The NONA-LISA Trial

Not Applicable

Recruiting

• Conditions: Respiratory Distress Syndrome in Premature Infant
• Interventions: Procedure: Less Invasive Surfactant Administration (LISA); Drug: Isotonic saline; Drug: Fentanyl; Behavioral: Non-pharmacological standard operating procedure

• Registration Number: NCT05609877
• Lead Sponsor: Rigshospitalet, Denmark

Brief Summary

The NONA-LISA trial will be an investigator-initiated, multicentre, pragmatic, parallel-group, blinded RCT conducted at four university hospitals across Denmark. A total of 324 inborn premature infants will be included within 36 months at four neonatal intensive care units (NICUs) across Denmark (approximately 2 infants per month per unit).

The aim is to compare LISA using a non-pharmacological approach alone with routine analgesic treatment combined with a non-pharmacological approach (according to local guidelines) regarding LISA failure defined as the need for positive pressure ventilation for 30 min or more (cumulated) within 24 hours after the procedure in infants born prior to 30 gestational weeks.

Detailed Description

Background

Less Invasive Surfactant Administration (LISA) is a way of applying surfactant in the trachea by use of a catheter during spontaneous breathing and after applying nasal continuous positive airway pressure (nCPAP). However, use of pre-procedure analgesia with risk of apnoea may prevent LISA to achieve its full potential.

Aim

This study aims to compare the LISA procedure using a non-pharmacological approach to the LISA procedure using analgesic treatment with 0.5-1 mcg/kg fentanyl in infants born at 24 to 29 completed gestational weeks who fulfil the criteria for surfactant treatment.

Trial design

The NONA-LISA trial will be an investigator-initiated, multicentre, pragmatic, parallel-group, blinded RCT conducted at four university hospitals across Denmark. A total of 324 inborn premature infants will be included within 36 months at four neonatal intensive care units (NICUs) across Denmark (approximately 2 infants per month per unit).

Participants

Eligible infants will be born at 24+0 to 29+6 weeks of gestation at one of the trial sites meeting the criteria for first-choice surfactant treatment by LISA as described by Sweet et al.: worsening babies with RDS and FiO2 \> 0.30 on CPAP pressure ≥6 cm H2O. Infants will be excluded if they have any of the exclusion criteria: 1) suspicion of lung hypoplasia, 2) endotracheal intubation at any time before randomisation, 3) suspicion of pneumothorax, pulmonary haemorrhage or pleural effusion before LISA, 4) major congenital anatomical anomalies as described by the European Surveillance of Congenital Anomalies (EUROCAT).

Interventions

The randomisation will be stratified according to trial site and gestational age (GA) less than 28 or 28+ gestational weeks. Both groups will receive treatment by experienced teams of neonatal nurses and neonatologists. Both groups will receive the non-pharmacological approach as the basic treatment (part of the routine). Additional analgesics will be provided at the clinician's discretion. Patients will receive the unit's standard pre-procedure and post-procedure care, and both procedures will use video laryngoscopes.

Participants in the control group will receive surfactant after receiving intravenous analgesics.

Participants in the intervention group (LISA using the non-pharmacological approach) will receive surfactant after receiving a similar volume of intravenous isotonic saline solution.

Outcomes

The primary outcome of this trial is the need for invasive ventilation, meaning mechanical or manual ventilation via an endotracheal tube for at least 30 min (cumulated) within 24 h of the procedure. Non-invasive ventilation (NIV) is not included in the primary outcome.

Sample size

We have calculated our sample size based on the primary outcome with an alpha of 5%, a power of 80%, and a ratio of 1:1 between intervention and control groups.

Based on previous studies, we anticipate an incidence of "positive pressure ventilation for at least 30 minutes (cumulated) within 24 hours after procedure" in the control group around 45%. Using 30% incidence reduction as anticipated intervention effect, we will need to randomise a total of 324 infants.

Study Timeline

• Study First Submitted: 2022-10-18
• Study First Submitted QC: 2022-11-01
• Study First Posted: 2022-11-08
• Study Start: 2024-06-01
• Status Verified: 2024-07
• Last Update Submitted: 2024-07-11
• Last Update Posted: 2024-07-16
• Primary Completion: 2028-05-31
• Study Completion: 2029-05-31

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 324

Inclusion Criteria

• Infants born at one of the trial sites with a gestational age of 24+0 to 29+6 weeks and meeting the criteria for first-choice surfactant treatment by LISA as described by Sweet et al.: worsening babies with RDS and FiO2 > 0.30 on CPAP pressure ≥6 cm H2O.

Read More

Exclusion Criteria

1. suspicion of lung hypoplasia,
2. endotracheal intubation at any time before randomisation,
3. suspicion of pneumothorax, pulmonary haemorrhage or pleural effusion before LISA,
4. major congenital anatomical anomalies as described by the European Surveillance of Congenital Anomalies (EUROCAT).

Read More

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Fentanyl group	Less Invasive Surfactant Administration (LISA)	Patients will receive 0.5-1 mcg/kg fentanyl intravenously as pre-procedure analgesia for Less Invasive Surfactant Administration (LISA). The staff will perform LISA using standard pre- and post-procedure care, including non-pharmacological treatment and the use of atropine, caffeine, and naloxone at the clinician's discretion, based on local protocols and guidelines. All medications will be registered.
Fentanyl group	Non-pharmacological standard operating procedure	Patients will receive 0.5-1 mcg/kg fentanyl intravenously as pre-procedure analgesia for Less Invasive Surfactant Administration (LISA). The staff will perform LISA using standard pre- and post-procedure care, including non-pharmacological treatment and the use of atropine, caffeine, and naloxone at the clinician's discretion, based on local protocols and guidelines. All medications will be registered.
Saline group	Isotonic saline	Patients will receive a placebo (isotonic saline) instead of pre-procedure analgesia for Less Invasive Surfactant Administration (LISA). The staff will perform LISA using standard pre- and post-procedure care, including non-pharmacological treatment and the use of atropine, caffeine, and naloxone at the clinician's discretion, based on local protocols and guidelines. All medications will be registered.
Saline group	Less Invasive Surfactant Administration (LISA)	Patients will receive a placebo (isotonic saline) instead of pre-procedure analgesia for Less Invasive Surfactant Administration (LISA). The staff will perform LISA using standard pre- and post-procedure care, including non-pharmacological treatment and the use of atropine, caffeine, and naloxone at the clinician's discretion, based on local protocols and guidelines. All medications will be registered.
Saline group	Non-pharmacological standard operating procedure	Patients will receive a placebo (isotonic saline) instead of pre-procedure analgesia for Less Invasive Surfactant Administration (LISA). The staff will perform LISA using standard pre- and post-procedure care, including non-pharmacological treatment and the use of atropine, caffeine, and naloxone at the clinician's discretion, based on local protocols and guidelines. All medications will be registered.
Fentanyl group	Fentanyl	Patients will receive 0.5-1 mcg/kg fentanyl intravenously as pre-procedure analgesia for Less Invasive Surfactant Administration (LISA). The staff will perform LISA using standard pre- and post-procedure care, including non-pharmacological treatment and the use of atropine, caffeine, and naloxone at the clinician's discretion, based on local protocols and guidelines. All medications will be registered.

Primary Outcome Measures

Name	Time	Method
LISA failure within 24 hours.	24 hours after procedure.	The primary outcome will be LISA failure in terms of the need for endotracheal intubation and mechanical ventilation for at least 30 minutes (cumulated) within 24 hours after the procedure.

Secondary Outcome Measures

Name	Time	Method
Cumulated duration of oxygen treatment with fraction of inspired oxygen (FiO2) >0.21.	Before discharge (through study completion, an average of 6 months).	This is a numerical variable.
Need for a second dose of surfactant	24 hours after procedure.	This is a categorical variable (yes/no).
Desaturation with SaO2 (right extremity measure) <85% during the procedure	24 hours after procedure.	This is a categorical variable (yes/no).
Procedural time consumption from the introduction of the laryngoscope blade into the oral cavity to removal of the catheter.	24 hours after procedure.	This is a categorical variable (yes/no).
Number of attempts of insertion of the catheter in the trachea.	24 hours after procedure.	This is a numerical variable.
Cumulated duration of positive pressure ventilation during hospitalisation.	Before discharge (through study completion, an average of 6 months).	This is a numerical variable.
Incidence of additional fentanyl administration	During the procedure, an average of 5-10 minutes.	This will include the number of injection(s), dosage, cumulated dose, and indications defined as pain/discomfort/sedation/other.
Pain or discomfort during the procedure (according to COMFORTneo score >14).	24 hours after procedure	This will include a numerical and a categorical variable (COMFORTneo score \>/\< 14).
Escalation from LISA to INSURE in the same attempt	24 hours after procedure.	This is a categorical variable (yes/no).
Apnoea that require bag and mask ventilation during the procedure	24 hours after procedure.	This is a categorical variable (yes/no).
Number of attempts of insertion of the laryngoscope in the oral cavity.	24 hours after procedure.	This is a numerical variable.
Incidence of endotracheal intubation.	48 hours after procedure	This is a categorical variable.
Incidence of massive pulmonary haemorrhage within 48 hours after LISA (defined as the aspiration of haemorrhagic secretions from the trachea concurrent with the need for escalated respiratory support).	48 hours after procedure.	This is a categorical variable.
Incidence of in-hospital mortality before discharge.	Through study completion, an average of 6 months.	This is a categorical variable.
Incidence of escalation of respiratory support from CPAP to other NIV modes during hospitalisation.	Before discharge (through study completion, an average of 6 months).	This is a categorical variable.
Incidence of necrotising enterocolitis (according to Bell's Staging Criteria).	Before discharge (through study completion, an average of 6 months).	This is a categorical variable.
Observed surfactant reflux	24 hours after procedure.	This is a categorical variable (yes/no).
Time from meeting the criteria for surfactant treatment until surfactant administration	24 hours after procedure.	This is a numerical variable in minutes.
Incidence of pneumothorax within 48 hours after LISA.	48 hours after procedure.	This is a categorical variable.
Cumulated duration of any repisratory support during hospitalisation.	Before discharge (through study completion, an average of 6 months).	This is a numerical variable.
Incidence of intraventricular haemorrhage grade 3-4 and periventricular leukomalacia.	Before discharge (through study completion, an average of 6 months).	This is a categorical variable.
Bradycardia <100 BPM for a minimum duration of 4 seconds.	24 hours after procedure.	This is a categorical variable (yes/no).
Cumulated duration of mechanical ventilation during hospitalisation.	Before discharge (through study completion, an average of 6 months).	This is a numerical variable.
Cumulated duration of all types of non-invasive respiratory support during hospitalisation.	Before discharge (through study completion, an average of 6 months).	This is a numerical variable.
Duration of hospitalisation.	Before discharge (through study completion, an average of 6 months).	This is a numerical variable.
Incidence of treatment-demanding retinopathy of prematurity.	Before discharge (through study completion, an average of 6 months).	This is a categorical variable.
Composite outcome of death or moderate/severe BPD at 36 weeks of corrected gestational age.	36 weeks of corrected gestational age.	This is a categorical variable.

Trial Locations

Locations (4)

Neonatalafsnittet, Børn- og Ungeafdelingen, Reberbansgade 15; 🇩🇰 Aalborg, Denmark

Department of Paediatrics (Intensive Care Neonatology) and Perinatal Research Unit; 🇩🇰 Aarhus, Denmark

Department of Neonatal and Pediatric Intensive Care, Blegdamsvej 9; 🇩🇰 Copenhagen, Denmark

H.C. Andersen Børne- og Ungehospital, Kløvervænget 23C, Indgang 60; 🇩🇰 Odense, Denmark