Clinical trial NCT02812433: Sildenafil Administration to Treat Neonatal Encephalopathy
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Neonatal Encephalopathy
Keywords: birth asphyxia
brain
hypoxic-ischemic encephalopathy
neonate
neuroprotection
neurorestoration
newborn
sildenafil
Lead sponsor: McGill University Health Centre/Research Institute of the McGill University Health Centre
Sponsor class: OTHER
First posted: 2016-06-24
Enrollment: 28
Sex: ALL
Minimum age (years): 0
Maximum age (years): 48
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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:

1. Safety (primary): ensure that sildenafil can be safely used in asphyxiated newborns treated with hypothermia;
2. Tolerability (secondary): study the pharmacokinetics and pharmacodynamics of sildenafil in these newborns;
3. Efficacy (exploratory): determine whether sildenafil improves neurodevelopment at 2 years of age, decreases brain injury on day 30 of life and decreases neuroinflammation.

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

Primary outcomes:
measure: Serious adverse events
timeFrame: Day 1 to 14 of life
Secondary outcomes:
measure: Plasmatic concentrations of sildenafil and N-desmethyl sildenafil
timeFrame: Day 2 to 10 of life
Other outcomes:
measure: Brain injury severity as per a previously described brain injury score
timeFrame: Day 30 of life, compared to day 2 of life
measure: panel of 45 inflammatory biomarkers known to be involved in neuroinflammation, including interleukin-1 (IL-1) alpha and its receptor, interleukin-6 (IL-6) and tumor necrosis factor (TNF) alpha
timeFrame: Day 2 to 30 of life
measure: Bayley Scale of Infant Development (BSID-III)
timeFrame: 1 year and 2 years of age
Locations:
city: Montreal
country: Canada
facility: Montreal Children's Hospital
state: Quebec
Study officials:
affiliation: McGill University Health Centre/Research Institute of the McGill University Health Centre
name: Pia Wintermark, Pia
role: PRINCIPAL_INVESTIGATOR
References: