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
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 120
- 试验地点
- 1
- 主要终点
- Multiple-Dose PK Parameter: AUCtau of Cilofexor
研究概览
简要总结
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).
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Double (Participant, Investigator)
入排标准
- 年龄范围
- 18 Years 至 45 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •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.
排除标准
- 未提供
研究组 & 干预措施
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.
干预措施: Cilofexor (Drug)
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.
干预措施: Placebo (Drug)
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.
干预措施: Cilofexor (Drug)
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.
干预措施: Placebo (Drug)
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.
干预措施: Cilofexor (Drug)
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.
干预措施: Placebo (Drug)
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.
干预措施: Cilofexor (Drug)
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.
干预措施: Placebo (Drug)
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.
干预措施: Cilofexor (Drug)
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.
干预措施: Placebo (Drug)
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.
干预措施: Cilofexor (Drug)
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.
干预措施: Placebo (Drug)
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.
干预措施: Cilofexor (Drug)
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.
干预措施: Placebo (Drug)
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.
干预措施: Cilofexor (Drug)
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.
干预措施: Placebo (Drug)
Cohort 9: Cilofexor
Participants will receive cilofexor up to 300 mg or placebo once daily in the evening on empty stomach.
干预措施: Cilofexor (Drug)
Cohort 9: Cilofexor
Participants will receive cilofexor up to 300 mg or placebo once daily in the evening on empty stomach.
干预措施: Placebo (Drug)
Cohort 10: Cilofexor
Participants will receive cilofexor up to 300 mg or placebo once daily in the evening on empty stomach.
干预措施: Cilofexor (Drug)
Cohort 10: Cilofexor
Participants will receive cilofexor up to 300 mg or placebo once daily in the evening on empty stomach.
干预措施: Placebo (Drug)
结局指标
主要结局
Multiple-Dose PK Parameter: AUCtau of Cilofexor
时间窗: 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: Ctau of Cilofexor
时间窗: 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.
Single-Dose Pharmacokinetic (PK) Parameter: AUClast of Cilofexor
时间窗: 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: Cmax of Cilofexor
时间窗: 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.
Percentage of Participants With at Least One Adverse Event (AE)
时间窗: 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.
Single-Dose PK Parameter: AUCinf of Cilofexor
时间窗: 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).
Percentage of Participants With Clinically Significant 12-Lead Electrocardiogram (ECG) Abnormalities
时间窗: First dose date up to last dose date (Maximum: 20 days) plus 30 days
Investigator determined the ECG findings were clinically significant.
Multiple-Dose PK Parameter: Cmax of Cilofexor
时间窗: 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.
Percentage of Participants With Clinical Laboratory Abnormalities
时间窗: 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.
次要结局
- PD Parameter: 7alpha-hydroxy-4-cholesten-3-one (C4) AUC2-12 Ratio(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)
- PD Parameter: C4 Cmin Ratio(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)
- Pharmacodynamic (PD) Parameter: Fibroblast Growth Factor 19 (FGF19) AUC2-12 Ratio(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)
- PD Parameter: FGF19 Cmax Ratio(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)