen due to prescription opioid-based medication are eligible if the prescription and diagnosis are reviewed and approved by the investigator
* Clinically significant cardiac disease
* History of cholangiocarcinoma
* History of other cancers,other than non-melanomatous skin cancer, within 5 years prior to screening
* Ascending cholangitis within 60 days of screening
* Presence of a percutaneous drain or bile duct stent
* Known hypersensitivity to the investigation product or any of its formulation excipients
* History of bleeding diathesis within 6 months of screening
* Unavailable for follow-up assessment or concern for individual's compliance with the protocol procedures;
* Participation in an investigational trial of a drug or device within 30 days prior to screening
* Major surgical procedure within 30 days prior to screening or the presence of an open wound

Note: Other protocol defined Inclusion/Exclusion criteria may apply.

Primary outcomes:
measure: Change From Baseline in MQC on Liver Biopsy at Week 96
timeFrame: Baseline; Week 96
Secondary outcomes:
measure: Percentage of Participants Who Permanently Discontinued Any Study Drug Due to an Adverse Event
timeFrame: First dose date up to Week 96
measure: Study Drug Exposure
timeFrame: First dose date up to Week 96
measure: Percentage of Participants Experiencing Any Treatment-Emergent Laboratory Abnormality
timeFrame: First dose date up to Week 96 plus 30 days
Other outcomes:
Locations:
city: Phoenix
country: United States
facility: Mayo Clinic Hospital
state: Arizona
city: Tucson
country: United States
facility: University of Arizona Health Sciences Center
state: Arizona
city: Chula Vista
country: United States
facility: Southern California Liver Center
state: California
city: Coronado
country: United States
facility: Southern California Liver Centers
state: California
city: La Jolla
country: United States
facility: Scripps Clinic
state: California
city: Palo Alto
country: United States
facility: Verterans Adminstration Hospital
state: California
city: Sacramento
country: United States
facility: UC Davis Medical Center
state: California
city: San Diego
country: United States
facility: University of San Diego Medical Center
state: California
city: San Francisco
country: United States
facility: University of California San Francisco
state: California
city: Aurora
country: United States
facility: University of Colorado Denver
state: Colorado
city: Miami
country: United States
facility: University of Miami Center for Liver Diseases
state: Florida
city: Chicago
country: United States
facility: Northwestern University
state: Illinois
city: Indianapolis
country: United States
facility: Indiana University
state: Indiana
city: Indianapolis
country: United States
facility: Indianapolis Gastroenterology Research Foundation
state: Indiana
city: Clive
country: United States
facility: Iowa Digestive Disease Center
state: Iowa
city: Louisville
country: United States
facility: University of Louisville
state: Kentucky
city: New Orleans
country: United States
facility: Tulane University Health Sciences Center
state: Louisiana
city: Bethesda
country: United States
facility: Walter Reed National Military Medical Center
state: Maryland
city: Boston
country: United States
facility: Beth Israel Deaconess Medical Center
state: Massachusetts
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Saint Paul
country: United States
facility: Minnesota Gastroenterology, PA
state: Minnesota
city: Saint Louis
country: United States
facility: St. Louis University
state: Missouri
city: New York
country: United States
facility: Weill Cornell Medical College
state: New York
city: New York
country: United States
facility: Mount Sinai Hospital
state: New York
city: Durham
country: United States
facility: Duke Clinical Research Institute
state: North Carolina
city: Cleveland
country: United States
facility: University Hospitals Case Medical Center
state: Ohio
city: Cleveland
country: United States
facility: Cleveland Clinic
state: Ohio
city: Philadelphia
country: United States
facility: University of Pennsylvania
state: Pennsylvania
city: Providence
country: United States
facility: University Gastroenterology
state: Rhode Island
city: Nashville
country: United States
facility: Vanderbilt University Medical Center
state: Tennessee
city: Dallas
country: United States
facility: UT Southwestern Medical Center
state: Texas
city: Fort Sam Houston
country: United States
facility: Brooke Army Medical Center
state: Texas
city: Houston
country: United States
facility: St. Luke Episcopal Hospital
state: Texas
city: San Antonio
country: United States
facility: Alamo Medical Research
state: Texas
city: Murray
country: United States
facility: Intermountain Medical Center
state: Utah
city: Salt Lake City
country: United States
facility: University of Utah
state: Utah
city: Charlottesville
country: United States
facility: University of Virginia Health Center
state: Virginia
city: Newport News
country: United States
facility: Liver Institute of Virginia
state: Virginia
city: Norfolk
country: United States
facility: Digestive and Liver Disease Specialists
state: Virginia
city: Richmond
country: United States
facility: Bon Secours Richmond Health System
state: Virginia
city: Richmond
country: United States
facility: Virginia Commonwealth University Health System
state: Virginia
city: Seattle
country: United States
facility: Virginia Mason Medical Center
state: Washington
city: Seattle
country: United States
facility: University of Washington
state: Washington
city: Brussels
country: Belgium
facility: Hôpital Erasme
city: Bruxelles
country: Belgium
facility: Université Catholique de Louvain
city: Edegem
country: Belgium
facility: UZ Antwerpen
city: Gent
country: Belgium
facility: UZ Gent
city: Leuven
country: Belgium
facility: UZ Leuven
city: Calgary
country: Canada
facility: University of Calgary
state: Alberta
city: Edmonton
country: Canada
facility: University of Alberta
state: Alberta
city: Winnepeg
country: Canada
facility: University of Manitoba
state: Manitoba
city: Halifax
country: Canada
facility: Dalhousie University
state: Nova Scotia
city: London
country: Canada
facility: London Health Science Center
state: Ontario
city: Toronto
country: Canada
facility: Toronto Liver Centre
state: Ontario
city: Hvidovre
country: Denmark
facility: Hvidovre Hospital
city: Kobenhavn O
country: Denmark
facility: Rigshospitalet
city: Århus C
country: Denmark
facility: Århus Universitetshospital, Århus Sygehus
city: Frankfurt
country: Germany
facility: Klinikum der Johann Wolfgang Goethe Universitat
city: Hannover
country: Germany
facility: Medizinische Hochschule Hannover
city: Kiel
country: Germany
facility: Gastroenterologisch Hepatologisches Zentrum Kiel
city: Leipzig
country: Germany
facility: EUGASTRO GmbH
city: Rozzano
country: Italy
facility: Istituto Clinico Humanitas
state: Milano
city: Roma
country: Italy
facility: Azienda Ospedaliera San Camillo Forlanini
city: Torino
country: Italy
facility: Azienda Ospedaliera Città della Salute e della Scienza di Torino
city: Rotterdam
country: Netherlands
facility: Eramus MC
city: Barcelona
country: Spain
facility: Hospital Universitario Vall d'Hebron
state: Cataluna
city: Majadahonda
country: Spain
facility: Hospital Universitario Puerta de Hierro
city: San Sebastian
country: Spain
facility: Hospital Donostia
city: Goteborg
country: Sweden
facility: Avd för invärtesmedicin och klinisk nutrition
city: Birmingham
country: United Kingdom
facility: New Queen Elizabeth Hospital
city: Headington
country: United Kingdom
facility: John Radcliffe Hospital
city: London
country: United Kingdom
facility: Imperial College Healthcare NHS Trust- St. Mary's Hospital
city: London
country: United Kingdom
facility: University College London
city: Norwich
country: United Kingdom
facility: Norfolk and Norwich University Hospital
city: Nottingham
country: United Kingdom
facility: University of Nottingham
Study officials:
affiliation: Gilead Sciences
name: Gilead Study Director
role: STUDY_DIRECTOR
References:
citation: Shea P, Hirschfield G, Shiffman M, McColgan B, Goodman Z, Myers, R, et al. Common variation near glial-derived neurotrophic factor is associated with progression of hepatic collagen content in a genome-wide association study of liver fibrosis phenotypes in patients with primary sclerosing cholangitis. J Hepatol 2017; 66 (1): S4-S5.
citation: Muir A, Goodman Z, Levy C, Janssen H, Montano-Loza A, Bowlus C, et al. Efficacy and safety of simtuzumab for the treatment of primary sclerosing cholangitis: results of a phase 2b, dose-ranging, randomized, placebo-controlled trial. J Hepatol 2017; 66 (1): S73.
citation: Bowlus CL, Patel K, Hirschfield G, Guha I, Chapman R, Chazouilleres O, et al. Prospective validation of the Enhanced Liver Fibrosis test for the prediction of disease progression in a randomized trial of patients with primary sclerosing cholangitis. J Hepatol 2017; 66 (1): S359.
citation: Levy C, Eksteen B, Shiffman M, Janssen H, Montano-Loza A, Ding D, et al. Prospective validation of serum alkaline phosphatase for the prediction of disease progression in a randomized trial of patients with primary sclerosing cholangitis. J Hepatol 2017; 66 (1): S360-S361.
citation: Levy C, Shiffman M, Caldwell S, Luketic V, Invernizzi P, Minuk G, et al. Serum fibroblast growth factor 19, 7α-Hydroxy-4-Cholesten-3-one, and bile acids and their associations with clinical characteristics in primary sclerosing cholangitis. J Hepatol 2017; 66 (1): S361.
citation: French D, Huntzicker EG, Goodman ZD, Shea PR, Ding D, Aguilar Schall, RE, et al. Hepatic expression of lysyl oxidase-like-2 (LOXL2) in primary sclerosing cholangitis (PSC). Hepatol 2016; 64 (1): 194A.
citation: Bowlus CL, Montano-Loza AJ, Invernizzi P, Chazouilleres O, Hirschfield G, Metselaar HJ, et al. Liver stiffness measurement by transient elastography for the prediction of fibrosis in patients with primary sclerosing cholangitis in a randomized trial of simtuzumab. J Hepatol 2016; 64 (2): S434.
citation: Goodman Z, Patel K, Guha I, Hameed B, Kowdley K, Alaparthi L, et al. Correlations between hepatic morphometric collagen content, histologic fibrosis stage, and serum markers in patients with primary sclerosing cholangitis (PSC). J Hepatol 2016; 64 (2): S652-S653.
citation: Muir AJ, Goodman Z, Bowlus CL, Caldwell S, Invernizzi P, Luketic V, et al. Serum lysyl oxidase-like-2 (SLOXL2) levels correlate with disease severity in patients with primary sclerosing cholangitis. J Hepatol 2016; 64 (2): S428.
citation: Shea PR, Eksteen B, Hirschfield GM, Shiffman ML, Janssen HLA, Montano-Loza AJ, et al. Genome-wide association study (GWAS) of liver fibrosis phenotypes in patients with primary sclerosing cholangitis (PSC) reveals common genetic variation influencing serum levels of lysyl oxidase-like-2 (LOXL2). J Hepatol 2016; 64 (2): S180-S182.
citation: Manns MP, Eksteen B, Shiffman ML, Levy C, Kowdley KV, Montano-Loza AJ, et al. Association between elevated serum IgG4 (sIgG4) concentrations and the phenotype of patients with primary sclerosing cholangitis (PSC). Hepatol 2015; 62 (1): 515A.
citation: Bowlus CL, Patel K, Chuha IN, Chapman RW, Chazouilleres O, Chalasani NP, et al. Validation of serum fibrosis marker panels in patients with primary sclerosing cholangitis (PSC) in a randomized trial of simtuzumab. Hepatol 2015; 62 (1): 519A.
citation: French D, Goodman ZD, Huntzicker EG, Newstrom D, Karnik S, Smith V, et al. Expression of matrix metalloproteinase 9 (MMP9) and the apoptosis signal-regulating kinase 1 (ASK1) pathway activation marker, phospho-P38 (p-P38), in primary sclerosing cholangitis (PSC). Hepatol 2015; 62 (1): 523A-524A.
citation: Muir AJ, Levy C, Janssen HLA, Montano-Loza AJ, Shiffman ML, Caldwell S, Luketic V, Ding D, Jia C, McColgan BJ, McHutchison JG, Mani Subramanian G, Myers RP, Manns M, Chapman R, Afdhal NH, Goodman Z, Eksteen B, Bowlus CL; GS-US-321-0102 Investigators. Simtuzumab for Primary Sclerosing Cholangitis: Phase 2 Study Results With Insights on the Natural History of the Disease. Hepatology. 2019 Feb;69(2):684-698. doi: 10.1002/hep.30237. Epub 2019 Jan 11.