Sildenafil to Repair Brain Injury Secondary to Birth Asphyxia

Study Overview
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Brief Summary
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The investigators will determine the maximum tolerable dose of sildenafil and establish the pharmacokinetic and pharmacodynamic profile of sildenafil in human asphyxiated neonates treated with hypothermia. They will use a 3+3 design to escalate the sildenafil dose up to 6 mg/kg/day (3mg/kg/dose q12h) in asphyxiated neonates demonstrating brain injury despite hypothermia treatment and assess whether we observe any beneficial effects of sildenafil on their brain and cardiopulmonary hemodynamics, without causing serious adverse events

Official Title
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Treatment of Neonatal Encephalopathy With Oral Sildenafil Suspension to Repair Brain Injury Secondary to Birth Asphyxia: An Open-label Dose-finding Clinical Trial (Phase Ib Study)

Conditions
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Birth Asphyxia

Intervention / Treatment
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* Drug: Sildenafil Citrate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male and female neonates meeting the criteria for induced hypothermia: Gestational age ≥ 36 weeks and birth weight ≥ 1800 g; Evidence of fetal distress, i.e., history of an acute perinatal event, cord pH ≤ 7.0 or base deficit ≤ - 16 mEq/L; Evidence of neonatal distress, such as an Apgar score ≤ 5 at 10 minutes, 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). Evidence of brain injury on a brain magnetic resonance imaging (MRI) performed on day 2 of life. Exclusion Criteria: Neonates with complex congenital heart disease Neonates with cerebral malformations Neonates with genetic syndrome Neonates with intraventricular and/or intraparenchymal hemorrhage on MRI performed on day 2 of life

Ages Eligible for Study
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Minimum Age: 0 Days
Maximum Age: 2 Days

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: 3+3 design to escalate the sildenafil dose up to 6 mg/kg/day (3mg/kg/dose q12h)
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Sildenafil<br> | Drug: Sildenafil Citrate<br>* Cohort 1 of 3-6 neonates: 1st dose of 2mg/kg/dose, 2nd dose of 2.5 mg/kg/dose, and subsequent doses of 2.5mg/kg/dose q12h (= 5 mg/kg/day from dose #2) Cohort 2 of 3-6 neonates: 1st dose of 2mg/kg/dose, 2nd dose of 2.5 mg/kg/dose, 3rd dose of 3mg/kg/dose, and subsequent doses of 3mg/kg/dose q12h (= 6 mg/kg/day from dose #3) dose expansion phase in up to 5-15 asphyxiated neonates<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Death | Number of participants with death | within first 10 days of life | 
| Hypotension | Number of participants with hypotension | within first 10 days of life | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Peak Plasma Concentration (Cmax) | Peak Plasma Concentration (Cmax) | within first 10 days of life |