Study of Sildenafil to Treat Newborns 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.

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 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.