Clinical trial NCT00695305: An Imaging Study in Patients With Atherosclerosis Taking Rilapladib or Placebo for 12 Weeks
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Atherosclerosis
Keywords: rilapladib,
Lp-PLA2,
atherosclerosis
SB-659032,
FDG-PET,
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
First posted: 2008-06-11
Enrollment: 83
Sex: ALL
Minimum age (years): 50
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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

Primary outcomes:
measure: Safety from AE reporting, vital signs, clinical labs, ECGs, slit lamp eye exams and electron microscopy of peripheral blood lymphocytes.
timeFrame: 12 weeks
measure: LP-PLA2 activity;
timeFrame: 12 weeks
measure: changes in mean standard values of 18 FDG uptake as assessed by PET and MRI imaging
timeFrame: 12 weeks
Secondary outcomes:
measure: Estimation of PK parameters (such as: apparent volume of distribution, apparent clearance, etc.) of rilapladib and their associated variability, appropriate to the final model
timeFrame: 12 weeks
measure: Estimation of PK/PD parameters (such as: IC50, Eo) and their associated variability, appropriate to the final model
timeFrame: 12 weeks
measure: 24 hour ambulatory blood pressure monitoring
timeFrame: 12 weeks
measure: PAF levels in human plasma as feasible
timeFrame: 12 weeks
Other outcomes:
Locations:
city: Boston
country: United States
facility: GSK Investigational Site
state: Massachusetts
city: Brockton
country: United States
facility: GSK Investigational Site
state: Massachusetts
city: Haverhill
country: United States
facility: GSK Investigational Site
state: Massachusetts
city: Linden
country: United States
facility: GSK Investigational Site
state: New Jersey
city: New York
country: United States
facility: GSK Investigational Site
state: New York
city: New York
country: United States
facility: GSK Investigational Site
state: New York
city: New York
country: United States
facility: GSK Investigational Site
state: New York
city: New York
country: United States
facility: GSK Investigational Site
state: New York
city: North Massapequa
country: United States
facility: GSK Investigational Site
state: New York
city: Warwick
country: United States
facility: GSK Investigational Site
state: Rhode Island
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References: