Single-blind, Randomised, Placebo-controlled Study to Assess the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Repeat Doses of GSK2647544 and Its Potential Pharmacokinetic Interaction With Simvastatin in Healthy Volunteers
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 入组人数
- 12
- 试验地点
- 1
- 主要终点
- Safety and tolerability of GSK2647544 as assessed by number of subjects with adverse events (AE)s
研究概览
简要总结
GSK2647544 is an orally available, selective inhibitor of Lp PLA2 that is being developed for the treatment of Alzheimer's disease. The current study is a single-blind, randomised, placebo-controlled, 4-cohort study to assess the safety, tolerability, pharmacokinetics and pharmacodynamics of repeat doses of GSK2647544. Cohorts 1, 2 and 3 will evaluate escalating doses of GSK2647544 in young healthy volunteers for 7 days, 7 days, and 14 days, respectively. Cohort 4 will evaluate repeat doses of GSK2647544 in healthy elderly volunteers for 14 days. Additionally, Cohorts 1 and 3 will include an assessment of potential drug-drug interaction with simvastatin to examine CYP3A4 inhibition by GSK2647544.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Crossover
- 主要目的
- Treatment
- 盲法
- Single (Participant)
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •Males and females who are 18 to 64 years of age inclusive, defined as young subjects in this study, are eligible for Cohorts 1-3 only
- •Males and females who are ≥65 years of age, defined as elderly subjects in this study, are eligible for Cohort 4 only
- •Healthy as determined by a responsible and experienced physician
- •A female subject is eligible to participate if she is of non-childbearing potential
- •Male subjects with female partners of child-bearing potential must agree to use one of the contraception methods
- •Body weight > 50 kg (110 pounds) and body mass index (BMI) between 19 and 32
- •Aspartate aminotransferase (AST), Alanine transaminase (ALT), alkaline phosphatase and bilirubin <= 1.5xUpper Limit of Normal (ULN)
- •Average of triplicate QTcB values and average of triplicate QTcF values must both < 450 msec
- •Capable of giving written informed consent
排除标准
- •Subjects with Lp-PLA2 activity <=20 nanomole/minute/milliliter (mL)(for subjects with 2 known birth parents of at least 50% Japanese, Chinese, or Korean ancestry)
- •History of asthma, anaphylaxis or anaphalactoid reactions, severe allergic responses
- •History of hypercoagulable state or history of thrombosis
- •History of biliary tract disease including a history of liver disease with elevated liver function tests of known or unknown etiology
- •Positive Human immunodeficiency virus (HIV), Hepatitis B or Hepatitis C at screening
- •History of regular use of tobacco or nicotine-containing products within 6 months of the study
- •Unable to abstain from alcohol or caffeine or xanthine-containing products for 24 h prior to the start of dosing
- •Unable to refrain from use of prescription or non-prescription drugs and vitamins within 7 days or 5 half-lives (whichever is longer) prior to administration of study
- •Urinary cotinine levels indicative of smoking or history or regular use of tobacco- or nicotine-containing products within 6 months prior to screening (Note: This applies to healthy young subjects screened for Cohorts 1-3 only. Healthy elderly subjects for cohort 4 who are social smokers must give up smoking for the period that they will be on the unit)
- •positive pre-study drug/alcohol screen
- •Unable to refrain from consumption of Seville oranges, grapefruit or grapefruit juice within 7 days prior to the first dose of study medication until the follow-up visit
- •Subjects who have taken statins, medicines that are contraindications of statins, know potent inhibitiors or inducers of CYP3A4 in the 4 weeks or 5 half-lives (whichever is longer) prior to screening and are not able to discontinue use throughout participation in the clinical trial
研究组 & 干预措施
GSK2647544
The planned repeat doses of GSK2647544 are 80 mg bid, 200 mg bid, and 350 mg bid
干预措施: GSK2647544 (Drug)
Placebo
Matching placebo
干预措施: GSK2647544 (Drug)
simvastatin
for drug-drug interaction
干预措施: drug-drug interaction (Drug)
simvastatin co-dosed with GSK2647544
for drug-drug interaction
干预措施: drug-drug interaction (Drug)
结局指标
主要结局
Safety and tolerability of GSK2647544 as assessed by number of subjects with adverse events (AE)s
时间窗: up to 19 days in each dosing session
Safety and tolerability parameters will include recording of AEs
Safety and tolerability of GSK2647544 as assessed by change from Baseline in laboratory values
时间窗: up to 15 days in each dosing session
Safety and tolerability parameters will include laboratory (haematology, clinical chemistry, urinalysis) values at Screening, Day-1, Day 1 to up to Day 15 and Follow-up (7-14 days post-last dose)
Safety and tolerability of GSK2647544 as assessed by change from Baseline in ECG readings
时间窗: up to 19 days in each dosing session
Safety and tolerability parameter will include the electrocardiogram (ECG) readings at Screening, Day -1, Day 1 to up to Day 19, and follow-up (7-14 days post-last dose)
Safety and tolerability of GSK2647544 as assessed by change from Baseline in Telemetry ECG parameters
时间窗: 2 days in Cohorts 1, 2 and 4; 3 days in Cohort 4
Safety and tolerability parameter will include the Telemetry ECG readings from 30 minutes pre-dosing till 24 hours post-dosing
Safety and tolerability of GSK2647544 as assessed by change from Baseline in vital signs
时间窗: up to 19 days in each dosing session
Vital signs measurement include systolic and diastolic blood pressure and pulse rate at Screening, Day -1, Day 1 to up to Day 19, and Follow-up (7-14 days post-last dose)
Peak plasma concentration (Cmax) of GSK2647544
时间窗: up to 17 days in GSK2647544 dosing sessions
To assess PK profile of GSK2647544, Cmax of GSK2647544 will be measured
Time of peak plasma concentration (tmax) of GSK2647544
时间窗: up to 17 days in GSK2647544 dosing sessions
To assess PK profile of GSK2647544, tmax of GSK2647544 will be measured
Area under the time concentration curve (AUC) of GSK2647544
时间窗: up to 17 days in GSK2647544 dosing sessions
To assess PK profile of GSK2647544, AUC of GSK2647544 will be measured
Safety and tolerability of GSK2647544 as assessed by Columbia Suicide Severity Rating Scale (C-SSRS)
时间窗: 4 days in Cohorts 1 and 2; 8 days in Cohorts 3 and 4
C-SSRS will be measured at Screening, Day-1, dispersed days during dosing sessions, prior to discharge, and Follow-up (7-14 days post-last dose)
Terminal half-life (t½ ) of GSK2647544
时间窗: up to 17 days in GSK2647544 dosing sessions
To assess PK profile of GSK2647544, t1/2 of GSK2647544 will be measured
Time of peak plasma concentration (tmax) of simvastatin
时间窗: 4 days in Cohorts 1 and 3
To assess the effect of GSK2647544 on PK profile of simvastatin, tmax of simvastatin will be measured
Area under the time concentration curve (AUC) of simvastatin
时间窗: 4 days in Cohorts 1 and 3
To assess the effect of GSK2647544 on PK profile of simvastatin, AUC of simvastatin will be measured
次要结局
- Predose plasma lipoprotein-associated phospholipase A2 (Lp-PLA2) activity and postdose Lp-PLA2 activity(up to 18 days in GSK2647544 dosing sessions)