GSK2647544 RD, DDI in Healthy Young and Elderly Volunteers

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Alzheimer's Disease

Intervention / Treatment
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* Drug: GSK2647544
* Drug: drug-drug interaction


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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 Exclusion Criteria: 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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: GSK2647544<br>The planned repeat doses of GSK2647544 are 80 mg bid, 200 mg bid, and 350 mg bid | Drug: GSK2647544<br>* repeat dose<br>|
| Placebo Comparator: Placebo<br>Matching placebo | Drug: GSK2647544<br>* repeat dose<br>|
| Experimental: simvastatin<br>for drug-drug interaction | Drug: drug-drug interaction<br>* drug-drug interaction<br>|
| Experimental: simvastatin co-dosed with GSK2647544<br>for drug-drug interaction | Drug: drug-drug interaction<br>* drug-drug interaction<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and tolerability of GSK2647544 as assessed by number of subjects with adverse events (AE)s | Safety and tolerability parameters will include recording of AEs | up to 19 days in each dosing session | 
| Safety and tolerability of GSK2647544 as assessed by change from Baseline in laboratory values | 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) | up to 15 days in each dosing session | 
| Safety and tolerability of GSK2647544 as assessed by change from Baseline in ECG readings | 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) | up to 19 days in each dosing session | 
| Safety and tolerability of GSK2647544 as assessed by change from Baseline in Telemetry ECG parameters | Safety and tolerability parameter will include the Telemetry ECG readings from 30 minutes pre-dosing till 24 hours post-dosing | 2 days in Cohorts 1, 2 and 4; 3 days in Cohort 4 | 
| Safety and tolerability of GSK2647544 as assessed by change from Baseline in vital signs | 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) | up to 19 days in each dosing session | 
| Safety and tolerability of GSK2647544 as assessed by Columbia Suicide Severity Rating Scale (C-SSRS) | 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) | 4 days in Cohorts 1 and 2; 8 days in Cohorts 3 and 4 | 
| Peak plasma concentration (Cmax) of GSK2647544 | To assess PK profile of GSK2647544, Cmax of GSK2647544 will be measured | up to 17 days in GSK2647544 dosing sessions | 
| Time of peak plasma concentration (tmax) of GSK2647544 | To assess PK profile of GSK2647544, tmax of GSK2647544 will be measured | up to 17 days in GSK2647544 dosing sessions | 
| Area under the time concentration curve (AUC) of GSK2647544 | To assess PK profile of GSK2647544, AUC of GSK2647544 will be measured | up to 17 days in GSK2647544 dosing sessions | 
| Terminal half-life (t½ ) of GSK2647544 | To assess PK profile of GSK2647544, t1/2 of GSK2647544 will be measured | up to 17 days in GSK2647544 dosing sessions | 
| Time of peak plasma concentration (tmax) of simvastatin | To assess the effect of GSK2647544 on PK profile of simvastatin, tmax of simvastatin will be measured | 4 days in Cohorts 1 and 3 | 
| Area under the time concentration curve (AUC) of simvastatin | To assess the effect of GSK2647544 on PK profile of simvastatin, AUC of simvastatin will be measured | 4 days in Cohorts 1 and 3 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Predose plasma lipoprotein-associated phospholipase A2 (Lp-PLA2) activity and postdose Lp-PLA2 activity | 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 | up to 18 days in GSK2647544 dosing sessions | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Alzheimer's disease, GSK2647544, drug-drug interaction, healthy subjects, Lp-PLA2, simvastatin