Clinical trial NCT01702467: Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Single, Oral Escalating Doses of GSK2647544 in Healthy Volunteers
Official title: A Single-Blind, Randomized, Placebo-Controlled Study to Evaluate Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Single, Oral Escalating Doses of GSK2647544 in Healthy Volunteers
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Alzheimer's Disease
Keywords: Lp-PLA2
Alzheimer's disease
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
First posted: 2012-10-08
Enrollment: 27
Sex: MALE
Minimum age (years): 18
Maximum age (years): 55
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

Brief summary: 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.


Eligibility criteria: 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

Primary outcomes:
measure: Safety and tolerability of GSK2647544 as assessed by number of subjects with adverse events (AE)s
timeFrame: 5 days in each of the 4 dosing session
measure: Safety and tolerability of GSK2647544 as assessed by change from Baseline in laboratory values
timeFrame: 5 days in each of the 4 dosing session
measure: Safety and tolerability of GSK2647544 as assessed by change from Baseline in ECG readings
timeFrame: 5 days in each of the 4 dosing session
measure: Safety and tolerability of GSK2647544 as assessed by change from Baseline in Telemetry ECG parameters
timeFrame: 3 Days in each of the 4 dosing session
measure: Safety and tolerability of GSK2647544 as assessed by change from Baseline in vital signs
timeFrame: 5 days in each of the 4 dosing session
measure: Safety and tolerability of GSK2647544 as assessed by using the Columbia Suicide Severity Rating Scale (C-SSRS)
timeFrame: 5 days in each of the 4 dosing session
Secondary outcomes:
measure: Peak plasma concentration (Cmax) of GSK2647544
timeFrame: 4 Days in each of the 4 dosing session
measure: Time of peak plasma concentration (tmax) of GSK2647544
timeFrame: 4 Days in each of the 4 dosing session
measure: Area under the time concentration curve (AUC) of GSK2647544
timeFrame: 4 Days in each of the 4 dosing session
measure: Terminal half-life (t½ ) of GSK2647544
timeFrame: 4 Days in each of the 4 dosing session
measure: Apparent oral clearance (CL/F) of GSK2647544
timeFrame: 4 Days in each of the 4 dosing session
measure: Predose plasma lipoprotein-associated phospholipase A2 (Lp-PLA2) activity and postdose Lp-PLA2 activity
timeFrame: 5 Days in each of the 4 dosing session
Other outcomes:
Locations:
city: Randwick
country: Australia
facility: GSK Investigational Site
state: New South Wales
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References: