Sildenafil Administration to Treat Neonatal Encephalopathy

Study Overview
=================
Brief Summary
-----------------
Despite improvements in neonatal care, birth asphyxia in term newborns remains a serious condition causing significant mortality and long-term morbidity, including cerebral palsy and mental retardation. Currently, no treatment exists to repair brain injuries secondary to neonatal asphyxia. The only available treatment for this condition is hypothermia that may prevent but not repair the development of brain injury. The success of this therapy is limited. Sildenafil already is used with some newborns for other purposes (i.e., persistent pulmonary hypertension), but, surprisingly, its effect on the newborn brain has never been studied systematically. The findings of the investigators in the rat model of term neonatal encephalopathy demonstrated that the administration of sildenafil following asphyxia promotes brain injury recovery. Thus, the investigators hypothesize that sildenafil may improve neurodevelopmental outcome in term asphyxiated newborns, in whom hypothermia treatment has failed to prevent the development of brain injury.

Detailed Description
-----------------
Before being able to run a large multicenter randomized trial to prove this hypothesis, the investigators need to run a phase Ib pilot trial to ensure the feasibility and safety of using sildenafil in this population of newborns. Thus, for this phase Ib study, the investigators hypothesize that sildenafil can be safely used with term asphyxiated newborns treated with hypothermia. The investigators will test this hypothesis with the following specific aims: Safety (primary): ensure that sildenafil can be safely used in asphyxiated newborns treated with hypothermia; Tolerability (secondary): study the pharmacokinetics and pharmacodynamics of sildenafil in these newborns; Efficacy (exploratory): determine whether sildenafil improves neurodevelopment at 2 years of age, decreases brain injury on day 30 of life and decreases neuroinflammation.

Official Title
-----------------
Sildenafil Administration to Treat Neonatal Encephalopathy (SANE) and Repair Brain Injury Secondary to Birth Asphyxia: A Randomized, Double-blind, Placebo-controlled Pilot Phase Ib Study

Conditions
-----------------
Neonatal Encephalopathy

Intervention / Treatment
-----------------
* Drug: Sildenafil
* Drug: Ora-Blend


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Male and female asphyxiated newborns meeting the criteria for induced hypothermia: Gestational age ≥ 36 weeks and birth weight ≥ 1800 g Evidence of fetal distress, such as a history of an acute perinatal event, a cord pH ≤ 7.0 or base deficit ≤ - 16 mEq/L Evidence of neonatal distress, such as an Apgar score ≤ 5 at 10 minutes, a postnatal blood gas pH obtained within the first hour of life ≤ 7.0 or base deficit ≤ - 16 mEq/L, or a continued need for ventilation initiated at birth and continued for at least 10 minutes Evidence of moderate to severe neonatal encephalopathy by an abnormal neurological exam and/or an amplitude-integrated electroencephalogram (aEEG) These newborns will receive whole-body cooling to an esophageal temperature of 33.5°C, initiated within the first 6 hours of life, continued for 72 hours, and then they were slowly rewarmed using standard protocol . Evidence on a brain MRI performed on day 2 of life (while they are treated with hypothermia) of any type of brain parenchymal injury patterns typically encountered in asphyxiated newborns. If they meet the criteria for hypothermia treatment and demonstrate brain injury on day 2 of life, they will be randomized to sildenafil or placebo treatment. Exclusion Criteria: Newborns with complex congenital heart disease Newborns with cerebral malformations Newborns with genetic syndrome Newborns with intraventricular and/or intraparenchymal hemorrhage on the MRI performed on day 2 of life Moribund infants not expected to survive

Ages Eligible for Study
-----------------
Minimum Age: 0 Minutes
Maximum Age: 48 Hours

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Sildenafil<br>Sildenafil 2 mg/kg/dose per os twice a day for seven consecutive days (from day 2 of life to day 9 of life) if brain injury on day 2 of life | Drug: Sildenafil<br>* sildenafil 2 mg/kg/dose per os twice a day for seven consecutive days (from day 2 of life to day 9 of life) if brain injury on day 2 of life<br>|
| Placebo Comparator: Ora-Blend<br>Ora-Blend 2 mg/kg/dose per os twice a day for seven consecutive days (from day 2 of life to day 9 of life) if brain injury on day 2 of life | Drug: Ora-Blend<br>* Ora-Blend, 2 mg/kg/dose per os twice a day for seven consecutive days (from day 2 of life to day 9 of life) if brain injury on day 2 of life<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Serious adverse events | Close monitoring for adverse events such as death, hypotension, persistent pulmonary hypertension, altered renal or hepatic function, etc to assess the safety of sildenafil | Day 1 to 14 of life | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Plasmatic concentrations of sildenafil and N-desmethyl sildenafil | To determine the tolerability of sildenafil (pharmacokinetics/pharmacodynamics) | Day 2 to 10 of life | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
birth asphyxia, brain, hypoxic-ischemic encephalopathy, neonate, neuroprotection, neurorestoration, newborn, sildenafil