Sildenafil for Neonatal Encephalopathy

Recruiting at 2 trial locations

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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to test whether sildenafil, a drug already safely used for other conditions in babies, can help repair brain damage in newborns who didn't receive enough oxygen at birth (a condition called asphyxia). Researchers believe sildenafil might improve brain function in these babies after such a traumatic birth event. Babies suitable for this trial have shown signs of brain injury on an MRI scan (a type of detailed brain imaging) two days after birth. Through this trial, scientists hope to discover a potential new treatment that could enhance these babies' future health and quality of life. As a Phase 2 trial, this research focuses on measuring sildenafil's effectiveness in an initial, smaller group of newborns, offering a chance to contribute to potentially groundbreaking treatment advancements.

Will I have to stop taking my current medications?

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

Is there any evidence suggesting that sildenafil is likely to be safe for human babies?

Research has shown that sildenafil, commonly used to treat high blood pressure in infants' lungs, might aid in brain injuries caused by oxygen deprivation at birth. Studies have found that administering sildenafil to newborns with brain injuries is safe and well-tolerated. Specifically, doses up to 3.0 mg/kg given twice daily were tested in newborns, and results indicated the drug's safety. No major safety concerns emerged in these early small studies, suggesting promise for the drug's potential to help these infants. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Sildenafil is unique because, unlike traditional treatments for neonatal encephalopathy, which often focus on supportive care, it targets blood flow to the brain. This medication is traditionally used for erectile dysfunction and pulmonary hypertension, but researchers believe it could help improve oxygen delivery to the brain in newborns with brain injury. Its ability to potentially enhance cerebral circulation makes it an exciting option, offering a novel mechanism of action compared to existing supportive care methods.

What evidence suggests that sildenafil might be an effective treatment for neonatal encephalopathy?

Research has shown that sildenafil, a drug often used for lung problems in babies, might help heal brain damage caused by a lack of oxygen at birth. Lab studies suggest it could repair the brain under low-oxygen conditions. In this trial, some participants will receive sildenafil, which small studies have safely administered to babies showing signs of brain injury. Early results from these studies indicate possible improvements in brain function. These findings suggest that sildenafil could be a promising treatment for newborns with brain damage due to lack of oxygen. ^{1 2 3 4 5}

Who Is on the Research Team?

Pia Wintermark, MD

Principal Investigator

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

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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, 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]

Citations

1.

pubmed.ncbi.nlm.nih.gov

pubmed.ncbi.nlm.nih.gov/40562301/

Testing Higher Doses of Sildenafil to Repair Brain Injury ...

Conclusions: Enteral sildenafil up to 3.0 mg/kg q12 h was safe and well tolerated in a small single-center cohort of neonates with HIE treated with TH. Phase 2 ...

2.

sciencedirect.com

sciencedirect.com/science/article/pii/S0022347625002422

Testing Higher Doses of Sildenafil to Repair Brain Injury ...

Enteral sildenafil up to 3.0 mg/kg q12 h was safe and well tolerated in a small single-center cohort of neonates with HIE treated with TH. Phase 2 trials are ...

3.

clinicaltrials.gov

clinicaltrials.gov/study/NCT06098833

Treatment of Neonatal Encephalopathy With Oral Sildenafil ...

Recent studies using a laboratory model of asphyxia at birth suggest that sildenafil may also repair the brain damage caused by asphyxia. Similarly, recent ...

4.

jpeds.com

jpeds.com/article/S0022-3476(23)00743-6/fulltext

Feasibility and Safety of Sildenafil to Repair Brain Injury ...

The composite outcome of death or survival to 18-month with severe neurodevelopmental impairment was present in 57% (4/7) in the sildenafil ...

5.

pubmed.ncbi.nlm.nih.gov

pubmed.ncbi.nlm.nih.gov/38142044/

Feasibility and Safety of Sildenafil to Repair Brain Injury ...

Among surviving neonates, partial recovery of injury, fewer cystic lesions, and less brain volume loss on day-30 magnetic resonance imaging were noted in 71% (5 ...