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

Study Overview
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Brief Summary
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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.

Official Title
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A Multi-centre, Randomised, Double-blind, Placebo-controlled, Parallel-group Study to Investigate the Effect of the Lp-PLA2 Inhibitor SB-480848 (40, 80mg od) on Carotid Plaque Composition in Patients With Carotid Artery Disease and Planned Carotid Endarterectomy, Stratified for Statin Use and Gender, After 14+/-4 Days Treatment

Conditions
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Atherosclerosis

Intervention / Treatment
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* Drug: SB-480848 40 mg
* Drug: SB-480848 80 mg
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 35 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: SB-480848 40 mg<br>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. | Drug: SB-480848 40 mg<br>* Study Drug<br>Drug: Placebo<br>* Study Drug<br>|
| Experimental: SB-480848 80 mg<br>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. | Drug: SB-480848 80 mg<br>* Study Drug<br>|
| Placebo Comparator: Matching Placebo<br>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. | Drug: Placebo<br>* Study Drug<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Lp-PLA2 activity in the atherosclerotic plaque removed during carotid endarterectomy |  | 14 +/- 4 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Lp-PLA2 mass in plaque removed during the carotid endarterectomy |  | 14 +/- 4 days | 
| Lp-PLA2 mass and activity in blood |  | 14 +/- days | 
| Lipid and Non-Lipid Biomarkers in Plasma | Lipids: total cholesterol, HDL, LDL, and triglycerides Non-Lipids: hsCRP, CD40L, ICAM-1, E-selectin, PAI-1 antibody, PAI-1 antigen, and MMP-9 | 14 +/- days | 
| Oxidised Lipids and Their Metabolites, and Biomarkers in Plaque | 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) | 14 +/- 4 days |