Sildenafil for Bronchopulmonary Dysplasia

(SIL02 Trial)

No longer recruiting at 14 trial locations

Overseen By Talaya McCright-Gill, MA

Age: < 18

Sex: Any

Trial Phase: Phase 2

Sponsor: University of North Carolina, Chapel Hill

Must not be taking: Vasopressors, Inhaled nitric oxide

Disqualifiers: Sickle cell disease, 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: Unknown

Duration: 4 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests the safety and effectiveness of sildenafil, a medication commonly used for erectile dysfunction and pulmonary hypertension, in premature infants with breathing issues. It specifically aims to assist babies at risk of bronchopulmonary dysplasia, a serious lung condition. Eligible babies are those born before 29 weeks of pregnancy and currently requiring breathing support, such as a ventilator or oxygen. The study compares different doses of sildenafil with a placebo (a harmless sugar solution) to evaluate the treatment's effectiveness. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group, contributing to important early-stage findings.

Do I have to stop taking my current medications for the trial?

The trial protocol does not specify if you need to stop taking your current medications. However, you cannot participate if you are currently receiving vasopressors or inhaled nitric oxide.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that sildenafil might be safe for premature babies at risk of bronchopulmonary dysplasia (BPD), a lung condition. Previous studies suggest that although sildenafil is not officially approved for this purpose, it is sometimes used in these infants and may help reduce lung damage.

Studies have also found that sildenafil does not increase the risk of serious eye problems in very low birth weight babies. However, the FDA has not provided specific guidelines for using sildenafil in newborns, resulting in limited detailed safety information. As this trial begins, it primarily aims to assess the safety of sildenafil and how well infants tolerate it.

Overall, while some safety information is encouraging, more research is needed to confirm the safety and effectiveness of sildenafil for this specific use. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for bronchopulmonary dysplasia?

Most treatments for bronchopulmonary dysplasia (BPD) focus on managing symptoms and supporting lung function, often using steroids or oxygen therapy. But sildenafil offers a fresh approach. Unlike conventional treatments, sildenafil works by relaxing blood vessels in the lungs, potentially improving blood flow and reducing lung pressure. This unique mechanism could offer a new way to address the underlying issues in BPD, which excites researchers looking for more effective options. Additionally, sildenafil's flexible administration, either intravenously or enterally, provides versatility in treating infants with this challenging condition.

What evidence suggests that sildenafil might be an effective treatment for bronchopulmonary dysplasia?

Research has shown that sildenafil, which participants in this trial may receive, might help with breathing problems in premature babies at risk of bronchopulmonary dysplasia (BPD). Studies have found that sildenafil can lower lung pressure and improve breathing in these babies. In early tests, sildenafil also protected the lungs and maintained healthy blood vessels. Initial clinical experiences suggest that sildenafil might prevent lung issues related to BPD by reducing the risk of high blood pressure in the lungs (pulmonary hypertension). These findings indicate that sildenafil could be a promising treatment for managing BPD in infants. ^{1 2 6 7 8}

Who Is on the Research Team?

Matthew M Laughon, MD, MPH

Principal Investigator

University of North Carolina, Chapel Hill

Are You a Good Fit for This Trial?

This trial is for premature infants born before 29 weeks of gestation, who need help breathing and are between 7-28 days old. Infants cannot participate if they have certain liver issues, blood pressure lower than a specific threshold, are on blood pressure medications, have an allergy to sildenafil, are receiving inhaled nitric oxide or have sickle cell disease.

Inclusion Criteria

I was born before reaching 29 weeks of pregnancy.

My baby is between 7 and 28 days old.

I am on a breathing support machine or receiving high-flow oxygen.

Exclusion Criteria

I am currently on medication to raise my blood pressure.

My blood pressure is lower than expected for my age in weeks, before taking sildenafil.

I am currently using inhaled nitric oxide.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive sildenafil or placebo in a dose-escalating manner for 28 days

4 weeks

Daily administration

Follow-up

Participants are monitored for safety and effectiveness after treatment

14 days

What Are the Treatments Tested in This Trial?

Interventions

• Placebo
• Sildenafil

Trial Overview The study is testing the safety and initial effectiveness of sildenafil in these young patients at risk for lung problems (bronchopulmonary dysplasia). It will also look at how the drug moves through and leaves their bodies. Some babies will get sildenafil while others will receive a placebo with no active medicine.

How Is the Trial Designed?

Group I: Sildenafil cohort 3 Experimental Treatment 1 Intervention

Cohort 3 infants will receive sildenafil 1 mg/kg daily every 8 hours intravenously (IV) or 2 mg/kg daily every 8 hours enterally for 28 days.

Group II: Sildenafil cohort 2 Experimental Treatment 1 Intervention

Cohort 2 infants will receive sildenafil 0.5 mg/kg daily every 8 hours intravenously (IV) or 1 mg/kg daily every 8 hours enterally for 28 days.

Group III: Sildenafil cohort 1 Experimental Treatment 1 Intervention

Within cohort 1 infants will be randomized using a 3:1 scheme to receive sildenafil or placebo. Infants randomized to sildenafil will receive 0.125 mg/kg daily every 8 hours intravenously (IV), or 0.25 mg/kg daily every 8 hours enterally for 28 days.

Group IV: Placebo cohort 3 Placebo Group 1 Intervention

Infants randomized to the placebo treatment group will receive the equivalent of dextrose 5% (sugar water) to be administered IV or enteral use.

Group V: Placebo cohort 1 Placebo Group 1 Intervention

Infants randomized to the placebo treatment group will receive the equivalent of dextrose 5% (sugar water) to be administered IV or enteral use.

Group VI: Placebo cohort 2 Placebo Group 1 Intervention

Infants randomized to the placebo treatment group will receive the equivalent of dextrose 5% (sugar water) to be administered IV or enteral use.

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?

University of North Carolina, Chapel Hill

Lead Sponsor

Trials

1,588

Recruited

4,364,000+

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

Collaborator

Trials

2,103

Recruited

2,760,000+

The Emmes Company, LLC

Industry Sponsor

Trials

149

Recruited

1,052,000+

Peter Ronco

The Emmes Company, LLC

Chief Executive Officer since 2023

BSc from Nottingham University

Dr. Joe Sliman

The Emmes Company, LLC

Chief Medical Officer since 2020

MD from Uniformed Services University of the Health Sciences, MPH from Johns Hopkins University, BSc in Molecular and Cell Biology from Pennsylvania State University

Duke University

Collaborator

Trials

2,495

Recruited

5,912,000+

Published Research Related to This Trial

Sildenafil citrate, a phosphodiesterase-V inhibitor, shows promise as a safe and potentially effective treatment for pulmonary hypertension (PH) secondary to bronchopulmonary dysplasia (BPD) in infants, although evidence is limited.

Continuing sildenafil treatment until the resolution of PH may lead to reduced mortality in infants suffering from this serious condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sildenafil, pulmonary hypertension and bronchopulmonary dysplasia. Herbert, S., Tulloh, R.[2017]

Oral sildenafil was successfully used in a 5-month-old preterm infant with severe bronchopulmonary dysplasia and pulmonary arterial hypertension that did not respond to other treatments, leading to significant improvements in heart function and reduced pulmonary arterial pressure within 48 hours.

The treatment was continued for 6 months, resulting in the complete resolution of pulmonary arterial hypertension without any adverse effects, suggesting that sildenafil can be a safe and effective option for this condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Oral sildenafil for treatment of severe pulmonary hypertension in an infant. Hon, KL., Cheung, KL., Siu, KL., et al.[2015]

In a Phase II clinical trial involving 40 extremely and very preterm infants, sildenafil did not show any significant benefits in preventing bronchopulmonary dysplasia (BPD) or death compared to a placebo, indicating it may not be effective for this purpose.

The study found no side effects associated with sildenafil, but it also highlighted the need for further research on different dosing regimens before considering sildenafil as a treatment option for BPD.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Prophylactic Sildenafil in Preterm Infants at Risk of Bronchopulmonary Dysplasia: A Pilot Randomized, Double-Blinded, Placebo-Controlled Trial. Abounahia, FF., Abu-Jarir, R., Abounahia, MF., et al.[2021]

Sildenafil is a safe and effective treatment for pulmonary hypertension (PH) in infants with bronchopulmonary dysplasia (BPD), showing improved survival rates from 61% to 81% at 12 months when treatment is continued until PH resolution.

Starting doses of sildenafil should be 0.5 mg/kg every 8 hours, increasing to 2 mg/kg every 6 hours as needed, and in cases where PH is resistant to treatment, combining sildenafil with endothelin antagonists and prostacyclin analogues may enhance outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The utility of sildenafil in pulmonary hypertension: a focus on bronchopulmonary dysplasia. Wardle, AJ., Wardle, R., Luyt, K., et al.[2015]

In a pilot study involving 20 extremely preterm infants, oral sildenafil treatment did not improve short-term respiratory outcomes compared to placebo, as measured by the length of invasive and non-invasive ventilation.

Sildenafil was associated with more postnatal steroid treatments and one case of hypotension, indicating potential safety concerns in this vulnerable population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The effect of sildenafil on evolving bronchopulmonary dysplasia in extremely preterm infants: a randomised controlled pilot study. König, K., Barfield, CP., Guy, KJ., et al.[2015]

Sildenafil treatment significantly improves survival and lung function in experimental models of bronchopulmonary dysplasia (BPD) by increasing lung cGMP levels and reducing inflammation and right ventricular hypertrophy.

Starting sildenafil treatment during hyperoxia exposure enhances alveolarization and restores pulmonary angiogenesis, demonstrating its potential as a therapeutic intervention for preterm infants with BPD.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sildenafil attenuates pulmonary inflammation and fibrin deposition, mortality and right ventricular hypertrophy in neonatal hyperoxic lung injury. de Visser, YP., Walther, FJ., Laghmani, el H., et al.[2021]

In a study of 21 preterm infants with bronchopulmonary dysplasia-associated pulmonary hypertension, sildenafil citrate significantly reduced estimated right ventricular peak systolic pressure, indicating a positive effect on pulmonary artery pressures.

Despite the reduction in pulmonary pressures, most infants did not show improvement in gas exchange after 48 hours of treatment, highlighting a potential limitation in the efficacy of sildenafil for this condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sildenafil citrate, bronchopulmonary dysplasia and disordered pulmonary gas exchange: any benefits? Nyp, M., Sandritter, T., Poppinga, N., et al.[2015]

This study is a multicenter, randomized, placebo-controlled trial involving 120 premature infants with severe bronchopulmonary dysplasia, aimed at assessing the safety and preliminary effectiveness of sildenafil in preventing pulmonary hypertension.

Sildenafil, a known pulmonary vasodilator, may improve lung development in premature infants, and this trial will provide crucial safety data and insights into its pharmacokinetics, which could inform future efficacy trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety of sildenafil in premature infants with severe bronchopulmonary dysplasia (SILDI-SAFE): a multicenter, randomized, placebo-controlled, sequential dose-escalating, double-masked, safety study. Schneider, S., Bailey, M., Spears, T., et al.[2022]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6681505/

Sildenafil for bronchopulmonary dysplasia and pulmonary ... Our results show that sildenafil appears to be associated with improvements in estimates of PAP and respiratory scores; however, sildenafil showed no effect on ...

2. mdpi.com mdpi.com/2227-9067/10/8/1397

Efficacy of Sildenafil in Infants with Bronchopulmonary ... We also found improvement in clinical outcomes at 14 weeks following sildenafil treatment initiation. However, since there is no control arm in ...

3. sciencedirect.com sciencedirect.com/science/article/pii/S2451865422001429

Safety of sildenafil in premature infants at risk ... Sildenafil reduces lung injury and preserves normal vasculature in preclinical models, and improves outcomes in children with pulmonary hypertension, and thus ...

4. scholars.duke.edu scholars.duke.edu/individual/pub1468839

Safety of sildenafil in premature infants with severe ... Sildenafil may therefore prevent the development of pulmonary hypertension associated with lung disease of prematurity by reducing pulmonary ...

5. publications.aap.org publications.aap.org/hospitalpediatrics/article/6/1/27/26295/Sildenafil-Treatment-of-Infants-With

Sildenafil Treatment of Infants With Bronchopulmonary ... Early clinical experience indicates that sildenafil treatment may be efficacious for infants with BPD-PH, with evidence suggesting that ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT04447989

Safety of Sildenafil in Premature Infants With Severe ... This is a multicenter, randomized, placebo-controlled, sequential dose-escalating, double-masked, safety study of sildenafil in premature infants.

7. nature.com nature.com/articles/jp2015201

More safety data: what about efficacy of sildenafil? The study did not show an increased risk for severe retinopathy of prematurity for very low birth weight infants on sildenafil.

8. bmcpediatr.biomedcentral.com bmcpediatr.biomedcentral.com/articles/10.1186/s12887-020-02453-7

Safety of sildenafil in premature infants with severe ... The FDA does not recommend sildenafil for PH in children 1 to 17 years of age and there are no recommendations regarding its use in neonates and ...