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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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ClinicalTrials.gov Identifier: NCT02654002
Recruitment Status : Completed
First Posted : January 13, 2016
Results First Posted : October 12, 2020
Last Update Posted : October 12, 2020
Sponsor:
Information provided by (Responsible Party):
Gilead Sciences

Tracking Information
First Submitted Date  ICMJE January 11, 2016
First Posted Date  ICMJE January 13, 2016
Results First Submitted Date  ICMJE September 16, 2020
Results First Posted Date  ICMJE October 12, 2020
Last Update Posted Date October 12, 2020
Actual Study Start Date  ICMJE January 20, 2016
Actual Primary Completion Date July 14, 2016   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: September 16, 2020)
  • Single-Dose Pharmacokinetic (PK) Parameter: AUClast of Cilofexor [ 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 ]
    AUClast is defined as the concentration of drug from time zero to the last quantifiable concentration.
  • Single-Dose PK Parameter: AUCinf of Cilofexor [ 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 ]
    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 [ 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 ]
    Cmax is defined as the maximum observed concentration of drug in plasma.
  • Multiple-Dose PK Parameter: AUCtau of Cilofexor [ 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 ]
    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 [ 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 ]
    Cmax is defined as the maximum observed concentration of drug in plasma.
  • Multiple-Dose PK Parameter: Ctau of Cilofexor [ 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 ]
    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) [ Time Frame: First dose date up to last dose date (Maximum: 20 days) plus 30 days ]
    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 [ Time Frame: First dose date up to last dose date (Maximum: 20 days) plus 30 days ]
    Investigator determined the ECG findings were clinically significant.
  • Percentage of Participants With Clinical Laboratory Abnormalities [ Time Frame: First dose date up to last dose date (Maximum: 20 days) plus 30 days ]
    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.
Original Primary Outcome Measures  ICMJE
 (submitted: January 11, 2016)
  • Single-dose PK Parameter: AUClast of GS-9674 [ Time Frame: Predose, 0, 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 postdose ]
    AUClast is defined as the concentration of drug from time zero to the last quantifiable concentration.
  • Single-dose PK Parameter: AUCinf of GS-9674 [ Time Frame: Predose, 0, 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 postdose ]
    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 GS-9674 [ Time Frame: Predose, 0, 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 postdose ]
    Cmax is defined as the maximum observed concentration of drug in plasma.
  • Multiple-dose plasma PK parameter: AUCtau of GS-9674 [ Time Frame: Predose, 0, 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 postdose ]
    AUCtau is the concentration of drug over time (area under the plasma concentration versus time curve over the dosing interval).
  • Multiple-dose plasma PK parameter: Cmax of GS-9674 [ Time Frame: Predose, 0, 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 postdose ]
  • Multiple-dose plasma PK parameter: Ctau of GS-9674 [ Time Frame: Predose, 0, 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 postdose ]
    Ctau is defined as the observed drug concentration at the end of the dosing interval.
  • Incidence of Adverse Events [ Time Frame: Up to 15 days plus 30 days ]
  • Proportion of Participants with 12-lead ECG Abnormalities [ Time Frame: Up to 15 days plus 30 days ]
  • Proportion of Participants with Clinical Laboratory Abnormalities [ Time Frame: Up to 15 days plus 30 days ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: September 16, 2020)
  • Pharmacodynamic (PD) Parameter: Fibroblast Growth Factor 19 (FGF19) AUC2-12 Ratio [ 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 ]
    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 [ 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 ]
    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 [ 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 ]
    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 [ 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 ]
    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.
Original Secondary Outcome Measures  ICMJE
 (submitted: January 11, 2016)
  • Measurement of PD Biomarker Level of Fibroblast Growth Factor 19 (FGF19) [ Time Frame: Predose, 0, 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 10, 12, 16, 24, 48, 72, and 96 hours postdose ]
  • Measurement of PD Biomarker Level of Bile Acids [ Time Frame: Predose, 0, 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 10, 12, 16, 24, 48, 72, and 96 hours postdose ]
  • Measurement of PD Biomarker Level of C4 [ Time Frame: Predose, 0, 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 10, 12, 16, 24, 48, 72, and 96 hours postdose ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE 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  ICMJE 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
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).

Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Condition  ICMJE Nonalcoholic Steatohepatitis (NASH)
Intervention  ICMJE
  • Drug: Cilofexor
    Tablets administered orally
    Other Name: GS-9674
  • Drug: Placebo
    Tablets administered orally
Study Arms  ICMJE
  • Experimental: Cohort 1: Cilofexor 10 mg
    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.
    Interventions:
    • Drug: Cilofexor
    • Drug: Placebo
  • Experimental: Cohort 2: Cilofexor 30 mg
    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.
    Interventions:
    • Drug: Cilofexor
    • Drug: Placebo
  • Experimental: Cohort 3: Cilofexor 100 mg
    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.
    Interventions:
    • Drug: Cilofexor
    • Drug: Placebo
  • Experimental: Cohort 4: Cilofexor 300 mg
    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.
    Interventions:
    • Drug: Cilofexor
    • Drug: Placebo
  • Experimental: Cohort 5: Cilofexor 100 mg
    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.
    Interventions:
    • Drug: Cilofexor
    • Drug: Placebo
  • Experimental: Cohort 6: Cilofexor 50 mg
    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.
    Interventions:
    • Drug: Cilofexor
    • Drug: Placebo
  • Experimental: Cohort 7: Cilofexor 15 mg
    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.
    Interventions:
    • Drug: Cilofexor
    • Drug: Placebo
  • Experimental: Cohort 8: Cilofexor 10 mg
    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.
    Interventions:
    • Drug: Cilofexor
    • Drug: Placebo
  • Experimental: Cohort 9: Cilofexor
    Participants will receive cilofexor up to 300 mg or placebo once daily in the evening on empty stomach.
    Interventions:
    • Drug: Cilofexor
    • Drug: Placebo
  • Experimental: Cohort 10: Cilofexor
    Participants will receive cilofexor up to 300 mg or placebo once daily in the evening on empty stomach.
    Interventions:
    • Drug: Cilofexor
    • Drug: Placebo
Publications *
  • 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.
  • 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.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: January 11, 2016)
120
Original Estimated Enrollment  ICMJE Same as current
Actual Study Completion Date  ICMJE July 14, 2016
Actual Primary Completion Date July 14, 2016   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.

Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 45 Years   (Adult)
Accepts Healthy Volunteers  ICMJE Yes
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02654002
Other Study ID Numbers  ICMJE GS-US-402-1851
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  ICMJE Not Provided
Responsible Party Gilead Sciences
Study Sponsor  ICMJE Gilead Sciences
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Gilead Study Director Gilead Sciences
PRS Account Gilead Sciences
Verification Date September 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP