To test feasibility and safety of administering sildenafil in neonates with neonatal encephalopathy (NE), developing brain injury despite therapeutic hypothermia (TH).
We performed a randomized, double-blind, placebo-controlled phase Ib clinical trial between 2016 and 2019 in neonates with moderate or severe NE, displaying brain injury on day of life 2 magnetic resonance imaging (MRI) despite TH. Neonates were randomized (2:1) to 7-day sildenafil or placebo (2 mg/kg/dose enterally q12h, 14 doses). Outcomes included feasibility and safety (primary outcomes), pharmacokinetics (secondary), day-30 neuroimaging and 18-month neurodevelopment assessments (exploratory).
Of the 24 enrolled neonates, 8 were randomized to sildenafil and 3 to placebo. A mild decrease in blood pressure was reported in 2/8 neonates after initial dose, but not with subsequent doses. Sildenafil plasma steady-state concentration was rapidly reached, but decreased after TH discontinuation. Twelve percent (1/8) of neonates died in sildenafil group and 0% (0/3) in placebo group. Among surviving neonates, partial recovery of injury, fewer cystic lesions, and less brain volume loss on day-30 MRI were noted in 71% (5/7) of the sildenafil group and in 0% (0/3) in placebo group. Rate of death or survival to 18-month with severe neurodevelopmental impairment was 57% (4/7) in the sildenafil group and 100% (3/3) in placebo group.
Sildenafil was safe and well absorbed in neonates with NE treated with TH. Optimal dosing needs to be established. Evaluation of a larger number of neonates through subsequent phases II and III trials will then be required to establish efficacy.
Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.
