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

Study Overview
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Brief Summary
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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)

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 2 (LOXL2), in Subjects With Compensated 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 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.

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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: SIM 200 mg<br>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<br>* Intravenous infusion over 30 minutes every 2 weeks<br>* Other names: GS-6624;|
| Experimental: SIM 700 mg<br>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<br>* Intravenous infusion over 30 minutes every 2 weeks<br>* Other names: GS-6624;|
| Placebo Comparator: Placebo<br>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<br>* Placebo to match SIM intravenous infusion over 30 minutes every 2 weeks<br>Biological: SIM<br>* Intravenous infusion over 30 minutes every 2 weeks<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 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Ishak, Compensated Liver disease, NASH, cirrhosis, Monoclonal antibody, LOXL2, Simtuzumab, Nonalcoholic Steatohepatitis, Hepatic venous pressure gradient, HVPG, NAFLD, MRE, Liver biopsy, Liver fibrosis