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GSK2647544 RD, DDI in Healthy Young and Elderly Volunteers

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ClinicalTrials.gov Identifier: NCT01978327
Recruitment Status : Terminated (Given the strength of CYP3A4 inhibition observed in Cohort 1, there is no rationale to investigate higher doses of GSK2647544 in the following two cohorts)
First Posted : November 7, 2013
Last Update Posted : June 8, 2017
Sponsor:
Information provided by (Responsible Party):
GlaxoSmithKline

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.

Condition or disease Intervention/treatment Phase
Alzheimer's Disease Drug: GSK2647544 Drug: drug-drug interaction Phase 1

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 12 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Single (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
Actual Study Start Date : November 22, 2013
Actual Primary Completion Date : March 3, 2014
Actual Study Completion Date : March 3, 2014


Arm Intervention/treatment
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




Primary Outcome Measures :
  1. 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

  2. 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)

  3. 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)

  4. 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

  5. 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)

  6. 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)

  7. 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

  8. 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

  9. 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

  10. 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

  11. 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

  12. 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 :
  1. 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



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01978327


Locations
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United Kingdom
GSK Investigational Site
Harrow, Middlesex, United Kingdom, HA1 3UJ
Sponsors and Collaborators
GlaxoSmithKline
Investigators
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Study Director: GSK Clinical Trials GlaxoSmithKline

Study Data/Documents: Dataset Specification  This link exits the ClinicalTrials.gov site
Identifier: 200592
For additional information about this study please refer to the GSK Clinical Study Register
Clinical Study Report  This link exits the ClinicalTrials.gov site
Identifier: 200592
For additional information about this study please refer to the GSK Clinical Study Register
Informed Consent Form  This link exits the ClinicalTrials.gov site
Identifier: 200592
For additional information about this study please refer to the GSK Clinical Study Register
Individual Participant Data Set  This link exits the ClinicalTrials.gov site
Identifier: 200592
For additional information about this study please refer to the GSK Clinical Study Register
Annotated Case Report Form  This link exits the ClinicalTrials.gov site
Identifier: 200592
For additional information about this study please refer to the GSK Clinical Study Register
Study Protocol  This link exits the ClinicalTrials.gov site
Identifier: 200592
For additional information about this study please refer to the GSK Clinical Study Register
Statistical Analysis Plan  This link exits the ClinicalTrials.gov site
Identifier: 200592
For additional information about this study please refer to the GSK Clinical Study Register

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Responsible Party: GlaxoSmithKline
ClinicalTrials.gov Identifier: NCT01978327    
Other Study ID Numbers: 200592
First Posted: November 7, 2013    Key Record Dates
Last Update Posted: June 8, 2017
Last Verified: June 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
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.
Keywords provided by GlaxoSmithKline:
Alzheimer's disease
GSK2647544
drug-drug interaction
healthy subjects
Lp-PLA2
simvastatin
Additional relevant MeSH terms:
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Alzheimer Disease
Dementia
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Tauopathies
Neurodegenerative Diseases
Neurocognitive Disorders
Mental Disorders
Simvastatin
Anticholesteremic Agents
Hypolipidemic Agents
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Lipid Regulating Agents
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Enzyme Inhibitors