SB-480848 In Subjects With Coronary Heart Disease

Study Overview
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Brief Summary
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This trial of SB-480848 in approximately 920 subjects with Coronary Heart Disease (CHD) or CHD-risk equivalent will examine whether SB-480848 produces sustained inhibition of plasma Lp-PLA2 activity, explore the effects of SB-480848 on other circulating biomarkers associated with cardiovascular risk, and evaluate the pharmacokinetics, safety and tolerability of SB-480848 over 12 weeks of once-daily oral dosing. Subjects will first be randomized 1:1 to double-blind atorvastatin 20 mg or 80 mg once daily for a minimum of 3 weeks. Subjects will then be randomized 1:1:1:1 to oral doses of SB-480848 40 mg, 80 mg, 160 mg or placebo once daily for 12 weeks. Blood samples will be collected at various timepoints. Vital signs, electrocardiograms, clinical laboratory safety tests and adverse event assessments will be performed to evaluate the safety and tolerability of SB-480848.

Detailed Description
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A multicenter, randomized, double-blind, placebo-controlled, parallel-group, dose-ranging study of SB-480848, an oral lipoprotein-associated phospholipase A2 (Lp-PLA2) inhibitor, in subjects with stable coronary heart disease (CHD) or CHD-risk equivalent to examine chronic inhibition of Lp-PLA2, effects on circulating biomarkers associated with cardiovascular risk, safety and tolerability over 12 weeks

Official Title
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A Multicenter, Randomized, Double-blind, Placebo-controlled, Parallel-group, Dose-ranging Study of SB-480848, an Oral Lipoprotein-associated Phospholipase A2 (Lp-PLA2) Inhibitor, in Subjects With Stable Coronary Heart Disease (CHD) or CHD-risk Equivalent to Examine Chronic Inhibition of Lp-PLA2 Effects on Circulating Biomarkers Associated With Cardiovascular Risk, Safety and Tolerability Over 12 Weeks

Conditions
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Atherosclerosis

Intervention / Treatment
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* Drug: SB-480848
* Drug: placebo


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Female subjects must be of non-childbearing potential. Stable CHD or CHD-risk equivalent. Must have been on a stable dose of a statin for =4 weeks with LDL <130 mg/dL (3.4 mmol/L) or off statin therapy for =4 weeks with LDL <160 mg/dL (4.1 mmol/L). On a stable dose of at least one oral antiplatelet agent (e.g., aspirin, clopidogrel, or ticlopidine). Exclusion criteria: Recent cardiovascular event and / or vascular procedure. History of difficult to manage dyslipidemia. Planned cardiac surgery or PCI (percutaneous coronary intervention) or planned major non-cardiac surgery. Inadequately controlled hypertension. Poorly controlled diabetes mellitus. Serum triglycerides >400 mg/dL (4.52 mmol/L). Recent or ongoing acute infection. History of chronic inflammatory disease. Receiving topical, oral, inhaled or injectable corticosteroids. History of chronic viral hepatitis, or other chronic hepatic disorders. History of kidney transplant. History of myopathy or inflammatory muscle disease, or elevated total serum CK (3 x ULN). Severe heart failure (NYHA class III or IV), or severe left ventricular dysfunction (ejection fraction <30%). Asthma manifested by bronchospasm in the past 6 months, or currently taking inhaled bronchodilator on regular basis. History of anaphylaxis, anaphylactoid reactions or severe allergic responses within the past 6 months. Malignancy within the past 2 years, other than non-melanoma skin cancer. Current life-threatening condition other than vascular disease that may prevent a subject from completing the study. QTc interval >440 msec (males) or >450 msec (females). Alcohol or drug abuse within the past 6 months. Previous exposure to SB-480848. Use of an investigational drug within 30 days or 5 half-lives (whichever is the longer) preceding the first dose of study medication (blinded atorvastatin).

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 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: Arm 1<br>SB-480848 | Drug: SB-480848<br>* SB-480848<br>|
| Placebo Comparator: Arm 2<br>placebo | Drug: placebo<br>* placebo<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| On treatment sustained inhibition of plasma Lp-PLA2 activity. |  | 12 Weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Difference in dose-dependent effects of SB-480848 on plasma Lp-PLA2 activity, other biomarkers, and safety. |  | 12 Weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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CHD, Lp-PLA2, SB-480848