Clinical trial NCT01978327: GSK2647544 RD, DDI in Healthy Young and Elderly Volunteers
Official title: 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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
Conditions: Alzheimer's Disease
Keywords: Alzheimer's disease
GSK2647544
drug-drug interaction
healthy subjects
Lp-PLA2
simvastatin
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
First posted: 2013-11-07
Enrollment: 12
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

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.


Eligibility criteria: 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

Primary outcomes:
measure: Safety and tolerability of GSK2647544 as assessed by number of subjects with adverse events (AE)s
timeFrame: up to 19 days in each dosing session
measure: Safety and tolerability of GSK2647544 as assessed by change from Baseline in laboratory values
timeFrame: up to 15 days in each dosing session
measure: Safety and tolerability of GSK2647544 as assessed by change from Baseline in ECG readings
timeFrame: up to 19 days in each dosing session
measure: Safety and tolerability of GSK2647544 as assessed by change from Baseline in Telemetry ECG parameters
timeFrame: 2 days in Cohorts 1, 2 and 4; 3 days in Cohort 4
measure: Safety and tolerability of GSK2647544 as assessed by change from Baseline in vital signs
timeFrame: up to 19 days in each dosing session
measure: Safety and tolerability of GSK2647544 as assessed by Columbia Suicide Severity Rating Scale (C-SSRS)
timeFrame: 4 days in Cohorts 1 and 2; 8 days in Cohorts 3 and 4
measure: Peak plasma concentration (Cmax) of GSK2647544
timeFrame: up to 17 days in GSK2647544 dosing sessions
measure: Time of peak plasma concentration (tmax) of GSK2647544
timeFrame: up to 17 days in GSK2647544 dosing sessions
measure: Area under the time concentration curve (AUC) of GSK2647544
timeFrame: up to 17 days in GSK2647544 dosing sessions
measure: Terminal half-life (t½ ) of GSK2647544
timeFrame: up to 17 days in GSK2647544 dosing sessions
measure: Time of peak plasma concentration (tmax) of simvastatin
timeFrame: 4 days in Cohorts 1 and 3
measure: Area under the time concentration curve (AUC) of simvastatin
timeFrame: 4 days in Cohorts 1 and 3
Secondary outcomes:
measure: Predose plasma lipoprotein-associated phospholipase A2 (Lp-PLA2) activity and postdose Lp-PLA2 activity
timeFrame: up to 18 days in GSK2647544 dosing sessions
Other outcomes:
Locations:
city: Harrow
country: United Kingdom
facility: GSK Investigational Site
state: Middlesex
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References: