An Imaging Study in Patients With Atherosclerosis Taking Rilapladib or Placebo for 12 Weeks

Study Overview
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Brief Summary
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A study in patients with atherosclerosis to assess safety, effect and PK of rilapladib vs. placebo over 12 weeks of dosing.

Detailed Description
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Study LP2105521 is a randomized, double-blind, placebo-controlled, parallel-group study to examine the safety, tolerability, and effects of rilapladib on plasma Lp-PLA2 activity, plaque inflammation, and PAF (if feasible). Subjects will receive placebo or rilapladib once daily for 12 weeks. The study will be conducted in subjects with established atherosclerosis.

Official Title
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A Multicenter, Randomized, 12 Week, Double-blind, Placebo-controlled, Parallel-group, Phase IIa Study Using 18F Fluorodeoxyglucose (FDG)-PET to Measure the Effects of Rilapladib on Macrophage Activity in Subjects With Atherosclerosis

Conditions
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Atherosclerosis

Intervention / Treatment
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* Drug: rilapladib
* Drug: placebo
* Other: 18F Fluorodeoxylucose (FDG)-PET


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Capable of giving written informed consent and able to understand and comply with protocol requirements, instructions and protocol-stated restrictions. Male or female, aged 50 to 80 years inclusive, at screening. Females must be of non-childbearing potential Body weight ≥ 50 kg and BMI within the range 19-35 kg/m2 Documented atherosclerotic vascular disease (e.g. prior MI, prior revascularization, peripheral arterial disease, carotid disease, or cerebrovascular disease) and clinically stable for at least 6 months If diabetic, have well controlled diabetes, defined for the purpose of this study as HbA1c ≤8% or FPG ≤200 mg/dL Evidence of plaque inflammation [carotid artery or ascending aorta plaque inflammation defined as a tissue to background ratio (TBR) ≥ 1.6] On a stable dose of a statin for 3 months prior to screening with no evidence of statin intolerance Exclusion Criteria: Recent (i.e., <6 months from Screening Visit) CV event defined as ST-elevation MI or non-ST-elevation MI, confirmed by cardiac enzyme elevation and ECG changes, coronary revascularization (PCI or CABG), stroke of any etiology, resuscitated sudden death, prior carotid surgery or stenting procedure Evidence of clinical instability or abnormal clinical laboratory findings prior to randomization that, in the opinion of the Investigator, makes the subject unsuitable for the study. Exposure to substantial radiation within the past 12 months Planned cardiac surgery (e.g., CABG, valve repair or replacement, or aneurysmectomy), PCI or major non-cardiac surgery within the study period Current inadequately controlled hypertension (blood pressure ≥160 mmHg systolic or ≥100 mmHg diastolic) on a stable dose of anti-hypertensive medication Diabetics taking injectable insulin at screening Serum triglycerides >400 mg/dL, LDLc >130 mg/dL Recent (<1 month) or ongoing acute infection. History of chronic inflammatory disease Recently received (<1 month) or currently receiving oral or injectable corticosteroids, or regular use of nasal, inhaled or topical corticosteroids. Subjects who will commence, or who are likely to commence regular treatment with oral, non-steroidal anti-inflammatory drugs (NSAIDs) from screening until study completion Currently receiving oral or injectable potent CYP3A4 inhibitor(s) History of chronic viral hepatitis or other chronic hepatic disorders; or ALT or AST >1.5 x ULN, or alkaline phosphatase or total bilirubin >1.5 x ULN of laboratory reference range at Screen Renal impairment with serum creatinine >2.0 mg/dl or history of kidney transplant or status post nephrectomy. History of myopathy or inflammatory muscle disease, or elevated total CPK at screening History of severe heart failure defined as NYHA class III or IV or those with known severe left ventricular dysfunction (ejection fraction<30%) regardless of symptomatic status History of adult asthma (or reactive airway disease) manifested by bronchospasm in the past 6 months, or currently taking regular anti-asthmatic medication(s) History of anaphylaxis, anaphylactoid (resembling anaphylaxis) reactions or severe allergic responses History of malignancy within the past 2 years. A history of glaucoma or any other findings in the baseline eye exam Current life-threatening condition other than vascular disease that may prevent a subject from completing the study QTc interval ≥450msec at screening or ≥480 msec for subjects with bundle branch block History of drug abuse within the past 6 months Previous exposure to rilapladib. Contraindication to MRI scanning Use of an investigational drug within 30 days or 5 half-lives (whichever is the longer) preceding the first dose of study medication Any other subject the Investigator deems unsuitable for the study

Ages Eligible for Study
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Minimum Age: 50 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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: placebo<br>placebo to match | Drug: placebo<br>* placebo<br>|
| Active Comparator: rilapladib<br>250 mg/day | Drug: rilapladib<br>* 250 mg oral dose once daily<br>* Other names: SB-659032;Other: 18F Fluorodeoxylucose (FDG)-PET<br>* FDG-PET<br>* Other names: FDG marker;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety from AE reporting, vital signs, clinical labs, ECGs, slit lamp eye exams and electron microscopy of peripheral blood lymphocytes. |  | 12 weeks | 
| LP-PLA2 activity; |  | 12 weeks | 
| changes in mean standard values of 18 FDG uptake as assessed by PET and MRI imaging |  | 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Estimation of PK parameters (such as: apparent volume of distribution, apparent clearance, etc.) of rilapladib and their associated variability, appropriate to the final model |  | 12 weeks | 
| Estimation of PK/PD parameters (such as: IC50, Eo) and their associated variability, appropriate to the final model |  | 12 weeks | 
| 24 hour ambulatory blood pressure monitoring |  | 12 weeks | 
| PAF levels in human plasma as feasible |  | 12 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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rilapladib,, Lp-PLA2,, atherosclerosis, SB-659032,, FDG-PET,