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Trial details imported from ClinicalTrials.gov

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




Registration number
NCT02781584
Ethics application status
Date submitted
20/05/2016
Date registered
24/05/2016

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
Trial website
Trial related presentations / publications
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

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment


What supporting documents are/will be available?




Results publications and other study-related documents

TypeCitations or Other Details
Journal Lawitz E, Bhandari BR, Ruane P, Kohli A, Harting E... [More Details]


Results are available at https://clinicaltrials.gov/study/NCT02781584