Aerosolized Surfactant in Neonatal RDS (AS-02)

Respiratory distress syndrome (RDS), caused by surfactant deficiency, is the leading cause of mortality and morbidity in preterm infants. Intratracheal instillation, the only approved means of surfactant delivery, requires endotracheal intubation and mechanical ventilation with their attendant risks. Interventions that decrease need for intubation and mechanical ventilation like noninvasive ventilation (NIV) including nasal continuous positive airway pressure, high flow nasal cannula or nasal intermittent mandatory ventilation are increasingly being used for initial respiratory support in preterm neonates with RDS to improve outcomes. Aerosolized surfactant delivered during NIV is an innovative and promising concept for the treatment of RDS - retaining the advantages of early surfactant with alveolar recruitment while obviating the risks of intubation and mechanical ventilation. The investigators overall hypothesis is that treatment of RDS with aerosolized surfactant in preterm infants undergoing NIV is safe and feasible and will result in short-term improvement in oxygenation and ventilation. The objective of this proposal is to perform a single-center unblinded Phase II randomized clinical trial of aerosolized surfactant for the treatment of RDS in preterm neonates undergoing NIV. Funding Source - FDA-OOPD.

Two doses of surfactant to be administered as aerosol will be tested - 100 mg phospholipid/kg and 200 mg phospholipid/kg. Each dose will be tested at two dilutions and with two nebulizers. Each enrolled infant may receive a maximum of two aerosol treatments of a single dilution with a single nebulizer.

Since surfactant reflux is typically considered to be one of the most likely adverse events associated with the intervention, it was planned to report the number of participants specifically with surfactant reflux for this Outcome Measure

During and within 6 hours after end of study drug administration, expected maximum of approximately 14 hours

Optimal dosing schedule was determined by preliminary evidence of efficacy (Need for intubation within 72 hours), lack of adverse effects, and overall infant comfort as assessed by bedside clinical caregivers.

During study drug administration, expected maximum of approximately 8 hours for adverse effects and infant comfort; need for intubation was assessed within 72 hours of study intervention.

It will be suggested that infants be intubated and receive MV if they met 2 or more of 5 failure criteria: i). worsening clinical signs of respiratory distress (increasing tachypnea; expiratory grunting; intercostal, subcostal, and/or sternal recession); ii). apnea treated with positive pressure ventilation (PPV) by mask on 2 or more occasions in 1 hour; iii). FIO2 >0.5 to maintain pulse oxygen saturations 90%-95% for >30 minutes; iv). pH <7.2 on 2 arterial or capillary blood gases taken >30 minutes apart; and v). partial pressure of CO2 (PCO2) of >65 mm Hg on 2 CBG/ABGs taken 30 minutes apart.

During and within 6 hours after end of study intervention, expected maximum of approximately 14 hours

Inclusion Criteria: Infants admitted to the NICU at Hutzel Women's Hospital (HWH)/Children's Hospital of Michigan (CHM) Gestational age of 240/7-366/7 weeks Postnatal age ≤ 24 hours Clinical diagnosis of RDS based on (i) presence of at least two of the four classic symptoms (need of supplemental oxygen, tachypnea, intercostal retractions or grunting), and (ii) exclusion of other causes of respiratory failure and (iii) Clinician intent to administer surfactant if infant requires intubation Respiratory support with NIV (CPAP or NIPPV or HFNC) with FiO2 ≥25% or PEEP ≥ 4 cmH20 or HFNC rate ≥ 2 LPM for ≤8 hours Written informed consent from parent/guardian Exclusion Criteria: Previous receipt of surfactant Infants with respiratory distress who are unstable and require immediate intubation Active air leak syndrome (e.g. pneumothorax, pneumomediastinum) Lethal congenital malformations; death anticipated within first 3 days of life; decision to withhold support Serious abdominal, cardiac, airway or respiratory malformations including tracheal esophageal fistula, intestinal atresia, omphalocele, gastroschisis, pulmonary hypoplasia, or diaphragmatic hernia Neuromuscular disorder resulting in respiratory compromise

Sood BG, Cortez J, Kolli M, Sharma A, Delaney-Black V, Chen X. Aerosolized surfactant in neonatal respiratory distress syndrome: Phase I study. Early Hum Dev. 2019 Jul;134:19-25. doi: 10.1016/j.earlhumdev.2019.05.005. Epub 2019 May 20.

Sood BG, Thomas R, Delaney-Black V, Xin Y, Sharma A, Chen X. Aerosolized Beractant in neonatal respiratory distress syndrome: A randomized fixed-dose parallel-arm phase II trial. Pulm Pharmacol Ther. 2021 Feb;66:101986. doi: 10.1016/j.pupt.2020.101986. Epub 2020 Dec 16.