Chronic Sildenafil for Severe Diaphragmatic Hernia

Study Overview
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Brief Summary
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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 presence of prolonged pulmonary hypertension or prolonged oxygen supplementation on mechanical ventilation), as measured by the estimated pulmonary artery systolic pressure following treatment.

Detailed Description
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Congenital diaphragmatic hernia (CDH) is a condition characterized by pulmonary parenchymal and vascular hypoplasia. Severe CDH carries a high rate of mortality, and significant morbidity among survivors. This proposal is a randomized, blinded, placebo-controlled study designed to evaluate the efficacy and potential mechanisms of activity of sildenafil, a phosphodiesterase-5 inhibitor, for treatment of severe CDH. Infants who meet criteria at ≥10d of age predicting a poor outcome [death or chronic lung disease (CLD) severe enough to require hospital discharge on supplemental oxygen (O2)] will be eligible for the study. Infants whose parents consent for the study will undergo an initial echocardiogram to assess the degree of pulmonary hypertension. They will then begin either sildenafil or placebo therapy for a 45d course. A final echocardiogram will be performed after the experimental drug course is completed. The pulmonary arterial systolic pressure estimate during hyperoxic conditions will be compared between the sildenafil and placebo groups. Infants from either group who have severely elevated pulmonary arterial pressure (despite supplemental O2) will be considered for open-label sildenafil, which will continue after hospital discharge, depending on the results of a cardiac catheterization performed for clinical care.

Official Title
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Chronic Sildenafil for Severe Diaphragmatic Hernia

Conditions
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Hernia, Diaphragmatic, Hypertension, Pulmonary, Hypoplasia, Pulmonary

Intervention / Treatment
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* Drug: sildenafil
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Congenital diaphragmatic hernia 10-42 days (d) of age Significant illness severity as demonstrated by: Receiving assisted ventilation and FiO2 >= 0.40 at 10-14d of age, or FiO2 >= 0.40 for >=48hours at 15-27d of age, or FiO2 >= 0.35 at 28-42d of age Or, need for extracorporeal support at >=10d of age Or, estimated pulmonary arterial or right ventricular systolic pressure of >= 2/3 systemic pressure at 14-42d of age Exclusion Criteria: Structural congenital heart disease (other than patent ductus arteriosus or patent foramen ovale/atrial septal defect [ASD] or non-hemodynamically significant ventricular septal defect [VSD]) Sildenafil contraindicated (until condition resolves): Unable to absorb oral medication, or Unstable systemic blood pressure, or Receiving a drug that may interfere with sildenafil metabolism, or Renal insufficiency Hepatic insufficiency Previous use of sildenafil

Ages Eligible for Study
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Minimum Age: 10 Days
Maximum Age: 42 Days

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1<br>Sildenafil x 45 days | Drug: sildenafil<br>* Sildenafil 0.5 mg/kg every 6 hours orally x 45 d<br>* Other names: Viagra, Revatio;|
| Placebo Comparator: 2<br>Placebo x 45 d | Drug: Placebo<br>* Placebo suspension (equal volume to experimental drug) x 45 days<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Estimated Systolic Pulmonary Arterial Pressure at Final Echocardiogram |  | 7 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Systemic Levels of Vasoactive Substances at the Time of Final Echocardiogram |  | 7 weeks | 
| Adverse Effects of Sildenafil Therapy |  | 2 years | 
| Somatic Growth at 1 and 2 Years of Age |  | 2 years | 
| Neurodevelopmental Outcome at 1 and 2 Years of Age |  | 2 years | 
| Respiratory Status at 1 and 2 Years of Age |  | 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Chronic lung disease, Nitric oxide, cyclic guanosine monophosphate, phosphodiesterase inhibitor