Study of Sildenafil to Treat Newborns With Persistent Pulmonary Hypertension

Study Overview
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Brief Summary
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The purpose of this study is to determine whether intravenous sildenafil reduces pulmonary artery pressure and improves oxygenation in near-term and term infants with persistent pulmonary hypertension.

Detailed Description
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Term infants with respiratory failure and persistent pulmonary hypertension (PPHN) are among the most critically ill infants in the NICU, with significant mortality and morbidity reported even for infants with moderate disease. Currently, management is largely supportive, and includes oxygen, mechanical ventilation (conventional or high frequency ventilation), and exogenous surfactant therapy. Inhaled nitric oxide (iNO) is a pulmonary vasodilator that was approved for the treatment of hypoxic respiratory failure (HRF) and PPHN of the newborn in 1999 based on clinical trials showing a reduction in the need for rescue treatment with extracorporeal membrane oxygenation (ECMO). One promising therapy to decrease pulmonary arterial pressure and improve oxygenation is sildenafil. Sildenafil is a cGMP-specific phosphodiesterase inhibitor that causes relatively selective pulmonary vasodilation. The use of intravenous (IV) sildenafil was recently FDA approved for use in adults in PPHN. A pilot trial studying dose response and pharmacokinetics in 36 term newborns with PPHN found that IV sildenafil was well tolerated and has the potential to induce marked improvements in oxygenation. The data from this pilot trial provided background to support the dosing regimen for this Phase II trial. We hypothesize that IV sildenafil will acutely reduce pulmonary artery pressure and improve oxygenation in near-term and term infants with PPHN, thus reducing the need for rescue therapy iNO and/or ECMO.

Official Title
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Phase II Trial of Sildenafil in Newborns With Persistent Pulmonary Hypertension

Conditions
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Persistent Pulmonary Hypertension, Respiratory Failure

Intervention / Treatment
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* Drug: Intravenous Sildenafil
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed informed consent from legally acceptable guardian PPHN or hypoxemic respiratory failure associated with: Idiopathic PPHN Meconium aspiration syndrome Respiratory distress syndrome Sepsis Pneumonia Greater than or equal to 35 weeks gestation Age at enrollment less than 72 hours Moderate hypoxemic respiratory failure, with 12<OI<35 (oxygenation index, calculated as FiO2 * mean airway pressure * 100 / postductal PaO2) Absence of structural heart disease (except patent ductus arteriosus, atrial septal defect <1cm, or muscular ventricular septal defect < 2mm) Absence of lethal congenital anomaly Not participating in another concurrent experimental study Exclusion Criteria: Prior or immediate need for iNO or ECMO Profound hypoxemia: qualifying PaO2 <30 mmHg, from a blood gas drawn within 30 minutes of starting study drug infusion. Hypotension: Mean arterial pressure <35 mmHg Congenital heart disease, except patent ductus arteriosus, atrial septal defect <1cm, or muscular ventricular septal defect <2mm Congenital diaphragmatic hernia or lung hypoplasia syndromes, diagnosed on the basis of prolonged oligohydramnios Active seizures Apgar score of <3 at 5 minutes Bleeding diathesis Receipt of any other experimental drug or device Receipt of any prohibited concurrent medication: Potent cytochrome P450 3A4 inhibitors (e.g., erythromycin, ketoconazole, itraconazole and protease inhibitors) Endothelin antagonists (e.g. Tracleer/bosentan) Intravenous nitrates or nitric oxide donors Known hereditary degenerative retinal disorders such as retinitis pigmentosa. In the opinion of the investigator, a subject who is not likely to complete the study or would be considered inappropriate for the study, for any reason.

Ages Eligible for Study
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Maximum Age: 72 Hours

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: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Intravenous Sildenafil<br> | Drug: Intravenous Sildenafil<br>* 0.4 mg/kg bolus, followed by a continuous infusion of 1.6 mg/kg/day or an equivalent volume of placebo (D5W); infusion will be initiated as a bolus over 3 hours, followed by a controlled continuous infusion for up to 7 days.<br>* Other names: Revatio;|
| Placebo Comparator: Placebo<br>0.4 mg/kg bolus, followed by a continuous infusion of 1.6 mg/kg/day or an equivalent volume of placebo (D5W); infusion will be initiated as a bolus over 3 hours, followed by a controlled continuous infusion for up to 7 days. | Other: Placebo<br>* An equivalent volume of placebo (D5W)infusion will be initiated as a bolus over 3 hours, followed by a controlled continuous infusion for up to 7 days.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Improvement in Oxygenation |  | From baseline values at 4 and 24 hours | 
| Receipt of Standard Therapy at Any Point During the 7-day Treatment Period | Receipt of standard therapy (inhaled nitric oxide [iNO] and/or extracorporeal membrane oxygenation [ECMO]) at any point during the 7-day treatment period | 7-day treatment period | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Pulmonary Arterial Pressure | Change in pulmonary arterial pressure as calculated by echocardiography | Baseline and 4 hours post study drug administration | 
| Duration of Supplemental O2 |  | Participants will be on supplemental O2 an average of 2 weeks | 
| Age at Hospital Discharge |  | Participants will be followed for the duration of hospital stay, an expected average of 3 weeks | 
| Duration of Mechanical Ventilation |  | Participants will be on mechanical ventilation an average of 1 week | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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newborns, respiratory failure, pulmonary hypertension, treatment