Aerosolized Surfactant in Neonatal RDS

Study Overview
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Brief Summary
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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.

Official Title
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Aerosolized Survanta in Neonatal Respiratory Distress Syndrome: Phase I/II Study

Conditions
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Respiratory Distress Syndrome, Newborn

Intervention / Treatment
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* Drug: Surfactant


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Maximum Age: 24 Hours

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Dose Schedule I<br>Surfactant dose to be administered as aerosol - 100 mg phospholipid/kg. Surfactant Dilution 1:1 | Drug: Surfactant<br>* 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.<br>* Other names: Survanta;|
| Active Comparator: Dose Schedule II<br>Surfactant dose to be administered as aerosol - 100 mg phospholipid/kg. Surfactant Dilution 1:2 | Drug: Surfactant<br>* 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.<br>* Other names: Survanta;|
| Active Comparator: Dose Schedule III<br>Surfactant dose to be administered as aerosol - 200 mg phospholipid/kg. Surfactant Dilution 1:1 | Drug: Surfactant<br>* 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.<br>* Other names: Survanta;|
| Active Comparator: Dose Schedule IV<br>Surfactant dose to be administered as aerosol - 200 mg phospholipid/kg. Surfactant Dilution 1:2 | Drug: Surfactant<br>* 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.<br>* Other names: Survanta;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Adverse Events as a Measure of Safety and Feasibility | 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 | 
| Patient Status as Evaluated by Dose Level | 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. | 
| Short Term Efficacy as Assessed by Need for Intubation | 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. | Within 72 hours of study intervention | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Blood Gas Parameters - pH | Blood gas pH | 60±30 minutes after end of study intervention | 
| Blood Gas Parameters - pCO2 | Blood gas pCO2. | 60±30 minutes after end of study intervention | 
| Pulse Oximetry | Transcutaneous Pulse oximetry | 60±30 minutes after end of study intervention | 
| Vital Signs - Heart Rate | Vital signs included heart rate, respiratory rate and systolic blood pressure | 60±30 minutes after end of study intervention | 
| Vital Signs - Respiratory Rate | Vital signs included heart rate, respiratory rate and systolic blood pressure | 60±30 minutes after end of study intervention | 
| Vital Signs - Systolic Blood Pressure | Systolic blood pressure | 60±30 minutes after end of study intervention | 
| Number of Doses of Surfactant - Aerosolized & Intratracheal |  | Within 72 hours of study intervention | 
| Pneumothorax, Pneumomediastinum or Other Air Leak |  | Within 72 hours of study intervention | 
| Changes in Cerebral Oxygenation From Baseline as Evaluated at End of Study Intervention | Changes in cerebral oxygenation from baseline as evaluated at end of study intervention | During and within 6 hours after end of study intervention, expected maximum of approximately 14 hours | 
| Changes in Surfactant Activity in Gastric Aspirates | Concentration of major surfactant lipid (PC 16:0/16:0) | During study intervention, expected maximum of approximately 8 hours | 
| Cumulative Duration of Non-invasive and Invasive Ventilation | Cumulative duration of non-invasive and invasive ventilation at discharge | at discharge | 
| Duration of Supplemental Oxygen, Intensive Care, Hospital Stay | Duration of supplemental oxygen, and hospital stay | During initial hospital stay, expected <= 120 days | 
| Age at Start of Feeds, Feeding Progression, Age at Full Enteral Feeds | Age at start of feeds, and age at full enteral feeds presented in days | During initial hospital stay, expected 1st 2 weeks of life | 
| Need for Blood Transfusions | Number of infants requiring blood transfusions | During initial hospital stay, expected <= 120 days | 
| Growth Parameters | Weight at discharge | At 7 days, 28 days, 36 weeks corrected GA and discharge | 
| Morbidities Associated With Prematurity | Grade III & IV IVH PDA requiring ligation ROP treated with Laser Surgical NEC BPD | During initial hospital stay, expected <= 120 days | 
| Survival to Hospital Discharge | Survival to hospital discharge | During initial hospital stay, expected <= 120 days | 
| Survival to Discharge Without Severe Morbidity | Survival to discharge without severe BPD, severe IVH, surgical NEC or ROP treated with Laser | During initial hospital stay, expected <= 120 days |