A Randomized, Placebo-Controlled Study of the Effect of RO4607381 on Progression or Regression of Atherosclerotic Plaque in Patients With Coronary Heart Disease (CHD) Including Patients With Other CHD Risk Factors - dal-PLAQUE

Description:

Despite multiple attempts, no pharmacological agent thus far has been successful in increasing high-density lipoprotein (HDL) while reducing coronary events. Dalcetrapib is a cholesteryl ester transfer protein (CETP) inhibitor that has not shown off-target effects such as blood pressure elevation (noted with torcetrapib, another CETP inhibitor in the ILLUSTRATE and ILLUMINATE trials) in early trials.

The current trial was a phase II trial designed to assess the efficacy and safety of dalcetrapib on plaque inflammation as evaluated by 18F-fluorodeoxyglucose positron emission tomography (18F-FDG-PET), and atherosclerotic plaque progression as determined by magnetic resonance imaging (MRI) plaque burden.

Hypothesis:

Dalcetrapib would be superior to placebo in reducing plaque inflammation as evaluated by 18F-FDG-PET, and atherosclerotic plaque progression as determined by MRI plaque burden in patients with established coronary heart disease (CHD) or at risk for CHD.

Study Design

  • Placebo Controlled
  • Blinded
  • Randomized
  • Parallel
  • Stratified

Patient Populations:

  • Age 18-75 years
  • Diagnosis of CHD or CHD risk equivalents based on the National Cholesterol Education Program Adult Treatment Panel III
  • Triglycerides level ≤400 mg/dl
  • Carotid or aortic plaque inflammation TBR ≥1.6 determined by 18F-FDG uptake on PET/CT
  • Clinically stable
  • On appropriate treatment with statin and/or other LDL-C lowering drugs to a stable LDL-C level of <100 mg/dl unless taking maximum tolerated doses of therapy based on their medical condition or intolerant to statins

    Number of screened applicants: 189
    Number of enrollees: 130
    Duration of follow-up: 2 years
    Mean patient age: 63.6
    Percentage female: 18%

Exclusions:

  • Concomitant HDL-C raising therapy (niacin, fibrates, bile acid sequestrants, rimonabant, CETP therapy, or other)
  • Uncontrolled blood pressure
  • Uncontrolled diabetes (hemoglobin A1c ≥10%)
  • Recent (<3 months) clinically significant coronary or cerebral vascular event
  • Patients with familial hypercholesterolemia
  • Glomerular filtration rate <30 ml/min (Cockcroft-Gault formula)
  • Liver disease
  • History of malignancies
  • Standard contraindications for MRI and PET/CT

Primary Endpoints:

  • Primary PET/CT endpoint is the change in arterial wall 18F-FDG uptake within an index vessel (right carotid, or left carotid, or ascending thoracic aorta) after 6 months
  • Primary MRI endpoint is the change in atherosclerotic plaque burden, measured by four indices: wall area, wall thickness, total vessel area, and wall area/total vessel area ratio, based on the average of the right and left carotids after 12 months

Secondary Endpoints:

  • Change from baseline in TBR from the index vessel (right and left carotid or ascending thoracic aorta) based on the standardized 18F-FDG uptake measured with PET after 3 months
  • Change from baseline in MRI-derived atherosclerotic plaque burden indices on the right carotid, left carotid, and descending abdominal aorta after 6 and 24 months

Drug/Procedures Used:

Patients entered into a prerandomization screening phase of up to 8 weeks, to allow for adjustments in lipid-lowering therapy, to achieve stable low-density lipoprotein cholesterol (LDL-C) concentrations <100 mg/dl. During this period, patients underwent 18F-FDG-PET/computed tomography (CT), and those with average maximum target-to-background ratio (TBR) of 1.6 or higher (in an index vessel—i.e., either right carotid, left carotid, or ascending aorta) were eligible for randomization.

Patients were randomized to either 600 mg/day of dalcetrapib or matching placebo, in addition to standard of care medications.

Concomitant Medications:

Statin (87%)

Principal Findings:

A total of 130 patients were randomized, 64 to dalcetrapib and 66 to placebo. About 30% had diabetes mellitus, 73% had hypertension, 85% had established CHD, 8% had symptomatic carotid disease, and 12% had peripheral arterial disease. The mean baseline total, LDL, and HDL-C values were 145.8, 74.2, and 44.4 mg/dl, respectively. Baseline PET-FDG and MRI measurements were similar between the two arms.

Dalcetrapib resulted in a 31% increase in HDL, 0.1% increase in LDL, 7% increase in total cholesterol, and 7.3% decrease in triglycerides after 24 months as compared with placebo, in addition to a 33% increase in high-sensitivity C-reactive protein. Based on MRI findings (average values for carotid), a significant reduction in total vessel area and a trend towards reduction in average wall area were observed with dalcetrapib vs. placebo at 24 months (-4.01 mm2; 95% confidence interval [CI] -7.23 to -0.80; p = 0.04 and -2.20 mm2; 95% CI -4.54 to 0.13; p = 0.12, respectively). Based on PET/CT, the most diseased segment mean of maximum TBR was unchanged with dalcetrapib versus placebo after 6 months (-0.07; 95% CI -0.11 to 0.25; p = 0.51).

Safety profile seemed to be similar between the two arms, with no increase in mean blood pressure noted with dalcetrapib, with a similar number of patients increasing from baseline to high systolic blood pressure and diastolic blood pressure at 24 months. All cardiovascular events were similar between the dalcetrapib and placebo arms (3% vs. 11%).

Interpretation:

The results of this small phase II trial indicate that dalcetrapib is not associated with any difference in plaque inflammation (as assessed by 18F-FDG-PET uptake, suggesting no pro- or anti-inflammatory effects), with a slight reduction in plaque volume at 2 years, as compared with placebo in patients with established CHD or at risk for CHD. The results of larger, ongoing phase III trials with dalcetrapib powered for clinical endpoints are awaited.

References:

Fayad ZA, Mani V, Woodward M, et al., on behalf of the dal-PLAQUE Investigators. Safety and efficacy of dalcetrapib on atherosclerotic disease using novel non-invasive multimodality imaging (dal-PLAQUE): a randomised clinical trial. Lancet 2011;Sep 12:[Epub ahead of print].

Presented by Dr. Zahi Fayad at the European Society of Cardiology Congress, Paris, France, August 2011.

Fayad ZA, Mani V, Woodward M, et al. Rationale and design of dal-PLAQUE: a study assessing efficacy and safety of dalcetrapib on progression or regression of atherosclerosis using magnetic resonance imaging and 18F-fluorodeoxyglucose positron emission tomography/computed tomography. Am Heart J 2011;162:214-221.e2.

Clinical Topics: Diabetes and Cardiometabolic Disease, Dyslipidemia, Noninvasive Imaging, Prevention, Vascular Medicine, Lipid Metabolism, Nonstatins, Novel Agents, Statins, Computed Tomography, Magnetic Resonance Imaging, Nuclear Imaging, Hypertension

Keywords: Inflammation, Coronary Artery Disease, Follow-Up Studies, Plaque, Atherosclerotic, Sulfhydryl Compounds, Cholesterol, LDL, Tomography, X-Ray Computed, Standard of Care, Quinolines, Peripheral Arterial Disease, Magnetic Resonance Imaging, Positron-Emission Tomography, Fluorodeoxyglucose F18, Cholesterol Ester Transfer Proteins, C-Reactive Protein, Maximum Tolerated Dose, Confidence Intervals, Triglycerides, Lipoproteins, HDL, Hypertension, Diabetes Mellitus


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