Simtuzumab (GS-6624) in the Prevention of Progression of Liver Fibrosis in Adults With Primary Sclerosing Cholangitis (PSC)

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)

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).

Study Overview

• Status: Completed
• Conditions: Primary Sclerosing Cholangitis (PSC)
• Intervention / Treatment: Biological: Simtuzumab; Biological: Placebo

• Study Type: Interventional
• Enrollment (Actual): 235
• Phase: Phase 2

Contacts and Locations

Study Locations

• Belgium
  • Brussels, Belgium, 1070
    • Hôpital Erasme
  • Bruxelles, Belgium, 1200
    • Université Catholique de Louvain
  • Edegem, Belgium, 2650
    • UZ Antwerpen
  • Gent, Belgium, B-9000
    • UZ Gent
  • Leuven, Belgium, 3000
    • UZ Leuven
• Canada
  • Alberta
    • Calgary, Alberta, Canada, T2N 4Z6
      • University of Calgary
    • Edmonton, Alberta, Canada, T6G 2X8
      • University of Alberta
  • Manitoba
    • Winnepeg, Manitoba, Canada, R3E 3P4
      • University of Manitoba
  • Nova Scotia
    • Halifax, Nova Scotia, Canada, B3H 2Y9
      • Dalhousie University
  • Ontario
    • London, Ontario, Canada, N6C 5A5
      • London Health Science Center
    • Toronto, Ontario, Canada, M6H 3M1
      • Toronto Liver Centre
• Denmark
  • Hvidovre, Denmark, DK-2650
    • Hvidovre Hospital
  • Kobenhavn O, Denmark, DK-2100
    • Rigshospitalet
  • Århus C, Denmark, DK-8000
    • Århus Universitetshospital, Århus Sygehus
• Germany
  • Frankfurt, Germany, 60590
    • Klinikum Der Johann Wolfgang Goethe Universitat
  • Hannover, Germany, 30625
    • Medizinische Hochschule Hannover
  • Kiel, Germany, 24146
    • Gastroenterologisch Hepatologisches Zentrum Kiel
  • Leipzig, Germany, 4103
    • Eugastro GmbH
• Italy
  • Roma, Italy, 144
    • Azienda Ospedaliera San Camillo Forlanini
  • Torino, Italy, 10126
    • Azienda Ospedaliera Città della Salute e della Scienza di Torino
  • Milano
    • Rozzano, Milano, Italy, 20089
      • Istituto Clinico Humanitas
• Netherlands
  • Rotterdam, Netherlands, 3015 CE
    • Eramus MC
• Spain
  • Majadahonda, Spain, 28222
    • Hospital Universitario Puerta de Hierro
  • San Sebastian, Spain, 20080
    • Hospital Donostia
  • Cataluna
    • Barcelona, Cataluna, Spain, 8035
      • Hospital Universitario Vall d'Hebron
• Sweden
  • Goteborg, Sweden, 413 45
    • Avd för invärtesmedicin och klinisk nutrition
• United Kingdom
  • Birmingham, United Kingdom, B15 2WB
    • New Queen Elizabeth Hospital
  • Headington, United Kingdom, OX3 9DU
    • John Radcliffe Hospital
  • London, United Kingdom, WC1E 6HX
    • University College London
  • London, United Kingdom, W2 1NY
    • Imperial College Healthcare NHS Trust- St. Mary's Hospital
  • Norwich, United Kingdom, NR4 7UY
    • Norfolk and Norwich University Hospital
  • Nottingham, United Kingdom, NG7 2UH
    • University of Nottingham
• United States
  • Arizona
    • Phoenix, Arizona, United States, 85054
      • Mayo Clinic Hospital
    • Tucson, Arizona, United States, 85724
      • University of Arizona Health Sciences Center
  • California
    • Chula Vista, California, United States, 91910
      • Southern California Liver Center
    • Coronado, California, United States, 92118
      • Southern California Liver Centers
    • La Jolla, California, United States, 92037
      • Scripps Clinic
    • Palo Alto, California, United States, 94304
      • Verterans Adminstration Hospital
    • Sacramento, California, United States, 95817
      • UC Davis Medical Center
    • San Diego, California, United States, 92103
      • University of San Diego Medical Center
    • San Francisco, California, United States, 94143
      • University of California San Francisco
  • Colorado
    • Aurora, Colorado, United States, 80045
      • University of Colorado Denver
  • Florida
    • Miami, Florida, United States, 33136
      • University of Miami Center for Liver Diseases
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Northwestern University
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Indiana University
    • Indianapolis, Indiana, United States, 46237
      • Indianapolis Gastroenterology Research Foundation
  • Iowa
    • Clive, Iowa, United States, 50325
      • Iowa Digestive Disease Center
  • Kentucky
    • Louisville, Kentucky, United States, 40202
      • University of Louisville
  • Louisiana
    • New Orleans, Louisiana, United States, 70112
      • Tulane University Health Sciences Center
  • Maryland
    • Bethesda, Maryland, United States, 20889
      • Walter Reed National Military Medical Center
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital
    • Boston, Massachusetts, United States, 01125
      • Beth Israel Deaconess Medical Center
  • Minnesota
    • Saint Paul, Minnesota, United States, 55114
      • Minnesota Gastroenterology, PA
  • Missouri
    • Saint Louis, Missouri, United States, 63104
      • St. Louis University
  • New York
    • New York, New York, United States, 10029
      • Mount Sinai Hospital
    • New York, New York, United States, 10021
      • Weill Cornell Medical College
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke Clinical Research Institute
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic
    • Cleveland, Ohio, United States, 44106
      • University Hospitals Case Medical Center
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • University of Pennsylvania
  • Rhode Island
    • Providence, Rhode Island, United States, 02905
      • University Gastroenterology
  • Tennessee
    • Nashville, Tennessee, United States, 37212
      • Vanderbilt University Medical Center
  • Texas
    • Dallas, Texas, United States, 75390
      • UT Southwestern Medical Center
    • Fort Sam Houston, Texas, United States, 78234
      • Brooke Army Medical Center
    • Houston, Texas, United States, 77030
      • St. Luke Episcopal Hospital
    • San Antonio, Texas, United States, 78215
      • Alamo Medical Research
  • Utah
    • Murray, Utah, United States, 84107
      • Intermountain Medical Center
    • Salt Lake City, Utah, United States, 84132
      • University of Utah
  • Virginia
    • Charlottesville, Virginia, United States, 22908
      • University of Virginia Health Center
    • Newport News, Virginia, United States, 23603
      • Liver Institute of Virginia
    • Norfolk, Virginia, United States, 23502
      • Digestive and Liver Disease Specialists
    • Richmond, Virginia, United States, 23298
      • Virginia Commonwealth University Health System
    • Richmond, Virginia, United States, 23226
      • Bon Secours Richmond Health System
  • Washington
    • Seattle, Washington, United States, 98101
      • Virginia Mason Medical Center
    • Seattle, Washington, United States, 98103
      • University of Washington

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Treatment Arm A; Simtuzumab 75 mg for 96 weeks	Biological: Simtuzumab; Subcutaneous injections weekly for a total of 96 injections; Other Names: GS-6624
Experimental: Treatment Arm B; Simtuzumab 125 mg for 96 weeks	Biological: Simtuzumab; Subcutaneous injections weekly for a total of 96 injections; Other Names: GS-6624
Placebo Comparator: Treatment Arm C; Placebo for 96 weeks	Biological: Placebo; Subcutaneous injections weekly for a total of 96 injections

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Change From Baseline in MQC on Liver Biopsy at Week 96	Baseline; Week 96

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants Who Permanently Discontinued Any Study Drug Due to an Adverse Event		First dose date up to Week 96
Study Drug Exposure	The average SIM exposure was summarized.	First dose date up to Week 96
Percentage of Participants Experiencing Any Treatment-Emergent Laboratory Abnormality	A treatment-emergent graded laboratory abnormality was defined as an increase of at least 1 abnormality grade from the predose assessment and occurring after the predose visit and on or before the date of the administration of study drug plus 30 days. The most severe graded abnormality from all tests was counted for each participant [Grade 1 (mild); Grade 2 (moderate); Grade 3 (severe); Grade 4 (life-threatening)].	First dose date up to Week 96 plus 30 days

Collaborators and Investigators

• Sponsor: Gilead Sciences

Publications and helpful links

General Publications

• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): March 4, 2013
• Primary Completion (Actual): August 8, 2016
• Study Completion (Actual): August 24, 2016

Study Registration Dates

• First Submitted: August 22, 2012
• First Submitted That Met QC Criteria: August 24, 2012
• First Posted (Estimate): August 27, 2012

Study Record Updates

• Last Update Posted (Actual): October 22, 2019
• Last Update Submitted That Met QC Criteria: October 3, 2019
• Last Verified: October 1, 2019

More Information

Terms related to this study

• Keywords: Monoclonal antibody; PSC; Liver fibrosis; MRE; LOXL2; Simtuzumab; Liver biopsy; Liver disease; Primary sclerosing cholangitis; MRCP; Sclerosis
• Additional Relevant MeSH Terms: Digestive System Diseases; Biliary Tract Diseases; Bile Duct Diseases; Cholangitis; Cholangitis, Sclerosing
• Other Study ID Numbers: GS-US-321-0102; 2012-002473-61 (EudraCT Number)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No