REspiratory MEchanics for Delivering Individualised Exogenous Surfactant (REMEDIES)

A Randomized Controlled Trial of Oscillatory Mechanics Versus Oxygenation-based Criteria for Surfactant Therapy

This study is an interventional, non-pharmacological, multicentric, randomized, controlled, superiority, non-profit study. Its primary objective is to evaluate if the administration of surfactant based on FOT assessment will allow a 5-day reduction in the duration of respiratory support as compared to standard practice in preterm infants between 27+0 and 32+6 weeks' gestation. The secondary objectives are:

1. to determine if a lung mechanics-based approach for administering surfactant will change treatment timing; and
2. to assess the impact of the novel approach on other neonatal general outcomes. The study will take place within the neonatal intensive care units. Non-invasive respiratory support will be delivered by nasal CPAP with a starting pressure of 5-8 cmH2O. FiO2 will be titrated in order to achieve the target SpO2 91-95%.

Infants matching the clinical criteria for inclusion will be randomized in two arms following the current data protection and confidentiality regulations. Central, computer-generated randomization (allocation 1:1) with variable block sizes according to gestational age will be used. Infants will be stratified according to gestational age (27+0 -28+6 weeks; 29+0 -30+6 weeks; 31+0 -32+6 weeks) and center.

Study Arms:

A) Surfactant administration following oxygenation-based criteria (clinical assessment) (control) B) Surfactant administration following both lung mechanics assessment OR oxygenation-based criteria (clinical assessment) (intervention).

Study Overview

• Status: Not yet recruiting
• Conditions: Respiratory Distress Syndrome in Premature Infant
• Intervention / Treatment: Other: Surfactant administration following clinical assessment; Other: Surfactant administration following lung mechanics assessment in addition to clinical assessment

• Study Type: Interventional
• Enrollment (Anticipated): 458
• Phase: Not Applicable

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 6 months to 7 months (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Gestational age (GA) ≥ 27+0 and < 33+0 weeks
2. Spontaneously breathing infants, requiring non-invasive respiratory support (nasal CPAP or bilevel nasal CPAP). Criteria for commencement of non-invasive respiratory support: FiO2 >0.30 for target SpO2 88-93% or Silverman score ≥ 5.
3. Inborn
4. Written parental consent obtained
5. Administration of Caffeine bolus 20 mg/kg IV or PO as per standard care

Exclusion Criteria:

1. Major congenital anomalies
2. Need of intubation in delivery suite according to the AAP guidelines for neonatal resuscitation or early at the admission in NICU (within one hour from birth).
3. Surfactant therapy prior to the study entry
4. Severe birth asphyxia, defined by APGAR score ≤ 5 at 10 minutes after birth OR continued need for resuscitation 10 minutes after birth OR pH < 7.0 or base excess (BE) < -12 mmol/l on umbilical cord or on an arterial or capillary blood sample obtained within 1 hour from birth OR moderate to severe encephalopathy
5. Respiratory failure secondary to conditions other that RDS as identified by lung imaging (air leaks, lung malformations…)
6. Any clinical condition which may place the infants at undue risk as deemed by clinicians
7. Participation to trials with competitive outcomes or likely to have an impact on the primary outcome of the study
8. Outborn patients

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: A/Control; Surfactant administration following clinical assessment	Other: Surfactant administration following clinical assessment; Surfactant is administered following oxygenation-based criteria
Experimental: B/Intervention; Surfactant administration following both lung mechanics assessment and clinical assessment	Other: Surfactant administration following lung mechanics assessment in addition to clinical assessment; Surfactant is administered following oxygenation-based criteria and if the Xrs is ≤ -23.3 cmH2O*s /L

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Days of respiratory support	Number of days of required respiratory support	From date of randomization until the date of discharge from hospital or date of death from any cause, whichever came first, assessed up to 48 months"

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
First surfactant administration	Time of first surfactant administration (in hours)	From date of randomization until the date of discharge from hospital or date of death from any cause, whichever came first, assessed up to 48 months"
Days of non-invasive respiratory support	Number of days of non-invasive respiratory support	From date of randomization until the date of discharge from hospital or date of death from any cause, whichever came first, assessed up to 48 months"
Days of invasive respiratory support	Number of days of invasive respiratory support	From date of randomization until the date of discharge from hospital or date of death from any cause, whichever came first, assessed up to 48 months"
Patients intubated and mechanically ventilated	Number of patients intubated and mechanically ventilated	From date of randomization until the date of discharge from hospital or date of death from any cause, whichever came first, assessed up to 48 months"
Patients receiving multiple surfactant doses	Number of patients receiving multiple surfactant doses	From date of randomization until the date of discharge from hospital or date of death from any cause, whichever came first, assessed up to 48 months"
Days on supplemental oxygen	Number of days on supplemental oxygen	From date of randomization until the date of discharge from hospital or date of death from any cause, whichever came first, assessed up to 48 months"
Total cumulative oxygen exposure	Total cumulative oxygen exposure computed as the time integral of the FiO2 values	From date of randomization until the date of discharge from hospital or date of death from any cause, whichever came first, assessed up to 48 months"
Infants receiving more than 28 days of respiratory support	Number of infants receiving more than 28 days of respiratory support	From date of randomization until the date of discharge from hospital or date of death from any cause, whichever came first, assessed up to 48 months"
Infants developing BPD	Number of infants developing BPD according to the definition by NICHD 2016	From date of randomization until the date of discharge from hospital or date of death from any cause, whichever came first, assessed up to 48 months"
Infants developing air-leaks	Number of infants developing air-leaks	From date of randomization until the date of discharge from hospital or date of death from any cause, whichever came first, assessed up to 48 months"
Infants developing prematurity-associated complications	Number of infants developing prematurity-associated complications (severe intraventricular haemorrhage (IVH), periventricular leukomalacia (PVL), necrotizing enterocolitis (NEC), sepsis, retinopathy of prematurity (ROP), patent ductus arteriosus requiring pharmacological or surgical treatment)	From date of randomization until the date of discharge from hospital or date of death from any cause, whichever came first, assessed up to 48 months"
Infants discharged home with oxygen or respiratory support	Number of infants discharged home with oxygen or respiratory support	From date of randomization until the date of discharge from hospital or date of death from any cause, whichever came first, assessed up to 48 months"
Days to achieve full-enteral feeding	Number of days to achieve full-enteral feeding (160 ml/kg/day of milk intake)	From date of randomization until the date of discharge from hospital or date of death from any cause, whichever came first, assessed up to 48 months"
Days of hospitalization	Number of days of hospitalization	From date of randomization until the date of discharge from hospital or date of death from any cause, whichever came first, assessed up to 48 months"
Infants receiving postnatal steroids	Number of infants receiving postnatal steroids	From date of randomization until the date of discharge from hospital or date of death from any cause, whichever came first, assessed up to 48 months"

Collaborators and Investigators

• Sponsor: Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico
• Collaborators: Politecnico di Milano

Study record dates

Study Major Dates

• Study Start (Anticipated): May 18, 2023
• Primary Completion (Anticipated): May 30, 2025
• Study Completion (Anticipated): December 31, 2025

Study Registration Dates

• First Submitted: December 9, 2022
• First Submitted That Met QC Criteria: March 28, 2023
• First Posted (Actual): March 30, 2023

Study Record Updates

• Last Update Posted (Actual): March 30, 2023
• Last Update Submitted That Met QC Criteria: March 28, 2023
• Last Verified: March 1, 2023

More Information

Terms related to this study

• Keywords: CPAP; Respiratory mechanics; Surfactant; CPAP failure; Premature infant; Neonatal RDS; Respiratory Oscillometry; Forced Oscillation technique
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Respiration Disorders; Lung Diseases; Infant, Newborn, Diseases; Infant, Premature, Diseases; Respiratory Distress Syndrome; Respiratory Distress Syndrome, Newborn; Respiratory System Agents; Pulmonary Surfactants
• Other Study ID Numbers: Sperimentazione 3115; Studio Numero 6379 (Other Identifier: Comitato Etico Milano Area 2)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No