The main objective of this study is to assess pharmacokinetics features of IV sildenafil in neonates with hypoxic-ischemic encephalopathy and treated by controlled hypothermia. This phase 2 study will prepare a large phase 3 randomized controlled trial to demonstrate the superiority of a combinatory therapy associating IV sildenafil and controlled hypothermia compared to Placebo and controlled hypothermia, on survival without brain lesions on MRI at discharge, in neonates born after 36 weeks of gestation.
1/Neonates born at or after 36 weeks' gestation, treated by therapeutic servo-controlled hypothermia for neonatal hypoxic ischemic encephalopathy.
2/ Social security coverage
3/ Informed consent of one of the two holders of parental authority.
1/ Chromosomal aberrations and major malformations evidenced after birth
2/ Decision for "comfort care only" before study drug administration,
3/ Uncontrolled hemorrhagic syndrome,
4/ Severe hemodynamic failure at initiation, requiring at least two therapies (including either volume expansion, hydrocortisone or inotropes)
Single group
Sildenafil Citrate (IV)
DrugControlled hypothermia initiated before 6h after birth (servo-controlled 33.5°C during 72h followed by a 12-h rewarming period up to 36.5°C), open-label IV Sildenafil Citrate (Revatio®, 10 mg/12.5 mL, Pfizer) 0.4 mg/kg delivered over 3 hours, followed by a maintenance infusion at 1.6 mg/kg/day for 72h
Plasma concentrations of Sildenafil within the first 5 days following treatment initiation.
Pharmacokinetics features of IV sildenafil in neonates with HIE and treated by controlled hypothermia.
Estimated clearance parameters
Pharmacokinetics features of IV sildenafil in neonates with HIE and treated by controlled hypothermia.
volumes of distribution for IV sildenafil (l)
Pharmacokinetics features of IV sildenafil in neonates with HIE and treated by controlled hypothermia.
Area under the plasma sildenafil concentration-time curve
Pharmacokinetics features of IV sildenafil in neonates with HIE and treated by controlled hypothermia.
Maximum plasma sildenafil concentration achieved (individual exposure)
Pharmacokinetics features of IV sildenafil in neonates with HIE and treated by controlled hypothermia.
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Assistance Publique - Hôpitaux de Paris
Lead sponsor
URC-CIC Paris Descartes Necker Cochin
Collaborator
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