Phospholipase Levels and Serological Markers of Atherosclerosis - PLASMA

Feb 25, 2009
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Author/Summarized by Author:
Anthony A. Bavry, MD, MPH, FACC
Summary Reviewer:
Deepak L. Bhatt, MD, MPH, MBA, FACC
Trial Sponsor:
Anthera Pharmaceuticals
Date Published:
01/01/2009
Date Updated:
02/25/2009
Original Posted Date:
02/25/2009
References

Description:

Secretory phospholipase A2 is important in the development of atherosclerosis.

The goal of this dose-response trial was to evaluate the safety and efficacy of one of four doses of secretory phospholipase A2 inhibitor compared with placebo on secretory phospholipase A2 concentration.

Hypothesis:

Secretory phospholipase A2 inhibitor (A-002) would reduce the concentration of secretory phospholipase A2.

Study Design

  • Placebo Controlled
  • Randomized
  • Blinded
  • Parallel

Patients Screened: 436
Patients Enrolled: 393
Mean Follow Up: 8 weeks
Mean Patient Age: 62 years
Female: 21%

Patient Populations:

  • Patients with stable coronary disease at least 18 years of age
  • Coronary disease was defined as prior myocardial infarction (>12 weeks before enrollment), unstable angina (>6 weeks before enrollment), objective evidence of coronary artery disease, or prior coronary revascularization procedure

Exclusions:

  • Active inflammatory disease
  • Medications likely to alter the inflammatory response (aspirin was allowed at a dose less than 350 mg daily)

Primary Endpoints:

  • Change in secretory phospholipase A2 concentration or activity from baseline to 8 weeks of follow-up

Secondary Endpoints:

  • Change in inflammatory markers, lipid and biochemical indices, lipoprotein subclasses, and oxidized LDL from baseline to 8 weeks of follow-up
  • Treatment emergent adverse events
  • Serious adverse events
  • Electrocardiographic and hemodynamic data
  • Clinical chemistry
  • Hematological measurements

Drug/Procedures Used:

Patients with stable coronary disease were randomized to one of four doses of A-002: (50 mg, n = 79), (100 mg, n = 80), (250 mg, n = 78), (500 mg, n = 77), or placebo (n = 79).

Concomitant Medications:

Baseline medication use was similar between the groups. Overall, the use of aspirin was 92%, thienopyridine was 28%, beta-blocker was 74%, angiotensin-converting enzyme inhibitor or angiotensin-receptor blocker was 56%, and statin was 66%.

Principal Findings:

Overall, 393 patients were randomized. Baseline characteristics were similar between the groups. The mean age was 62 years, proportion of women was 21%, mean body mass index was 30 kg/m2, prior myocardial infarction was 66%, and history of diabetes was 26%.

Secretory phospholipase A2 (pmol/L) from baseline to 8 weeks was: 15.0-5.0 for the 50 mg dose (p < 0.0001), 15.7-2.1 for the 100 mg dose (p < 0.0001), 14.3-2.1 for the 250 mg dose (p < 0.0001), 17.1-0.6 for the 500 mg dose (p < 0.0001), and 15.7-14.3 for placebo (p = NS). These findings were similar in a subgroup of statin-treated patients.

Over the 8-week follow-up, for all the secretory phospholipase A2 groups combined, low-density lipoprotein (LDL) cholesterol was reduced 8.0% (p < 0.01 vs. placebo), oxidized LDL cholesterol was reduced 3.8% (p < 0.01 vs. placebo), non–high-density lipoprotein (HDL) cholesterol was reduced 5.9% (p < 0.001 vs. placebo), HDL cholesterol was reduced 1.5% (p < 0.01 vs. baseline), and apolipoprotein B was reduced 1.8% (p < 0.05 vs. placebo).

There was one serious adverse event in the 500 mg A-002 group, which was an exacerbation of chronic obstructive pulmonary disease. There were no deaths reported. The following adverse events were recorded for treatment versus placebo: headache (6% vs. 0%), nausea (5% vs. 3%), diarrhea (4% vs. 4%), elevated alanine transaminase (3% vs. 0%), and back pain (2% vs. 1%).

Interpretation:

Among patients with stable coronary artery disease, secretory phospholipase A2 inhibitor reduced secretory phospholipase A2 concentrations in a dose-dependent manner. LDL cholesterol was also reduced, mainly by reducing small LDL particle size. The findings appeared to be similar among patients treated with a statin. This agent was generally well tolerated since there were similar adverse events with treatment compared with placebo; however, there was one serious adverse event reported in the 500 mg dose group. Future studies are needed to examine the effect of this novel agent on important cardiovascular outcomes.

References:

Rosenson RS, Hislop C, McConnell D, et al. Effects of 1-H-indole-3-glyoxamide (A-002) on concentration of secretory phospholipase A2 (PLASMA study): a phase II double-blind, randomized, placebo-controlled trial. Lancet 2009;373:649-58.

Keywords: Phospholipases A2, Secretory, Nausea, Coronary Artery Disease, Myocardial Infarction, Follow-Up Studies, Atherosclerosis, Cholesterol, LDL, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Diarrhea, Back Pain, Headache, Lipoproteins, LDL, Pulmonary Disease, Chronic Obstructive, Body Mass Index, Indoles, Phospholipase A2 Inhibitors, Cholesterol, HDL, Lipoproteins, HDL, Diabetes Mellitus


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