GSK2647544 RD, DDI in Healthy Young and Elderly Volunteers - Full Text View

Purpose

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.

Condition	Intervention	Phase
Alzheimer's Disease	Drug: GSK2647544 Drug: drug-drug interaction	Phase 1


Study Type:	Interventional
Study Design:	Allocation: Randomized Intervention Model: Crossover Assignment Masking: Participant Primary Purpose: Treatment
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

Resource links provided by NLM:

Genetics Home Reference related topics: Alzheimer disease

MedlinePlus related topics: Alzheimer's Disease Drug Reactions

Drug Information available for: Simvastatin

Genetic and Rare Diseases Information Center resources: Familial Alzheimer Disease

U.S. FDA Resources

Further study details as provided by GlaxoSmithKline:

Primary Outcome Measures:

Safety and tolerability of GSK2647544 as assessed by number of subjects with adverse events (AE)s [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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) [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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:

Predose plasma lipoprotein-associated phospholipase A2 (Lp-PLA2) activity and postdose Lp-PLA2 activity [ Time Frame: 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


Enrollment:	12
Actual Study Start Date:	November 22, 2013
Study Completion Date:	March 3, 2014
Primary Completion Date:	March 3, 2014 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Experimental: GSK2647544 The planned repeat doses of GSK2647544 are 80 mg bid, 200 mg bid, and 350 mg bid	Drug: GSK2647544 repeat dose
Placebo Comparator: Placebo Matching placebo	Drug: GSK2647544 repeat dose
Experimental: simvastatin for drug-drug interaction	Drug: drug-drug interaction drug-drug interaction
Experimental: simvastatin co-dosed with GSK2647544 for drug-drug interaction	Drug: drug-drug interaction drug-drug interaction

Eligibility


Ages Eligible for Study:	18 Years and older (Adult, Senior)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	Yes

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

Contacts and Locations

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01978327

Locations


United Kingdom
GSK Investigational Site
Harrow, Middlesex, United Kingdom, HA1 3UJ

Sponsors and Collaborators

GlaxoSmithKline

Investigators


Study Director:	GSK Clinical Trials	GlaxoSmithKline

More Information

Additional Information:

Results for study 200592 can be found on the GSK Clinical Study Register. This link exits the ClinicalTrials.gov site