Clinical trial NCT01672866: Safety and Efficacy of Simtuzumab (SIM, GS-6624) in Adults With Advanced Liver Fibrosis But Not Cirrhosis Secondary to Non-Alcoholic Steatohepatitis (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 Molecule 2 (LOXL2), in Subjects With Advanced Liver Fibrosis But Not Cirrhosis Secondary to Non-Alcoholic Steatohepatitis (NASH)
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Liver Fibrosis Due to NASH
Keywords: NASH
noncirrhotic
Monoclonal antibody
LOXL2
Simtuzumab
Nonalcoholic Steatohepatitis
NAFLD
Liver biopsy
MRE
Liver fibrosis
Ishak
Lead sponsor: Gilead Sciences
Sponsor class: INDUSTRY
First posted: 2012-08-27
Enrollment: 222
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 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)


Eligibility criteria: 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.

Primary outcomes:
measure: Change From Baseline in MQC on Liver Biopsy
timeFrame: Baseline to Week 96
measure: Event Free Survival (EFS) Using Kaplan-Meier
timeFrame: Baseline up to the time of progression to cirrhosis or last dose date (maximum: 240 weeks in the 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
state: Colorado
city: Miami
country: United States
facility: Miami Veterans Administration Healthcare System
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: Indianapolis Gastroenterology Research Foundation
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: Boston
country: United States
facility: Beth Israel Deaconess Medical Center
state: Massachusetts
city: Burlington
country: United States
facility: Lahey Clinic
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of Michigan
state: Michigan
city: Saint Paul
country: United States
facility: Minnnesota Gastroenterology, PA
state: Minnesota
city: Jackson
country: United States
facility: University of Mississippi Medical Center
state: Mississippi
city: Saint Louis
country: United States
facility: Saint Louis University Hospital
state: Missouri
city: Buffalo
country: United States
facility: State University Of New York
state: New York
city: New York
country: United States
facility: Weill Cornell Medical College
state: New York
city: New York
country: United States
facility: Mount Sinai Hospital
state: New York
city: Durham
country: United States
facility: Duke University
state: North Carolina
city: Cleveland
country: United States
facility: University Hospitals Case Medical Center
state: Ohio
city: Cleveland
country: United States
facility: Cleveland Clinic
state: Ohio
city: Philadelphia
country: United States
facility: University of Pennsylvania
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: Arlington
country: United States
facility: Texas Clinical Research Institute, LLC
state: Texas
city: Fort Sam Houston
country: United States
facility: Brooke Army Medical Center
state: Texas
city: Houston
country: United States
facility: St. Luke's Episcopal Hospital
state: Texas
city: San Antonio
country: United States
facility: Alamo Clinical Research Associates
state: Texas
city: Salt Lake City
country: United States
facility: University of Utah
state: Utah
city: Charlottesville
country: United States
facility: University of Virginia Health System
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 Health System
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: Brussels
country: Belgium
facility: Hôpital Erasme
city: Bruxelles
country: Belgium
facility: Université Catholique de Louvain
city: Gent
country: Belgium
facility: UZ Ghent
city: Calgary
country: Canada
facility: University of Calgary
state: Alberta
city: Winnipeg
country: Canada
facility: University of Manitoba
state: Manitoba
city: London
country: Canada
facility: London Health Science Center
state: Ontario
city: Toronto
country: Canada
facility: Toronto Liver Centre
state: Ontario
city: Clichy
country: France
facility: Hopital Beaujon
city: Paris
country: France
facility: Hospital Saint-Antoine
city: Paris
country: France
facility: Groupe Hospitalier Pitié- Salpétrière
city: Strasbourg
country: France
facility: CHU Strasbourg Hôpital Civil
city: Hannover
country: Germany
facility: Medizinische Hochschule Hannover
city: Kiel
country: Germany
facility: Gastroenterologisch-Hepatologisches Zentrum Kiel
city: Leipzig
country: Germany
facility: EUGASTRO GmbH
city: Modena
country: Italy
facility: Azienda Ospedaliero-Universitaria di Modena Policlinico
city: Roma
country: Italy
facility: Azienda Ospedaliera San Camillo Forlanini
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
city: Barcelona
country: Spain
facility: Hospital Clinic de Barcelona
city: Majadahonda
country: Spain
facility: Hospital Universitario Puerta de Hierro
city: San Sebastian
country: Spain
facility: Hospital Donostia
city: Headington
country: United Kingdom
facility: John Radcliffe Hospital
city: London
country: United Kingdom
facility: The Royal London Hospital
city: London
country: United Kingdom
facility: Royal Free Hospital, Pond Street
city: London
country: United Kingdom
facility: King's College Hospital NHS Foundation Trust No. 1 Account
city: Nottingham
country: United Kingdom
facility: Nottingham University Hospitals Queens Medica
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: 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 Hepatol 2017; 66 (1): S594.
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: 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: 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.