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

Liver Fibrosis Due to NASH Clinical Trial

— NASH  

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 2 (LOXL2), in Subjects With Compensated Cirrhosis Secondary to Non-Alcoholic Steatohepatitis (NASH)

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT01672879
• Other study ID #: GS-US-321-0106
• Secondary ID: 2012-002489-11
• Status: Terminated
• Phase: Phase 2
• Start date: October 29, 2012
• Est. completion date: January 3, 2017

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 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)

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 259
• Est. completion date: January 3, 2017
• Est. primary completion date: September 26, 2016
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 65 Years

Eligibility

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.

Related Conditions & MeSH terms

• Fibrosis
• Liver Cirrhosis
• Liver Fibrosis Due to NASH

Intervention

Biological:
• Placebo
Placebo to match SIM intravenous infusion over 30 minutes every 2 weeks
• SIM
Intravenous infusion over 30 minutes every 2 weeks

Locations

Country	Name	City	State
Canada	Dalhousie University	Halifax	Nova Scotia
Canada	Toronto Liver Centre	Toronto	Ontario
Canada	University of Manitoba	Winnipeg	Manitoba
France	Hôpital de la Croix Rousse	Lyon
France	CHU Pitié-Salpêtrière	Paris
France	Hospital Saint-Antoine	Paris
France	Fonds de Recherche Honoraires	Strasbourg
Germany	Gastroenterologisch-Hepatologisches Zentrum Kiel	Kiel
Germany	Eugastro Gmbh	Leipzig
Italy	Azienda Ospedaliero-Universitaria Policlinico di Modena	Modena
Italy	Istituto Clinico Humanitas	Rozzano	Milano
Italy	Azienda Ospedaliera Città della Salute e della Scienza di Torino	Torino
Puerto Rico	Fundacion De Investigacion	San Juan
Spain	Hospital Vall D´Hebron	Barcelona	Cataluna
Spain	Hospital Universitario Puerta de Hierro	Majadahonda	Madrid
United Kingdom	King's College Hospital NHS Trust	London
United Kingdom	Royal Free Hospital, Pond Street	London
United Kingdom	Nottingham University Hospitals Queen's Medical Centre	Nottingham
United States	Texas Clinical Research Institute	Arlington	Texas
United States	University of Colorado, Denver	Aurora	Colorado
United States	Mercy Medical Center	Baltimore	Maryland
United States	Walter Reed National Military Medical Center	Bethesda	Maryland
United States	State University Of New York at Buffalo	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 Center	Charlottesville	Virginia
United States	Northwestern University	Chicago	Illinois
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 Medical Center	Durham	North Carolina
United States	Brooke Army Medical Center	Fort Sam Houston	Texas
United States	St. Luke Episcopal Hospital	Houston	Texas
United States	Indiana University School of Medicine, Division of Gastroenterology/Hepatology	Indianapolis	Indiana
United States	University of Mississippi Medical Center	Jackson	Michigan
United States	University of Louisville	Louisville	Kentucky
United States	North Shore University Health System	Manhasset	New York
United States	Methodist University Hospital	Memphis	Tennessee
United States	University of Miami	Miami	Florida
United States	Intermountain Transplant Center	Murray	Utah
United States	Vanderbilt University Medical Center	Nashville	Tennessee
United States	Tulane University	New Orleans	Louisiana
United States	Columbia University Medical Center	New York	New York
United States	New York University	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 Hospital	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	Richmond	Virginia
United States	Saint Louis University Hospital	Saint Louis	Missouri
United States	Minnnesota Gastroenterology, PA	Saint Paul	Minnesota
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,  Canada,  France,  Germany,  Italy,  Puerto Rico,  Spain,  United Kingdom, 

References & Publications (11)

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; 6

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).

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 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, 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

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

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 201

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.

* Note: There are 11 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change From Baseline in Hepatic Venous Pressure Gradient (HVPG)		Baseline to Week 96
Primary	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