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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

Tracking Information
First Submitted Date  ICMJE August 22, 2012
First Posted Date  ICMJE August 27, 2012
Results First Submitted Date  ICMJE March 1, 2019
Results First Posted Date  ICMJE March 27, 2019
Last Update Posted Date March 27, 2019
Actual Study Start Date  ICMJE October 29, 2012
Actual Primary Completion Date September 26, 2016   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: March 1, 2019)
  • Change From Baseline in Hepatic Venous Pressure Gradient (HVPG) [ Time Frame: Baseline to Week 96 ]
  • 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
Original Primary Outcome Measures  ICMJE
 (submitted: August 22, 2012)
Reverse cirrhosis in subjects with cirrhosis due to NASH by using GS-6624 [ Time Frame: Baseline to Week 100 ]
The subjects will receive intravenous (IV) infusions of blinded study drug every 2 weeks for 96 weeks.Regression of fibrosis as assessed by change from baseline in morphometric quantitative collagen on liver biopsy.
Change History
Current Secondary Outcome Measures  ICMJE Not Provided
Original Secondary Outcome Measures  ICMJE
 (submitted: August 22, 2012)
Assess the safety of GS-6624 in subjects with compensated cirrhosis due to NASH [ Time Frame: Baseline through Week 100 ]
Subjects will be assessed throughout the trial for safety and tolerability.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Simtuzumab (SIM, GS-6624) in the Treatment of Cirrhosis Due to NASH
Official Title  ICMJE 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)
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)
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE Liver Fibrosis Due to NASH
Intervention  ICMJE
  • 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
Study Arms  ICMJE
  • 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.
    Intervention: Biological: SIM
  • 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.
    Intervention: Biological: SIM
  • 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.
    Interventions:
    • Biological: Placebo
    • Biological: SIM
Publications *
  • 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.
  • 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.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Terminated
Actual Enrollment  ICMJE
 (submitted: February 16, 2015)
259
Original Estimated Enrollment  ICMJE
 (submitted: August 22, 2012)
225
Actual Study Completion Date  ICMJE January 3, 2017
Actual Primary Completion Date September 26, 2016   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.

Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 65 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Canada,   France,   Germany,   Italy,   Puerto Rico,   Spain,   United Kingdom,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01672879
Other Study ID Numbers  ICMJE GS-US-321-0106
2012-002489-11 ( EudraCT Number )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Gilead Sciences
Study Sponsor  ICMJE Gilead Sciences
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Gilead Study Director Gilead Sciences
PRS Account Gilead Sciences
Verification Date March 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP