Multicenter Stroke Preclinical Assessment Network Analysis of Cardiovascular Risk Factor Subgroups Treated With the Poly(ADP-Ribose) Polymerase Inhibitor Veliparib

Abstract

BACKGROUND: The Stroke Preclinical Assessment Network tested 6 therapeutic interventions initiated at the time of reperfusion after focal ischemic stroke in young mice, aging mice, obese mice, and spontaneously hypertensive rats. This randomized, controlled trial was conducted across 6 sites with concealed treatment and blinded neurobehavior assessments. The trial had an adaptive design with preset levels of efficacy and futility interrogated after each of 4 stages. The primary outcome was turning preference on the corner test at 1month. The PARP (poly(ADP-ribose) polymerase) inhibitor, veliparib, was considered futile after the second stage when pooling all animal models (n=231 veliparib; n=344 placebo). METHODS: A secondary analysis was performed to evaluate veliparib treatment on primary and secondary outcomes in individual subgroup models. RESULTS: Intravenous injection of veliparib at reperfusion failed to show a benefit on the corner test at 7 or 30days of recovery in young mice, obese mice, or spontaneously hypertensive rats. However, in aging mice (15–18 months old), veliparib significantly improved performance on the corner test at 7 (P=0.007) and 30 (P=0.03) days and reduced foot-faults on the grid walk test at 7 (P=0.024) and 30 (P=0.008) days. These effects were independent of sex. Treatment had no effect on magnetic resonance imaging-determined lesion volume. The survival was similar with placebo and veliparib treatments across subgroups, although mortality was high in aging mice. CONCLUSIONS: Veliparib improved functional outcome in aging mice. Because ischemic stroke predominantly occurs in the aging population, further research into the benefit of PARP inhibitors in aged animal models of stroke is warranted.