Aerosolized Surfactant in Neonatal RDS (AS-02)

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

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.

Study Overview

• Status: Completed
• Conditions: Respiratory Distress Syndrome, Newborn
• Intervention / Treatment: Drug: Surfactant

• Study Type: Interventional
• Enrollment (Actual): 159
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • Michigan
    • Detroit, Michigan, United States, 48201
      • Hutzel Women's Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 1 day (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Infants admitted to the NICU at Hutzel Women's Hospital (HWH)/Children's Hospital of Michigan (CHM)
2. Gestational age of 240/7-366/7 weeks
3. Postnatal age ≤ 24 hours
4. 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
5. Respiratory support with NIV (CPAP or NIPPV or HFNC) with FiO2 ≥25% or PEEP ≥ 4 cmH20 or HFNC rate ≥ 2 LPM for ≤8 hours
6. Written informed consent from parent/guardian

Exclusion Criteria:

1. Previous receipt of surfactant
2. Infants with respiratory distress who are unstable and require immediate intubation
3. Active air leak syndrome (e.g. pneumothorax, pneumomediastinum)
4. Lethal congenital malformations; death anticipated within first 3 days of life; decision to withhold support
5. Serious abdominal, cardiac, airway or respiratory malformations including tracheal esophageal fistula, intestinal atresia, omphalocele, gastroschisis, pulmonary hypoplasia, or diaphragmatic hernia
6. Neuromuscular disorder resulting in respiratory compromise

Study Plan

How is the study designed?

Design Details

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

Number of Arms

4

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Sood, Beena G., MD, MS
• Investigators: Principal Investigator: Beena G. Sood, MD, MS, Wayne State University

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start: December 1, 2014
• Primary Completion (Actual): July 1, 2019
• Study Completion (Actual): July 1, 2020

Study Registration Dates

• First Submitted: November 12, 2014
• First Submitted That Met QC Criteria: November 15, 2014
• First Posted (Estimate): November 19, 2014

Study Record Updates

• Last Update Posted (Actual): August 25, 2021
• Last Update Submitted That Met QC Criteria: July 30, 2021
• Last Verified: July 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Respiratory Tract Diseases; Respiration Disorders; Lung Diseases; Disease; Infant, Newborn, Diseases; Infant, Premature, Diseases; Syndrome; Respiratory Distress Syndrome; Respiratory Distress Syndrome, Newborn; Respiratory System Agents; Pulmonary Surfactants
• Other Study ID Numbers: 1206011023; 1R01FD004793-01A1 (U.S. FDA Grant/Contract); FD004793 (Other Identifier: FDA - OOPD)