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

Liver Fibrosis Due to NASH Clinical Trial

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT01672866
• Other study ID #: GS-US-321-0105
• Secondary ID: 2012-002488-88
• Status: Terminated
• Phase: Phase 2
• Start date: December 5, 2012
• Est. completion date: December 29, 2016

Study information

• Verified date: March 2019
• Source: Gilead Sciences
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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)

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 222
• Est. completion date: December 29, 2016
• Est. primary completion date: August 2, 2016
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 65 Years

Eligibility

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.

Related Conditions & MeSH terms

• Fatty Liver
• Fibrosis
• Liver Cirrhosis
• Liver Fibrosis Due to NASH
• Non-alcoholic Fatty Liver Disease

Intervention

Biological:
• Placebo
Placebo to match SIM via subcutaneous injection every week
• SIM
Subcutaneous injection every week

Locations

Country	Name	City	State
Belgium	Hôpital Erasme	Brussels
Belgium	Université Catholique de Louvain	Bruxelles
Belgium	UZ Ghent	Gent
Canada	University of Calgary	Calgary	Alberta
Canada	London Health Science Center	London	Ontario
Canada	Toronto Liver Centre	Toronto	Ontario
Canada	University of Manitoba	Winnipeg	Manitoba
France	Hopital Beaujon	Clichy
France	Groupe Hospitalier Pitié- Salpétrière	Paris
France	Hospital Saint-Antoine	Paris
France	CHU Strasbourg Hôpital Civil	Strasbourg
Germany	Medizinische Hochschule Hannover	Hannover
Germany	Gastroenterologisch-Hepatologisches Zentrum Kiel	Kiel
Germany	EUGASTRO GmbH	Leipzig
Italy	Azienda Ospedaliero-Universitaria di Modena Policlinico	Modena
Italy	Azienda Ospedaliera San Camillo Forlanini	Roma
Italy	Azienda Ospedaliera Città della Salute e della Scienza di Torino	Torino
Puerto Rico	Fundacion De Investigacion	San Juan
Spain	Hospital Clinic de Barcelona	Barcelona
Spain	Hospital Vall d'Hebron	Barcelona
Spain	Hospital Universitario Puerta de Hierro	Majadahonda
Spain	Hospital Donostia	San Sebastian
United Kingdom	John Radcliffe Hospital	Headington
United Kingdom	King's College Hospital NHS Foundation Trust No. 1 Account	London
United Kingdom	Royal Free Hospital, Pond Street	London
United Kingdom	The Royal London Hospital	London
United Kingdom	Nottingham University Hospitals Queens Medica	Nottingham
United States	University of Michigan	Ann Arbor	Michigan
United States	Texas Clinical Research Institute, LLC	Arlington	Texas
United States	University of Colorado	Aurora	Colorado
United States	Mercy Medical Center	Baltimore	Maryland
United States	Walter Reed National Military Medical Center	Bethesda	Maryland
United States	Beth Israel Deaconess Medical Center	Boston	Massachusetts
United States	State University Of New York	Buffalo	New York
United States	Lahey Clinic	Burlington	Massachusetts
United States	Medical University of South Carolina	Charleston	South Carolina
United States	University of Virginia Health System	Charlottesville	Virginia
United States	Northwestern University	Chicago	Illinois
United States	Cleveland Clinic	Cleveland	Ohio
United States	University Hospitals Case Medical Center	Cleveland	Ohio
United States	Iowa Digestive Disease Center	Clive	Iowa
United States	Southern California Liver Centers	Coronado	California
United States	Duke University	Durham	North Carolina
United States	Brooke Army Medical Center	Fort Sam Houston	Texas
United States	St. Luke's Episcopal Hospital	Houston	Texas
United States	Indianapolis Gastroenterology Research Foundation	Indianapolis	Indiana
United States	University of Mississippi Medical Center	Jackson	Mississippi
United States	University of Louisville	Louisville	Kentucky
United States	Miami Veterans Administration Healthcare System	Miami	Florida
United States	Tulane University	New Orleans	Louisiana
United States	Mount Sinai Hospital	New York	New York
United States	Weill Cornell Medical College	New York	New York
United States	Liver Institute of Virginia	Newport News	Virginia
United States	Digestive and Liver Disease Specialists	Norfolk	Virginia
United States	University of Pennsylvania	Philadelphia	Pennsylvania
United States	Mayo Clinic Hospital	Phoenix	Arizona
United States	University Gastroenterology	Providence	Rhode Island
United States	Bucheon St. Marys Hospital	Richmond	Virginia
United States	Virginia Commonwealth University Health System	Richmond	Virginia
United States	Saint Louis University Hospital	Saint Louis	Missouri
United States	Minnnesota Gastroenterology, PA	Saint Paul	Minnesota
United States	University of Utah	Salt Lake City	Utah
United States	Alamo Clinical Research Associates	San Antonio	Texas
United States	University of California, San Diego (UCSD)	San Diego	California
United States	University of California San Francisco (UCSF)	San Francisco	California
United States	University of Washington	Seattle	Washington
United States	Virginia Mason Medical Center	Seattle	Washington
United States	Tampa General Hospital	Tampa	Florida

Sponsors (1)

Lead Sponsor	Collaborator
Gilead Sciences

Countries where clinical trial is conducted

United States,  Belgium,  Canada,  France,  Germany,  Italy,  Puerto Rico,  Spain,  United Kingdom, 

References & Publications (8)

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 (NAS

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.

Ratziu V, Sanyal A, Torres D, Hinrichsen H, Serfaty L, Bambha K, et al. Impact of weight reduction on serum markers and liver histology including progression to cirrhosis in patients with nonalcoholic steatohepatitis (NASH) and bridging fibrosis. J Hepato

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.

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-c

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 He

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.

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change From Baseline in MQC on Liver Biopsy		Baseline to Week 96
Primary	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