Fast Assessment of Surfactant Deficiency in Preterm Infants to Speed up Treatment (FAST2)

FAST TRIAL 2 - Fourier-transform Infrared Spectroscopy(FTIR) Guided Surfactant Therapy - RCT

Recently the investigators have developed a point of care test (LS-test) to measure surfactant as lecithin in gastric aspirates from preterm infants.

This test can be done immediately at delivery and potentially be used to guide surfactant treatment.

To obtain evidence-based knowledge on harms and benefit of surfactant therapy guided by the L/S test, a randomized clinical trial with relevant clinical short-and long-term outcomes needs to be performed, which is why the FAST 2 Trial has been designed.

Study Overview

• Status: Not yet recruiting
• Conditions: Respiratory Distress Syndrome, Newborn; Bronchopulmonary Dysplasia; Surfactant Deficiency Syndrome Neonatal
• Intervention / Treatment: Diagnostic test: LS test

Detailed Description

Treatment of respiratory distress syndrome (RDS) has evolved greatly over the past three decades. Major advances in treatment include antenatal steroids, early nasal continuous positive airway pressure (nCPAP) combined with early rescue surfactant replacement strategies such as Intubation Surfactant Extubation (INSURE) and Less Invasive Surfactant Administration (LISA), together with use of lung protective ventilation and overall reduced use of mechanical ventilation. However, RDS and bronchopulmonary dysplasia (BPD) are still major causes of mortality and morbidity in premature infants. To improve the outcome, very early treatment with surfactant is necessary. However, only about half of infants with a gestational age (GA) below 30 weeks need surfactant treatment and prophylactic surfactant treatment increases the combined mortality and incidence of BPD contrary to selective rescue surfactant treatment. Therefore, there is a need for a rapid test to guide early targeted surfactant treatment.

The investigators have recently developed a new test of lung maturity based on measuring the lecithin sphingomyelin ratio (L/S) in fresh gastric aspirates (GAS) from newborn preterm infants using mid-red Fourier Transform Infrared spectroscopy (FTIR). The sphingomyelin concentration in amniotic fluid and accordingly in GAS is relatively constant during the pregnancy, whereas the lecithin (or dipalmitoylphosphatidylcholine (DPPC), the lung surfactant phospholipid with the highest surface activity) concentration increases with the lung maturation.

It has been demonstrated in clinical observational trials that this laboratory based L/S-test predicts development of RDS when measured immediately at delivery (FAST 1 Trial).

The L/S-test has now been developed into an easy-to-use Point of Care (POC) test for bedside use that expresses the L/S ratio in approximately 10 minutes. It is believed this new POC test can be used to guide surfactant therapy, enabling very early rescue treatment, potentially even before symptoms occur.

To obtain evidence-based knowledge on harms and benefit of surfactant therapy guided by the L/S test, a randomized clinical trial with relevant clinical short-and long-term outcomes needs to be performed, which is why the FAST 2 Trial has been designed.

During design and development of the FAST 2 Trial protocol extensive engineering work has been conducted towards building a fully automated L/S POC Device (AIMI 1.0/2.0) from the prototypes in the first L/S studies (including FAST 1 Trial).

During this process the accuracy of the L/S algorithm has been improved through machine learning and use of artificial intelligence. Consequently, the previously defined cut-off ratio from the FAST 1 Trial needs to be re-validated using the L/S POC Device in a new population of preterm infants.

The FAST 2 Trial therefore consists of two individual studies starting with the FAST 2 Validation Study which will followed by the FAST 2 Randomized Clinical Trial (FAST 2 RCT) once completed. The FAST 2 Validation study has been registered separately on clinicaltrials.gov (NCT05615428).

This registration concerns the FAST 2 RCT

Participants:

Preterm newborn infants with gestational age at birth of ≤ 29+6 weeks who have not received prophylactic surfactant.

Intervention:

Surfactant treatment guided by fast determination of the L/S-ratio in a fresh gastric aspirate (GAS) obtained at birth, measured by Fourier Transform Mid-infrared Spectroscopy as a POC test.

Comparison:

Standard rescue surfactant treatment based on clinical criteria defined by the European Consensus Guidelines on the management of Respiratory Distress Syndrome

Outcome:

Infants surviving without moderate to severe BPD assessed at 36 weeks post menstrual age as per a modified NIH definition

The primary outcome is a composite of survival without moderate to severe BPD, defined as per a modified "NIH definition"

The primary objective is to compare the rate of survival without moderate to severe BPD between 2 groups:

• L/S guided treatment of surfactant deficiency with exogenous surfactant (intervention group) vs.
• Standard treatment of surfactant deficiency (comparison).

• Study Type: Interventional
• Enrollment (Estimated): 380
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Christian Heiring; Phone Number: +4535453545; Email: christian.heiring@regionh.dk

Study Locations

• Denmark
  • Aalborg, Denmark, 9000
    • Aalborg University Hospital
    • Contact: Anne-Cathrine Viuff, PhD
  • Aarhus, Denmark, 8200
    • Aarhus Universtity Hospital
    • Contact: Tine B Henriksen, Professor
  • Copenhagen, Denmark, 2100
    • Department of Neonatology, Rigshospitalet
  • Odense, Denmark
    • Odense University Hospital
    • Contact: Gitte Zachrariassen, Professor

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 45 minutes (Child)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• GA ≤ 29+6, inborn at a participating centre
• Age less than 45 minutes as GAS must be sampled within 45 minutes from delivery.

Exclusion Criteria:

• Treated with surfactant before randomisation and obtaining gastric aspirates
• Diagnosis of major malformations (major congenital heart defects, congenital diaphragmatic hernia, gastroschisis/omphalocele, pulmonary abnormalities including pulmonary hypoplasia and trachea-oesophageal fistula
• Antenatal suspicion of significant oligohydramnios and lung hypoplasia
• Any intrauterine intervention except if done for genetic testing

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Intervention arm LS guided treatment; all participating infants will have a gastric aspirate (GAS) sampled at birth within 45 minutes of life. The GAS will be analyzed immediately at the bedside by a LS-test POC device. For infants allocated to the interventional group the LS-result will be displayed as "treat with surfactant" or " do not treat with surfactant" depending on wether the LS-ratio is under or above the cut-off ratio for treatment. Those with LS-ratio above the cut-off ratio will be treated with surfactant as per routine in accordance with the European RDS guidelines based on oxygen requirement (FiO2 > 0.30) - ie same as in control group.	Diagnostic test: LS test; If the LS test indicated surfactant deficiency based on the cut off ratio early surfactant treatment will be done for patients in the intervention group If the LS test indicated no surfactant deficiency routine surfactant treatment will be done as per European RDS guidelines based on oxygen requirement (FiO2 > 0.30)
No Intervention: Control arm - routine surfactant treatment; all participating infants will have a gastric aspirate (GAS) sampled at birth within 45 minutes of life. The GAS will be analyzed immediately at the bedside by a LS-test POC device, but result will remain blinded. Infants allocated to the control group will be treated with surfactant as per routine in accordance with the European RDS guidelines based on oxygen requirement (FiO2 > 0.30). The LS-ratio for those infants will remain blinded

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Survival without moderate to severe bronchopulmonary dysplasia (BPD)	BPD is defined as per a modified "NIH definition" in which any degree of respiratory support for at least 28 days is considered equal to the need for oxygen: Treatment with oxygen > 21% or any degree of respiratory support for a least 28 days plus; Need for treatment with oxygen > 21% or any degree of respiratory support at PMA 36 weeks or at discharge, whichever comes first. Definitions: Moderate BPD is defined as treatment with oxygen > 21% or any degree of respiratory support for a least 28 days plus need of supplemental oxygen from >21% to < 30% (as low flow O2) at 36+0 weeks PMA; Severe BPD is defined as treatment with oxygen > 21% or any degree of respiratory support for a least 28 days plus need of > 30% oxygen and/or continuous need for any level of respiratory support providing positive airway pressure (nHFT, nCPAP, NIV or mechanical ventilation)	at 36 weeks PMA or discharge withever comes first

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
mortality	assessed at discharged	From date of birth until the date of death if this happens before discharge
Bronchopulmonary dysplasia	BPD is defined as per a modified "NIH definition" in which any degree of respiratory support for at least 28 days is considered equal to the need for oxygen: Treatment with oxygen > 21% or any degree of respiratory support for a least 28 days plus; Need for treatment with oxygen > 21% or any degree of respiratory support at PMA 36 weeks or at discharge, whichever comes first. Definitions: Moderate BPD is defined as treatment with oxygen > 21% or any degree of respiratory support for a least 28 days plus need of supplemental oxygen from >21% to < 30% (as low flow O2) at 36+0 weeks PMA; Severe BPD is defined as treatment with oxygen > 21% or any degree of respiratory support for a least 28 days plus need of > 30% oxygen and/or continuous need for any level of respiratory support providing positive airway pressure (nHFT, nCPAP, NIV or mechanical ventilation)	at 36 weeks PMA or discharge withever comes first
LS-ratio	POC measurement using FTIR Spectroscopy	72 hours
Nectrotizing enterocolitis	According to Bell classification/AXR	From date of birth to 44 weeks of gestational age (usually around 18 weeks)
Spontaneous intestinal perforation	As diagnosed on AXR	From date of birth to 44 weeks of gestational age (usually around 18 weeks)
Intraventricular hemorhage	According to Papile classification	From date of birth to 44 weeks of gestational age (usually around 18 weeks)
Airleak	Assessed on CXR or lung ultrasound	From date of birth to 44 weeks of gestational age (usually around 18 weeks)
surfactant treatment,	from medical record	72 hours
surfactant treatmentdose,	from medical record	72 hours
number of surfactant treatments,	from medical record	72 hours
timing surfactant treatments,	from medical record	72 hours
gastric aspirate obtained	from medical record	72 hours
gastric aspirate analyzed	from medical record	72 hours

Collaborators and Investigators

• Sponsor: Rigshospitalet, Denmark
• Collaborators: Odense University Hospital; Aarhus University Hospital; Aalborg University Hospital; Holbaek Sygehus
• Investigators: Principal Investigator: Christian Heiring, Rigshospitalet, Denmark

Study record dates

Study Major Dates

• Study Start (Estimated): July 1, 2024
• Primary Completion (Estimated): July 1, 2028
• Study Completion (Estimated): January 1, 2029

Study Registration Dates

• First Submitted: November 7, 2022
• First Submitted That Met QC Criteria: December 2, 2022
• First Posted (Actual): December 6, 2022

Study Record Updates

• Last Update Posted (Estimated): November 16, 2023
• Last Update Submitted That Met QC Criteria: November 14, 2023
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Keywords: surfactant assay; surfactant replacement therapy
• Additional Relevant MeSH Terms: Pathologic Processes; Respiratory Tract Diseases; Respiration Disorders; Lung Diseases; Disease; Infant, Newborn, Diseases; Lung Injury; Infant, Premature, Diseases; Ventilator-Induced Lung Injury; Syndrome; Respiratory Distress Syndrome; Respiratory Distress Syndrome, Newborn; Bronchopulmonary Dysplasia
• Other Study ID Numbers: H-22007105 RCT Study

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Sharing Time Frame: Study protocol will be published in peer reviewed journal as soon as possible SAP will be ublished in peer reviewed journal as soon as possible and prior to completion of primary data collection
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No