Sildenafil Administration to Treat Neonatal Encephalopathy (SANE-01)

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

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.

Study Overview

• Status: Completed
• Conditions: Neonatal Encephalopathy
• Intervention / Treatment: Drug: Sildenafil; Drug: Ora-Blend

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.

• Study Type: Interventional
• Enrollment (Actual): 28
• Phase: Phase 1

Contacts and Locations

Study Locations

• Canada
  • Quebec
    • Montreal, Quebec, Canada, H3C1H3
      • Montreal Children's Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 second to 2 days (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Sildenafil; 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; 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
Placebo Comparator: Ora-Blend; 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; 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

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Brain injury severity as per a previously described brain injury score	Exploratory outcome to explore efficacy (brain injury)	Day 30 of life, compared to day 2 of life
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	Exploratory outcome to explore efficacy (neuroinflammation)	Day 2 to 30 of life
Bayley Scale of Infant Development (BSID-III)	Exploratory outcome to explore efficacy (neurodevelopment)	1 year and 2 years of age

Collaborators and Investigators

• Sponsor: McGill University Health Centre/Research Institute of the McGill University Health Centre
• Investigators: Principal Investigator: Pia Wintermark, Pia, McGill University Health Centre/Research Institute of the McGill University Health Centre

Publications and helpful links

Helpful Links

• Related Info

Study record dates

Study Major Dates

• Study Start (Actual): July 1, 2016
• Primary Completion (Actual): January 1, 2019
• Study Completion (Actual): January 1, 2022

Study Registration Dates

• First Submitted: June 19, 2016
• First Submitted That Met QC Criteria: June 21, 2016
• First Posted (Estimate): June 24, 2016

Study Record Updates

• Last Update Posted (Actual): February 8, 2022
• Last Update Submitted That Met QC Criteria: February 7, 2022
• Last Verified: February 1, 2022

More Information

Terms related to this study

• Keywords: sildenafil; brain; newborn; neonate; neuroprotection; hypoxic-ischemic encephalopathy; neurorestoration; birth asphyxia
• Additional Relevant MeSH Terms: Central Nervous System Diseases; Nervous System Diseases; Brain Diseases; Molecular Mechanisms of Pharmacological Action; Vasodilator Agents; Urological Agents; Enzyme Inhibitors; Phosphodiesterase Inhibitors; Phosphodiesterase 5 Inhibitors; Sildenafil Citrate
• Other Study ID Numbers: SANE-01

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No