Inhaled Nitric Oxide for Preventing Chronic Lung Disease in Premature Infants

BACKGROUND:

Despite advances in medical, nursing, and respiratory care, CLD affects up to 50 percent of
premature infants. As a result, nearly 50,000 infants in the United States develop CLD. It
is desirable to investigate therapies that decrease the incidence of CLD because it is
associated with failure to thrive, developmental delay, increased risk of pulmonary
infection, reactive airway disease, pulmonary hypertension, and death.

DESIGN NARRATIVE:

This is a randomized, double-blind, placebo-controlled, multi-center study. Three specific
hypotheses will be tested: 1) iNO reduces the incidence of CLD; 2) iNO reduces serum and
lung (tracheal aspirate) markers of inflammation; and 3) iNO does not increase the incidence
of intraventricular hemorrhage in premature neonates. The primary endpoint is survival
without CLD (defined as continued oxygen requirement) at 36 weeks post conceptional age.

A total of 793 premature newborns will be enrolled from 14 centers within 48 hours of birth.
They will be randomly assigned to receive either placebo or iNO at 5 ppm until the breathing
tube can be safely removed or after 21 days. The iNO will be delivered by an INOvent
delivery system in such a way that physicians and nurses will not know which treatment each
participant is receiving. Management strategies for aspects of patient care including
mechanical ventilation, surfactant administration, fluid administration, and steroid use
will be determined by physicians at each center. Serial cranial ultrasounds and
methemoglobin levels will be monitored to determine adverse events. The first 200 patients
will have serial blood samples and tracheal aspirates obtained for measurements of
inflammatory mediators, including interleukin-6 (IL-6), interleukin-8 (IL-8), interleukin-10
(IL-10), endothelin-1, myeloperoxidase, neutrophil counts (tracheal aspirates), and
endothelin-1 (blood). Participants will be seen at 12 and 24 months of age to monitor the
long-term effects on the cardiopulmonary or neurologic systems. At these visits, a health
questionnaire will be administered and Bayley II scales of infant development will be
completed.

Inclusion Criteria:

- Weighing between 500 to 1250 grams at birth

- Gestational age of less than 34 weeks

- Less than 48 hours old

- Respiratory failure on mechanical ventilation

- Absence of structural heart disease (PDA, ASD less than 1 cm, or VSD less than 2 mm
are permitted if known prior to study entry)

- Absence of lethal congenital anomaly

Exclusion Criteria:

- Concurrent participation in another experimental study (observational studies will be
allowed with prior approval by the Steering Committee and Data and Safety Monitoring
Board)

- Active pulmonary hemorrhage

- Unevaluated pneumothorax

- High frequency jet ventilation

- Expected short duration of ventilation (less than 48 hours from birth)