GSK2647544 RD, DDI in Healthy Young and Elderly Volunteers
- Conditions
- Alzheimer's Disease
- Interventions
- Drug: drug-drug interaction
- Registration Number
- NCT01978327
- Lead Sponsor
- GlaxoSmithKline
- Brief Summary
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.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- TERMINATED
- Sex
- All
- Target Recruitment
- 12
- 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
- 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
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- CROSSOVER
- Arm && Interventions
Group Intervention Description simvastatin drug-drug interaction for drug-drug interaction simvastatin co-dosed with GSK2647544 drug-drug interaction for drug-drug interaction GSK2647544 GSK2647544 The planned repeat doses of GSK2647544 are 80 mg bid, 200 mg bid, and 350 mg bid Placebo GSK2647544 Matching placebo
- Primary Outcome Measures
Name Time Method Safety and tolerability of GSK2647544 as assessed by number of subjects with adverse events (AE)s 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 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 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 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 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 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 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 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) 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 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 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 4 days in Cohorts 1 and 3 To assess the effect of GSK2647544 on PK profile of simvastatin, AUC of simvastatin will be measured
- Secondary Outcome Measures
Name Time Method Predose plasma lipoprotein-associated phospholipase A2 (Lp-PLA2) activity and postdose Lp-PLA2 activity up to 18 days in GSK2647544 dosing sessions Lp-PLA2 activity will be measured at Days 1, 2, 3 and 4 in GSK2647544 single dose sessions; it will be measured at Days 1, 3, 4, 5, 7, 10, 14, 15, 16, 17 and 18 in GSK2647544 repeat dose sessions
Trial Locations
- Locations (1)
GSK Investigational Site
🇬🇧Harrow, Middlesex, United Kingdom