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

NCT01672853 | Completed Phase 2 Results FDA Drug

• 2 other identifiers: GS-US-321-01022012-002473-61
• Study Type: interventional
• Target: 235
• Locations: 10 countries
• Sites: 75

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).

Conditions

Primary Sclerosing Cholangitis (PSC)

Keywords

PSC; Sclerosis; Monoclonal antibody; LOXL2; Simtuzumab; Primary sclerosing cholangitis; Liver fibrosis; Liver disease; MRCP; MRE; Liver biopsy

Outcome Measures

Primary Outcomes (1)

• Change From Baseline in MQC on Liver Biopsy at Week 96

  Baseline; Week 96

Secondary Outcomes (3)

• Percentage of Participants Who Permanently Discontinued Any Study Drug Due to an Adverse Event

  First dose date up to Week 96

• Study Drug Exposure

  First dose date up to Week 96

• Percentage of Participants Experiencing Any Treatment-Emergent Laboratory Abnormality

  First dose date up to Week 96 plus 30 days

Study Arms (3)

Treatment Arm A

EXPERIMENTAL

Simtuzumab 75 mg for 96 weeks

Biological: Simtuzumab

Treatment Arm B

EXPERIMENTAL

Simtuzumab 125 mg for 96 weeks

Biological: Simtuzumab

Treatment Arm C

PLACEBO COMPARATOR

Placebo for 96 weeks

Biological: Placebo

Interventions

Simtuzumab BIOLOGICAL

Subcutaneous injections weekly for a total of 96 injections

Also known as: GS-6624

Treatment Arm A; Treatment Arm B

Placebo BIOLOGICAL

Subcutaneous injections weekly for a total of 96 injections

Treatment Arm C

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.
• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Gilead Sciences: lead

Study Sites (75)

Mayo Clinic Hospital

Phoenix, Arizona, 85054, United States

Location

University of Arizona Health Sciences Center

Tucson, Arizona, 85724, United States

Location

Southern California Liver Center

Chula Vista, California, 91910, United States

Location

Southern California Liver Centers

Coronado, California, 92118, United States

Location

Scripps Clinic

La Jolla, California, 92037, United States

Location

Verterans Adminstration Hospital

Palo Alto, California, 94304, United States

Location

UC Davis Medical Center

Sacramento, California, 95817, United States

Location

University of San Diego Medical Center

San Diego, California, 92103, United States

Location

University of California San Francisco

San Francisco, California, 94143, United States

Location

University of Colorado Denver

Aurora, Colorado, 80045, United States

Location

University of Miami Center for Liver Diseases

Miami, Florida, 33136, United States

Location

Northwestern University

Chicago, Illinois, 60611, United States

Location

Indiana University

Indianapolis, Indiana, 46202, United States

Location

Indianapolis Gastroenterology Research Foundation

Indianapolis, Indiana, 46237, United States

Location

Iowa Digestive Disease Center

Clive, Iowa, 50325, United States

Location

University of Louisville

Louisville, Kentucky, 40202, United States

Location

Tulane University Health Sciences Center

New Orleans, Louisiana, 70112, United States

Location

Walter Reed National Military Medical Center

Bethesda, Maryland, 20889, United States

Location

Beth Israel Deaconess Medical Center

Boston, Massachusetts, 01125, United States

Location

Massachusetts General Hospital

Boston, Massachusetts, 02114, United States

Location

Minnesota Gastroenterology, PA

Saint Paul, Minnesota, 55114, United States

Location

St. Louis University

St Louis, Missouri, 63104, United States

Location

Weill Cornell Medical College

New York, New York, 10021, United States

Location

Mount Sinai Hospital

New York, New York, 10029, United States

Location

Duke Clinical Research Institute

Durham, North Carolina, 27710, United States

Location

University Hospitals Case Medical Center

Cleveland, Ohio, 44106, United States

Location

Cleveland Clinic

Cleveland, Ohio, 44195, United States

Location

University of Pennsylvania

Philadelphia, Pennsylvania, 19104, United States

Location

University Gastroenterology

Providence, Rhode Island, 02905, United States

Location

Vanderbilt University Medical Center

Nashville, Tennessee, 37212, United States

Location

UT Southwestern Medical Center

Dallas, Texas, 75390, United States

Location

Brooke Army Medical Center

Fort Sam Houston, Texas, 78234, United States

Location

St. Luke Episcopal Hospital

Houston, Texas, 77030, United States

Location

Alamo Medical Research

San Antonio, Texas, 78215, United States

Location

Intermountain Medical Center

Murray, Utah, 84107, United States

Location

University of Utah

Salt Lake City, Utah, 84132, United States

Location

University of Virginia Health Center

Charlottesville, Virginia, 22908, United States

Location

Liver Institute of Virginia

Newport News, Virginia, 23603, United States

Location

Digestive and Liver Disease Specialists

Norfolk, Virginia, 23502, United States

Location

Bon Secours Richmond Health System

Richmond, Virginia, 23226, United States

Location

Virginia Commonwealth University Health System

Richmond, Virginia, 23298, United States

Location

Virginia Mason Medical Center

Seattle, Washington, 98101, United States

Location

University of Washington

Seattle, Washington, 98103, United States

Location

Hôpital Erasme

Brussels, 1070, Belgium

Location

Université Catholique de Louvain

Brussels, 1200, Belgium

Location

UZ Antwerpen

Edegem, 2650, Belgium

Location

UZ Gent

Ghent, B-9000, Belgium

Location

UZ Leuven

Leuven, 3000, Belgium

Location

University of Calgary

Calgary, Alberta, T2N 4Z6, Canada

Location

University of Alberta

Edmonton, Alberta, T6G 2X8, Canada

Location

University of Manitoba

Winnepeg, Manitoba, R3E 3P4, Canada

Location

Dalhousie University

Halifax, Nova Scotia, B3H 2Y9, Canada

Location

London Health Science Center

London, Ontario, N6C 5A5, Canada

Location

Toronto Liver Centre

Toronto, Ontario, M6H 3M1, Canada

Location

Århus Universitetshospital, Århus Sygehus

Århus C, DK-8000, Denmark

Location

Hvidovre Hospital

Hvidovre, DK-2650, Denmark

Location

Rigshospitalet

København Ø, DK-2100, Denmark

Location

Klinikum der Johann Wolfgang Goethe Universitat

Frankfurt, 60590, Germany

Location

Medizinische Hochschule Hannover

Hanover, 30625, Germany

Location

Gastroenterologisch Hepatologisches Zentrum Kiel

Kiel, 24146, Germany

Location

EUGASTRO GmbH

Leipzig, 4103, Germany

Location

Istituto Clinico Humanitas

Rozzano, Milano, 20089, Italy

Location

Azienda Ospedaliera San Camillo Forlanini

Roma, 144, Italy

Location

Azienda Ospedaliera Città della Salute e della Scienza di Torino

Torino, 10126, Italy

Location

Eramus MC

Rotterdam, 3015 CE, Netherlands

Location

Hospital Universitario Vall d'Hebron

Barcelona, Catalonia, 8035, Spain

Location

Hospital Donostia

Donostia / San Sebastian, 20080, Spain

Location

Hospital Universitario Puerta de Hierro

Majadahonda, 28222, Spain

Location

Avd för invärtesmedicin och klinisk nutrition

Gothenburg, 413 45, Sweden

Location

New Queen Elizabeth Hospital

Birmingham, B15 2WB, United Kingdom

Location

John Radcliffe Hospital

Headington, OX3 9DU, United Kingdom

Location

Imperial College Healthcare NHS Trust- St. Mary's Hospital

London, W2 1NY, United Kingdom

Location

University College London

London, WC1E 6HX, United Kingdom

Location

Norfolk and Norwich University Hospital

Norwich, NR4 7UY, United Kingdom

Location

University of Nottingham

Nottingham, NG7 2UH, United Kingdom

Location

Related Publications (16)

• 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.

  RESULT

• 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.

  RESULT

• 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.

  RESULT

• 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.

  RESULT

• 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.

  RESULT

• 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.

  RESULT

• 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.

  RESULT

• 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.

  RESULT

• 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.

  RESULT

• 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.

  RESULT

• 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.

  RESULT

• 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.

  RESULT

• 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.

  RESULT

• Laschtowitz A, Lindberg EL, Liebhoff AM, Liebig LA, Casar C, Steinmann S, Guillot A, Xu J, Schwinge D, Trauner M, Lohse AW, Bonn S, Hubner N, Schramm C. Liver transcriptome analysis reveals PSC-attributed gene set associated with fibrosis progression. JHEP Rep. 2024 Nov 12;7(3):101267. doi: 10.1016/j.jhepr.2024.101267. eCollection 2025 Mar.

  PMID: 39996122 DERIVED

• Thorburn D, Leeming DJ, Barchuk WT, Wang Y, Lu X, Malkov VA, Ito KL, Bowlus CL, Levy C, Goodman Z, Karsdal MA, Muir AJ, Xu J. Serologic extracellular matrix remodeling markers are related to fibrosis stage and prognosis in a phase 2b trial of simtuzumab in patients with primary sclerosing cholangitis. Hepatol Commun. 2024 Jul 5;8(7):e0467. doi: 10.1097/HC9.0000000000000467. eCollection 2024 Jul 1.

  PMID: 38967589 DERIVED

• 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.

  PMID: 30153359 DERIVED

MeSH Terms

Conditions

Cholangitis, Sclerosing; Sclerosis; Liver Cirrhosis; Liver Diseases

Interventions

simtuzumab

Condition Hierarchy (Ancestors)

Cholangitis; Bile Duct Diseases; Biliary Tract Diseases; Digestive System Diseases; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Fibrosis

Results Point of Contact

• Title: Gilead Clinical Study Information Center
• Organization: Gilead Sciences

GileadClinicalTrials@gilead.com

1-833-445-3230 (GILEAD-0)

Study Officials

• Gilead Study Director

  Gilead Sciences

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 22, 2012
• First Posted: August 27, 2012
• Study Start: March 4, 2013
• Primary Completion: August 8, 2016
• Study Completion: August 24, 2016
• Last Updated: October 22, 2019
• Results First Posted: October 22, 2019

Record last verified: 2019-10

Locations

ES (3); GB (6); SE (1); DK (3); US (43); CA (6); BE (5); DE (4); IT (3); NL (1)