Alzheimer's Disease
Conditions
Keywords
Alzheimer's disease, GSK2647544, drug-drug interaction, healthy subjects, Lp-PLA2, simvastatin
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.
Interventions
DRUGGSK2647544
repeat dose
DRUGdrug-drug interaction
drug-drug interaction
Sponsors
GlaxoSmithKline
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
SINGLE (Subject)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
Yes
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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 |
| 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) |
| 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) |
| 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 |
| 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 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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 |
Countries
United Kingdom
Outcome results
None listed