Sildenafil for Diaphragmatic Hernia

Overseen By Carrie A Rau, RN

Age: Any Age

Sex: Any

Trial Phase: Phase 2

Sponsor: University of Utah

Must not be taking: Fluconazole

Disqualifiers: Severe heart defect, ECMO, others

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

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 14 days

40 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

Congenital diaphragmatic hernia (CDH) occurs in approximately 1 in 3000 US live births, similar to the incidence seen within the Utah Birth Defects cohort. The diaphragmatic defect compromises lung growth and alters pulmonary vascular development. This is reflected postnatally as respiratory failure, pulmonary hypertension (PH) and overall cardiopulmonary dysfunction, particularly post-repair. Currently, optimal management of post-repair PH remains poorly investigated. Sildenafil citrate is a highly selective phosphodiesterase-5 inhibitor that increases cGMP levels, leading to smooth muscle relaxation and an anti-proliferative effect within the pulmonary vasculature. It is used off-label for many neonatal PH disorders, including PH associated with bronchopulmonary dysplasia and idiopathic persistent PH. Most neonates with CDH born within the Mountain West referral basin are managed at a quaternary care center, Primary Children's Hospital (PCH). Of these neonates with PH, approximately 25% have been treated with off-label sildenafil. However, neither the PCH clinical care group nor others have developed/published a standardized approach for either initiating or discontinuing sildenafil therapy in this group of patients. Thus, the aim of this study is to assess the safety and effectiveness of sildenafil therapy for PH in neonates with CDH within the Utah cohort. Given the relatively short-term outcome and small sample size for this trial, the plan is to use this data to support a larger multicenter randomized trial targeting long-term cardiopulmonary outcomes of infants with CDH and post-repair PH.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you cannot participate if you are on fluconazole when starting the study drug.

Is sildenafil generally safe for humans?

Sildenafil, known as Viagra or Revatio, is generally safe for humans, with common mild side effects like headache, flushing, and indigestion. It has been well-tolerated in studies involving thousands of patients, including those with erectile dysfunction and pulmonary hypertension. ^{1 2 3 4 5}

How is the drug sildenafil unique in treating diaphragmatic hernia?

Sildenafil is unique in treating diaphragmatic hernia because it can be administered intra-amniotically (directly into the amniotic fluid) to improve lung development and reduce pulmonary hypertension before birth, which is not a common approach with other treatments. ^{1 5 6 7 8}

What data supports the effectiveness of the drug sildenafil for diaphragmatic hernia?

Research shows that sildenafil can help improve lung blood flow and reduce high blood pressure in the lungs (pulmonary hypertension) in infants with congenital diaphragmatic hernia. Studies in both humans and animals have demonstrated that sildenafil can stabilize and improve the condition by enhancing oxygenation and reducing the need for other treatments. ^{5 6 7 8 9}

Are You a Good Fit for This Trial?

This trial is for newborns with a birth defect called congenital diaphragmatic hernia (CDH) who are in the NICU at Primary Children's Hospital. They must have had surgery to repair the hernia and show signs of pulmonary hypertension on an echocardiogram taken within 48-72 hours after surgery. Babies can't join if they didn't have surgery, need ECMO, or are allergic to sildenafil.

Inclusion Criteria

Infants admitted to PCH NICU

Has an echocardiogram 48-72 hours after repair with left ventricular eccentricity index (LVEI) ≥ 1.4

Parental consent obtained within 24 hours after the above echocardiogram

Exclusion Criteria

Newborns with a condition called CDH who have not had surgery to fix it.

Receiving extracorporeal membrane oxygenation (ECMO) at the time of the study

Does not have an echocardiogram 48-72 hours post-repair

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

1-2 weeks

Treatment

Participants receive sildenafil citrate 1mg/kg every 8 hours or placebo for up to 14 days

14 days

Follow-up

Participants are monitored for safety and effectiveness after treatment, including incidence of open-label sildenafil use and other outcomes

3 months

What Are the Treatments Tested in This Trial?

Interventions

• Placebo
• Sildenafil Oral Suspension

Trial Overview The study tests whether Sildenafil Oral Suspension, a drug that relaxes blood vessels in the lungs and is used off-label for neonatal pulmonary hypertension, is safe and effective for babies with CDH post-surgery. Some infants will receive this medication while others will get a placebo to compare outcomes.

How Is the Trial Designed?

Group I: Sildenafil citrate Active Control 1 Intervention

Sildenafil citrate 1mg/kg every 8 hours (PO or NG) for up to 14 days

Group II: Placebo Placebo Group 1 Intervention

Equivalent volume of Ora-sweet©/Ora-plus© every 8 hours (PO or NG) for up to 14 days

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

Approved in United States as Viagra for:

• Erectile dysfunction
• Pulmonary arterial hypertension

Approved in United States as Revatio for:

• Pulmonary arterial hypertension

Approved in European Union as Viagra for:

• Erectile dysfunction
• Pulmonary arterial hypertension

Approved in European Union as Revatio for:

• Pulmonary arterial hypertension

Approved in Canada as Viagra for:

• Erectile dysfunction
• Pulmonary arterial hypertension

Approved in Canada as Revatio for:

• Pulmonary arterial hypertension

Who Is Running the Clinical Trial?

University of Utah

Lead Sponsor

Trials

1,169

Recruited

1,623,000+

Published Research Related to This Trial

In a study of 44 neonates with congenital diaphragmatic hernia (CDH), intravenous sildenafil improved oxygenation in 42.3% of treated infants within the first 24 hours of life.

While sildenafil showed potential benefits in oxygenation and reduced pulmonary arterial pressure, it also led to a significant increase in vasopressor support, indicating a need for careful monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Continuous intravenous sildenafil as an early treatment in neonates with congenital diaphragmatic hernia. Kipfmueller, F., Schroeder, L., Berg, C., et al.[2019]

In a study of nine infants with congenital diaphragmatic hernia (CDH), intravenous (IV) sildenafil significantly improved oxygenation and reduced pulmonary artery pressure (PAP) after 72 to 96 hours of treatment.

The use of IV sildenafil also changed the flow dynamics of the patent ductus arteriosus (PDA), indicating a shift from right-to-left to left-to-right flow, which is beneficial for these infants' heart function.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intravenous sildenafil in the management of pulmonary hypertension associated with congenital diaphragmatic hernia. Bialkowski, A., Moenkemeyer, F., Patel, N.[2016]

Intra-amniotic administration of sildenafil in pregnant rabbits shows rapid absorption into fetal organs, with maximum concentrations reached within 1 hour, indicating effective delivery to the fetus.

There was no evidence of organ toxicity in the fetuses after a single dose of sildenafil, confirming the safety of this method and supporting its potential use in treating pulmonary hypertension in congenital diaphragmatic hernia (CDH) cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intra-amniotic sildenafil administration in rabbits: Safety, pharmacokinetics, organ distribution and histologic evaluation. Yoshida, S., Kreger, AM., Shaik, IH., et al.[2023]

In a case study of a 7-week-old infant with congenital diaphragmatic hernia and chronic pulmonary hypertension, sildenafil therapy led to temporary stabilization and allowed for the successful discontinuation of inhaled nitric oxide.

While sildenafil showed some improvement in right ventricular pressure, the infant ultimately did not survive, indicating the need for further research on the safety and efficacy of sildenafil in similar cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment of rebound and chronic pulmonary hypertension with oral sildenafil in an infant with congenital diaphragmatic hernia. Keller, RL., Hamrick, SE., Kitterman, JA., et al.[2019]

Intra-amniotic administration of sildenafil in a rat model of congenital diaphragmatic hernia (CDH) significantly improved pulmonary blood flow and lung development, particularly when administered early at E13.5, leading to better fetal survival rates.

The treatment did not show any negative effects on control fetuses, suggesting that sildenafil is a safe prenatal therapy option for managing CDH-induced pulmonary hypertension.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intra-amniotic sildenafil treatment improves lung blood flow and pulmonary hypertension in congenital diaphragmatic hernia rats. Yoshida, S., Kreger, AM., Gittes, GK.[2023]

Antenatal administration of sildenafil in a fetal rabbit model for congenital diaphragmatic hernia (DH) was safe and maintained therapeutic drug levels without causing maternal or fetal side effects.

Sildenafil treatment improved pulmonary vascular structure and function, reducing vascular resistance and enhancing airway development, which could benefit lung function in fetuses with DH.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Transplacental sildenafil rescues lung abnormalities in the rabbit model of diaphragmatic hernia. Russo, FM., Toelen, J., Eastwood, MP., et al.[2018]

Sildenafil citrate is an effective and well-tolerated treatment for erectile dysfunction, evaluated in over 3700 patients across various studies, with a low discontinuation rate due to adverse events (2.5% for sildenafil vs. 2.3% for placebo).

The most common side effects were mild to moderate, including headache (16% for sildenafil), flushing (10%), and dyspepsia (7%), with no serious complications like priapism reported, indicating a favorable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical safety of oral sildenafil citrate (VIAGRA) in the treatment of erectile dysfunction. Morales, A., Gingell, C., Collins, M., et al.[2022]

Revatio, a medication used to treat pulmonary hypertension, is actually the same drug as sildenafil, which is commonly known as Viagra, highlighting the need for healthcare practitioners to be aware of this dual branding.

There have been incidents where the contraindication of using nitroglycerin with sildenafil was overlooked, emphasizing the importance of educating healthcare providers about the risks associated with Revatio to prevent medication errors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

ALERT: Revatio is another brand name for sildenafil. Koczmara, C., Hyland, S., Greenall, J.[2017]

In a study of 546 men with erectile dysfunction, sildenafil was found to be well tolerated, with common mild side effects including headache (19%), flushing (14%), and dyspepsia (6%).

The adverse events were generally transient and did not lead to significant discontinuation of therapy, indicating that sildenafil is a safe option for treating erectile dysfunction, even in patients with stable cardiovascular conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tolerability and safety profile of sildenafil citrate (Viagra) in Latin American patient populations. Coelho, OR.[2015]

Citations

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

Continuous intravenous sildenafil as an early treatment in neonates with congenital diaphragmatic hernia. [2019]

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

Intravenous sildenafil in the management of pulmonary hypertension associated with congenital diaphragmatic hernia. [2016]

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

Intra-amniotic sildenafil administration in rabbits: Safety, pharmacokinetics, organ distribution and histologic evaluation. [2023]

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

Treatment of rebound and chronic pulmonary hypertension with oral sildenafil in an infant with congenital diaphragmatic hernia. [2019]

5. Switzerland pubmed.ncbi.nlm.nih.gov

Intra-amniotic sildenafil treatment improves lung blood flow and pulmonary hypertension in congenital diaphragmatic hernia rats. [2023]

6. England pubmed.ncbi.nlm.nih.gov

Transplacental sildenafil rescues lung abnormalities in the rabbit model of diaphragmatic hernia. [2018]

7. England pubmed.ncbi.nlm.nih.gov

Clinical safety of oral sildenafil citrate (VIAGRA) in the treatment of erectile dysfunction. [2022]

8. Canada pubmed.ncbi.nlm.nih.gov

ALERT: Revatio is another brand name for sildenafil. [2017]

9. England pubmed.ncbi.nlm.nih.gov

Tolerability and safety profile of sildenafil citrate (Viagra) in Latin American patient populations. [2015]