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Sildenafil Administration to Treat Neonatal Encephalopathy (SANE-01)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02812433
Recruitment Status : Active, not recruiting
First Posted : June 24, 2016
Last Update Posted : October 8, 2019
Sponsor:
Information provided by (Responsible Party):
Pia Wintermark, McGill University Health Centre/Research Institute of the McGill University Health Centre

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.


Condition or disease Intervention/treatment Phase
Neonatal Encephalopathy Drug: Sildenafil Drug: Ora-Blend Phase 1

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 80 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
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
Actual Study Start Date : July 2016
Actual Primary Completion Date : February 2019
Estimated Study Completion Date : June 2022

Resource links provided by the National Library of Medicine


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




Primary Outcome Measures :
  1. Serious adverse events [ Time Frame: Day 1 to 14 of life ]
    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 :
  1. Plasmatic concentrations of sildenafil and N-desmethyl sildenafil [ Time Frame: Day 2 to 10 of life ]
    To determine the tolerability of sildenafil (pharmacokinetics/pharmacodynamics)


Other Outcome Measures:
  1. Brain injury severity as per a previously described brain injury score [ Time Frame: Day 30 of life, compared to day 2 of life ]
    Exploratory outcome to explore efficacy (brain injury)

  2. 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 [ Time Frame: Day 2 to 30 of life ]
    Exploratory outcome to explore efficacy (neuroinflammation)

  3. Bayley Scale of Infant Development (BSID-III) [ Time Frame: 1 year and 2 years of age ]
    Exploratory outcome to explore efficacy (neurodevelopment)



Information from the National Library of Medicine

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Ages Eligible for Study:   up to 48 Hours   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02812433


Locations
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Canada, Quebec
Montreal Children's Hospital
Montreal, Quebec, Canada, H3C1H3
Sponsors and Collaborators
McGill University Health Centre/Research Institute of the McGill University Health Centre
Investigators
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Principal Investigator: Pia Wintermark, Pia McGill University Health Centre/Research Institute of the McGill University Health Centre
Additional Information:
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Responsible Party: Pia Wintermark, Assistant Professor of Paediatrics, McGill University Health Centre/Research Institute of the McGill University Health Centre
ClinicalTrials.gov Identifier: NCT02812433    
Other Study ID Numbers: SANE-01
First Posted: June 24, 2016    Key Record Dates
Last Update Posted: October 8, 2019
Last Verified: October 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Keywords provided by Pia Wintermark, McGill University Health Centre/Research Institute of the McGill University Health Centre:
birth asphyxia
brain
hypoxic-ischemic encephalopathy
neonate
neuroprotection
neurorestoration
newborn
sildenafil
Additional relevant MeSH terms:
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Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Sildenafil Citrate
Vasodilator Agents
Phosphodiesterase 5 Inhibitors
Phosphodiesterase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Urological Agents