Safety and Efficacy of Simtuzumab (SIM, GS-6624) in Adults With Advanced Liver Fibrosis But Not Cirrhosis Secondary to Non-Alcoholic Steatohepatitis (NASH)

NCT01672866 | Terminated Phase 2 Results DMC FDA Drug

• 2 other identifiers: GS-US-321-01052012-002488-88
• Study Type: interventional
• Target: 222
• Locations: 9 countries
• Sites: 68

Brief Summary

The primary objective of this study is to evaluate whether SIM (formerly referred to as GS-6624) is effective at preventing the histologic progression of liver fibrosis and the clinical progression to cirrhosis in participants with NASH. It will consist of 2 phases:

• Randomized Double-Blind Phase
• Open-Label Phase (optional)

Conditions

Liver Fibrosis Due to NASH

Keywords

NASH; noncirrhotic; Monoclonal antibody; LOXL2; Simtuzumab; Nonalcoholic Steatohepatitis; NAFLD; Liver biopsy; MRE; Liver fibrosis; Ishak

Outcome Measures

Primary Outcomes (2)

• Change From Baseline in MQC on Liver Biopsy

  Baseline to Week 96

• Event Free Survival (EFS) Using Kaplan-Meier

  The EFS was the primary clinical efficacy endpoint and was assessed by the time to progression to cirrhosis. Participants were considered to have become cirrhotic if they had a post-baseline biopsy consistent with cirrhosis or developed overt signs and symptoms of cirrhosis. All overt signs and symptoms went through an adjudication process and were confirmed before they were considered for the EFS analysis.

  Baseline up to the time of progression to cirrhosis or last dose date (maximum: 240 weeks in the Blinded Phase), which ever occurred first

Study Arms (3)

SIM 75 mg

EXPERIMENTAL

During the Randomized Double-Blind Phase, participants will receive SIM 75 mg via subcutaneous injection once weekly for up to 240 weeks. During the optional Open-Label Phase, participants will receive SIM 125 mg via subcutaneous injection once weekly for up to an additional 240 weeks.

Biological: SIM

SIM 125 mg

EXPERIMENTAL

During the Randomized Double-Blind Phase, participants will receive SIM 125 mg via subcutaneous injection once weekly for up to 240 weeks. During the optional Open-Label Phase, participants will receive SIM 125 mg via subcutaneous injection once weekly for up to an additional 240 weeks.

Biological: SIM

Placebo

PLACEBO COMPARATOR

During the Randomized Double-Blind Phase, participants will receive placebo to match SIM via subcutaneous injection once weekly for up to 240 weeks. During the optional Open-Label Phase, participants will receive SIM 125 mg via subcutaneous injection once weekly for up to an additional 240 weeks.

Biological: Placebo; Biological: SIM

Interventions

Placebo BIOLOGICAL

Placebo to match SIM via subcutaneous injection every week

Placebo

SIM BIOLOGICAL

Subcutaneous injection every week

Also known as: GS-6624

Placebo; SIM 125 mg; SIM 75 mg

Eligibility Criteria

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

You may qualify if:

• Adults with chronic liver disease due to NASH defined as macrovesicular steatosis involving \> 5% of hepatocytes on a liver biopsy with associated lobular inflammation
• Stage 3-4 fibrosis by Ishak score on a liver biopsy
• Must have aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 10 x Central Laboratory Upper Limit of Normal (clULN)
• Must have serum creatinine \< 2.0 mg/dL
• A negative serum pregnancy test is required for females of childbearing potential
• All sexually active females of childbearing potential must agree to use a protocol recommended method of contraception during 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 heterosexual 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
• Cirrhosis of the liver
• Any history of hepatic decompensation including ascites, hepatic encephalopathy or variceal bleeding
• Weight reduction surgery in the past 5 years
• Positive for hepatitis C virus (HCV) RNA
• Positive for HBsAg
• Alcohol consumption greater than 21oz/week for males or 14oz/week for females
• Positive urine screen for amphetamines, cocaine or opiates (i.e. heroin, morphine) at screening.
• Clinically significant cardiac disease
• History of malignancy, other than non-melanomatous skin cancer, within 5 years prior to screening
• Major surgical procedure within 30 days prior to screening or the presence of an open wound
• 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

Sponsors & Collaborators

• Gilead Sciences: lead

Study Sites (68)

Mayo Clinic Hospital

Phoenix, Arizona, 85054, United States

Location

Southern California Liver Centers

Coronado, California, 92118, United States

Location

University of California, San Diego (UCSD)

San Diego, California, 92103, United States

Location

University of California San Francisco (UCSF)

San Francisco, California, 94143, United States

Location

University of Colorado

Aurora, Colorado, 80045, United States

Location

Miami Veterans Administration Healthcare System

Miami, Florida, 33136, United States

Location

Tampa General Hospital

Tampa, Florida, 33606, United States

Location

Northwestern University

Chicago, Illinois, 60611, 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

New Orleans, Louisiana, 70112, United States

Location

Mercy Medical Center

Baltimore, Maryland, 21202, United States

Location

Walter Reed National Military Medical Center

Bethesda, Maryland, 20889, United States

Location

Beth Israel Deaconess Medical Center

Boston, Massachusetts, 02215, United States

Location

Lahey Clinic

Burlington, Massachusetts, 01805, United States

Location

University of Michigan

Ann Arbor, Michigan, 48109, United States

Location

Minnnesota Gastroenterology, PA

Saint Paul, Minnesota, 55114, United States

Location

University of Mississippi Medical Center

Jackson, Mississippi, 39216, United States

Location

Saint Louis University Hospital

St Louis, Missouri, 63110, United States

Location

State University Of New York

Buffalo, New York, 14203, 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 University

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

Medical University of South Carolina

Charleston, South Carolina, 29425, United States

Location

Texas Clinical Research Institute, LLC

Arlington, Texas, 76012, United States

Location

Brooke Army Medical Center

Fort Sam Houston, Texas, 78234, United States

Location

St. Luke's Episcopal Hospital

Houston, Texas, 77030, United States

Location

Alamo Clinical Research Associates

San Antonio, Texas, 78215, United States

Location

University of Utah

Salt Lake City, Utah, 84132, United States

Location

University of Virginia Health System

Charlottesville, Virginia, 22908, United States

Location

Liver Institute of Virginia

Newport News, Virginia, 23602, United States

Location

Digestive and Liver Disease Specialists

Norfolk, Virginia, 23502, United States

Location

Bucheon St. Marys Hospital

Richmond, Virginia, 23229, 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, 98104, United States

Location

Hôpital Erasme

Brussels, 1070, Belgium

Location

Université Catholique de Louvain

Brussels, 1200, Belgium

Location

UZ Ghent

Ghent, B-9000, Belgium

Location

University of Calgary

Calgary, Alberta, T2N 4Z6, Canada

Location

University of Manitoba

Winnipeg, Manitoba, R3E 3P4, Canada

Location

London Health Science Center

London, Ontario, N6A 5A5, Canada

Location

Toronto Liver Centre

Toronto, Ontario, M6H 3M1, Canada

Location

Hopital Beaujon

Clichy, 92110, France

Location

Hospital Saint-Antoine

Paris, 75012, France

Location

Groupe Hospitalier Pitié- Salpétrière

Paris, 75013, France

Location

CHU Strasbourg Hôpital Civil

Strasbourg, 67091, France

Location

Medizinische Hochschule Hannover

Hanover, 30625, Germany

Location

Gastroenterologisch-Hepatologisches Zentrum Kiel

Kiel, 24146, Germany

Location

EUGASTRO GmbH

Leipzig, 4103, Germany

Location

Azienda Ospedaliero-Universitaria di Modena Policlinico

Modena, 41100, Italy

Location

Azienda Ospedaliera San Camillo Forlanini

Roma, 152, Italy

Location

Azienda Ospedaliera Città della Salute e della Scienza di Torino

Torino, 10126, Italy

Location

Fundacion De Investigacion

San Juan, 00927, Puerto Rico

Location

Hospital Vall d'Hebron

Barcelona, 08035, Spain

Location

Hospital Clinic de Barcelona

Barcelona, 08036, Spain

Location

Hospital Donostia

Donostia / San Sebastian, 20080, Spain

Location

Hospital Universitario Puerta de Hierro

Majadahonda, 28222, Spain

Location

John Radcliffe Hospital

Headington, OX3 9DU, United Kingdom

Location

The Royal London Hospital

London, E1 1BB, United Kingdom

Location

Royal Free Hospital, Pond Street

London, NW3 2QG, United Kingdom

Location

King's College Hospital NHS Foundation Trust No. 1 Account

London, SE5 9RS, United Kingdom

Location

Nottingham University Hospitals Queens Medica

Nottingham, NG7 2UH, United Kingdom

Location

Related Publications (11)

• Sanyal A, Harrison S, Ratziu V, Abdelmalek M, Diehl A, Caldwell S, et al. Changes in fibrosis, but not the NAFLD Activity Score (NAS), are associated with disease progression in patients with nonalcoholic steatohepatitis (NASH) and advanced fibrosis. J Hepatol 2017; 66 (1): S2.

  RESULT

• Sanyal A, Abdelmalek M, Diehl A, Caldwell S, Shiffman M, Ghalib R, et al. Efficacy and safety of simtuzumab for the treatment of nonalcoholic steatohepatitis with bridging fibrosis or cirrhosis: results of two phase 2b, dose-ranging, randomized, placebo-controlled trials. J Hepatol 2017; 66 (1): S54.

  RESULT

• Ratziu V, Sanyal A, Torres D, Hinrichsen H, Serfaty L, Bambha K, et al. Impact of weight reduction on serum markers and liver histology including progression to cirrhosis in patients with nonalcoholic steatohepatitis (NASH) and bridging fibrosis. J Hepatol 2017; 66 (1): S594.

  RESULT

• Shea PR, Sanyal A, Harrison S, Ratziu V, Loomba R, Caldwell S, et al. PNPLA3 variants confer an increased risk of advanced fibrosis due to non-alcoholic steatohepatitis. J Hepatol 2016; 64 (2): S493.

  RESULT

• Shea PR, Sanyal A, Rockey DC, Loomba R, Diehl AM, Kleinstein SE, et al. Genome-wide association study of clinically significant portal hypertension in patients with nonalcoholic steatohepatitis and advanced fibrosis. J Hepatol 2016; 64 (2): S280.

  RESULT

• Goodman ZD, Alaparthi L, Monge F, Patel K, Loomba R, Caldwell SH, et al. Correlations between hepatic morphometric collagen content, histologic fibrosis staging, and serum markers in patients with advanced fibrosis due to nonalcoholic steatohepatitis (NASH). Hepatol 2015; 62 (1): 906A.

  RESULT

• Harrison SA, Goodman ZD, Ratziu V, Loomba R, Diehl AM, Lawitz E, et al. Serum lysyl oxidase-like-2 (sLOXL2) levels correlate with fibrosis stage in patients with nonalcoholic steatohepatitis (NASH). Hepatol 2015; 62 (1): 910A.

  RESULT

• Ratziu V, Sanyal AJ, Loomba R, Caldwell SH, Ghalib RH, Torres DM, et al. Characterization of insulin resistance in patients with advanced fibrosis due to nonalcoholic steatohepatitis (NASH). Hepatol 2015; 62 (1): 1298A-1299A.

  RESULT

• Loomba R, Huang DQ, Sanyal AJ, Anstee QM, Trauner M, Lawitz EJ, Ding D, Ma L, Jia C, Billin A, Huss RS, Chung C, Goodman Z, Wong VW, Okanoue T, Romero-Gomez M, Abdelmalek MF, Muir A, Afdhal N, Bosch J, Harrison S, Younossi ZM, Myers RP. Liver stiffness thresholds to predict disease progression and clinical outcomes in bridging fibrosis and cirrhosis. Gut. 2023 Mar;72(3):581-589. doi: 10.1136/gutjnl-2022-327777. Epub 2022 Sep 9.

  PMID: 36750244 DERIVED

• Younossi ZM, Anstee QM, Wai-Sun Wong V, Trauner M, Lawitz EJ, Harrison SA, Camargo M, Kersey K, Subramanian GM, Myers RP, Stepanova M. The Association of Histologic and Noninvasive Tests With Adverse Clinical and Patient-Reported Outcomes in Patients With Advanced Fibrosis Due to Nonalcoholic Steatohepatitis. Gastroenterology. 2021 Apr;160(5):1608-1619.e13. doi: 10.1053/j.gastro.2020.12.003. Epub 2020 Dec 8.

  PMID: 33307033 DERIVED

• Harrison SA, Abdelmalek MF, Caldwell S, Shiffman ML, Diehl AM, Ghalib R, Lawitz EJ, Rockey DC, Schall RA, Jia C, McColgan BJ, McHutchison JG, Subramanian GM, Myers RP, Younossi Z, Ratziu V, Muir AJ, Afdhal NH, Goodman Z, Bosch J, Sanyal AJ; GS-US-321-0105 and GS-US-321-0106 Investigators. Simtuzumab Is Ineffective for Patients With Bridging Fibrosis or Compensated Cirrhosis Caused by Nonalcoholic Steatohepatitis. Gastroenterology. 2018 Oct;155(4):1140-1153. doi: 10.1053/j.gastro.2018.07.006. Epub 2018 Jul 7.

  PMID: 29990488 DERIVED

MeSH Terms

Conditions

Non-alcoholic Fatty Liver Disease; Liver Cirrhosis

Interventions

simtuzumab

Condition Hierarchy (Ancestors)

Fatty Liver; Liver Diseases; Digestive System Diseases; Fibrosis; Pathologic Processes; Pathological Conditions, Signs and Symptoms

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: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 22, 2012
• First Posted: August 27, 2012
• Study Start: December 5, 2012
• Primary Completion: August 2, 2016
• Study Completion: December 29, 2016
• Last Updated: March 27, 2019
• Results First Posted: March 27, 2019

Record last verified: 2019-03

Locations

US (41); FR (4); CA (4); PR (1); IT (3); BE (3); GB (5); ES (4); DE (3)