Atherosclerosis
Conditions
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.
Interventions
DRUGSB-480848 40 mg
Study Drug
DRUGSB-480848 80 mg
Study Drug
DRUGPlacebo
Study Drug
Sponsors
GlaxoSmithKline
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
35 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Lp-PLA2 activity in the atherosclerotic plaque removed during carotid endarterectomy | 14 +/- 4 days |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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 | 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) |
Outcome results
None listed