A randomized controlled, phase 2 trial of the viral serpin Serp-1 in patients with acute coronary syndromes undergoing percutaneous coronary intervention.

Abstract

BACKGROUND:

Vascular inflammation can lead to plaque instability and acute coronary syndromes (ACS). Viruses produce potent immunomodulating proteins that regulate key inflammatory pathways. A myxoma virus-derived serpin Serp-1 reduces inflammatory cell invasion and plaque growth in vascular injury models. Our objective was to evaluate the safety and efficacy of Serp-1 in patients with ACS undergoing percutaneous coronary intervention.

METHODS AND RESULTS:

This double-blind pilot trial included 48 ACS patients undergoing percutaneous coronary intervention randomly assigned to Serp-1 at doses of 5 μg/kg (n=19) or 15 μg/kg (n=17) or to placebo (n=12). Serp-1 was given by intravenous bolus immediately before intervention and 24 and 48 hours later. Patients were assessed for safety (primary objective) and efficacy outcomes, including biomarker analysis. In-stent neointimal hyperplasia was evaluated by intravascular ultrasound at 6 months. Key safety outcomes including coagulation parameters and adverse events did not differ between Serp-1 and placebo groups. A dose-dependent reduction in troponin I levels was observed with Serp-1 at 8, 16, 24, and 54 hours (P<0.05) and in creatine kinase-MB levels at 8, 16, and 24 hours after dose (P<0.05). The composite of death, myocardial infarction, or coronary revascularization occurred in 2 of 12 patients with placebo, 5 of 19 in the low-dose group, and none of 17 patients with the high-dose (P=0.058). Intravascular ultrasound did not detect changes in neointimal hyperplasia among groups.

CONCLUSIONS:

This is the first study of a viral serpin demonstrating its safety in ACS patients. The significant reduction in myocardial damage biomarkers supports further assessment of Serp-1 in ACS patients undergoing stent deployment.

CLINICAL TRIAL REGISTRATION:

URL: http://www.clinicaltrials.gov. Unique identifier: NCT00243308.

• Authors: Jean-Claude Tardif, Philippe L L'Allier, Jean Grégoire, Reda Ibrahim, Grant McFadden, William Kostuk, Merril Knudtson, Marino Labinaz, Ron Waksman, Carl J Pepine, Colin Macaulay, Marie-Claude Guertin, Alexandra Lucas
• Journal: Circulation. Cardiovascular interventions (Circ Cardiovasc Interv) Vol. 3 Issue 6 Pg. 543-8 (Dec 2010) ISSN: 1941-7632 [Electronic] United States
• PMID: 21062996 (Publication Type: Clinical Trial, Phase II, Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)

Chemical References

• Biomarkers
• Serine Proteinase Inhibitors
• Serpins

Topics

• Acute Coronary Syndrome (surgery)
• Adult
• Aged
• Angioplasty, Balloon, Coronary (methods)
• Biomarkers
• Double-Blind Method
• Female
• Humans
• Inflammation (etiology)
• Male
• Middle Aged
• Myocardium (pathology)
• Necrosis
• Serine Proteinase Inhibitors (therapeutic use)
• Serpins (adverse effects, therapeutic use)
• Ultrasonography, Interventional