A Trial of Phosphodiesterase-5 Inhibitor in Neonatal Congenital Diaphragmatic Hernia (TOP-CDH)

NCT05201144 | Recruiting Phase 2 DMC FDA Drug

• 1 other identifier: 148087
• Study Type: interventional
• Target: 40
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Congenital Diaphragmatic Hernia; Pulmonary Hypertension

Outcome Measures

Primary Outcomes (1)

• Change in Left Ventricular Eccentricity Index (LVEI) on echocardiogram after 14 days of study treatment compared to baseline echocardiogram as compared to placebo.

  On echocardiogram, the septal position at end systole with either flattening or bowing into the left ventricle indicates elevated right ventricular pressures, a surrogate for elevated pulmonary arterial pressures and can be used to determine pulmonary hypertension (PH). LVEI has been shown to adequately quantify septal flattening when correlated to cardiac catheterization measures. Its use decreases inter-observer variability and is a reliable assessment of neonatal PH. Elevated values of LVEI ≥ 1.4 are associated with right ventricular half to suprasystemic pressures, consistent with PH. Normative values of LVEI in neonates without PH are ≤1.

  14 days

Secondary Outcomes (5)

• Compare incidence of extracorporeal membrane oxygenation support (ECMO) between study and placebo groups

  14 days

• Compare incidence of death between study and placebo groups

  14 days

• Compare use of additional pulmonary vasodilators between study and placebo groups

  14 days

• Compare new onset hypotension between study and placebo groups

  4 hours

• Compare new onset of oliguria between study and placebo groups

  36 hours

Other Outcomes (2)

• Compare incidence of open-label sildenafil use during/after study period between study and placebo groups

  3 months

• Compare number of ventilator days between study and placebo group

  14 days

Study Arms (2)

Sildenafil citrate

ACTIVE COMPARATOR

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

Drug: Sildenafil Oral Suspension

Placebo

PLACEBO COMPARATOR

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

Other: Placebo

Interventions

Sildenafil Oral Suspension DRUG

Sildenafil citrate is a highly selective PDE-5 inhibitor found in pulmonary vascular smooth muscle cells. Sildenafil acts by increasing cGMP levels in the nitric oxide pathway, leading to smooth muscle relaxation and an anti-proliferative effect within the pulmonary vasculature.

Sildenafil citrate

Placebo OTHER

Equal volume of placebo

Placebo

Eligibility Criteria

• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• Infants admitted to PCH NICU
• Diagnosis of congenital diaphragmatic hernia (CDH)
• Status post-surgical repair of diaphragmatic defect
• 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

You may not qualify if:

• Infants with CDH who do not undergo surgical repair
• Does not have an echocardiogram 48-72 hours post-repair
• Has LVEI \< 1.4 on above echocardiogram
• Has concurrent severe congenital heart defect that requires neonatal cardiac repair
• Has a documented sildenafil allergy
• Concurrent therapy with fluconazole at time of study drug initiation
• Inability to obtain parental consent within 24 hours of the echocardiogram
• Receiving extracorporeal membrane oxygenation (ECMO) at the time of the study

Sponsors & Collaborators

• University of Utah: lead

Study Sites (1)

Primary Children's Hospital

Salt Lake City, Utah, 84113, United States

RECRUITING

MeSH Terms

Conditions

Hernias, Diaphragmatic, Congenital; Hypertension, Pulmonary

Condition Hierarchy (Ancestors)

Congenital Abnormalities; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Hernia, Diaphragmatic; Internal Hernia; Hernia; Pathological Conditions, Anatomical; Pathological Conditions, Signs and Symptoms; Lung Diseases; Respiratory Tract Diseases; Hypertension; Vascular Diseases; Cardiovascular Diseases

Central Study Contacts

Carrie A Rau, RN

CONTACT

801-213-3360; carrie.rau@hsc.utah.edu

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: Study drug/placebo will be drawn up in amber syringes by investigational pharmacy to blind the bedside RN who will be administering the study drug. Only investigational pharmacy is unblinded.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Model Details: randomized, double blinded, placebo controlled pilot trial

Study Record Dates

• First Submitted: January 7, 2022
• First Posted: January 21, 2022
• Study Start: September 15, 2022
• Primary Completion: March 31, 2026
• Study Completion (Estimated): September 30, 2026
• Last Updated: April 4, 2025

Record last verified: 2025-01

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)