Study to Determine the Effect of 14 Days Dosing With Darapladib (SB-480848) on Carotid Plague Composition in Patients With Planned Carotid Endarterectomy

Phase 2

Completed

• Conditions: Atherosclerosis
• Interventions: Drug: SB-480848 40 mg; Drug: SB-480848 80 mg; Drug: Placebo

• Registration Number: NCT01916720
• Lead Sponsor: GlaxoSmithKline

Brief Summary

The primary objective is to determine Lp-PLA2 activity in atherosclerotic carotid plaques after 14 (+/-4) days treatment with darapladib, compared to placebo. Secondary objectives include determination of the change in Lp-PLA2 activity in blood, Lp-PLA2 mass in blood and plaque, specified biomarkers in blood and plaque and their respective correlation's with Lp-PLA2. In addition, the study aims to characterise the PK/PD of repeat oral doses of SB-480848, and safety and tolerability in this population.

Detailed Description

Not available

Study Timeline

• Study Start: 2003-01
• Primary Completion: 2003-07
• Study Completion: 2003-07
• Study First Submitted: 2013-07-31
• Study First Submitted QC: 2013-08-02
• Study First Posted: 2013-08-06
• Status Verified: 2016-12
• Last Update Submitted: 2016-12-02
• Last Update Posted: 2016-12-05

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 103

Inclusion Criteria

• Male or female, >35 years of age
• Females of childbearing potential must be using approved contraceptive measures
• Male patients must be willing to abstain from sexual intercourse or use a form of contraception if engaging in sexual intercourse with a woman who could become pregnant
• Planned carotid endarterectomy within a timeframe compatible with recruitment for the study and able to comply with the requirements of the study, as deemed by the investigator
• Written, informed consent to participate

Exclusion Criteria

• Recent myocardial infarction (within the previous 4 weeks)
• Currently taking corticosteroids, warfarin, digoxin or a potent CYP3A4 inhibitor
• Recent (<3 months) or ongoing acute infection or significant trauma associated with bruising and/or taking antibiotics. Prophylactic antibiotics for surgery are allowed
• Change in dose of lipid-lowering therapy during the previous 4 weeks from randomisation
• History of chronic liver disease (e.g. cirrhosis, hepatitis) OR ALT OR AST ≥1.5 times the upper limit of normal (ULN) at screening
• Diagnosis of systemic lupus erythematosis (SLE) or rheumatoid arthritis (RA)
• Clinically significant anaemia
• History of severe renal impairment (serum creatinine >1.8mg/dL)
• Unstable angina
• History of asthma , anaphylaxis or anaphylactoid reactions, severe allergic responses
• Abuse of alcohol or drugs within the last 6 months
• Any factor or clinical disease state that, in the investigator's opinion, would preclude completion of a safe surgical procedure and/or completion of the study
• Use of an investigational drugs within 30 days or 5 half-lives of their last dose prior to starting the study, whichever is the longest

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
SB-480848 40 mg	SB-480848 40 mg	SB-480848 40 milligrams (mg) once a day (od) for 14 +/- 4 days followed by carotid endarterectomy. SB-480848 40 mg was administered as 2 SB-480848 20 mg tablets plus 2 placebo tablets.
SB-480848 40 mg	Placebo	SB-480848 40 milligrams (mg) once a day (od) for 14 +/- 4 days followed by carotid endarterectomy. SB-480848 40 mg was administered as 2 SB-480848 20 mg tablets plus 2 placebo tablets.
SB-480848 80 mg	SB-480848 80 mg	SB-480848 80 mg od for 14 +/- 4 days followed by carotid endarterectomy.SB-480848 80 mg was administered as 4 20 mg SB-480848 tablets.
Matching Placebo	Placebo	Placebo for 14 +/- 4 days followed by carotid endarterectomy. Placebo was administered as 4 placebo tablets. Placebo tablets were identical in appearance to the SB-480848 20 mg tablets.

Primary Outcome Measures

Name	Time	Method
Lp-PLA2 activity in the atherosclerotic plaque removed during carotid endarterectomy	14 +/- 4 days

Secondary Outcome Measures

Name	Time	Method
Lp-PLA2 mass and activity in blood	14 +/- days
Lp-PLA2 mass in plaque removed during the carotid endarterectomy	14 +/- 4 days
Lipid and Non-Lipid Biomarkers in Plasma	14 +/- days	Lipids: total cholesterol, HDL, LDL, and triglycerides Non-Lipids: hsCRP, CD40L, ICAM-1, E-selectin, PAI-1 antibody, PAI-1 antigen, and MMP-9
Oxidised Lipids and Their Metabolites, and Biomarkers in Plaque	14 +/- 4 days	Oxidised Lipids and Their Metabolites: total lyso-PC, total phospholipid, and total phosphatidylcholine Biomarkers: CD68 (macrophages), CD3 (T cells), CD20 or CD22 (B cells), alpha-actin (smooth muscle cells), CD40L, MMP-2, MMP-9, PAI-1, ICAM-1, IL-6, and Lp-PLA2 (mRNA expression)