First Major Clinical Trial of an Oral Agent Inducing ApoA-1 Synthesis: A New Approach to Raising HDL and CV Risk Modification - ASSERT

Description:

The goal of the trial was to compare treatment with the oral inducer of apoA-1 synthesis, RVX-208, compared with placebo among statin-treated patients with stable coronary artery disease (CAD).

Hypothesis:

This is a short-term dose-ranging study to characterize the efficacy, safety, and tolerability of RVX-208.

Study Design

  • Placebo Controlled
  • Randomized
  • Parallel

Patient Populations:

  • Statin-treated patients with stable CAD

    Number of enrollees: 299
    Duration of follow-up: 12 weeks
    Mean patient age: 66 years
    Percentage female: 25%

Primary Endpoints:

  • Median percent change in apoA-1 from baseline

Drug/Procedures Used:

Statin-treated patients with stable CAD were randomized to 12 weeks of RVX-208: 100 mg twice daily (n = 76), 200 mg twice daily (n = 75), or 300 mg twice daily (n = 74) versus placebo (n = 74).

Concomitant Medications:

Concomitant treatment with statin medication

Principal Findings:

Overall, 299 patients were randomized. The mean age was 66 years, 25% were women, body mass index was 31 kg/m2, 29% were diabetics, 17% were smokers, total cholesterol was 150 mg/dl, triglyceride level was 115 mg/dl, high-density lipoprotein (HDL) cholesterol was 44 mg/dl, low-density lipoprotein (LDL) cholesterol was 76 mg/dl, apoA-1 was 141 mg/dl, and high-sensitivity C-reactive protein (hs-CRP) was 1.8 mg/L.

The median change from baseline in apoA-1 was 0.1% in the RVX 100 mg twice daily group (p = 0.09 vs. placebo), 3.8% in the RVX 200 mg twice daily group (p = 0.10 vs. placebo), 5.6% in the RVX 300 mg twice daily group (p = 0.06 vs. placebo), and 0.9% in the placebo group.

The median change from baseline in HDL cholesterol was 3.3% in the RVX 100 mg twice daily group, 6.3% in the RVX 200 mg twice daily group (p < 0.05 vs. placebo), 8.3% in the RVX 300 mg twice daily group (p < 0.01 vs. placebo), with no change in the placebo group. The median change from baseline in large HDL cholesterol was 11.1% in the RVX 100 mg twice daily group, 20.2% in the RVX 200 mg twice daily group (p < 0.01 vs. placebo), 21.1% in the RVX 300 mg twice daily group (p < 0.0001 vs. placebo), and -0.5% in the placebo group. There was no difference in LDL cholesterol, triglycerides, or hs-CRP.

Alanine aminotransferase/aspartate aminotransferase (ALT/AST) >3x upper limit of normal occurred in three patients in the RVX 100 mg twice daily group, eight patients in the RVX 200 mg twice daily group, seven patients in the RVX 300 mg twice daily group, and no patients in the placebo group (p = 0.009 for RVX vs. placebo).

Interpretation:

Among statin-treated patients with stable CAD, the use of RVX-208 nonsignificantly increased apoA-1; however, HDL cholesterol and large HDL particles were increased in a dose-dependent fashion. Elevation in liver transaminase levels will need to be carefully monitored. The impact of RVX-208 on clinical outcomes is unknown.

References:

Presented by Dr. Stephen Nicholls at the American Heart Association Scientific Sessions, Chicago, IL, November 17, 2010.

Clinical Topics: Diabetes and Cardiometabolic Disease, Dyslipidemia, Atherosclerotic Disease (CAD/PAD), Lipid Metabolism, Nonstatins, Novel Agents, Statins, Triglycerides

Keywords: Cholesterol, Coronary Artery Disease, Quinazolines, C-Reactive Protein, Follow-Up Studies, Body Mass Index, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Apolipoprotein A-I, Triglycerides, Diabetes Mellitus


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