Sildenafil for Bronchopulmonary Dysplasia

(SIL02 Trial)

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

106 Participants Needed

Trial Summary

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.

What data supports the idea that Sildenafil for Bronchopulmonary Dysplasia is an effective drug?

The available research shows that Sildenafil might be effective for treating Bronchopulmonary Dysplasia (BPD) in infants. One study suggests that Sildenafil can help improve lung growth and blood vessel development in animal models, which could be beneficial for infants with BPD. Another study indicates that Sildenafil might help with breathing issues related to BPD by improving gas exchange in the lungs. Additionally, some evidence suggests that using Sildenafil could reduce the risk of death in infants with BPD-related lung problems. However, the research is still limited, and more studies are needed to confirm these findings. ^{1 2 3 4 5}

What safety data is available for using sildenafil in treating bronchopulmonary dysplasia?

Several studies have investigated the safety of sildenafil for bronchopulmonary dysplasia. The SILDI-SAFE study is a multicenter, randomized, placebo-controlled trial focusing on safety, pharmacokinetics, and preliminary effectiveness in premature infants. Another pilot study assessed the feasibility of oral sildenafil in extremely preterm infants. Evidence suggests sildenafil is safe and possibly effective, with potential benefits in reducing mortality when used until pulmonary hypertension resolution. However, more clinical trial evidence is needed to confirm these findings. ^{1 2 4 5 6}

Is the drug Sildenafil a promising treatment for Bronchopulmonary Dysplasia?

Yes, Sildenafil shows promise as a treatment for Bronchopulmonary Dysplasia. It has been effective in reducing lung pressure and improving heart function in infants with this condition. Studies suggest it can help improve lung growth and reduce the need for oxygen therapy, potentially improving survival rates. ^{1 2 3 7 8}

What is the purpose of this trial?

Describe the safety of sildenafil in premature infants at risk of bronchopulmonary dysplasia and determine preliminary effectiveness and pharmacokinetics (PK) of sildenafil. Funding Source - FDA OOPD.

Research Team

Matthew M Laughon, MD, MPH

Principal Investigator

University of North Carolina, Chapel Hill

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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]

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]

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]

References

1. New Zealand pubmed.ncbi.nlm.nih.gov

Prophylactic Sildenafil in Preterm Infants at Risk of Bronchopulmonary Dysplasia: A Pilot Randomized, Double-Blinded, Placebo-Controlled Trial. [2021]

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

The effect of sildenafil on evolving bronchopulmonary dysplasia in extremely preterm infants: a randomised controlled pilot study. [2015]

3. England pubmed.ncbi.nlm.nih.gov

Sildenafil attenuates pulmonary inflammation and fibrin deposition, mortality and right ventricular hypertrophy in neonatal hyperoxic lung injury. [2021]

4. Ireland pubmed.ncbi.nlm.nih.gov

Sildenafil, pulmonary hypertension and bronchopulmonary dysplasia. [2017]

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

Sildenafil citrate, bronchopulmonary dysplasia and disordered pulmonary gas exchange: any benefits? [2015]

6. England 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. [2022]

7. Switzerland pubmed.ncbi.nlm.nih.gov

Oral sildenafil for treatment of severe pulmonary hypertension in an infant. [2015]

8. England pubmed.ncbi.nlm.nih.gov

The utility of sildenafil in pulmonary hypertension: a focus on bronchopulmonary dysplasia. [2015]