GSK2647544 RD, DDI in Healthy Young and Elderly Volunteers

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

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.

Study Overview

• Status: Terminated
• Conditions: Alzheimer's Disease
• Intervention / Treatment: Drug: GSK2647544; Drug: drug-drug interaction

• Study Type: Interventional
• Enrollment (Actual): 12
• Phase: Phase 1

Contacts and Locations

Study Locations

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

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Single

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo; Matching placebo	Drug: GSK2647544; repeat dose
Experimental: GSK2647544; The planned repeat doses of GSK2647544 are 80 mg bid, 200 mg bid, and 350 mg bid	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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: GlaxoSmithKline

Study record dates

Study Major Dates

• Study Start (Actual): November 22, 2013
• Primary Completion (Actual): March 3, 2014
• Study Completion (Actual): March 3, 2014

Study Registration Dates

• First Submitted: October 31, 2013
• First Submitted That Met QC Criteria: October 31, 2013
• First Posted (Estimate): November 7, 2013

Study Record Updates

• Last Update Posted (Actual): June 8, 2017
• Last Update Submitted That Met QC Criteria: June 7, 2017
• Last Verified: June 1, 2017

More Information

Terms related to this study

• Keywords: Alzheimer's disease; healthy subjects; drug-drug interaction; simvastatin; GSK2647544; Lp-PLA2
• Additional Relevant MeSH Terms: Mental Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neurocognitive Disorders; Neurodegenerative Diseases; Dementia; Tauopathies; Alzheimer Disease
• Other Study ID Numbers: 200592

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: Patient-level data for this study will be made available through www.clinicalstudydatarequest.com following the timelines and process described on this site.

Study Data/Documents

1. Dataset Specification
   Information identifier: 200592
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
2. Clinical Study Report
   Information identifier: 200592
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
3. Informed Consent Form
   Information identifier: 200592
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
4. Individual Participant Data Set
   Information identifier: 200592
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
5. Annotated Case Report Form
   Information identifier: 200592
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
6. Study Protocol
   Information identifier: 200592
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
7. Statistical Analysis Plan
   Information identifier: 200592
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register