Atherosclerosis
Conditions
Keywords
rilapladib,, Lp-PLA2,, atherosclerosis, SB-659032,, FDG-PET,
Brief summary
A study in patients with atherosclerosis to assess safety, effect and PK of rilapladib vs. placebo over 12 weeks of dosing.
Detailed description
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.
Interventions
DRUGrilapladib
250 mg oral dose once daily
DRUGplacebo
placebo
OTHER18F Fluorodeoxylucose (FDG)-PET
FDG-PET
Sponsors
GlaxoSmithKline
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
50 Years to 80 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | 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
| Measure | 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 |
| PAF levels in human plasma as feasible | 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 |
Countries
United States
Outcome results
None listed