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

NCT01672879 | Terminated Phase 2 Results DMC FDA Drug

• 2 other identifiers: GS-US-321-01062012-002489-11
• Study Type: interventional
• Target: 259
• Locations: 8 countries
• Sites: 59

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

Keywords

NASH; cirrhosis; Compensated Liver disease; Monoclonal antibody; LOXL2; Simtuzumab; Nonalcoholic Steatohepatitis; Hepatic venous pressure gradient; HVPG; NAFLD; MRE; Liver biopsy; Liver fibrosis; Ishak

Outcome Measures

Primary Outcomes (2)

• Change From Baseline in Hepatic Venous Pressure Gradient (HVPG)

  Baseline to Week 96

• Event-Free Survival (EFS) Using Kaplan-Meier

  Event free survival (EFS) was the primary clinical efficacy endpoint and was assessed by time to first liver-related event or death, whichever occurs first. Liver-related events included any of the following: * Liver transplantation * Qualification for liver transplantation * Model for End-Stage Liver Disease (MELD) ≥ 15 * Events indicative of hepatic decompensation * Esophageal variceal bleeding * Ascites * Hepatic Encephalopathy * ≥ 2 point increase in Child Pugh-Turcotte (CPT) score * Newly diagnosed varices in a subject without prior varices

  Baseline up to the time of clinical event or last dose date (maximum: 240 weeks in Blinded Phase); which ever occurred first

Study Arms (3)

SIM 200 mg

EXPERIMENTAL

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.

Biological: SIM

SIM 700 mg

EXPERIMENTAL

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.

Biological: SIM

Placebo

PLACEBO COMPARATOR

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.

Biological: Placebo; Biological: SIM

Interventions

Placebo BIOLOGICAL

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

Placebo

SIM BIOLOGICAL

Intravenous infusion over 30 minutes every 2 weeks

Also known as: GS-6624

Placebo; SIM 200 mg; SIM 700 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 cirrhosis of the liver defined as an Ishak fibrosis stage ≥ 5
• Liver biopsy consistent with NASH or cryptogenic cirrhosis
• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Gilead Sciences: lead

Study Sites (59)

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, Denver

Aurora, Colorado, 80045, United States

Location

University of Miami

Miami, Florida, 33136, United States

Location

Tampa General Hospital

Tampa, Florida, 33606, United States

Location

Northwestern University

Chicago, Illinois, 60611, United States

Location

Indiana University School of Medicine, Division of Gastroenterology/Hepatology

Indianapolis, Indiana, 46202, 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

Lahey Clinic

Burlington, Massachusetts, 01805, United States

Location

University of Mississippi Medical Center

Jackson, Michigan, 39216, United States

Location

Minnnesota Gastroenterology, PA

Saint Paul, Minnesota, 55114, United States

Location

Saint Louis University Hospital

St Louis, Missouri, 63110, United States

Location

State University Of New York at Buffalo

Buffalo, New York, 14203, United States

Location

North Shore University Health System

Manhasset, New York, 11030, United States

Location

New York University

New York, New York, 10016, United States

Location

Columbia University Medical Center

New York, New York, 10032, United States

Location

Duke University Medical Center

Durham, North Carolina, 27710, United States

Location

University Hospitals Case Medical Center

Cleveland, Ohio, 44106, United States

Location

University of Pennsylvania Hospital

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

Methodist University Hospital

Memphis, Tennessee, 38104, United States

Location

Vanderbilt University Medical Center

Nashville, Tennessee, 37212, United States

Location

Texas Clinical Research Institute

Arlington, Texas, 76012, 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 Clinical Research Associates

San Antonio, Texas, 78215, United States

Location

Intermountain Transplant Center

Murray, Utah, 84107, United States

Location

University of Virginia Health Center

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, 23226, United States

Location

Virginia Commonwealth University

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

University of Manitoba

Winnipeg, Manitoba, R3E 3P4, Canada

Location

Dalhousie University

Halifax, Nova Scotia, B3H 2Y9, Canada

Location

Toronto Liver Centre

Toronto, Ontario, M6H 3M1, Canada

Location

Hôpital de la Croix Rousse

Lyon, 69317, France

Location

Hospital Saint-Antoine

Paris, 75012, France

Location

CHU Pitié-Salpêtrière

Paris, 75013, France

Location

Fonds de Recherche Honoraires

Strasbourg, 67091, France

Location

Gastroenterologisch-Hepatologisches Zentrum Kiel

Kiel, 24146, Germany

Location

Eugastro Gmbh

Leipzig, 4129, Germany

Location

Istituto Clinico Humanitas

Rozzano, Milano, 20089, Italy

Location

Azienda Ospedaliero-Universitaria Policlinico di Modena

Modena, 41100, 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, Catalonia, 08035, Spain

Location

Hospital Universitario Puerta de Hierro

Majadahonda, Madrid, 28222, Spain

Location

Royal Free Hospital, Pond Street

London, NW3 2QG, United Kingdom

Location

King's College Hospital NHS Trust

London, SE5 9RS, United Kingdom

Location

Nottingham University Hospitals Queen's Medical Centre

Nottingham, NG7 2UH, United Kingdom

Location

Related Publications (14)

• 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

• 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.

  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.

  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

• 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.

  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

• 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.

  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

Fibrosis; Non-alcoholic Fatty Liver Disease; Liver Cirrhosis

Interventions

simtuzumab

Condition Hierarchy (Ancestors)

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

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: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, 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: October 29, 2012
• Primary Completion: September 26, 2016
• Study Completion: January 3, 2017
• Last Updated: March 27, 2019
• Results First Posted: March 27, 2019

Record last verified: 2019-03

Locations

CA (3); DE (2); FR (4); IT (3); ES (2); GB (3); PR (1); US (41)