Clinical trial NCT01672879: Simtuzumab (SIM, GS-6624) in the Treatment of Cirrhosis Due to 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)
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Liver Fibrosis Due to NASH
Keywords: NASH
cirrhosis
Compensated Liver disease
Monoclonal antibody
LOXL2
Simtuzumab
Nonalcoholic Steatohepatitis
Hepatic venous pressure gradient
HVPG
NAFLD
MRE
Liver biopsy
Liver fibrosis
Ishak
Lead sponsor: Gilead Sciences
Sponsor class: INDUSTRY
First posted: 2012-08-27
Enrollment: 259
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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)


Eligibility criteria: 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.

Primary outcomes:
measure: Change From Baseline in Hepatic Venous Pressure Gradient (HVPG)
timeFrame: Baseline to Week 96
measure: Event-Free Survival (EFS) Using Kaplan-Meier
timeFrame: Baseline up to the time of clinical event or last dose date (maximum: 240 weeks in Blinded Phase); which ever occurred first
Secondary outcomes:
Other outcomes:
Locations:
city: Phoenix
country: United States
facility: Mayo Clinic Hospital
state: Arizona
city: Coronado
country: United States
facility: Southern California Liver Centers
state: California
city: San Diego
country: United States
facility: University of California, San Diego (UCSD)
state: California
city: San Francisco
country: United States
facility: University of California San Francisco (UCSF)
state: California
city: Aurora
country: United States
facility: University of Colorado, Denver
state: Colorado
city: Miami
country: United States
facility: University of Miami
state: Florida
city: Tampa
country: United States
facility: Tampa General Hospital
state: Florida
city: Chicago
country: United States
facility: Northwestern University
state: Illinois
city: Indianapolis
country: United States
facility: Indiana University School of Medicine, Division of Gastroenterology/Hepatology
state: Indiana
city: Clive
country: United States
facility: Iowa Digestive Disease Center
state: Iowa
city: Louisville
country: United States
facility: University of Louisville
state: Kentucky
city: New Orleans
country: United States
facility: Tulane University
state: Louisiana
city: Baltimore
country: United States
facility: Mercy Medical Center
state: Maryland
city: Bethesda
country: United States
facility: Walter Reed National Military Medical Center
state: Maryland
city: Burlington
country: United States
facility: Lahey Clinic
state: Massachusetts
city: Jackson
country: United States
facility: University of Mississippi Medical Center
state: Michigan
city: Saint Paul
country: United States
facility: Minnnesota Gastroenterology, PA
state: Minnesota
city: Saint Louis
country: United States
facility: Saint Louis University Hospital
state: Missouri
city: Buffalo
country: United States
facility: State University Of New York at Buffalo
state: New York
city: Manhasset
country: United States
facility: North Shore University Health System
state: New York
city: New York
country: United States
facility: New York University
state: New York
city: New York
country: United States
facility: Columbia University Medical Center
state: New York
city: Durham
country: United States
facility: Duke University Medical Center
state: North Carolina
city: Cleveland
country: United States
facility: University Hospitals Case Medical Center
state: Ohio
city: Philadelphia
country: United States
facility: University of Pennsylvania Hospital
state: Pennsylvania
city: Providence
country: United States
facility: University Gastroenterology
state: Rhode Island
city: Charleston
country: United States
facility: Medical University of South Carolina
state: South Carolina
city: Memphis
country: United States
facility: Methodist University Hospital
state: Tennessee
city: Nashville
country: United States
facility: Vanderbilt University Medical Center
state: Tennessee
city: Arlington
country: United States
facility: Texas Clinical Research Institute
state: Texas
city: Fort Sam Houston
country: United States
facility: Brooke Army Medical Center
state: Texas
city: Houston
country: United States
facility: St. Luke Episcopal Hospital
state: Texas
city: San Antonio
country: United States
facility: Alamo Clinical Research Associates
state: Texas
city: Murray
country: United States
facility: Intermountain Transplant Center
state: Utah
city: Charlottesville
country: United States
facility: University of Virginia Health Center
state: Virginia
city: Newport News
country: United States
facility: Liver Institute of Virginia
state: Virginia
city: Norfolk
country: United States
facility: Digestive and Liver Disease Specialists
state: Virginia
city: Richmond
country: United States
facility: Bucheon St. Marys Hospital
state: Virginia
city: Richmond
country: United States
facility: Virginia Commonwealth University
state: Virginia
city: Seattle
country: United States
facility: Virginia Mason Medical Center
state: Washington
city: Seattle
country: United States
facility: University of Washington
state: Washington
city: Winnipeg
country: Canada
facility: University of Manitoba
state: Manitoba
city: Halifax
country: Canada
facility: Dalhousie University
state: Nova Scotia
city: Toronto
country: Canada
facility: Toronto Liver Centre
state: Ontario
city: Lyon
country: France
facility: Hôpital de la Croix Rousse
city: Paris
country: France
facility: Hospital Saint-Antoine
city: Paris
country: France
facility: CHU Pitié-Salpêtrière
city: Strasbourg
country: France
facility: Fonds de Recherche Honoraires
city: Kiel
country: Germany
facility: Gastroenterologisch-Hepatologisches Zentrum Kiel
city: Leipzig
country: Germany
facility: Eugastro Gmbh
city: Rozzano
country: Italy
facility: Istituto Clinico Humanitas
state: Milano
city: Modena
country: Italy
facility: Azienda Ospedaliero-Universitaria Policlinico di Modena
city: Torino
country: Italy
facility: Azienda Ospedaliera Città della Salute e della Scienza di Torino
city: San Juan
country: Puerto Rico
facility: Fundacion De Investigacion
city: Barcelona
country: Spain
facility: Hospital Vall D´Hebron
state: Cataluna
city: Majadahonda
country: Spain
facility: Hospital Universitario Puerta de Hierro
state: Madrid
city: London
country: United Kingdom
facility: Royal Free Hospital, Pond Street
city: London
country: United Kingdom
facility: King's College Hospital NHS Trust
city: Nottingham
country: United Kingdom
facility: Nottingham University Hospitals Queen's Medical Centre
Study officials:
affiliation: Gilead Sciences
name: Gilead Study Director
role: STUDY_DIRECTOR
References:
citation: 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 Hepatol 2017; 66 (1): S2.
citation: 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-controlled trials. J Hepatol 2017; 66 (1): S54.
citation: 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; 66 (1): S159-S160.
citation: 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 Hepatol 2016; 64 (2): S251.
citation: 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.
citation: 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.
citation: 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). Hepatol 2015; 62 (1): 578A.
citation: 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 (NASH). Hepatol 2015; 62 (1): 906A.
citation: 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.
citation: 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 2015; 62 (1): 577A.
citation: 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.
citation: Younossi ZM, Anstee QM, Wai-Sun Wong V, Trauner M, Lawitz EJ, Harrison SA, Camargo M, Kersey K, Subramanian GM, Myers RP, Stepanova M. The Association of Histologic and Noninvasive Tests With Adverse Clinical and Patient-Reported Outcomes in Patients With Advanced Fibrosis Due to Nonalcoholic Steatohepatitis. Gastroenterology. 2021 Apr;160(5):1608-1619.e13. doi: 10.1053/j.gastro.2020.12.003. Epub 2020 Dec 8.
citation: Harrison SA, Abdelmalek MF, Caldwell S, Shiffman ML, Diehl AM, Ghalib R, Lawitz EJ, Rockey DC, Schall RA, Jia C, McColgan BJ, McHutchison JG, Subramanian GM, Myers RP, Younossi Z, Ratziu V, Muir AJ, Afdhal NH, Goodman Z, Bosch J, Sanyal AJ; GS-US-321-0105 and GS-US-321-0106 Investigators. Simtuzumab Is Ineffective for Patients With Bridging Fibrosis or Compensated Cirrhosis Caused by Nonalcoholic Steatohepatitis. Gastroenterology. 2018 Oct;155(4):1140-1153. doi: 10.1053/j.gastro.2018.07.006. Epub 2018 Jul 7.