Phospholipase Levels and Serological Markers of Atherosclerosis - PLASMA


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.


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


  • 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%).


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.


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.

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

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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