Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Single, Oral Escalating Doses of GSK2647544 in Healthy Volunteers

A Single-Blind, Randomized, Placebo-Controlled Study to Evaluate Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Single, Oral Escalating Doses of GSK2647544 in Healthy Volunteers

The current study will examine the safety, tolerability, plasma pharmacokinetics (PK), and plasma pharmacodynamics (PD) of single-doses of GSK2647544.The study will be conducted as a randomized, single-blind, placebo controlled, 4-way crossover single oral ascending dose design in 2 independent cohorts, eight healthy male subjects in each of the cohorts. Each potential subject will undergo Screening visit, Treatment Phase and Follow-up visit.

Study Overview

• Status: Completed
• Conditions: Alzheimer's Disease
• Intervention / Treatment: Drug: GSK2647544; Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 27
• Phase: Phase 1

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Randwick, New South Wales, Australia, 2031
      • GSK Investigational Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 55 years (ADULT)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: Male

Description

Inclusion Criteria:

• Healthy males who are 18 to 55 years of age, inclusive
• Healthy as determined by a responsible and experienced physician
• 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 millisecond (msec)
• Body weight > 50 kg (110 pounds) and body mass index (BMI) between 19 and 30
• Male subjects with female partners of child-bearing potential must agree to use one of the contraception methods
• Capable of giving written informed consent

Exclusion Criteria:

• Those 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
• A 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 three months of the study and/or has a positive breath CO at screening
• History of alcohol consumption exceeding, on average, 21 drinks/week for men (1 drink = 100 mL of wine or 240 mL of beer or 30 mL of hard liquor in Australia) within 6 months of the first dose of study medication
• Positive urine drug or positive breath alcohol test at screening or at admission to Clinical Research Unit
• 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
• Unable to refrain from use of dietary/herbal supplements including (but not limited to) St. John's wort, kava, ephedra (ma huang), gingko biloba, DHEA, yohimbe, saw palmetto, ginseng and red yeast rice within 14 days prior to treatment with study medication
• Treatment with an investigational drug within 30 days or 5 half-lives (whichever is longer) prior to dosing
• Unable to refrain from consumption of grapefruit or grapefruit juice within 7 days prior to the first dose of study medication
• For male subjects, an unwillingness to abstain from sexual intercourse with pregnant or lactating women or an unwillingness to use a condom plus partner use of a highly effective contraceptive if engaging in sexual intercourse with a woman who could become pregnant until discharge from the study
• Donation of blood in excess of 500 mL within 56 days prior to dosing
• History of sensitivity to heparin or heparin-induced thrombocytopenia
• Subjects, who in the investigator's judgement, pose a significant suicide risk. Evidence of serious suicide risk may include any history of suicidal behaviour and/or any suicidal ideation of type 4 or 5 on the C-SSRS in the last 6 months

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: CROSSOVER
• Masking: SINGLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
PLACEBO_COMPARATOR: Placebo; Matching placebo	Drug: Placebo; Matching placebo capsules.
EXPERIMENTAL: GSK2647544; The starting dose of GSK2647544 is 0.5 mg. The escalating doses to be administered will be determined based on study results from previous dose (s).	Drug: GSK2647544; Capsules containing 0.5mg to 50mg of GSK2647544.

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	5 days in each of the 4 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 3 and Follow-up (7-14 days post-last dose)	5 days in each of the 4 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, Day 2, Day 3 and Follow-up (7-14 days post-last dose)	5 days in each of the 4 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 48 hours post-dosing	3 Days in each of the 4 dosing session
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, Day 2, Day 3, Day 4 and Follow-up (7-14 days post-last dose)	5 days in each of the 4 dosing session
Safety and tolerability of GSK2647544 as assessed by using the Columbia Suicide Severity Rating Scale (C-SSRS)	C-SSRS will be measured at Screening, Day -1, Day 1 (conducted prior to discharge) and Follow-up (7-14 days post-last dose)	5 days in each of the 4 dosing session

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Peak plasma concentration (Cmax) of GSK2647544	To assess PK profile of GSK2647544, Cmax of GSK2647544 will be measured	4 Days in each of the 4 dosing session
Time of peak plasma concentration (tmax) of GSK2647544	To assess PK profile of GSK2647544 tmax of GSK2647544 will be measured	4 Days in each of the 4 dosing session
Area under the time concentration curve (AUC) of GSK2647544	To assess PK profile of GSK2647544 AUC of GSK2647544 will be measured	4 Days in each of the 4 dosing session
Terminal half-life (t½ ) of GSK2647544	To assess PK profile of GSK2647544 t½ of GSK2647544 will be measured	4 Days in each of the 4 dosing session
Apparent oral clearance (CL/F) of GSK2647544	To assess PK profile of GSK2647544 CL/F of GSK2647544 will be measured	4 Days in each of the 4 dosing session
Predose plasma lipoprotein-associated phospholipase A2 (Lp-PLA2) activity and postdose Lp-PLA2 activity	It will be measured at Day 1, Day 2, Day 3, Day 4 and Day 5	5 Days in each of the 4 dosing session

Collaborators and Investigators

• Sponsor: GlaxoSmithKline

Study record dates

Study Major Dates

• Study Start (ACTUAL): October 19, 2012
• Primary Completion (ACTUAL): May 15, 2013
• Study Completion (ACTUAL): May 15, 2013

Study Registration Dates

• First Submitted: October 4, 2012
• First Submitted That Met QC Criteria: October 4, 2012
• First Posted (ESTIMATE): October 8, 2012

Study Record Updates

• Last Update Posted (ACTUAL): October 18, 2017
• Last Update Submitted That Met QC Criteria: October 16, 2017
• Last Verified: October 1, 2017

More Information

Terms related to this study

• Keywords: Alzheimer's disease; 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: 116698

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. Clinical Study Report
   Information identifier: 116698
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
2. Annotated Case Report Form
   Information identifier: 116698
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
3. Informed Consent Form
   Information identifier: 116698
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
4. Dataset Specification
   Information identifier: 116698
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
5. Study Protocol
   Information identifier: 116698
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
6. Individual Participant Data Set
   Information identifier: 116698
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
7. Statistical Analysis Plan
   Information identifier: 116698
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register