A Two-part Phase I Study Composed of a Randomized, Double-blind, 4-parallel Group Study to Evaluate the Effect of Multiple Oral Doses of GFT505 on the QT/QTc Interval Compared to Placebo With Moxifloxacin (400 mg in Single Oral Dose) as a Positive Control, in Healthy Male and Female Volunteers, Preceded by a Double-blind, Placebo-controlled, Safety, Tolerability and Pharmacokinetic Study in Healthy Male Volunteers in Order to Define the Supra-therapeutic GFT505 Dose in a Multiple Dosing Regimen.
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 发起方
- Genfit
- 入组人数
- 200
- 试验地点
- 1
- 主要终点
- Effect on QTcF compared to placebo (Study Part II)
研究概览
简要总结
In accordance with International Conference on Harmonisation (ICH) E14 guidelines, this Phase I thorough QT (TQT) study will assess the arrhythmogenic potential of GFT505, by evaluating its effect on QT/QTc prolongation in healthy male and female subjects. According to the guidelines, such studies should typically be performed at the expected therapeutic dose and a supra-therapeutic dose that is 3-4-fold higher than the therapeutic dose.
GFT505 has previously been tested at 240 mg/d in 14-day multiple administration to healthy overweight subjects (study GFT505-111-7), and both safety and tolerability were very good. However, this dose corresponds to only 2-fold the expected therapeutic dose of 120 mg/d. Therefore, the current TQT study will be preceded by a multiple ascending dose study in which the safety and tolerability of 2 dose levels of GFT505 (300 and 360 mg) corresponding to 2.5 and 3 times the expected therapeutic dose will be evaluated. The highest dose level for which safety and tolerability are considered satisfactory will be the supra-therapeutic dose used in the TQT study.
详细描述
The present trial is split into two successive parts:
- Study Part I is a double-blind, randomized, placebo-controlled study designed to obtain safety, tolerability and pharmacokinetic (PK) data after 14-day multiple oral administrations of once-daily increasing doses of GFT505 (300 and 360 mg) in healthy male subjects. The starting dose of 300 mg/day has been selected on the basis of the results of previous clinical trials and corresponds to the highest dose given in healthy subjects according to a single dose regimen (study GFT505-111-7). A total of 24 male subjects will be included, 12 for each cohort (a cohort corresponding to a dose level). In each cohort, 9 subjects will receive GFT505 and 3 will receive placebo. A Safety Review Committee (SRC) will have a formal meeting after full completion of at least 10 out of 12 subjects of each dose level to review under blinded conditions all safety data and to conclude on the safety and tolerability of a given dose level. Between the first and the second dose level, the SRC will give its agreement on the dose escalation, and at completion of the second level the SRC will define the supra-therapeutic dose to be administered in Study Part II.
- Study Part II will be a parallel group, randomized, placebo-controlled study, with stratification by gender. The study is designed to investigate the potential impact of 14-day multiple oral administrations of once-daily GFT505 on QT/QTc prolongation under conditions of maximal GFT505 exposure, i.e. by administering the expected therapeutic dose of 120 mg/d and a supra-therapeutic dose (defined according to the results of Study Part I), to healthy male and female subjects. A single oral dose of 400 mg moxifloxacin will be used as a positive control in order to document the sensitivity of the experimental conditions. The study treatment administration will be double-blind for placebo and GFT505 and open for moxifloxacin. The ECG readings will be performed under blinded conditions. A preliminary sample size of 128 subjects to have at least 124 evaluable subjects has been fixed by formal justification on a theoretical basis. ECG data collected during Study Part I will support a formal determination using observed data and thus will lead to a final sample size. In all cases, it is anticipated that the sample size could not be less than 124 evaluable subjects. Each gender will represent at least 40% of the study population. Both sub-groups will be balanced between the 4 treatment groups.
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
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
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 males aged 18 to 45 years inclusive
- •Body Mass Index (BMI) ≥ 18 ≤ 30 kg/m²
- •No clinically relevant abnormalities in blood pressure (BP) or heart rate (HR)
- •No clinically relevant abnormalities in 12-lead ECG results
- •Healthy males and females aged 18 to 45 years inclusive
- •For female subjects of childbearing potential, use of double contraception method
- •Body Mass Index (BMI) ≥ 18 ≤ 30 kg/m²
- •No clinically relevant abnormalities in blood pressure (BP) or heart rate (HR)
- •No clinically relevant abnormalities in 12-lead ECG results
排除标准
- •Evidence of clinically relevant cardiovascular, renal, hepatic, hematological, gastrointestinal, pulmonary, metabolic-endocrine, neurological, urogenital or psychiatric diseases
- •A history of risk factors for "Torsades de Pointe" (e.g., heart failure, hypokalemia, family history of Long QT Syndrome)
- •Any condition requiring regular concomitant medication, including herbal products and over-the-counter (OTC) medication or predicted need of any concomitant medication during the study
- •Current drug or alcohol abuse [including regular alcohol drinking of more than 21 units per week (1 unit = 4 cL spirits or equivalent)] or a history of drug or alcohol abuse within 1 year before screening
- •Current use of nicotine containing products, i.e., more than 5 cigarettes or equivalent/day and the inability to stop using nicotine containing products during confinement in the clinical center
- •Use of caffeine containing beverages exceeding 500 mg caffeine/day (5 cups of coffee) and the inability to refrain from the use of caffeine containing beverages during confinement in the clinical center
- •Blood donation or loss of significant amount of blood within 2 months prior to the first dosing
- •Any other condition that in the opinion of the Investigator would interfere with the evaluation of the results or constitute a health risk for the subject.
- •Evidence of clinically relevant cardiovascular, renal, hepatic, hematological, gastrointestinal, pulmonary, metabolic-endocrine, neurological, urogenital or psychiatric diseases
- •A history of risk factors for "Torsades de Pointe" (e.g., heart failure, hypokalemia, family history of Long QT Syndrome)
- •The use of concomitant medications that prolong the QT/QTc interval
- •Any condition requiring regular concomitant medication, including herbal products and over-the-counter (OTC) medication or predicted need of any concomitant medication during the study
- •Current drug or alcohol abuse [including regular alcohol drinking of more than 21 units (for male) or 14 units (for female) (1 unit = 4 cL spirits or equivalent)] or a history of drug or alcohol abuse within 1 year before screening
- •Current use of nicotine containing products, i.e., more than 5 cigarettes or equivalent/day and the inability to stop using nicotine containing products during confinement in the clinical center
- •Use of caffeine containing beverages exceeding 500 mg caffeine/day (5 cups of coffee) and the inability to refrain from the use of caffeine containing beverages during confinement in the clinical center
- •Blood donation or loss of significant amount of blood within 2 months prior to the first dosing
- •For women: Positive pregnancy test at screening or on Day -2; Pregnancy or trying to become pregnant; Breastfeeding
- •Any other condition that in the opinion of the Investigator would interfere with the evaluation of the results or constitute a health risk for the subject.
研究组 & 干预措施
Placebo (Study Part I)
Hard gelatin capsules, oral administration, 5 or 6 capsules per day before breakfast with a glass of water
干预措施: Placebo (Drug)
GFT505 300 mg (Study Part I)
Hard gelatin capsules dosed at 60mg, oral administration, 5 capsules per day before breakfast with a glass of water
干预措施: GFT505 (Drug)
GFT505 360 mg (Study Part I)
Hard gelatin capsules dosed at 60mg, oral administration, 6 capsules per day before breakfast with a glass of water
干预措施: GFT505 (Drug)
Placebo (Study Part II)
Hard gelatin capsules, oral administration, 4 to 6 capsules per day before breakfast with a glass of water
干预措施: Placebo (Drug)
GFT505 120 mg (Study Part II)
Hard gelatin capsules dosed at 60mg, oral administration, 2 capsules per day plus 2 to 4 capsules of placebo per day before breakfast with a glass of water
干预措施: GFT505 (Drug)
GFT505 xx mg (Study Part II)
Supra-therapeutic dose: hard gelatin capsules dosed at 60mg, oral administration, 4 to 6 capsules per day before breakfast with a glass of water
干预措施: GFT505 (Drug)
Moxifloxacin 400 mg (Study Part II)
On days 1 to 13, 4 to 6 placebo capsules per day, then one 400 mg moxifloxacin tablet (Izilox®, Bayer Pharmaceuticals Corporation) administered orally on Day 14
干预措施: Moxifloxacin 400 mg (Drug)
结局指标
主要结局
Effect on QTcF compared to placebo (Study Part II)
时间窗: 14 days
To evaluate the impact on QTcF of two dose levels (one therapeutic and one supra-therapeutic according to ICH E14) of GFT505, after multiple dose administration once daily for 14 days in healthy male and female subjects compared to placebo and a positive control.
Safety parameters such as adverse event monitoring, vital signs, ECG, and clinical laboratory tests (Study Part I)
时间窗: 14 days
To evaluate the safety and tolerability of two dose levels of GFT505 (300 and 360 mg), after multiple dose administration once daily for 14 days in male healthy subjects in order to determine the supra-therapeutic dose to be administered in Study Part II.
次要结局
- Pharmacokinetic parameters including Cmax, Tmax, AUCt (Study Part I)(14 days)
- Effect on QTcB compared to placebo (Study Part II)(14 days)
- Safety parameters such as adverse event monitoring, vital signs, ECG, and clinical laboratory tests (Study Part II)(14 days)