Simtuzumab (SIM, GS-6624) in the Treatment of Cirrhosis Due to NASH

NCT ID: NCT01672879

Last Updated: 2019-03-27

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE2
• Total Enrollment: 259 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2012-10-29
• Study Completion Date: 2017-01-03

Brief Summary

The primary objective of this study is to evaluate the safety and efficacy of SIM (formerly referred to as GS-6624) in adults with compensated cirrhosis due to Non-Alcoholic Steatohepatitis (NASH). It will consist of 2 phases:

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

Conditions

Liver Fibrosis Due to NASH

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

SIM 200 mg

During the Randomized Double-Blind Phase, participants will receive SIM 200 mg via intravenous infusion every 2 weeks for up to 240 weeks. During the optional Open-Label Phase, participants will receive SIM 700 mg via intravenous infusion every 2 weeks for up to an additional 240 weeks.

Group Type: EXPERIMENTAL

SIM

Intervention Type: BIOLOGICAL

Intravenous infusion over 30 minutes every 2 weeks

SIM 700 mg

During the Randomized Double-Blind Phase, participants will receive SIM 700 mg via intravenous infusion every 2 weeks for up to 240 weeks. During the optional Open-Label Phase, participants will receive SIM 700 mg via intravenous infusion every 2 weeks for up to an additional 240 weeks.

Group Type: EXPERIMENTAL

SIM

Intervention Type: BIOLOGICAL

Intravenous infusion over 30 minutes every 2 weeks

Placebo

During the Randomized Double-Blind Phase, participants will receive placebo to match SIM administered via intravenous infusion every 2 weeks for up to 240 weeks. During the optional Open-Label Phase, participants will receive SIM 700 mg administered via intravenous infusion every 2 weeks for up to an additional 240 weeks.

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: BIOLOGICAL

Placebo to match SIM intravenous infusion over 30 minutes every 2 weeks

SIM

Intervention Type: BIOLOGICAL

Intravenous infusion over 30 minutes every 2 weeks

Interventions

Placebo

Placebo to match SIM intravenous infusion over 30 minutes every 2 weeks

Intervention Type: BIOLOGICAL

SIM

Intravenous infusion over 30 minutes every 2 weeks

Intervention Type: BIOLOGICAL

Other Intervention Names

GS-6624

Eligibility Criteria

Inclusion Criteria

• Adults with cirrhosis of the liver defined as an Ishak fibrosis stage ≥ 5
• Liver biopsy consistent with NASH or cryptogenic cirrhosis
• Exclusion of other causes of liver disease including viral hepatitis and alcoholic liver disease
• The liver biopsy sample must be determined to be adequate for evaluation by the Central pathologist
• Must have aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 10 x the upper limit of the normal range (ULN)
• Must have serum creatinine < 2.0 mg/dL
• A negative serum pregnancy test is required for female subjects of childbearing potential
• All sexually active female subjects 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
• Male subjects, 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

Exclusion Criteria

• Pregnant or breast feeding
• Any history of hepatic decompensation including ascites, hepatic encephalopathy or variceal bleeding
• Weight reduction surgery in the past 5 year
• Child-Pugh-Turcotte (CPT) score >7; Model for End-Stage Liver Disease (MELD) score > 12 and Body Mass Index (BMI) <18kg/m2
• 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. Subjects on stable methadone or buprenorphine maintenance treatment for at least 6 months prior to screening may be included in the study. Subjects 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 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 subject's compliance with the protocol procedures;
• Participation in an investigational trial of a drug or device within 30 days prior to screening
• History of solid-organ transplant; poor venous access or requirement for permanent or semi-permanent central vein catheter such as portacath

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 65 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Gilead Sciences

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Gilead Study Director

Role: STUDY_DIRECTOR

Gilead Sciences

Locations

Mayo Clinic Hospital

Phoenix, Arizona, United States

Southern California Liver Centers

Coronado, California, United States

University of California, San Diego (UCSD)

San Diego, California, United States

University of California San Francisco (UCSF)

San Francisco, California, United States

University of Colorado, Denver

Aurora, Colorado, United States

University of Miami

Miami, Florida, United States

Tampa General Hospital

Tampa, Florida, United States

Northwestern University

Chicago, Illinois, United States

Indiana University School of Medicine, Division of Gastroenterology/Hepatology

Indianapolis, Indiana, United States

Iowa Digestive Disease Center

Clive, Iowa, United States

University of Louisville

Louisville, Kentucky, United States

Tulane University

New Orleans, Louisiana, United States

Mercy Medical Center

Baltimore, Maryland, United States

Walter Reed National Military Medical Center

Bethesda, Maryland, United States

Lahey Clinic

Burlington, Massachusetts, United States

University of Mississippi Medical Center

Jackson, Michigan, United States

Minnnesota Gastroenterology, PA

Saint Paul, Minnesota, United States

Saint Louis University Hospital

St Louis, Missouri, United States

State University Of New York at Buffalo

Buffalo, New York, United States

North Shore University Health System

Manhasset, New York, United States

New York University

New York, New York, United States

Columbia University Medical Center

New York, New York, United States

Duke University Medical Center

Durham, North Carolina, United States

University Hospitals Case Medical Center

Cleveland, Ohio, United States

University of Pennsylvania Hospital

Philadelphia, Pennsylvania, United States

University Gastroenterology

Providence, Rhode Island, United States

Medical University of South Carolina

Charleston, South Carolina, United States

Methodist University Hospital

Memphis, Tennessee, United States

Vanderbilt University Medical Center

Nashville, Tennessee, United States

Texas Clinical Research Institute

Arlington, Texas, United States

Brooke Army Medical Center

Fort Sam Houston, Texas, United States

St. Luke Episcopal Hospital

Houston, Texas, United States

Alamo Clinical Research Associates

San Antonio, Texas, United States

Intermountain Transplant Center

Murray, Utah, United States

University of Virginia Health Center

Charlottesville, Virginia, United States

Liver Institute of Virginia

Newport News, Virginia, United States

Digestive and Liver Disease Specialists

Norfolk, Virginia, United States

Bucheon St. Marys Hospital

Richmond, Virginia, United States

Virginia Commonwealth University

Richmond, Virginia, United States

Virginia Mason Medical Center

Seattle, Washington, United States

University of Washington

Seattle, Washington, United States

University of Manitoba

Winnipeg, Manitoba, Canada

Dalhousie University

Halifax, Nova Scotia, Canada

Toronto Liver Centre

Toronto, Ontario, Canada

Hôpital de la Croix Rousse

Lyon, , France

Hospital Saint-Antoine

Paris, , France

CHU Pitié-Salpêtrière

Paris, , France

Fonds de Recherche Honoraires

Strasbourg, , France

Gastroenterologisch-Hepatologisches Zentrum Kiel

Kiel, , Germany

Eugastro Gmbh

Leipzig, , Germany

Istituto Clinico Humanitas

Rozzano, Milano, Italy

Azienda Ospedaliero-Universitaria Policlinico di Modena

Modena, , Italy

Azienda Ospedaliera Città della Salute e della Scienza di Torino

Torino, , Italy

Fundacion De Investigacion

San Juan, , Puerto Rico

Hospital Vall D´Hebron

Barcelona, Catalonia, Spain

Hospital Universitario Puerta de Hierro

Majadahonda, Madrid, Spain

Royal Free Hospital, Pond Street

London, , United Kingdom

King's College Hospital NHS Trust

London, , United Kingdom

Nottingham University Hospitals Queen's Medical Centre

Nottingham, , United Kingdom

Countries

United States; Canada; France; Germany; Italy; Puerto Rico; Spain; United Kingdom

References

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.

Reference Type: 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.

Reference Type: RESULT

Bosch J, Harrison S, Ratziu V, Shiffman M, Diehl A, Caldwell S, et al. Impact of modest weight reduction on liver histology, portal pressure, and clinical events in patients with compensated cirrhosis due to nonalcoholic steatohepatitis. J Hepatol 2017; 66 (1): S159-S160.

Reference Type: RESULT

Sanyal A, Goodman Z, Harrison S, Rockey DC, Diehl AM, Caldwell S, et al. Correlation between the hepatic venous pressure gradient and alpha-smooth muscle actin (SMA) expression in patients with compensated cirrhosis due to nonalcoholic steatohepatitis. J Hepatol 2016; 64 (2): S251.

Reference Type: 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.

Reference Type: 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.

Reference Type: RESULT

Bosch J, Ratziu V, Rockey DC, Ghalib RH, Thuluvath PJ, Shiefke I, et al. Correlation between noninvasive markers of fibrosis and the hepatic venous pressure gradient (HVPG) in patients with compensated cirrhosis due to nonalcoholic steatohepatitis (NASH). Hepatol 2015; 62 (1): 578A.

Reference Type: 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.

Reference Type: 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.

Reference Type: RESULT

Sanyal AJ, Goodman ZD, Abdelmalek MF, Harrison SA, Rockey DC, Diehl AM, et al. Clinical and histologic correlates of the hepatic venous pressure gradient (HVPG) in patients with compensated cirrhosis due to nonalcoholic steatohepatitis (NASH). Hepatol 2015; 62 (1): 577A.

Reference Type: 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.

Reference Type: 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.

Reference Type: DERIVED

PMID: 36750244 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 33307033 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 29990488 (View on PubMed)

Other Identifiers

2012-002489-11

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

GS-US-321-0106

Identifier Type: -

Identifier Source: org_study_id