the Inhaled β2-adrenergic Receptor Agonist for Transient Tachypnoea of the Newborn (the REFSAL Trial) (REFSAL)

a Multicentre, Double-blind, Randomized, Placebo-controlled Phase III Trial of the Inhaled β2-adrenergic Receptor Agonist Salbutamol for Transient Tachypnoea of the Newborn (the REFSAL Trial)

Clinical trial evaluating the efficacy and safety of salbutamol for the treatment of neonates with a gestational age between 32 and 42 weeks with transient tachypnoea of the newborn (TTN).

Study Overview

• Status: Recruiting
• Conditions: Respiratory Failure; TTN; PPHN
• Intervention / Treatment: Drug: 0,9% Chloride Sodium; Drug: Salbutamol

Detailed Description

Multicentre, double-blind, phase III trial will include infants with a gestational age between 32 and 42 weeks and respiratory disorders treated in neonatal intensive care units in Poland. Infants will be enrolled no later than 24 h after birth and will be randomly assigned (1:1) to receive nebulized salbutamol with nCPAP or placebo (nebulized 0.9% NaCl) with nCPAP. The primary outcome is the percentage of infants with TTN who develop PPHN.

• Study Type: Interventional
• Enrollment (Estimated): 608
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Renata Bokiniec, MD, PhD, Assoc Prof; Phone Number: +48225966155; Email: renata.bokiniec@wum.edu.pl
• Study Contact Backup: Name: Dariusz Madajczak, MD, PhD; Phone Number: +48223179827; Email: dariusz.madajczak@wum.edu.pl

Study Locations

• Poland
  • Warsaw, Poland
    • Recruiting
    • Medical University of Warsaw
    • Contact: Renata Bokiniec, Assoc; Phone Number: +48225966155; Email: renata.bokiniec@wum.edu.pl
    • Contact: Dariusz P. Madajczak, PhD; Phone Number: +48225966267; Email: dariusz.madajczak@wum.edu.pl

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

1. Gestational age at birth between 32 and 42 weeks.
2. Respiratory disorders (tachypnea and expiratory grunting) lasting longer than 15 minutes after birth, or present for at least 15 minutes in the first six hrs of life, or a need for non-invasive respiratory support between birth and six hrs of life.
3. Available chest radiographs obtained within six hrs after birth.
4. Available parameters of the acid-base balance (blood pH, partial pressure of O2 and CO2, base excess) and blood serum ionogram for Na+, K+, Ca2+ evaluated in the umbilical cord blood sample.

Exclusion Criteria:

1. Need for intubation directly after birth or perinatal asphyxia, defined as abnormal acid-base parameters detected in an umbilical cord blood sample (pH <7.0 or base excess < -14 mmol/L).
2. Multiple apnea-brady that require immediate intubation before a trial of NIV
3. Age >24 h.
4. Meconium aspiration syndrome.
5. Air leak syndrome.
6. Congenital heart disease.
7. Congenital diaphragmatic hernia.
8. Other severe congenital malformations and genetic disorders (diagnosed before and after birth) associated with increased risk of respiratory failure.
9. The need for a surfactant administration immediately after birth, regardless of the method of its administration (respiratory distress syndrome - RDS)

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: CPAP+Salbutamol; All patients will receive nCPAP at 5-6 cm H2O pressure with an oxygen concentration of 21% or more to maintain preductal saturation between 90% and 95%. Patients assigned to the active group will be treated with 0.15 mg/kg body weight (diluted in 3 mL 0.9% NaCl) nebulised salbutamol (Ventolin®, GlaxoSmithKline, Dublin, Ireland) for 30 min.	Drug: Salbutamol; Patients assigned to the active group will be treated with 0.15 mg/kg body weight (diluted in 3 mL 0.9% NaCl) nebulized salbutamol (Ventolin®, GlaxoSmithKline, Dublin, Ireland) for 30 min.; Other Names: Albuterol
Placebo Comparator: CPAP+Placebo; Patients in the placebo group will also receive nCPAP at 5-6 cm H2O pressure with an oxygen concentration of 21% or more to maintain preductal saturation between 90% and 95%. In addition, patients will receive 3 mL nebulised 0.9% NaCl administered for 30 min. as a placebo	Drug: 0,9% Chloride Sodium; 3 mL nebulized 0.9% NaCl administered for 30 min.; Other Names: 0,9% NaCl

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Persistent Pulmonary Hypertension of the Newborn (PPHN)	PPHN defined as the need for ventilation with FiO2 >0.30 and features of increased pulmonary pressure on echocardiogram	7 days of life

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
the severity of respiratory distress	assessed with the modified TTN Silverman score	48 hrs of life
need for intubation	frequency of need for intubation	7 days of life
duration of ventilation	duration of ventilation e.g. non-invasive ventilation	7 days of life
duration of hospitalization	duration of hospitalisation after birth	up to first month of life

Collaborators and Investigators

• Sponsor: Medical University of Warsaw
• Collaborators: Jagiellonian University; University of Ottawa; Pomeranian Medical University Szczecin; Poznan University of Medical Sciences; University of Rzeszow; Jan Biziel University Hospital No 2 in Bydgoszcz; Neonatology Unit, Specialist Hospital No 2, Bytom; University in Zielona Góra
• Investigators: Principal Investigator: Renata Bokiniec, MD, PhD, Medical University of Warsaw

Study record dates

Study Major Dates

• Study Start (Actual): December 31, 2021
• Primary Completion (Estimated): November 30, 2025
• Study Completion (Estimated): September 30, 2026

Study Registration Dates

• First Submitted: August 31, 2022
• First Submitted That Met QC Criteria: August 31, 2022
• First Posted (Actual): September 2, 2022

Study Record Updates

• Last Update Posted (Actual): April 18, 2024
• Last Update Submitted That Met QC Criteria: April 16, 2024
• Last Verified: September 1, 2023

More Information

Terms related to this study

• Keywords: PPHN; CPAP; TTN; Salbutamol
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Respiration Disorders; Lung Diseases; Infant, Newborn, Diseases; Signs and Symptoms, Respiratory; Infant, Premature, Diseases; Respiratory Distress Syndrome, Newborn; Respiratory Distress Syndrome; Respiratory Insufficiency; Tachypnea; Transient Tachypnea of the Newborn; Physiological Effects of Drugs; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Autonomic Agents; Peripheral Nervous System Agents; Adrenergic Agonists; Bronchodilator Agents; Anti-Asthmatic Agents; Respiratory System Agents; Reproductive Control Agents; Adrenergic beta-2 Receptor Agonists; Adrenergic beta-Agonists; Tocolytic Agents; Albuterol
• Other Study ID Numbers: 2019/ABM/01/00058/P/03; 2020-003913-36 (EudraCT Number)

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