Back to resultsStudy in Healthy Volunteers to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of GS-9674 (Cilofexor), and the Effect of Food on GS-9674 Pharmacokinetics and Pharmacodynamics
Primary Purpose
Nonalcoholic Steatohepatitis (NASH)
Status
Completed
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Cilofexor
Placebo
Sponsored by
About this trial
This is an interventional treatment trial for Nonalcoholic Steatohepatitis (NASH)
Eligibility Criteria
Key Inclusion Criteria:
- Healthy male and non-pregnant, non-lactating female volunteers
- Body mass index (BMI) 19 ≤ BMI ≤ 30 kg/m^2
- Normal 12-lead electrocardiogram (ECG) or one with abnormalities that are considered clinically insignificant by the investigator
- Normal renal function (estimated glomerular filtration rate calculated using the Cockcroft-Gault equation ≥ 80 mL/min)
- No significant medical history, and in good general health as determined by the investigator at screening evaluation performed no more than 28 days prior to the scheduled first dose.
Note: Other protocol defined Inclusion/Exclusion criteria may apply.
Sites / Locations
- SeaView Research, Inc
Arms of the Study
Arm 1
Arm 2
Arm 3
Arm 4
Arm 5
Arm 6
Arm 7
Arm 8
Arm 9
Arm 10
Arm Type
Experimental
Experimental
Experimental
Experimental
Experimental
Experimental
Experimental
Experimental
Experimental
Experimental
Arm Label
Cohort 1: Cilofexor 10 mg
Cohort 2: Cilofexor 30 mg
Cohort 3: Cilofexor 100 mg
Cohort 4: Cilofexor 300 mg
Cohort 5: Cilofexor 100 mg
Cohort 6: Cilofexor 50 mg
Cohort 7: Cilofexor 15 mg
Cohort 8: Cilofexor 10 mg
Cohort 9: Cilofexor
Cohort 10: Cilofexor
Arm Description
Participants in fasted state will receive cilofexor 10 mg or placebo once on Day 1 followed by a 5-day washout period then receive cilofexor 10 mg or placebo once daily from Day 7 to Day 20.
Participants in fasted state will receive cilofexor 30 mg or placebo once on Day 1 followed by a 5-day washout period then receive cilofexor 30 mg or placebo once daily from Day 7 to Day 20.
Participants in fasted state will receive cilofexor 100 mg or placebo once on Day 1 followed by a 5-day washout period then receive cilofexor 100 mg or placebo once daily from Day 7 to Day 20.
Participants in fasted state will receive cilofexor 300 mg or placebo once on Day 1 followed by a 5-day washout period then receive cilofexor 300 mg or placebo once daily from Day 7 to Day 20.
Participants in fed state will receive cilofexor 100 mg or placebo once with food on Day 1 followed by a 5-day washout period then receive cilofexor 100 mg or placebo tablet, orally, once daily with food from Day 7 to Day 20.
Participants in fed state will receive cilofexor 50 mg or placebo twice with food on Day 1 followed by a 5-day washout period then receive cilofexor 50 mg or placebo twice daily from Day 7 to Day 20.
Participants in fed state will receive cilofexor 15 mg or placebo twice with food on Day 1 followed by a 5-day washout period then receive cilofexor 15 mg or placebo twice daily from Day 7 to Day 20.
Participants in fed state will receive cilofexor 10 mg or placebo once with food on Day 1 followed by a 5-day washout period then receive cilofexor 10 mg or placebo once daily from Day 7 to Day 20.
Participants will receive cilofexor up to 300 mg or placebo once daily in the evening on empty stomach.
Participants will receive cilofexor up to 300 mg or placebo once daily in the evening on empty stomach.
Outcomes
Primary Outcome Measures
Single-Dose Pharmacokinetic (PK) Parameter: AUClast of Cilofexor
AUClast is defined as the concentration of drug from time zero to the last quantifiable concentration.
Single-Dose PK Parameter: AUCinf of Cilofexor
AUCinf is defined as the concentration of drug extrapolated to infinite time (area under the plasma concentration versus time curve extrapolated to infinite time).
Single-Dose PK Parameter: Cmax of Cilofexor
Cmax is defined as the maximum observed concentration of drug in plasma.
Multiple-Dose PK Parameter: AUCtau of Cilofexor
AUCtau is the concentration of drug over time (area under the plasma concentration versus time curve over the dosing interval).
Multiple-Dose PK Parameter: Cmax of Cilofexor
Cmax is defined as the maximum observed concentration of drug in plasma.
Multiple-Dose PK Parameter: Ctau of Cilofexor
Ctau is defined as the observed drug concentration at the end of the dosing interval.
Percentage of Participants With at Least One Adverse Event (AE)
An AE is any untoward medical occurrence in a clinical study participant administered a medicinal product, which does not necessarily have a causal relationship with the treatment. An AE can therefore be any unfavorable and/or unintended sign, symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product.
Percentage of Participants With Clinically Significant 12-Lead Electrocardiogram (ECG) Abnormalities
Investigator determined the ECG findings were clinically significant.
Percentage of Participants With Clinical Laboratory Abnormalities
Treatment-emergent laboratory (Hematology, Chemistry, and Urinalysis) abnormalities were defined as values that increase at least one toxicity grade from baseline. Laboratory Abnormalities are graded by the investigator as Grade 1, 2, 3, or 4 according to the modified Gilead Sciences, Inc (GSI) Grading Scale. The most severe graded abnormality from all tests was counted for each participant. Data is only reported for those Grades reported in 1 or more participants.
Secondary Outcome Measures
Pharmacodynamic (PD) Parameter: Fibroblast Growth Factor 19 (FGF19) AUC2-12 Ratio
AUC2-12 is defined as the AUC from time 2 to 12 hours. The ratios calculated were normalized to Day -1. Participants received a single placebo tablet at Day -1 for Baseline. The ratio reported for Day 1 is the AUC2-12 Day 1 /AUC2-12 Day-1. The ratio reported for Day 20 is the AUC2-12 Day 20 /AUC2-12 Day-1.
PD Parameter: FGF19 Cmax Ratio
Cmax is defined as the maximum observed concentration of FGF19 in plasma. The ratios calculated were normalized to Day -1. Participants received a single placebo tablet at Day -1 for Baseline. The ratio reported for Day 1 is the Cmax Day 1 /Cmax Day-1. The ratio reported for Day 20 is the Cmax Day 20 /Cmax Day-1.
PD Parameter: 7alpha-hydroxy-4-cholesten-3-one (C4) AUC2-12 Ratio
AUC2-12 is defined as the AUC from time 2 to 12 hours. The ratios calculated were normalized to Day -1. Participants received a single placebo tablet at Day -1 for Baseline. The ratio reported for Day 1 is the AUC2-12 Day 1 /AUC2-12 Day-1. The ratio reported for Day 20 is the AUC2-12 Day 20 /AUC2-12 Day-1.
PD Parameter: C4 Cmin Ratio
Cmin is defined as the minimum observed concentration of C4 in plasma. The ratios calculated were normalized to Day -1. Participants received a single placebo tablet at Day -1 for Baseline. The ratio reported for Day 1 is the Cmin Day 1 /Cmin Day-1. The ratio reported for Day 20 is the Cmin Day 20 /Cmin Day-1.
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT02654002
Brief Title
Study in Healthy Volunteers to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of GS-9674 (Cilofexor), and the Effect of Food on GS-9674 Pharmacokinetics and Pharmacodynamics
Official Title
A Phase 1 Study in Healthy Volunteers to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of GS-9674, and the Effect of Food on GS-9674 Pharmacokinetics and Pharmacodynamics
Study Type
Interventional
2. Study Status
Record Verification Date
September 2020
Overall Recruitment Status
Completed
Study Start Date
January 20, 2016 (Actual)
Primary Completion Date
July 14, 2016 (Actual)
Study Completion Date
July 14, 2016 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Gilead Sciences
4. Oversight
Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No
5. Study Description
Brief Summary
This study will evaluate the safety and tolerability of escalating single- and multiple-oral doses of cilofexor, and characterize the single- and multiple-dose pharmacokinetics (PK) of cilofexor. The study will be conducted in 3 parts (Part A, Part B, and Part C). Participants will receive either cilofexor or cilofexor placebo.
Part A will proceed in 4 prespecified staggered cohorts. Within each cohort, the cumulative, blinded safety data will be evaluated for dose escalation from single-dose (Period 1) to multiple-dose (Period 2). Based on the available safety, pharmacokinetics, and/or pharmacodynamics (PD) data from cohorts in Part A and Part C (if applicable), total daily doses and frequency of dosing will be chosen for the cohorts in Part B. Parts B and C will consist of adaptive cohorts and may be initiated in parallel. Part B cohorts may be initiated in parallel with cohorts in Part A if the total dose under evaluation is at or below a dose already evaluated.
This study is partially blinded (no one is blinded on Day -1).
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Nonalcoholic Steatohepatitis (NASH)
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Parallel Assignment
Masking
ParticipantInvestigator
Allocation
Randomized
Enrollment
120 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Cohort 1: Cilofexor 10 mg
Arm Type
Experimental
Arm Description
Participants in fasted state will receive cilofexor 10 mg or placebo once on Day 1 followed by a 5-day washout period then receive cilofexor 10 mg or placebo once daily from Day 7 to Day 20.
Arm Title
Cohort 2: Cilofexor 30 mg
Arm Type
Experimental
Arm Description
Participants in fasted state will receive cilofexor 30 mg or placebo once on Day 1 followed by a 5-day washout period then receive cilofexor 30 mg or placebo once daily from Day 7 to Day 20.
Arm Title
Cohort 3: Cilofexor 100 mg
Arm Type
Experimental
Arm Description
Participants in fasted state will receive cilofexor 100 mg or placebo once on Day 1 followed by a 5-day washout period then receive cilofexor 100 mg or placebo once daily from Day 7 to Day 20.
Arm Title
Cohort 4: Cilofexor 300 mg
Arm Type
Experimental
Arm Description
Participants in fasted state will receive cilofexor 300 mg or placebo once on Day 1 followed by a 5-day washout period then receive cilofexor 300 mg or placebo once daily from Day 7 to Day 20.
Arm Title
Cohort 5: Cilofexor 100 mg
Arm Type
Experimental
Arm Description
Participants in fed state will receive cilofexor 100 mg or placebo once with food on Day 1 followed by a 5-day washout period then receive cilofexor 100 mg or placebo tablet, orally, once daily with food from Day 7 to Day 20.
Arm Title
Cohort 6: Cilofexor 50 mg
Arm Type
Experimental
Arm Description
Participants in fed state will receive cilofexor 50 mg or placebo twice with food on Day 1 followed by a 5-day washout period then receive cilofexor 50 mg or placebo twice daily from Day 7 to Day 20.
Arm Title
Cohort 7: Cilofexor 15 mg
Arm Type
Experimental
Arm Description
Participants in fed state will receive cilofexor 15 mg or placebo twice with food on Day 1 followed by a 5-day washout period then receive cilofexor 15 mg or placebo twice daily from Day 7 to Day 20.
Arm Title
Cohort 8: Cilofexor 10 mg
Arm Type
Experimental
Arm Description
Participants in fed state will receive cilofexor 10 mg or placebo once with food on Day 1 followed by a 5-day washout period then receive cilofexor 10 mg or placebo once daily from Day 7 to Day 20.
Arm Title
Cohort 9: Cilofexor
Arm Type
Experimental
Arm Description
Participants will receive cilofexor up to 300 mg or placebo once daily in the evening on empty stomach.
Arm Title
Cohort 10: Cilofexor
Arm Type
Experimental
Arm Description
Participants will receive cilofexor up to 300 mg or placebo once daily in the evening on empty stomach.
Intervention Type
Drug
Intervention Name(s)
Cilofexor
Other Intervention Name(s)
GS-9674
Intervention Description
Tablets administered orally
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
Tablets administered orally
Primary Outcome Measure Information:
Title
Single-Dose Pharmacokinetic (PK) Parameter: AUClast of Cilofexor
Description
AUClast is defined as the concentration of drug from time zero to the last quantifiable concentration.
Time Frame
Day 1: -0.5, 0 (pre-dose), 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 16, 24, 48, 72, and 96 hours post-dose
Title
Single-Dose PK Parameter: AUCinf of Cilofexor
Description
AUCinf is defined as the concentration of drug extrapolated to infinite time (area under the plasma concentration versus time curve extrapolated to infinite time).
Time Frame
Day 1: -0.5, 0 (pre-dose), 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 16, 24, 48, 72, and 96 hours post-dose
Title
Single-Dose PK Parameter: Cmax of Cilofexor
Description
Cmax is defined as the maximum observed concentration of drug in plasma.
Time Frame
Day 1: -0.5, 0 (pre-dose), 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 16, 24, 48, 72, and 96 hours post-dose
Title
Multiple-Dose PK Parameter: AUCtau of Cilofexor
Description
AUCtau is the concentration of drug over time (area under the plasma concentration versus time curve over the dosing interval).
Time Frame
Day 20: -0.5, 0 (pre-dose), 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 16, 24, 48, 72, and 96 hours post-dose
Title
Multiple-Dose PK Parameter: Cmax of Cilofexor
Description
Cmax is defined as the maximum observed concentration of drug in plasma.
Time Frame
Day 20: -0.5, 0 (pre-dose), 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 16, 24, 48, 72, and 96 hours post-dose
Title
Multiple-Dose PK Parameter: Ctau of Cilofexor
Description
Ctau is defined as the observed drug concentration at the end of the dosing interval.
Time Frame
Day 20: -0.5, 0 (pre-dose), 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 16, 24, 48, 72, and 96 hours post-dose
Title
Percentage of Participants With at Least One Adverse Event (AE)
Description
An AE is any untoward medical occurrence in a clinical study participant administered a medicinal product, which does not necessarily have a causal relationship with the treatment. An AE can therefore be any unfavorable and/or unintended sign, symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product.
Time Frame
First dose date up to last dose date (Maximum: 20 days) plus 30 days
Title
Percentage of Participants With Clinically Significant 12-Lead Electrocardiogram (ECG) Abnormalities
Description
Investigator determined the ECG findings were clinically significant.
Time Frame
First dose date up to last dose date (Maximum: 20 days) plus 30 days
Title
Percentage of Participants With Clinical Laboratory Abnormalities
Description
Treatment-emergent laboratory (Hematology, Chemistry, and Urinalysis) abnormalities were defined as values that increase at least one toxicity grade from baseline. Laboratory Abnormalities are graded by the investigator as Grade 1, 2, 3, or 4 according to the modified Gilead Sciences, Inc (GSI) Grading Scale. The most severe graded abnormality from all tests was counted for each participant. Data is only reported for those Grades reported in 1 or more participants.
Time Frame
First dose date up to last dose date (Maximum: 20 days) plus 30 days
Secondary Outcome Measure Information:
Title
Pharmacodynamic (PD) Parameter: Fibroblast Growth Factor 19 (FGF19) AUC2-12 Ratio
Description
AUC2-12 is defined as the AUC from time 2 to 12 hours. The ratios calculated were normalized to Day -1. Participants received a single placebo tablet at Day -1 for Baseline. The ratio reported for Day 1 is the AUC2-12 Day 1 /AUC2-12 Day-1. The ratio reported for Day 20 is the AUC2-12 Day 20 /AUC2-12 Day-1.
Time Frame
Day -1: -0.5, 0 (pre-dose), 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 10, 12, and 16 hours post-dose; Days 1, and 20: -0.5, 0 (pre-dose), 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 16, 24, 48, 72, and 96 hours post-dose
Title
PD Parameter: FGF19 Cmax Ratio
Description
Cmax is defined as the maximum observed concentration of FGF19 in plasma. The ratios calculated were normalized to Day -1. Participants received a single placebo tablet at Day -1 for Baseline. The ratio reported for Day 1 is the Cmax Day 1 /Cmax Day-1. The ratio reported for Day 20 is the Cmax Day 20 /Cmax Day-1.
Time Frame
Day -1: -0.5, 0 (pre-dose), 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 10, 12, and 16 hours post-dose; Days 1, and 20: -0.5, 0 (pre-dose), 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 16, 24, 48, 72, and 96 hours post-dose
Title
PD Parameter: 7alpha-hydroxy-4-cholesten-3-one (C4) AUC2-12 Ratio
Description
AUC2-12 is defined as the AUC from time 2 to 12 hours. The ratios calculated were normalized to Day -1. Participants received a single placebo tablet at Day -1 for Baseline. The ratio reported for Day 1 is the AUC2-12 Day 1 /AUC2-12 Day-1. The ratio reported for Day 20 is the AUC2-12 Day 20 /AUC2-12 Day-1.
Time Frame
Day -1: -0.5, 0 (pre-dose), 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 10, 12, and 16 hours post-dose; Days 1, and 20: -0.5, 0 (pre-dose), 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 16, 24, 48, 72, and 96 hours post-dose
Title
PD Parameter: C4 Cmin Ratio
Description
Cmin is defined as the minimum observed concentration of C4 in plasma. The ratios calculated were normalized to Day -1. Participants received a single placebo tablet at Day -1 for Baseline. The ratio reported for Day 1 is the Cmin Day 1 /Cmin Day-1. The ratio reported for Day 20 is the Cmin Day 20 /Cmin Day-1.
Time Frame
Day -1: -0.5, 0 (pre-dose), 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 10, 12, and 16 hours post-dose; Days 1, and 20: -0.5, 0 (pre-dose), 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 16, 24, 48, 72, and 96 hours post-dose
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
45 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
Key Inclusion Criteria:
Healthy male and non-pregnant, non-lactating female volunteers
Body mass index (BMI) 19 ≤ BMI ≤ 30 kg/m^2
Normal 12-lead electrocardiogram (ECG) or one with abnormalities that are considered clinically insignificant by the investigator
Normal renal function (estimated glomerular filtration rate calculated using the Cockcroft-Gault equation ≥ 80 mL/min)
No significant medical history, and in good general health as determined by the investigator at screening evaluation performed no more than 28 days prior to the scheduled first dose.
Note: Other protocol defined Inclusion/Exclusion criteria may apply.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Gilead Study Director
Organizational Affiliation
Gilead Sciences
Official's Role
Study Director
Facility Information:
Facility Name
SeaView Research, Inc
City
Miami
State/Province
Florida
Country
United States
12. IPD Sharing Statement
Citations:
Citation
Djedjos CS, Kirby BJ, Billin A, Gosink J, Song Q, Srihari R, et al. Pharmacodynamic Effects of the Oral, Non-Steroidal Farnesoid X Receptor Agonist GS-9674 in Healthy Volunteers. The 67th Annual Meeting of the American Association for the Study of Liver Diseases: The Liver Meeting (AASLD); 2016 November 11-15; Boston MA United States.
Results Reference
background
Citation
Kirby BJ, Djedjos CS, Birkeback J, Song Q, Grycz K, Weston J, et al. Evaluation of the Safety and Pharmacokinetics of the Oral, Nonsteroidal Farnesoid X Receptor Agonist GS-9674 in Healthy Volunteers. The 67th Annual Meeting of the American Association for the Study of Liver Diseases: The Liver Meeting (AASLD); 2016 November 11-15; Boston MA United States.
Results Reference
background
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Study in Healthy Volunteers to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of GS-9674 (Cilofexor), and the Effect of Food on GS-9674 Pharmacokinetics and Pharmacodynamics
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