Study of Sildenafil to Treat Newborns With Persistent Pulmonary Hypertension

• Improvement in oxygenation [ Time Frame: From baseline values at 4 and 24 hours ] [ Designated as safety issue: No ]
• Receipt of standard therapy at any point during the 7-day treatment period [ Time Frame: 7-day treatment period ] [ Designated as safety issue: No ]
  Receipt of standard therapy (inhaled nitric oxide [iNO] and/or extracorporeal membrane oxygenation [ECMO]) at any point during the 7-day treatment period

• Change in pulmonary arterial pressure [ Time Frame: Baseline and 4 hours post study drug administration ] [ Designated as safety issue: No ]
  Change in pulmonary arterial pressure as calculated by echocardiography
• Duration of supplemental O2 [ Time Frame: Participants will be on supplemental O2 an average of 2 weeks ] [ Designated as safety issue: No ]
• Age at hospital discharge [ Time Frame: Participants will be followed for the duration of hospital stay, an expected average of 3 weeks ] [ Designated as safety issue: No ]
• Duration of mechanical ventilation [ Time Frame: Participants will be on mechanical ventilation an average of 1 week ] [ Designated as safety issue: No ]

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.

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.

• Persistent Pulmonary Hypertension
• Respiratory Failure

• Drug: Intravenous Sildenafil
  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 Name: Revatio
• Other: Placebo
  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.

• Experimental: Intravenous Sildenafil
  Intervention: Drug: Intravenous Sildenafil
• Placebo Comparator: Placebo
  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.
  Intervention: Other: Placebo

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 •≥35 weeks gestation
• Age at enrollment less than 72 hours
• Moderate hypoxemic respiratory failure, with 15<OI<25 (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, or need for hypothermia treatment for neonatal encephalopathy
• 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.

• State University of New York at Buffalo
• Vanderbilt University
• Ann & Robert H Lurie Children's Hospital of Chicago
• University of Utah
• University of Alabama at Birmingham