Finding Solutions to Thrive After Birth Asphyxia in Africa

Study Overview
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Brief Summary
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Neonatal encephalopathy (NE) is the third leading cause of under 5-year mortality and contributes substantially to long-term neurological morbidity worldwide. In low-income countries (LICs), families often lack the resources to care for affected children. For those with disabilities, stigma is high, and social and emotional impacts are substantial. Improving our understanding of NE in LICs is crucial if intervention strategies are developed. Providing access to an affordable and easy-to-administer treatment after birth may improve survival, early brain development and later outcome, maximizing developmental potential. The primary objective of this study is to investigate the feasibility, safety and tolerability of administering sildenafil as a neuroprotective/neurorestorative strategy to improve early brain development in a cohort of children with NE in Uganda.

Official Title
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Finding Solutions to Thrive After Birth Asphyxia in Africa: 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


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male and female neonates meeting the criteria for birth asphyxia Gestational age ≥ 36 weeks and birth weight ≥ 1800 g; Admitted to Kawempe Hospital or Nsambya Hospital within 48 hours of life; Need for continued resuscitation after birth and/or 5-minute Apgar score ≤5; Evidence of neonatal encephalopathy by an abnormal neurological exam (modified Sarnat score of 2-3 or abnormal aEEG). Exclusion Criteria: Absent heart rate at 10 minutes/imminent death Neonates with major congenital malformations Neonates with grade 3 AKI (serum creatinine rise ≥3x lowest previous creatinine or creatinine > 2.5 mg/dL = 221 mcmol/L or receipt of dialysis) Neonates with intraventricular and/or intraparenchymal hemorrhage on cranial ultrasound (cUS) performed on day 1-2 of life Mother living permanently outside 20km radius of Kawempe Hospital or Nsambya Hospital Neonates whose parents are unwilling or unable to give informed written consent to enter the study

Ages Eligible for Study
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Minimum Age: 0 Days
Maximum Age: 18 Months

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: Phase Ib open-label single-arm dose-finding clinical trial
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Sildenafil<br> | Drug: Sildenafil<br>* Dose group 1st dose 2nd dose 3rd dose 4-14th doses Treatment Total dose/day frequency dose/day Group 1: #1-14=2 mg/kg q12h (4 mg/kg/day) Group 2: #1 = 2 mg/kg, #2-14 = 2.5 mg/kg q12h (5 mg/kg/day) Group 3: #1 = 2 mg/kg, #2 = 2.5 mg/kg, #3-14 = 3 mg/kg q12h (6 mg/kg/day) Group 4: #1 = 2.5 mg/kg, #2-14 = 3 mg/kg q12h (6 mg/kg/day) Group 5: #1-14 = 3 mg/kg q12h (6 mg/kg/day)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum tolerable dose of sildenafil |  | within 30 days of drug administration | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of adverse events (Safety and Tolerability) | safety, assessed through the reporting of adverse events, such as death, hypotension, persistent pulmonary hypertension, altered hepatic function, seizures, intraventricular and/or intraparenchymal hemorrhage | within 30 days of drug administration | 
| Sildenafil concentrations |  | within 30 days of drug administration |