430 - Sildenafil administration to treat neonatal encephalopathy (SANE-01) and repair brain injury secondary to birth asphyxia: A randomized, double-blind, placebo-controlled pilot phase Ib study

Poster Number: 430
Publication Number: 430.223

Pia Wintermark, McGill University Faculty of Medicine and Health Sciences, Montreal, PQ, Canada; Anie Lapointe, CHU Ste-Justine, Montréal, PQ, Canada; Robin H. Steinhorn, University of California, San Diego and Rady Children's Hospitaliversity of California, San Diego School of Medicine, San Diego, CA, United States; Emmanouil Rampakakis, McGill University Faculty of Medicine and Health Sciences, Montreal, PQ, Canada; Juergen Burhenne, Heidelberg University Hospital, Heidelberg, Baden-Wurttemberg, Germany; May Khairy, McGill University Faculty of Medicine and Health Sciences, Montreal, PQ, Canada; Gabriel Altit, McGill University Faculty of Medicine and Health Sciences, Montreal, PQ, Canada; Marie-Therese Adamo, University of Montreal, McGill University Health Centre, Montreal, PQ, Canada; Patrick Colin, Patrick Colin Consultant Inc., Carignan, PQ, Canada; Walter E. Haefeli, Department of Clinical Pharmacology and Pharmacoepidemiology / Heidelberg University Hospital, Heidelberg, Baden-Wurttemberg, Germany

Background: Despite introduction of therapeutic hypothermia (TH), birth asphyxia still causes significant mortality and long-term morbidities. Preclinical studies have shown that sildenafil is both neuroprotective and neurorestorative in the neonatal brain after hypoxia-ischemia.

Objective: To test the feasibility and safety of enteral sildenafil in neonates with neonatal encephalopathy (NE) developing brain injury despite TH.

Design/Methods: Sildenafil administration to treat NE and repair brain injury secondary to birth asphyxia (SANE-01) was a phase Ib pilot trial run in a single tertiary level neonatal intensive care unit. Neonates born ≥36w and ≥1800g with moderate-severe NE treated with hypothermia and displaying brain injury on brain magnetic resonance imaging (MRI) on day of life (DOL) 2 were randomized (2:1) to enteral sildenafil (Viagra®) or placebo 2 mg/kg/dose q12h for 7d (DOL 2-9). Primary outcome was safety and included adverse events related to the drug. Secondary outcomes included sildenafil pharmacokinetics. Exploratory outcomes included oxygenation, extent of brain injury on brain MRI on DOL 30, and neurodevelopmental outcomes at 18 months of age. Trial was registered on ClinicalTrials.gov (NCT02812433).

Results: Of 79 screened neonates, 12 were included; 9 were randomized to enteral sildenafil, and 3 to placebo. 9/12 received a full treatment course (1 withdrawal of active care, 1 severe acute kidney injury, and 1dosage error); and 11 survived. No serious adverse events were observed. A mild decrease in blood pressure (≤5mmHg) was recorded in 2/9 neonates after initial sildenafil dose, but not subsequently. These episodes were not considered significant, since blood pressure remained within normal range (≥35mmHg). Average sildenafil plasma levels were >200ng/mL during TH, concentration previously associated with improvement in neonatal pulmonary hypertension. Sildenafil concentrations tended to drop after TH. Partial pressure of oxygen in arterial blood tended to improve after sildenafil. 5/6 neonates treated with sildenafil showed less extensive injury on DOL 30 compared to their MRI on DOL2, with reduced brain volume loss compared to placebo. 2/4 neonates treated with sildenafil followed up to 18 months of age did not display cerebral palsy, global developmental delay, or epilepsy, compared to none in the placebo group.Conclusion(s): Sildenafil appears to be safe in neonates with moderate-severe NE, who develop brain injury despite TH. Sildenafil absorption is adequate even during TH. Its dose may need to be increased after rewarming to achieve its full potential neurorestorative capacity.