SUMMARY Chronic lung disease and complications from preterm birth are the leading pediatric contributors to years of life lost in the USA. Bronchopulmonary dysplasia (BPD), a chronic lung disease, is the most common sequela of prematurity and is the leading respiratory cause of childhood morbidity. In the United States alone BPD accounts for over $2.4 billion in healthcare costs annually. Ventilator induced lung injury (VILI) is an accepted and important contributor to BPD. Exposure to oxygen and positive pressure ventilation leads to developmental arrest and parenchymal injury in the immature preterm lung. Lung protective strategies therefore prioritize non- invasive respiratory support for preterm infants with respiratory failure, but failure rates of non-invasive respiratory support (ie: continuous positive airway pressure [CPAP]) are high. In meta-analysis of trials of nasal non-invasive intermittent positive pressure ventilation (NIPPV), synchronized NIPPV significantly reduced the incidence of BPD when compared with CPAP. This benefit was not seen with non-synchronized NIPPV. However, current standard means of synchronization are unreliable and do not deliver consistent synchronization. Neurally Adjusted Ventilatory Assist (NAVA), an FDA approved technology, is a novel method to synchronize non-invasive support (NIV) with infant respiratory drive. This effective non-invasive synchronization matches electrical diaphragmatic activity to deliver synchronized and accurate tidal volumes in proportion to the neural signal. In these clustered UG3/UH3 and U24 applications, we propose a pragmatic, unblinded, Phase III, randomized controlled trial (RCT) in 358 preterm infants 240/7-276/7 weeks gestation in respiratory failure to determine if NIV-NAVA, compared with non-synchronized nasal intermittent positive pressure ventilation (NIPPV), will reduce the incidence of extubation failure within 5 days of extubation from mechanical ventilation.