Study to Evaluate the Pharmacokinetics of Firsocostat or Fenofibrate in Adults With Normal and Impaired Hepatic Function (HI)

• ClinicalTrials.gov Identifier: NCT02891408
• Recruitment Status: Completed
• First Posted: September 7, 2016
• Results First Posted: December 17, 2020
• Last Update Posted: December 17, 2020
• Sponsor: Gilead Sciences
• Information provided by (Responsible Party): Gilead Sciences

Tracking Information

• First Submitted Date: September 1, 2016
• First Posted Date: September 7, 2016
• Results First Submitted Date: September 3, 2020
• Results First Posted Date: December 17, 2020
• Last Update Posted Date: December 17, 2020
• Actual Study Start Date: September 23, 2016
• Actual Primary Completion Date: May 5, 2019 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: November 23, 2020)

• Pharmacokinetic (PK) Parameter: AUClast of Firsocostat, GS-834773 (Primary Metabolite of Firsocostat), and Fenofibric Acid (Primary Metabolite of Fenofibrate) [ Time Frame: Day 1: 0 (predose, ≤ 5 minutes prior to dosing), 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 48, 72, and 96 hours postdose; or 72 hours of early termination from the study (if applicable) ]
  AUClast is defined as the concentration of drug from time zero to the last observable concentration. The PK of fenofibric acid was evaluated in participants with mild hepatic impairment and matched participants with normal hepatic function (Cohort 4).
• PK Parameter: AUCinf of Firsocostat, GS-834773 (Primary Metabolite of Firsocostat), and Fenofibric Acid (Primary Metabolite of Fenofibrate) [ Time Frame: Day 1: 0 (predose, ≤ 5 minutes prior to dosing), 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 48, 72, and 96 hours postdose; or 72 hours of early termination from the study (if applicable) ]
  AUCinf is defined as the concentration of drug extrapolated to infinite time. The PK of fenofibric acid was evaluated in participants with mild hepatic impairment and matched participants with normal hepatic function (Cohort 4).
• PK Parameter: Cmax of Firsocostat, GS-834773 (Primary Metabolite of Firsocostat), and Fenofibric Acid (Primary Metabolite of Fenofibrate) [ Time Frame: Day 1: 0 (predose, ≤ 5 minutes prior to dosing), 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 48, 72, and 96 hours postdose; or 72 hours of early termination from the study (if applicable) ]
  Cmax is defined as the maximum observed concentration of drug. The PK of fenofibric acid was evaluated in participants with mild hepatic impairment and matched participants with normal hepatic function (Cohort 4).
• PK Parameter: % AUCexp of Firsocostat, GS-834773 (Primary Metabolite of Firsocostat), and Fenofibric Acid (Primary Metabolite of Fenofibrate) [ Time Frame: Day 1: 0 (predose, ≤ 5 minutes prior to dosing), 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 48, 72, and 96 hours postdose; or 72 hours of early termination from the study (if applicable) ]
  %AUCexp is defined as the percentage of AUC extrapolated between AUClast and AUCinf. The PK of fenofibric acid was evaluated in participants with mild hepatic impairment and matched participants with normal hepatic function (Cohort 4).
• PK Parameter: Tmax of Firsocostat, GS-834773 (Primary Metabolite of Firsocostat), and Fenofibric Acid (Primary Metabolite of Fenofibrate) [ Time Frame: Day 1: 0 (predose, ≤ 5 minutes prior to dosing), 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 48, 72, and 96 hours postdose; or 72 hours of early termination from the study (if applicable) ]
  Tmax is defined as the time (observed time point) of Cmax. The PK of fenofibric acid was evaluated in participants with mild hepatic impairment and matched participants with normal hepatic function (Cohort 4).
• PK Parameter: Clast of Firsocostat, GS-834773 (Primary Metabolite of Firsocostat), and Fenofibric Acid (Primary Metabolite of Fenofibrate) [ Time Frame: Day 1: 0 (predose, ≤ 5 minutes prior to dosing), 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 48, 72, and 96 hours postdose; or 72 hours of early termination from the study (if applicable) ]
  Clast is defined as the last observed quantifiable concentration of drug. The PK of fenofibric acid was evaluated in participants with mild hepatic impairment and matched participants with normal hepatic function (Cohort 4).
• PK Parameter: Tlast of Firsocostat, GS-834773 (Primary Metabolite of Firsocostat), and Fenofibric Acid (Primary Metabolite of Fenofibrate) [ Time Frame: Day 1: 0 (predose, ≤ 5 minutes prior to dosing), 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 48, 72, and 96 hours postdose; or 72 hours of early termination from the study (if applicable) ]
  Tlast is defined as the time (observed time point) of Clast. The PK of fenofibric acid was evaluated in participants with mild hepatic impairment and matched participants with normal hepatic function (Cohort 4).
• PK Parameter: λz of Firsocostat, GS-834773 (Primary Metabolite of Firsocostat), and Fenofibric Acid (Primary Metabolite of Fenofibrate) [ Time Frame: Day 1: 0 (predose, ≤ 5 minutes prior to dosing), 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 48, 72, and 96 hours postdose; or 72 hours of early termination from the study (if applicable) ]
  λz is defined as the terminal elimination rate constant, estimated by linear regression of the terminal elimination phase of the log plasma concentration of drug versus time curve of the drug. The PK of fenofibric acid was evaluated in participants with mild hepatic impairment and matched participants with normal hepatic function (Cohort 4).
• PK Parameter: CL/F of Firsocostat, GS-834773 (Primary Metabolite of Firsocostat), and Fenofibric Acid (Primary Metabolite of Fenofibrate) [ Time Frame: Day 1: 0 (predose, ≤ 5 minutes prior to dosing), 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 48, 72, and 96 hours postdose; or 72 hours of early termination from the study (if applicable) ]
  CL/F is defined as the apparent oral clearance following administration of the drug. The PK of fenofibric acid was evaluated in participants with mild hepatic impairment and matched participants with normal hepatic function (Cohort 4).
• PK Parameter: Vz/F of Firsocostat, GS-834773 (Primary Metabolite of Firsocostat), and Fenofibric Acid (Primary Metabolite of Fenofibrate) [ Time Frame: Day 1: 0 (predose, ≤ 5 minutes prior to dosing), 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 48, 72, and 96 hours postdose; or 72 hours of early termination from the study (if applicable) ]
  Vz/F is defined as the apparent volume of distribution of the drug. The PK of fenofibric acid was evaluated in participants with mild hepatic impairment and matched participants with normal hepatic function (Cohort 4).
• PK Parameter: t1/2 of Firsocostat, GS-834773 (Primary Metabolite of Firsocostat), and Fenofibric Acid (Primary Metabolite of Fenofibrate) [ Time Frame: Day 1: 0 (predose, ≤ 5 minutes prior to dosing), 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 48, 72, and 96 hours postdose; or 72 hours of early termination from the study (if applicable) ]
  t1/2 is defined as the estimate of the terminal elimination half-life of the drug. The PK of fenofibric acid was evaluated in participants with mild hepatic impairment and matched participants with normal hepatic function (Cohort 4).

Original Primary Outcome Measures (submitted: September 1, 2016)

• PK Parameter: AUClast of GS-0976 [ Time Frame: Predose and up to 96 hours postdose ]
  AUClast is defined as the concentration of drug from time zero to the last observable concentration.
• PK Parameter: AUCinf of GS-0976 [ Time Frame: Predose and up to 96 hours postdose ]
  AUCinf is defined as the concentration of drug extrapolated to infinite time.
• PK Parameter: Cmax of GS-0976 [ Time Frame: Predose and up to 96 hours postdose ]
  Cmax is defined as the maximum observed concentration of drug.
• PK Parameter: %AUCexp of GS-0976 [ Time Frame: Predose and up to 96 hours postdose ]
  %AUCexp is defined as the percentage of AUC extrapolated between AUClast and AUCinf.
• PK Parameter: Tmax of GS-0976 [ Time Frame: Predose and up to 96 hours postdose ]
  Tmax is defined as the time (observed time point) of Cmax.
• PK Parameter: Clast of GS-0976 [ Time Frame: Predose and up to 96 hours postdose ]
  Clast is defined as the last observable concentration of drug.
• PK Parameter: Tlast of GS-0976 [ Time Frame: Predose and up to 96 hours postdose ]
  Tlast is defined as the time (observed time point) of Clast.
• PK Parameter: λz of GS-0976 [ Time Frame: Predose and up to 96 hours postdose ]
  Vz is defined as the volume of distribution of the drug after intravenous administration.
• PK Parameter: CL/F of GS-0976 [ Time Frame: Predose and up to 96 hours postdose ]
  CL/F is defined as the apparent oral clearance following administration of the drug.
• PK Parameter: Vz/F of GS-0976 [ Time Frame: Predose and up to 96 hours postdose ]
  Vz/F is defined as the apparent volume of distribution of the drug.
• PK Parameter: t1/2 of GS-0976 [ Time Frame: Predose and up to 96 hours postdose ]
  t1/2 is defined as the estimate of the terminal elimination half-life of the drug.

Current Secondary Outcome Measures (submitted: November 23, 2020)

• Percentage of Participants Experiencing Treatment-Emergent Adverse Events (AEs) [ Time Frame: First dose date plus 30 days ]
  Treatment-emergent adverse events (TEAEs) were defined as 1 or both of the following:

  • Any AEs with an onset date on or after the study drug start date and no later than 30 days after permanent discontinuation of study drug. If the AE onset date is the same as the date of study drug start date then the AE onset time must be on or after the study drug start time. If the AE onset time is missing when the start dates are the same, the AE will be considered treatment emergent.
  • Any AEs leading to premature discontinuation of study drug.
• Percentage of Participants Experiencing Laboratory Abnormalities [ Time Frame: First dose date plus 30 days ]
  Treatment-emergent laboratory abnormalities are defined as values that increase at least 1 toxicity grade from predose at any postdose visit, up to and including the date of last dose of study drug plus 30 days for subjects who permanently discontinued study drug. The most severe graded abnormality from all tests was counted for each participant.

Original Secondary Outcome Measures (submitted: September 1, 2016)

• Incidence of adverse events [ Time Frame: Up to 31 days ]
• Incidence of laboratory abnormalities [ Time Frame: Up to 31 days ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Study to Evaluate the Pharmacokinetics of Firsocostat or Fenofibrate in Adults With Normal and Impaired Hepatic Function
• Official Title: A Phase 1 Open-Label, Parallel-Group, Single-Dose Study to Evaluate the Pharmacokinetics of GS-0976 or Fenofibrate in Subjects With Normal and Impaired Hepatic Function
• Brief Summary: The primary objectives of this study are to evaluate the single-dose pharmacokinetics (PK) of firsocostat in adults with normal hepatic function, and mild, moderate, or severe hepatic impairment and to evaluate the single-dose PK of fenofibrate in adults with normal hepatic function and mild hepatic impairment.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 1
• Study Design: Allocation: Non-Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Nonalcoholic Steatohepatitis (NASH)

Intervention

• Drug: Firsocostat
  Capsule(s) administered orally on Day 1
  Other Name: GS-0976
• Drug: Fenofibrate
  Tablet administered orally on Day 1

Study Arms

• Experimental: Cohort 1 (Mild Hepatic Impairment): Firsocostat 20 mg
  Participants with mild hepatic impairment will receive a single dose of firsocostat 20 mg (2 × 10 mg capsules).
  Intervention: Drug: Firsocostat
• Experimental: Cohort 1 (Normal Hepatic Function): Firsocostat 20 mg
  Matched normal hepatic function participants to mild hepatic impairment participants will receive a single dose of firsocostat 20 mg (2 × 10 mg capsules).
  Intervention: Drug: Firsocostat
• Experimental: Cohort 2 (Moderate Hepatic Impairment): Firsocostat 20 mg
  Participants with moderate hepatic impairment will receive a single dose of firsocostat 20 mg (2 × 10 mg capsules).
  Intervention: Drug: Firsocostat
• Experimental: Cohort 2 (Normal Hepatic Function): Firsocostat 20 mg
  Matched normal hepatic function participants to moderate hepatic impairment participants will receive a single dose of firsocostat 20 mg (2 × 10 mg capsules).
  Intervention: Drug: Firsocostat
• Experimental: Cohort 3 (Severe Hepatic Impairment): Firsocostat 5 mg
  Participants with severe hepatic impairment will receive a single dose of firsocostat 5 mg (1 × 5 mg capsule).
  Intervention: Drug: Firsocostat
• Experimental: Cohort 3 (Normal Hepatic Function) Firsocostat 5 mg
  Matched normal hepatic function participants to severe hepatic impairment participants will receive a single dose of firsocostat 5 mg (1 × 5 mg capsule).
  Intervention: Drug: Firsocostat
• Experimental: Cohort 4 (Mild Hepatic Impairment): Fenofibrate 48 mg
  Participants with mild hepatic impairment will receive a single dose of fenofibrate 48 mg (1 × 48 mg tablet).
  Intervention: Drug: Fenofibrate
• Experimental: Cohort 4 (Normal Hepatic Function) Fenofibrate 48 mg
  Matched normal hepatic function participants to mild hepatic impairment participants, will receive a single dose of fenofibrate 48 mg (1 × 48 mg tablet).
  Intervention: Drug: Fenofibrate

• Publications *: Nelson C, Weber E, Yue MS, Millward V, Qin AR, Marbury TC, et al. The Pharmacokinetics of GS-0976, an Acetyl-CoA Carboxylase (ACC) Inhibitor, in Subjects with Mild, Moderate, and Severe Hepatic Impairment [Abstract 1719]. Hepatology AASLD Abstracts 2018;68 (Suppl 1):979A-80A.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: May 16, 2019): 74
• Original Estimated Enrollment (submitted: September 1, 2016): 60
• Actual Study Completion Date: May 13, 2019
• Actual Primary Completion Date: May 5, 2019 (Final data collection date for primary outcome measure)

Eligibility Criteria

Key Inclusion Criteria:

Cohort 1 (Mild Hepatic Impairment):

• Male and non-pregnant/non-lactating females with mildly impaired and normal hepatic function.
• Individuals will be current non-smokers (no use of tobacco, nicotine-containing or tetrahydrocannabinol (THC)-containing products within the last 14 days).
• Each individual in the control group will be matched for age (± 10 years), gender, race, and body mass index (± 15% 18 ≤ body mass index (BMI) ≤ 36 kg/m^2) with an individual in the mild hepatic impairment group.
• Individuals with mild hepatic impairment must have a score of 5-6 on the Child-Pugh-Turcotte (CPT) Classification at screening, have diagnosis of chronic (> 6 months), and stable hepatic impairment with no clinically significant changes within 3 months (or 90 days) prior to study drug administration (Day 1).

Cohort 2 (Moderate Hepatic Impairment):

• Male and non-pregnant/non-lactating females with moderately impaired and normal hepatic function.
• Individuals will be current non-smokers (no smoking of tobacco, nicotine-containing or THC-containing products within the last 14 days).
• Each individual in the control group will be matched for age (± 10 years), gender, race, and body mass index (± 15% 18 ≤ BMI ≤ 36 kg/m^2) with an individual in the moderate hepatic impairment group.
• Individuals with moderate hepatic impairment must have a score of 7-9 on the CPT Classification at screening, have diagnosis of chronic (> 6 months), and stable hepatic impairment with no clinically significant changes within 3 months (or 90 days) prior to study drug administration (Day 1).

Cohort 3 (Severe Hepatic Impairment):

• Male and nonpregnant/non-lactating females with severely impaired and normal hepatic function.
• Individuals will be current non-smokers (no use of tobacco, nicotine-containing or THC-containing products within the last 14 days).
• Each individual in the control group will be matched for age (± 10 years), gender, race, and body mass index (± 15% 18 ≤ BMI ≤ 36 kg/m^2) with an individual in the severe hepatic impairment group.
• Individuals with severe hepatic impairment must have a score of 10-15 on the CPT Classification at screening, have diagnosis of chronic (> 6 months), and stable hepatic impairment with no clinically significant changes within 3 months (or 90 days) prior to study drug administration (Day 1).

Cohort 4 (Mild Hepatic Impairment):

• Male and non-pregnant/non-lactating females with mildly impaired and normal hepatic function.
• Individuals will be current non-smokers (no use of tobacco, nicotine-containing or THC-containing products within the last 14 days).
• Each individual in the control group will be matched for age (± 10 years), gender, race, and body mass index (± 15% 18 ≤ body mass index (BMI) ≤ 36 kg/m^2) with an individual in the mild hepatic impairment group.
• Individuals with mild hepatic impairment must have a score of 5-6 on the Child-Pugh-Turcotte (CPT) Classification at screening, have diagnosis of chronic (> 6 months), and stable hepatic impairment with no clinically significant changes within 3 months (or 90 days) prior to study drug administration (Day 1).

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 70 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT02891408
• Other Study ID Numbers: GS-US-426-3988
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Gilead Sciences
• Original Responsible Party: Same as current
• Current Study Sponsor: Gilead Sciences
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Gilead Study Director; Gilead Sciences

• PRS Account: Gilead Sciences
• Verification Date: November 2020