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?

This trial tests sildenafil, a medication that relaxes blood vessels, to treat lung problems in newborns with congenital diaphragmatic hernia (CDH) after surgery. CDH involves a hole in the diaphragm that affects lung development, often causing breathing issues and high blood pressure in the lungs. The trial aims to determine if sildenafil can safely improve lung function in these babies. Infants who have undergone CDH surgery and meet specific heart test criteria may be eligible to participate. As a Phase 2 trial, this research measures how well sildenafil works in an initial, smaller group of newborns.

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 there any evidence suggesting that sildenafil is likely to be safe for humans?

Research has shown that sildenafil is usually safe for infants. One study found no serious side effects in infants who took sildenafil. However, some children with lung problems experienced breathing issues and low oxygen levels, leading to the discontinuation of the medication. Despite this, sildenafil is often used to treat various lung conditions in newborns.

Since this trial is in the early stages, the treatment has shown some safety in humans, but researchers are still learning about all the possible effects. Sildenafil is already used for other health issues, providing some confidence about its safety. However, this new trial aims to gather more specific information about its use for conditions like congenital diaphragmatic hernia. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Unlike other treatments for diaphragmatic hernia, which typically focus on surgical repair, sildenafil citrate offers a novel approach by using medication to manage the condition. Researchers are excited about sildenafil because it is traditionally used for improving blood flow, and they believe it could help reduce pulmonary hypertension associated with diaphragmatic hernia. This oral suspension is administered in a way that could provide a non-invasive alternative to surgery, potentially improving outcomes for patients who are not ideal surgical candidates.

What evidence suggests that sildenafil might be an effective treatment for diaphragmatic hernia?

Research has shown that sildenafil can improve lung function in babies with congenital diaphragmatic hernia (CDH). One study found that nine babies with CDH experienced better oxygen levels and reduced high blood pressure in their lungs after receiving sildenafil through an IV. This treatment relaxes lung muscles, facilitating blood flow. This is crucial for newborns with CDH, who often struggle with breathing and lung development. Although few studies exist, these early results are promising for using sildenafil to manage lung issues in babies with CDH. In this trial, participants will receive either sildenafil oral suspension or a placebo to further evaluate its effectiveness. ^{6 7 8 9 10}

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 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]

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]

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]

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]

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]

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]

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]

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]

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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12467270/

Antenatal Sildenafil for Congenital Diaphragmatic Hernia Antenatal treatment with sildenafil has shown some promising protective effects in experimental CDH, but no systematic review has yet evaluated ...

2. withpower.com withpower.com/trial/phase-2-pulmonary-hypertension-ph-2-2022-7628a

Sildenafil for Diaphragmatic Hernia In a study of nine infants with congenital diaphragmatic hernia (CDH), intravenous (IV) sildenafil significantly improved oxygenation and reduced pulmonary ...

3. clinicaltrials.gov clinicaltrials.gov/study/NCT00133679

Chronic Sildenafil for Severe Diaphragmatic Hernia | ... The purpose of this study is to test if sildenafil is effective in the treatment of infants with severe congenital diaphragmatic hernia (determined by the ...

4. frontiersin.org frontiersin.org/journals/bioengineering-and-biotechnology/articles/10.3389/fbioe.2023.1195623/full

Intra-amniotic sildenafil treatment improves lung blood flow ... The E13.5-treated congenital diaphragmatic hernia fetuses also had an increase in lung weight-to-body weight ratio and an improved fetal survival. Intra- ...

5. mdpi.com mdpi.com/2227-9059/13/9/2274/review_report

Antenatal Sildenafil for Congenital Diaphragmatic Hernia Recent large-scale trials in term pregnancies found no benefit and no increase in adverse perinatal outcomes when sildenafil was administered intrapartum for ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT00133679

Chronic Sildenafil for Severe Diaphragmatic Hernia | ... A phase of research to describe clinical trials that focus on the safety of a drug. They are usually conducted with healthy volunteers, and the goal is to ...

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC4709254/

Safety of Sildenafil in Infants* - PMC There is currently no evidence of serious adverse event in infants exposed to sildenafil. Present safety concerns regarding the use of sildenafil in pediatric ...

8. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10399963/

Intra-amniotic sildenafil treatment improves lung blood flow ... Direct sildenafil administration via an intra-amniotic injection may be a promising option in congenital diaphragmatic hernia prenatal therapy. Keywords: ...

9. jpeds.com jpeds.com/article/S0022-3476(18)31402-1/abstract

Sildenafil Use in Children with Pulmonary Hypertension Eighteen deaths were related to PH and 36 from other systemic causes. Two patients stopped sildenafil owing to airway spasm with desaturation.

10. clinicaltrials.gov clinicaltrials.gov/study/NCT00133679?tab=results

Chronic Sildenafil for Severe Diaphragmatic Hernia An unfavorable change in the health of a participant, including abnormal laboratory findings, that happens during a clinical study or within a certain amount of ...