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

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ClinicalTrials.gov Identifier: NCT01672879
Recruitment Status : Terminated
First Posted : August 27, 2012
Results First Posted : March 27, 2019
Last Update Posted : March 27, 2019
Sponsor:
Information provided by (Responsible Party):
Gilead Sciences

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)

Condition or disease Intervention/treatment Phase
Liver Fibrosis Due to NASH Biological: Placebo Biological: SIM Phase 2

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 259 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: 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 Compensated Cirrhosis Secondary to Non-Alcoholic Steatohepatitis (NASH)
Actual Study Start Date : October 29, 2012
Actual Primary Completion Date : September 26, 2016
Actual Study Completion Date : January 3, 2017


Arm Intervention/treatment
Experimental: 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.
Biological: SIM
Intravenous infusion over 30 minutes every 2 weeks
Other Name: GS-6624

Experimental: 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.
Biological: SIM
Intravenous infusion over 30 minutes every 2 weeks
Other Name: GS-6624

Placebo Comparator: 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.
Biological: Placebo
Placebo to match SIM intravenous infusion over 30 minutes every 2 weeks

Biological: SIM
Intravenous infusion over 30 minutes every 2 weeks
Other Name: GS-6624




Primary Outcome Measures :
  1. Change From Baseline in Hepatic Venous Pressure Gradient (HVPG) [ Time Frame: Baseline to Week 96 ]
  2. Event-Free Survival (EFS) Using Kaplan-Meier [ Time Frame: Baseline up to the time of clinical event or last dose date (maximum: 240 weeks in Blinded Phase); which ever occurred first ]

    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



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Key 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

Key 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

Note: Other protocol defined Inclusion/Exclusion criteria may apply.


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01672879


  Show 59 Study Locations
Sponsors and Collaborators
Gilead Sciences
Investigators
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Study Director: Gilead Study Director Gilead Sciences

Publications of Results:
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Gilead Sciences
ClinicalTrials.gov Identifier: NCT01672879     History of Changes
Other Study ID Numbers: GS-US-321-0106
2012-002489-11 ( EudraCT Number )
First Posted: August 27, 2012    Key Record Dates
Results First Posted: March 27, 2019
Last Update Posted: March 27, 2019
Last Verified: March 2019

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Gilead Sciences:
Nonalcoholic Steatohepatitis
Hepatic venous pressure gradient
NASH
cirrhosis
Compensated Liver disease
Monoclonal antibody
LOXL2
Simtuzumab
HVPG
NAFLD
MRE
Liver biopsy
Liver fibrosis
Ishak

Additional relevant MeSH terms:
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Fibrosis
Liver Cirrhosis
Pathologic Processes
Liver Diseases
Digestive System Diseases
Antibodies, Monoclonal
Immunologic Factors
Physiological Effects of Drugs