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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/ct2/show/NCT02781584




Registration number
NCT02781584
Ethics application status
Date submitted
20/05/2016
Date registered
24/05/2016
Date last updated
16/03/2022

Titles & IDs
Public title
Safety, Tolerability, and Efficacy of Selonsertib, Firsocostat, and Cilofexor in Adults With Nonalcoholic Steatohepatitis (NASH)
Scientific title
A Proof of Concept, Open-Label Study Evaluating the Safety, Tolerability, and Efficacy of Regimens in Subjects With Nonalcoholic Steatohepatitis (NASH)
Secondary ID [1] 0 0
GS-US-384-3914
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Nonalcoholic Steatohepatitis (NASH) 0 0
Nonalcoholic Fatty Liver Disease (NAFLD) 0 0
Condition category
Condition code
Oral and Gastrointestinal 0 0 0 0
Other diseases of the mouth, teeth, oesophagus, digestive system including liver and colon
Cancer 0 0 0 0
Liver
Metabolic and Endocrine 0 0 0 0
Metabolic disorders
Diet and Nutrition 0 0 0 0
Obesity

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - SEL
Treatment: Drugs - FIR
Treatment: Drugs - CILO
Treatment: Drugs - FENO
Treatment: Drugs - VAS

Experimental: Cohort 1: SEL 18 mg (Non-cirrhotic) - Non-cirrhotic participants will receive selonsertib (SEL) 18 mg tablet orally once daily for 12 weeks.

Experimental: Cohort 2: FIR 20 mg (Non-cirrhotic) - Non-cirrhotic participants will receive firsocostat (FIR) 20 mg tablet orally once daily for 12 weeks.

Experimental: Cohort 3: CILO 30 mg (Non-cirrhotic) - Non-cirrhotic participants will receive cilofexor (CILO) 30 mg tablet once daily for 12 weeks.

Experimental: Cohort 4: SEL 18 mg + CILO 30 mg (Non-cirrhotic) - Non-cirrhotic participants will receive SEL 18 mg tablet + CILO 30 mg tablet once daily for 12 weeks.

Experimental: Cohort 5: SEL 18 mg + FIR 20 mg (Non-cirrhotic) - Non-cirrhotic participants will receive SEL 18 mg tablet + FIR 20 mg tablet once daily for 12 weeks.

Experimental: Cohort 6: CILO 30 mg + FIR 20 mg (Non-cirrhotic) - Non-cirrhotic participants will receive CILO 30 mg tablet + FIR 20 mg tablet once daily for 12 weeks.

Experimental: Cohort 7: CILO 20 mg (Cirrhotic) - Participants with Child-Pugh-Turcotte Class A cirrhosis will receive FIR 20 mg tablet once daily for 12 weeks.

Experimental: Cohort 8: CILO 30 mg (Cirrhotic) - Participants with Child-Pugh-Turcotte Class A cirrhosis will receive CILO 30 mg tablet once daily for 12 weeks.

Experimental: Cohort 9: SEL 18 mg + FIR 20 mg + CILO 30 mg (Non-cirrhotic) - Non-cirrhotic participants will receive SEL 18 mg tablet + FIR 20 mg tablet + CILO 30 mg tablet once daily for 12 weeks.

Experimental: Cohort 10: FIR 20 mg + FENO 48 mg - Participants will receive fenofibrate (FENO) 48 mg tablet orally once daily for 2 weeks in the pretreatment phase, then FIR 20 mg tablet + FENO 48 mg tablet orally once daily for 24 weeks in the treatment phase. Participants with compensated cirrhosis due to NASH will be accepted to participate in this cohort.

Experimental: Cohort 11: FIR 20 mg + FENO 145 mg - Participants will receive FENO 145 mg tablet orally once daily for 2 weeks in the pretreatment phase, then FIR 20 mg tablet + FENO 145 mg tablet orally once daily for 24 weeks in the treatment phase. Participants with compensated cirrhosis due to NASH will be accepted to participate in this cohort.

Experimental: Cohort 12: FIR 20 mg + CILO 30 mg + VAS 2g - Participants will receive Vascepa® (VAS) 2 g capsule orally twice daily for 2 weeks in the pretreatment phase, then FIR 20 mg tablet once daily + CILO 30 mg tablet once daily + VAS 2 g capsule twice daily for 6 weeks in the treatment phase. Participants with compensated cirrhosis due to NASH will be accepted to participate in this cohort.

Experimental: Cohort 13: FIR 20 mg + CILO 30 mg + FENO 145 mg - Participants will receive FENO 145 mg tablet orally once daily for 2 weeks in the pretreatment phase, then FIR 20 mg tablet once daily + CILO 30 mg tablet once daily + FENO 145 mg tablet orally once daily for 6 weeks in the treatment phase. Participants with compensated cirrhosis due to NASH will be accepted to participate in this cohort.


Treatment: Drugs: SEL
Administered orally once daily

Treatment: Drugs: FIR
Administered orally once daily

Treatment: Drugs: CILO
Administered orally once daily

Treatment: Drugs: FENO
Administered orally once daily

Treatment: Drugs: VAS
Administered orally two times daily
Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Percentage of Participants Who Experienced Treatment-Emergent Adverse Events
Timepoint [1] 0 0
Cohorts 1-9: First dose date up to 12 weeks plus 30 days; Cohorts 10-11: First dose date up to 26 weeks plus 30 days; Cohorts 12-13: First dose date up to 8 weeks plus 30 days. For Cohorts 10-13, the first dose date included the Pre-treatment Phase.
Primary outcome [2] 0 0
Percentage of Participants Who Experienced Treatment Emergent Serious Adverse Events
Timepoint [2] 0 0
Cohorts 1-9: First dose date up to 12 weeks plus 30 days; Cohorts 10-11: First dose date up to 26 weeks plus 30 days; Cohorts 12-13: First dose date up to 8 weeks plus 30 days. For Cohorts 10-13, the first dose date included the Pre-treatment Phase.
Primary outcome [3] 0 0
Percentage of Participants Who Experienced Grade 3 or Higher Laboratory Abnormalities
Timepoint [3] 0 0
Cohorts 1-9: First dose date up to 12 weeks plus 30 days; Cohorts 10-11: First dose date up to 26 weeks plus 30 days; Cohorts 12-13: First dose date up to 8 weeks plus 30 days. For Cohorts 10-13, the first dose date included the Pre-treatment Phase.

Eligibility
Key inclusion criteria
Key

- Males and females between 18-75 years of age (Cohorts 1-9: 18-75 years and Cohorts
10-13: = 18 years); inclusive based on the date of the screening visit

- Willing and able to provide informed consent prior to any study specific procedures
being performed

- For Cohorts 1 through 6 and 9, individuals must meet the following conditions:

- Clinical diagnosis of nonalcoholic fatty liver disease (NAFLD)

- Screening FibroTest® < 0.75, unless a historical liver biopsy within 12 months of
Screening does not reveal cirrhosis. In individuals with Gilbert's syndrome or
hemolysis, FibroTest® will be calculated using direct bilirubin instead of total
bilirubin,

- Screening magnetic resonance imaging - proton density fat fraction (MRI-PDFF)
with = 10% steatosis,

- Screening magnetic resonance elastography (MRE) with liver stiffness = 2.88 kPa,
OR

- A historical liver biopsy within 12 months of Screening consistent with NASH
(defined as the presence of steatosis, inflammation, and ballooning) with stage
2-3 fibrosis according to the NASH Clinical Research Network (CRN) classification
(or equivalent), AND

- No documented weight loss > 5% between the date of the liver biopsy and
Screening;

- For Cohorts 7 and 8, individuals must have a clinical diagnosis of NAFLD and have at
least one of the following criteria:

- Screening MRE with liver stiffness = 4.67 kPa,

- A historical FibroScan® = 14 kPa within 6 months of Screening,

- Screening FibroTest® = 0.75,

- A historical liver biopsy consistent with stage 4 fibrosis according to the NASH
CRN classification (or equivalent);

- For Cohorts 10 and 11, individuals must have a clinical diagnosis of NAFLD and meet at
least two criteria for metabolic syndrome modified from the NCEP ATP III Guidelines
and one of the following criteria at Screening:

- A historical liver biopsy within 6 months of Screening consistent with NASH and
bridging fibrosis (F3) or within 12 months of Screening consistent with NASH and
compensated cirrhosis (F4) in the opinion of the investigator,

- Screening liver stiffness by MRE = 3.64 kPa;

- Screening liver stiffness by FibroScan® = 9.9 kPa;

- For Cohorts 12 and 13, individuals must have a clinical diagnosis of NAFLD/NASH and at
least two criteria for metabolic syndrome as modified from the NCEPT ATP III
Guidelines, OR one of the following criteria:

- A historical liver biopsy within 6 months of Screening consistent with NASH for
individuals without compensated cirrhosis (F4); or within 12 months of Screening
consistent with NASH for individuals with compensated cirrhosis (F4) in the
opinion of the investigator,

- A historical MRE with liver stiffness = 2.88 kPa within 6 months of Screening,

- A historical FibroScan® with liver stiffness = 9.9 kPa within 6 months of
Screening, AND

- No documented weight loss > 5% between the date of the historical liver biopsy,
historical MRE, or historical FibroScan® and Screening;

- Platelet count = 100,000/µL;

- Serum creatinine < 2 mg/dL (Cohorts 1-9) at Screening;

- Estimated glomerular filtration rate (eGFR) = 80 mL/min (Cohorts 10-11) or = 60 mL/min
(Cohorts 12-13), as calculated by the Cockcroft-Gault equation at Screening;

- For Cohorts 10-13, serum triglyceride level = 150 mg/dL at Screening.

Key
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
- Pregnant or lactating females

- Other causes of liver disease including autoimmune, viral, and alcoholic liver disease

- Any history of decompensated liver disease, including ascites, hepatic encephalopathy
or variceal bleeding

- For Cohorts 7-8, 10-13, Child-Pugh-Turcotte (CPT) score > 6

- History of liver transplantation

- History of hepatocellular carcinoma;

- Weight reduction surgery in the past 2 years or planned during the study;

- Documented weight loss > 5% between the date of the historical liver biopsy and
Screening, if applicable;

- Body Mass Index (BMI) < 18 kg/m2;

- ALT > 5 x ULN at Screening;

- For Cohorts 10-13, HbA1c = 9.5% (or serum fructosamine = 381 µmol if HbA1c is unable
to be resulted) at Screening;

- For Cohorts 10-13, hemoglobin = 10.6 g/dL at Screening;

- INR > 1.2 (Cohorts 1-9) or INR > 1.4 (Cohorts 10-13) at Screening, unless on
anticoagulation therapy;

- Total bilirubin > 1x ULN (Cohorts 1 through 6 and 9), >1.5 x ULN (Cohorts 7 and 8), or
>1.3 x ULN (Cohorts 10-13) except in confirmed cases of Gilbert's syndrome;

- Triglycerides = 500 mg/dL (Cohorts 5-8 and 10-13) or = 250 mg/dL (Cohort 9) at
Screening;

- Model for End-Stage Liver Disease (MELD) score > 12 at Screening (Cohorts 10 -13),
unless due to an alternate etiology such as therapeutic anticoagulation;

- Chronic hepatitis B (HBsAg positive);

- Chronic hepatitis C (HCV RNA positive). individuals cured of HCV infection less than 2
years prior to the Screening visit are not eligible (Cohorts 10-13);

- HIV Ab positive;

- Presence of gallstones within 6 months of Screening (Cohorts 10-13);

- Alcohol consumption greater than 21 oz/week for males or 14 oz/week for females
(1oz/30 mL of alcohol is present in 1 12oz/360 mL beer, 1 4oz/120 mL glass of wine,
and a 1 oz/30 mL measure of 40% proof alcohol);

- Positive urine screen for amphetamines, cocaine or opiates (i.e., heroin, morphine) at
Screening. Individuals on stable methadone or buprenorphine maintenance treatment for
at least 6 months prior to Screening may be included in the study. Individuals 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;

- Unstable cardiovascular disease;

- History of intestinal resection of the extent that would result in malabsorption;

- Use of any prohibited concomitant medications as described in the protocol;

- History of a malignancy within 5 years of Screening with the following exceptions:

- Adequately treated carcinoma in situ of the cervix,

- Adequately treated basal or squamous cell cancer or other localized non-melanoma
skin cancer.

Note: Other protocol defined Inclusion/Exclusion criteria may apply.

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 2
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
13/06/2016
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
17/12/2020
Sample size
Target
Accrual to date
Final
220
Recruitment in Australia
Recruitment state(s)
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
Arizona
Country [2] 0 0
United States of America
State/province [2] 0 0
California
Country [3] 0 0
United States of America
State/province [3] 0 0
Florida
Country [4] 0 0
United States of America
State/province [4] 0 0
Louisiana
Country [5] 0 0
United States of America
State/province [5] 0 0
Tennessee
Country [6] 0 0
United States of America
State/province [6] 0 0
Texas
Country [7] 0 0
New Zealand
State/province [7] 0 0
Auckland

Funding & Sponsors
Primary sponsor type
Commercial sector/Industry
Name
Gilead Sciences
Address
Country

Ethics approval
Ethics application status

Summary
Brief summary
The primary objective of this study is to evaluate the safety and tolerability of
selonsertib, firsocostat, cilofexor, fenofibrate and/or Vascepa® in adults with nonalcoholic
fatty liver disease (NAFLD) or nonalcoholic steatohepatitis (NASH).
Trial website
https://clinicaltrials.gov/ct2/show/NCT02781584
Trial related presentations / publications
Lawitz E, Neff G, Ruane P, Ziad Y, Jia C, Chuang J, et al. Fenofibrate Mitigates Increases in Serum Triglycerides Due to the ACC Inhibitor Firsocostat in Patients with Advanced Fibrosis Due to NASH. Poster presented at: The American Association for the Study of Liver Diseases (AASLD): The Liver Meeting; November 8-12, 2019; Boston, MA.
Lawitz EJ, Coste A, Poordad F, Alkhouri N, Loo N, McColgan BJ, Tarrant JM, Nguyen T, Han L, Chung C, Ray AS, McHutchison JG, Subramanian GM, Myers RP, Middleton MS, Sirlin C, Loomba R, Nyangau E, Fitch M, Li K, Hellerstein M. Acetyl-CoA Carboxylase Inhibitor GS-0976 for 12 Weeks Reduces Hepatic De Novo Lipogenesis and Steatosis in Patients With Nonalcoholic Steatohepatitis. Clin Gastroenterol Hepatol. 2018 Dec;16(12):1983-1991.e3. doi: 10.1016/j.cgh.2018.04.042. Epub 2018 Apr 26.
Lawitz E, Herring R, Younes ZH, Gane E, Ruane P, Schall RA, et al. Proof of Concept Study of an Apoptosis-Signal Regulating Kinase (ASK1) Inhibitor (Selonsertib) in Combination With An Acetyl-CoA Carboxylase Inhibitor (GS-0976) or a Farnesoid X Receptor Agonist (GS-9674) in Nash [Abstract PS-105]. European Association for the Study of the Liver (EASL); 2018 11-15 April; Paris, France.
Lawitz E, Li K, Tarrant JM, Vimal M, Xu R, Song Q, et al. Hepatic de Novo Lipogenesis is Elevated in Patients with NASH Independent of Disease Severity [Abstract 2217]. American Association for the Study of Liver Diseases (AASLD); 2017 20-24 October Washington, DC.
Lawitz EJ, Poordad F, Coste A, Loo N, Djedjos CS, McColgan B, et al. Acetyl-CoA carboxylase (ACC) inhibitor GS-0976 leads to suppression of hepatic de novo lipogenesis and significant improvements in MRI-PDFF, MRE, and markers of fibrosis after 12 weeks of therapy in patients with NASH [Abstract GS-009]. The International Liver Congress™ 2017: European Association for the Study of the Liver (EASL); 2017 19-23 April; Amsterdam, the Netherlands.
Public notes

Contacts
Principal investigator
Name 0 0
Gilead Study Director
Address 0 0
Gilead Sciences
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries