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

Study Overview
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Brief Summary
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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)

Official Title
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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 Molecule 2 (LOXL2), in Subjects With Advanced Liver Fibrosis But Not Cirrhosis Secondary to Non-Alcoholic Steatohepatitis (NASH)

Conditions
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Liver Fibrosis Due to NASH

Intervention / Treatment
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* Biological: Placebo
* Biological: SIM


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: 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 Exclusion of other causes of liver disease including viral hepatitis and alcoholic liver disease 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. Key Exclusion Criteria: 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 BMI < 18 kg/m^2 Note: Other protocol defined Inclusion/Exclusion criteria may apply.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: SIM 75 mg<br>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<br>* Subcutaneous injection every week<br>* Other names: GS-6624;|
| Experimental: SIM 125 mg<br>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<br>* Subcutaneous injection every week<br>* Other names: GS-6624;|
| Placebo Comparator: Placebo<br>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<br>* Placebo to match SIM via subcutaneous injection every week<br>Biological: SIM<br>* Subcutaneous injection every week<br>* Other names: GS-6624;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Liver biopsy, NASH, noncirrhotic, Monoclonal antibody, LOXL2, Simtuzumab, Nonalcoholic Steatohepatitis, NAFLD, MRE, Liver fibrosis, Ishak