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


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.


BACKGROUND
URL: http://www.clinicaltrials.gov. Unique identifier: NCT00243308.
Department of Medicine, Montreal Heart Institute and Université de Montréal, Montreal, Quebec, Canada. jean-claude.tardif@icm-mhi.org
Jean-Claude
JC
Tardif
Philippe L
PL
L'Allier
Jean
J
Grégoire
Reda
R
Ibrahim
Grant
G
McFadden
William
W
Kostuk
Merril
M
Knudtson
Marino
M
Labinaz
Ron
R
Waksman
Carl J
CJ
Pepine
Colin
C
Macaulay
Marie-Claude
MC
Guertin
Alexandra
A
Lucas
D054058:Acute Coronary Syndrome / Q000601:surgery*; D000328:Adult; D000368:Aged; D015906:Angioplasty, Balloon, Coronary / Q000379:methods*; D015415:Biomarkers; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D007249:Inflammation / Q000209:etiology; D008297:Male; D008875:Middle Aged; D009206:Myocardium / Q000473:pathology; D009336:Necrosis; D015842:Serine Proteinase Inhibitors / Q000627:therapeutic use*; D015843:Serpins / Q000009:adverse effects / Q000627:therapeutic use*; D018084:Ultrasonography, Interventional
D015415:Biomarkers; D015842:Serine Proteinase Inhibitors; D015843:Serpins