Sildenafil for Neonatal Encephalopathy

Recruiting at 1 trial location

Overseen By Gabriel Altit, MD

Age: < 18

Sex: Any

Trial Phase: Phase 2

Sponsor: Pia Wintermark

Disqualifiers: Congenital heart disease, Cerebral malformations, Genetic syndrome, others

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 4 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 30

Duration: 7 days

60 Participants Needed

Trial Summary

What is the purpose of this trial?

Around the time of birth, some babies experience a condition called asphyxia, which means that their brain and other organs do not receive enough blood and/or oxygen to work properly. This life-threatening condition accounts for nearly 1 out of 4 deaths of all babies around the world, and often leads to severe brain damage, cerebral palsy, epilepsy, and trouble with learning and functioning in everyday life. At this time, no treatment is available to repair the brain damage caused by asphyxia. Excitingly, a drug called sildenafil (Viagra®) is already given safely to babies who suffer from increased blood pressure in their lungs' vessels. Recent studies using a laboratory model of asphyxia at birth suggest that sildenafil may also repair the brain damage caused by asphyxia. Similarly, recent small studies have shown that it is both feasible and safe to give sildenafil to human babies, who suffered from asphyxia at birth. These studies also highlight the first promising signs that sildenafil may improve how the brains of these babies work, which is consistent with the abovementioned laboratory studies. On the basis of these previous researches, the investigators predict that sildenafil can repair the damage to a baby's brain. The investigators will test whether sildenafil can be safely given to a large group of human babies who suffer from asphyxia at birth, and will confirm whether sildenafil improves or not how their brains and hearts/lungs work. This project will enable to determine whether sildenafil is a promising treatment for repairing brain damage in babies who suffer from asphyxia at birth. This project may also provide new solutions for these babies to improve their future life.

Will I have to stop taking my current medications?

The trial information does not specify whether participants must stop taking their current medications.

What evidence supports the effectiveness of the drug sildenafil for neonatal encephalopathy?

Research in animal models shows that sildenafil may help improve brain recovery after neonatal brain injury by increasing the number of neurons and reducing harmful inflammation. It has shown potential in promoting brain healing and development in conditions similar to neonatal encephalopathy. ^{1 2 3 4 5}

Is sildenafil safe for use in infants?

Sildenafil has been used in infants for conditions like pulmonary hypertension, but there is a reported case of cerebral hemorrhage (bleeding in the brain) in an infant after a rapid increase in dose. This suggests that while sildenafil can be beneficial, it must be used with caution, especially regarding dosing. ^{1 2 3 4 5}

How does the drug sildenafil differ from other treatments for neonatal encephalopathy?

Sildenafil is unique because it may help improve brain recovery after neonatal brain injury by promoting the growth of new neurons and protecting existing ones, which is not a feature of standard treatments like hypothermia. It works by increasing levels of a molecule called cGMP, which supports brain healing and development. ^{1 2 3 4 6}

Research Team

Pia Wintermark, MD

Principal Investigator

Research Institute of the McGill University Health Centre (The Institute)

Eligibility Criteria

This trial is for newborns with a condition called asphyxia, which can lead to brain damage. They must be at least 36 weeks old at birth, weigh over 1800g, show signs of distress during and after birth, require ventilation, and have evidence of moderate to severe brain issues. Babies with complex heart disease, genetic syndromes, brain malformations or significant bleeding in the brain are not eligible.

Inclusion Criteria

The baby shows signs of distress after birth, such as low Apgar score, abnormal blood gas levels, or needing help to breathe for an extended time.

There are signs of brain injury on a special picture taken of the brain within the first couple of days after birth.

My newborn has a severe brain condition and will undergo cooling treatment.

Exclusion Criteria

My newborn has a brain malformation.

My newborn had a brain bleed detected by MRI on their second day.

My newborn has a complex heart condition present from birth.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

1-2 days

Treatment

Neonates receive sildenafil or placebo for 7 consecutive days if brain injury is detected on day 2 MRI

7 days

Daily administration

Follow-up

Participants are monitored for safety and effectiveness after treatment, including assessment of brain injury and cardiopulmonary function

30 days

Day 30 MRI assessment

Treatment Details

Interventions

• Sildenafil

Trial Overview The trial is testing if sildenafil (Viagra®), known for treating high blood pressure in babies' lungs, can also repair brain damage caused by asphyxia at birth. The study will give sildenafil orally to these babies alongside standard treatments like cooling the body and will check if it improves their brains' and hearts'/lungs' functions.

Participant Groups

Group I: Sildenafil Active Control 1 Intervention

Sildenafil 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 (dose 1=2mg/kg/dose, dose 2=2.5mg/kg/dose, and doses 3-14=3mg/kg/dose)

Group II: Ora-Blend Placebo Group 1 Intervention

Ora-Blend 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 (dose 1=2mg/kg/dose, dose 2=2.5mg/kg/dose, and doses 3-14=3mg/kg/dose)

Sildenafil is already approved in United States, European Union, Canada, Japan for the following indications:

Approved in United States as Viagra for:

• Erectile dysfunction
• Pulmonary arterial hypertension

Approved in European Union as Viagra for:

• Erectile dysfunction
• Pulmonary arterial hypertension

Approved in United States as Revatio for:

• Pulmonary arterial hypertension

Approved in Canada as Sildenafil for:

• Erectile dysfunction
• Pulmonary arterial hypertension

Approved in Japan as Sildenafil for:

• Erectile dysfunction
• Pulmonary arterial hypertension

Who Is Running the Clinical Trial?

Pia Wintermark

Lead Sponsor

Trials

2

Recruited

80+

Findings from Research

In a study involving male Long-Evans rat pups, sildenafil treatment after neonatal hypoxia-ischemia (HI) improved neurological deficits and increased the size of the affected brain hemisphere, suggesting potential benefits for brain recovery.

Sildenafil also significantly increased the number of neurons near the injury site, indicating its possible role in promoting neuronal growth and recovery following brain injury in asphyxiated newborns.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sildenafil Improves Brain Injury Recovery following Term Neonatal Hypoxia-Ischemia in Male Rat Pups. Yazdani, A., Khoja, Z., Johnstone, A., et al.[2018]

In a study involving male Long-Evans rat pups, sildenafil treatment after hypoxia-ischemia (HI) significantly preserved hippocampal structure and increased the number of mature neurons, suggesting its potential neuroprotective effects.

Sildenafil not only reduced cell death and inflammation in the hippocampus but also restored the normal progression of neuronal development, possibly through the activation of the PI3K/Akt/mTOR pathway, indicating its neurorestorative properties.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sildenafil improves hippocampal brain injuries and restores neuronal development after neonatal hypoxia-ischemia in male rat pups. Yazdani, A., Howidi, B., Shi, MZ., et al.[2023]

Sildenafil treatment after hypoxic-ischemic injury in developing mice did not improve overall brain injury scores but did promote the generation of immature neurons, indicating a potential neurogenic response.

The study suggests that sildenafil may aid recovery from hypoxic-ischemic injury by activating the cGMP and PI3K/Akt/GSK-3β signaling pathways, leading to reduced neurological deficits despite no significant changes in histological injury.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sildenafil Enhances Quantity of Immature Neurons and Promotes Functional Recovery in the Developing Ischemic Mouse Brain. Engels, J., Elting, N., Braun, L., et al.[2018]

Sildenafil (Revatio) can effectively improve conditions like pulmonary arteriovenous fistula in infants, but it carries a risk of serious side effects, including cerebral hemorrhage.

In this case, an infant experienced cerebral hemorrhage after a rapid dose increase to 4.7 mg/kg/day, highlighting the need for cautious dose adjustments and awareness of potential complications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cerebral hemorrhage associated with sildenafil (Revatio) in an infant. Samada, K., Shiraishi, H., Aoyagi, J., et al.[2021]

Sildenafil citrate, a PDE-5 inhibitor, showed a significant reduction in brain lesion size in neonatal mice after ischemic stroke, particularly 8 days post-stroke, suggesting its potential as a treatment for neonatal ischemic stroke.

The study indicated that sildenafil may exert its protective effects by modulating the inflammatory response, as it decreased microglial density and altered the expression of inflammatory markers in the brain following the stroke.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sildenafil, a cyclic GMP phosphodiesterase inhibitor, induces microglial modulation after focal ischemia in the neonatal mouse brain. Moretti, R., Leger, PL., Besson, VC., et al.[2019]

Sildenafil, a PDE5 inhibitor that can cross the blood-brain barrier, shows promise as a neuroprotective agent for preventing or repairing brain injuries such as stroke and traumatic brain injury, based on preclinical data.

The review highlights the potential benefits of combining sildenafil with existing treatments to enhance therapeutic outcomes for brain injuries, suggesting a novel approach to managing these conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sildenafil-Mediated Neuroprotection from Adult to Neonatal Brain Injury: Evidence, Mechanisms, and Future Translation. Zinni, M., Pansiot, J., Léger, PL., et al.[2021]

References

1. Switzerland pubmed.ncbi.nlm.nih.gov

Sildenafil Improves Brain Injury Recovery following Term Neonatal Hypoxia-Ischemia in Male Rat Pups. [2018]

2. England pubmed.ncbi.nlm.nih.gov

Sildenafil improves hippocampal brain injuries and restores neuronal development after neonatal hypoxia-ischemia in male rat pups. [2023]

3. Switzerland pubmed.ncbi.nlm.nih.gov

Sildenafil Enhances Quantity of Immature Neurons and Promotes Functional Recovery in the Developing Ischemic Mouse Brain. [2018]

4. United States pubmed.ncbi.nlm.nih.gov

Cerebral hemorrhage associated with sildenafil (Revatio) in an infant. [2021]

5. England pubmed.ncbi.nlm.nih.gov

Sildenafil, a cyclic GMP phosphodiesterase inhibitor, induces microglial modulation after focal ischemia in the neonatal mouse brain. [2019]

6. Switzerland pubmed.ncbi.nlm.nih.gov

Sildenafil-Mediated Neuroprotection from Adult to Neonatal Brain Injury: Evidence, Mechanisms, and Future Translation. [2021]