SB-659032 Platelet Aggregation Study

A Double Blind Study to Evaluate Effects of Repeat Doses of SB-659032 on Platelet Aggregation in Healthy Volunteers

This study is designed to assess whether inhibition of plasma Lp-PLA2 activity impacts platelet function as assessed by ex vivo platelet aggregation tests and in vivo plasma biomarkers.

Study Overview

• Status: Completed
• Conditions: Atherosclerosis
• Intervention / Treatment: Drug: Placebo; Drug: SB-659032

Detailed Description

SB-659032 is a selective and orally active inhibitor of lipoprotein-associated phospholipase A2 (Lp-PLA2) that is being developed for the treatment of atherosclerosis. This study is designed to assess whether inhibition of plasma Lp-PLA2 activity impacts platelet function as assessed by ex vivo platelet aggregation tests and in vivo plasma biomarkers. Blood samples for PK analysis and measurement of Lp-PLA2 activity will also be collected. Questionnaires will be completed to evaluate the frequency of odorrelated AEs with non-enteric coated formulation of SB-659032 relative to placebo. This will be a double blind, repeat dose, randomized, placebo-controlled, two period, period balanced, crossover study. There will be a minimum of a 21 day washout period between dosing in each period.

• Study Type: Interventional
• Enrollment (Actual): 26
• Phase: Phase 1

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Randwick, Sydney, 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 adult males between 18 and 55 years of age, inclusive
• Body weight greater than 50 kg (110 pounds) and body mass index (BMI) between 19 and 32 where: BMI = weight in kg/(height in meters)2
• A signed and dated written informed consent prior to admission to the study
• The subject is able to understand and comply with protocol requirements, instructions and protocol-stated restrictions.

Exclusion Criteria:

• Any clinically relevant abnormality identified on the screening medical assessment, laboratory examination or ECG
• Platelet count below or above the reference range
• History of hypercoagulable state or history of thrombosis
• History of platelet dysfunction
• A known history of Gilbert's Syndrome
• History of asthma, anaphylaxis or anaphalactoid reactions, severe allergic responses
• A history of alcohol, substance or drug abuse within the last year or a positive alcohol breath test at screening or predose in each period. Abuse of alcohol is defined as an average weekly intake of greater than or equal to 21 units (male) or an average daily intake of greater than or equal to 3 units (male). 1 unit is equivalent to a 285mL glass of full strength beer or 425 mL schooner of light beer or 1 (30 mL) measure of spirits or 1 glass (100 mL) of wine
• Positive urine drug screen at screening or predose in each period
• History of use of tobacco or nicotine containing products within 6 months of screening or a positive urine cotinine at screening or exhaled carbon monoxide test at predose in each period
• Positive HIV, Hepatitis B or Hepatitis C at screening
• Use of aspirin, aspirin-containing products, non-steroidal anti-inflammatory agents or any antiplatelet medication within 14 days prior to Day -1 of the study (a list of these drugs will be reviewed with the subject at screening and provided to them to take home)
• Use of prescription (including hormone replacement therapy) or non-prescription drugs and vitamins within 7 days or 5 half-lives (whichever is longer) prior to Day -1 of the study. An exception is acetaminophen which is allowed at doses of ≤ 2g/day
• 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 Day -1 of the study
• Treatment with an investigational drug within 30 days or 5 half-lives (whichever is longer) prior to dosing
• Consumption of grapefruit or grapefruit juice within 7 days prior to Day -1 of the study
• A history of cholecystectomy or biliary tract disease including a history of liver disease with elevated liver function tests of known or unknown etiology
• An unwillingness to abstain from sexual intercourse with pregnant or lactating women or an unwillingness to use a condom and another form of contraception (e.g., IUD, birth control pills taken by female partner, diaphragm with spermicide) 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 or donation of blood in excess of 250 mL within 7 days prior to dosing
• Full ADP- and/or collagen-induced aggregation (greater than and equal to 40%) at all three concentrations of one or both agonists, as assessed within 6 months prior to first dose and at Day -1 of each period
• No ADP- or collagen-induced aggregation (less than 40%) at the highest concentration of either agonist, as assessed within 6 months prior to first dose and at Day -1 of each period

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: SB-659032; 250 mg non-enteric coated SB-659032	Drug: Placebo; Matched placebo
Placebo Comparator: Placebo; matched placebo QD for 14 days	Drug: SB-659032

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Platelet aggregation	Percent maximum platelet aggregation following ADP- and collagen-induced aggregation	14 days
Biomarkers of platelet aggregation	Urinary 11-dehydrothromboxane B2 and blood CD62 concentrations	14 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Lp-PLA2 inhibition	Lp-PLA2 activity, expressed in terms of percent inhibition relative to baseline	14 days
Clinical safety data	spontaneous adverse event reporting, 12-Lead ECG, vital signs, nursing/physician observation and safety and laboratory tests	14 days
Mean concentrations of SB-659032 and its major metabolite, SB-664601	SB-659032 and SB-664601 concentrations	14 days
Frequency and intensity of odor-related adverse events	The frequency and intensity of odor-related adverse events as reported by subjects will be summarized	14 days

Collaborators and Investigators

• Sponsor: GlaxoSmithKline

Publications and helpful links

General Publications

• Shaddinger BC, Xu Y, Roger JH, Macphee CH, Handel M, Baidoo CA, Magee M, Lepore JJ, Sprecher DL. Platelet aggregation unchanged by lipoprotein-associated phospholipase A(2) inhibition: results from an in vitro study and two randomized phase I trials. PLoS One. 2014 Jan 27;9(1):e83094. doi: 10.1371/journal.pone.0083094. eCollection 2014.

Study record dates

Study Major Dates

• Study Start: July 1, 2005
• Primary Completion (Actual): December 1, 2005
• Study Completion (Actual): December 1, 2005

Study Registration Dates

• First Submitted: December 6, 2012
• First Submitted That Met QC Criteria: December 6, 2012
• First Posted (Estimate): December 10, 2012

Study Record Updates

• Last Update Posted (Estimate): December 10, 2012
• Last Update Submitted That Met QC Criteria: December 6, 2012
• Last Verified: December 1, 2012

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Atherosclerosis
• Other Study ID Numbers: 104623