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Sildenafil Administration to Treat Neonatal Encephalopathy (SANE-01)

Primary Purpose

Neonatal Encephalopathy

Status
Completed
Phase
Phase 1
Locations
Canada
Study Type
Interventional
Intervention
Sildenafil
Ora-Blend
Sponsored by
McGill University Health Centre/Research Institute of the McGill University Health Centre
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Neonatal Encephalopathy focused on measuring birth asphyxia, brain, hypoxic-ischemic encephalopathy, neonate, neuroprotection, neurorestoration, newborn, sildenafil

Eligibility Criteria

0 Minutes - 48 Hours (Child)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Montreal Children's Hospital

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Placebo Comparator

Arm Label

Sildenafil

Ora-Blend

Arm Description

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

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

Outcomes

Primary Outcome Measures

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

Secondary Outcome Measures

Plasmatic concentrations of sildenafil and N-desmethyl sildenafil
To determine the tolerability of sildenafil (pharmacokinetics/pharmacodynamics)

Full Information

First Posted
June 19, 2016
Last Updated
February 7, 2022
Sponsor
McGill University Health Centre/Research Institute of the McGill University Health Centre
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1. Study Identification

Unique Protocol Identification Number
NCT02812433
Brief Title
Sildenafil Administration to Treat Neonatal Encephalopathy
Acronym
SANE-01
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

2. Study Status

Record Verification Date
February 2022
Overall Recruitment Status
Completed
Study Start Date
July 2016 (Actual)
Primary Completion Date
January 2019 (Actual)
Study Completion Date
January 2022 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
McGill University Health Centre/Research Institute of the McGill University Health Centre

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Neonatal Encephalopathy
Keywords
birth asphyxia, brain, hypoxic-ischemic encephalopathy, neonate, neuroprotection, neurorestoration, newborn, sildenafil

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
28 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Sildenafil
Arm Type
Active Comparator
Arm Description
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
Arm Title
Ora-Blend
Arm Type
Placebo Comparator
Arm Description
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
Intervention Type
Drug
Intervention Name(s)
Sildenafil
Intervention Description
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
Intervention Type
Drug
Intervention Name(s)
Ora-Blend
Intervention Description
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
Primary Outcome Measure Information:
Title
Serious adverse events
Description
Close monitoring for adverse events such as death, hypotension, persistent pulmonary hypertension, altered renal or hepatic function, etc to assess the safety of sildenafil
Time Frame
Day 1 to 14 of life
Secondary Outcome Measure Information:
Title
Plasmatic concentrations of sildenafil and N-desmethyl sildenafil
Description
To determine the tolerability of sildenafil (pharmacokinetics/pharmacodynamics)
Time Frame
Day 2 to 10 of life
Other Pre-specified Outcome Measures:
Title
Brain injury severity as per a previously described brain injury score
Description
Exploratory outcome to explore efficacy (brain injury)
Time Frame
Day 30 of life, compared to day 2 of life
Title
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
Description
Exploratory outcome to explore efficacy (neuroinflammation)
Time Frame
Day 2 to 30 of life
Title
Bayley Scale of Infant Development (BSID-III)
Description
Exploratory outcome to explore efficacy (neurodevelopment)
Time Frame
1 year and 2 years of age

10. Eligibility

Sex
All
Minimum Age & Unit of Time
0 Minutes
Maximum Age & Unit of Time
48 Hours
Accepts Healthy Volunteers
No
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Pia Wintermark, Pia
Organizational Affiliation
McGill University Health Centre/Research Institute of the McGill University Health Centre
Official's Role
Principal Investigator
Facility Information:
Facility Name
Montreal Children's Hospital
City
Montreal
State/Province
Quebec
ZIP/Postal Code
H3C1H3
Country
Canada

12. IPD Sharing Statement

Plan to Share IPD
No
Links:
URL
http://www.neobrainlab.org
Description
Related Info

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Sildenafil Administration to Treat Neonatal Encephalopathy

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