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

Phase 2

Terminated

Conditions: Liver Fibrosis Due to NASH

Interventions: Biological: Placebo
Biological: SIM

Registration Number: NCT01672879

Lead Sponsor: 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)

Detailed Description: Not available

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 259

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.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Placebo	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.
SIM 700 mg	SIM	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.
Placebo	SIM	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.
SIM 200 mg	SIM	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.

Primary Outcome Measures

Name	Time	Method
Change From Baseline in Hepatic Venous Pressure Gradient (HVPG)	Baseline to Week 96
Event-Free Survival (EFS) Using Kaplan-Meier	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

Secondary Outcome Measures

Name	Time	Method

Trial Locations

Locations (59): Mayo Clinic Hospital
🇺🇸
Phoenix, Arizona, United States
Southern California Liver Centers
🇺🇸
Coronado, California, United States
University of California, San Diego (UCSD)
🇺🇸
San Diego, California, United States
University of California San Francisco (UCSF)
🇺🇸
San Francisco, California, United States
Indiana University School of Medicine, Division of Gastroenterology/Hepatology
🇺🇸
Indianapolis, Indiana, United States
University of Colorado, Denver
🇺🇸
Aurora, Colorado, United States
Tulane University
🇺🇸
New Orleans, Louisiana, United States
Mercy Medical Center
🇺🇸
Baltimore, Maryland, United States
Walter Reed National Military Medical Center
🇺🇸
Bethesda, Maryland, United States
Northwestern University
🇺🇸
Chicago, Illinois, United States
Iowa Digestive Disease Center
🇺🇸
Clive, Iowa, United States
Saint Louis University Hospital
🇺🇸
Saint Louis, Missouri, United States
Minnnesota Gastroenterology, PA
🇺🇸
Saint Paul, Minnesota, United States
Lahey Clinic
🇺🇸
Burlington, Massachusetts, United States
State University Of New York at Buffalo
🇺🇸
Buffalo, New York, United States
North Shore University Health System
🇺🇸
Manhasset, New York, United States
Columbia University Medical Center
🇺🇸
New York, New York, United States
New York University
🇺🇸
New York, New York, United States
University Hospitals Case Medical Center
🇺🇸
Cleveland, Ohio, United States
University of Pennsylvania Hospital
🇺🇸
Philadelphia, Pennsylvania, United States
University Gastroenterology
🇺🇸
Providence, Rhode Island, United States
Duke University Medical Center
🇺🇸
Durham, North Carolina, United States
Medical University of South Carolina
🇺🇸
Charleston, South Carolina, United States
Methodist University Hospital
🇺🇸
Memphis, Tennessee, United States
Texas Clinical Research Institute
🇺🇸
Arlington, Texas, United States
Brooke Army Medical Center
🇺🇸
Fort Sam Houston, Texas, United States
Vanderbilt University Medical Center
🇺🇸
Nashville, Tennessee, United States
Intermountain Transplant Center
🇺🇸
Murray, Utah, United States
University of Virginia Health Center
🇺🇸
Charlottesville, Virginia, United States
Bucheon St. Marys Hospital
🇺🇸
Richmond, Virginia, United States
Liver Institute of Virginia
🇺🇸
Newport News, Virginia, United States
Digestive and Liver Disease Specialists
🇺🇸
Norfolk, Virginia, United States
University of Washington
🇺🇸
Seattle, Washington, United States
University of Manitoba
🇨🇦
Winnipeg, Manitoba, Canada
Virginia Mason Medical Center
🇺🇸
Seattle, Washington, United States
Toronto Liver Centre
🇨🇦
Toronto, Ontario, Canada
Hospital Saint-Antoine
🇫🇷
Paris, France
Hôpital de la Croix Rousse
🇫🇷
Lyon, France
CHU Pitié-Salpêtrière
🇫🇷
Paris, France
Istituto Clinico Humanitas
🇮🇹
Rozzano, Milano, Italy
Fonds de Recherche Honoraires
🇫🇷
Strasbourg, France
Gastroenterologisch-Hepatologisches Zentrum Kiel
🇩🇪
Kiel, Germany
Eugastro Gmbh
🇩🇪
Leipzig, Germany
Azienda Ospedaliera Città della Salute e della Scienza di Torino
🇮🇹
Torino, Italy
Fundacion De Investigacion
🇵🇷
San Juan, Puerto Rico
Hospital Universitario Puerta de Hierro
🇪🇸
Majadahonda, Madrid, Spain
Royal Free Hospital, Pond Street
🇬🇧
London, United Kingdom
Hospital Vall D´Hebron
🇪🇸
Barcelona, Cataluna, Spain
King's College Hospital NHS Trust
🇬🇧
London, United Kingdom
Nottingham University Hospitals Queen's Medical Centre
🇬🇧
Nottingham, United Kingdom
Azienda Ospedaliero-Universitaria Policlinico di Modena
🇮🇹
Modena, Italy
Dalhousie University
🇨🇦
Halifax, Nova Scotia, Canada
University of Mississippi Medical Center
🇺🇸
Jackson, Michigan, United States
University of Miami
🇺🇸
Miami, Florida, United States
University of Louisville
🇺🇸
Louisville, Kentucky, United States
Tampa General Hospital
🇺🇸
Tampa, Florida, United States
St. Luke Episcopal Hospital
🇺🇸
Houston, Texas, United States
Alamo Clinical Research Associates
🇺🇸
San Antonio, Texas, United States
Virginia Commonwealth University
🇺🇸
Richmond, Virginia, United States