The NONA-LISA Trial (NONA-LISA)

NON-pharmacological Approach Less Invasive Surfactant Administration (NONA-LISA) Trial: Protocol for a Randomised Controlled Trial

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.

Study Overview

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

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 Type: Interventional
• Enrollment (Estimated): 324
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Niklas Breindahl, MD; Phone Number: +4528566410; Email: niklas.breindahl@regionh.dk
• Study Contact Backup: Name: Lise Aunsholt, md, phd; Phone Number: +4561991137; Email: lise.aunsholt@regionh.dk

Study Locations

• Denmark
  • Aalborg, Denmark, 9000
    • Withdrawn
    • Neonatalafsnittet, Børn- og Ungeafdelingen, Reberbansgade 15
  • Aarhus, Denmark, 8200
    • Recruiting
    • Department of Paediatrics (Intensive Care Neonatology) and Perinatal Research Unit
    • Contact: Tine B Henriksen, MD, PhD; Email: tine.brink.henriksen@clin.au.dk
    • Contact: Peter Agergaard, MD
  • Copenhagen, Denmark, 2100
    • Recruiting
    • Department of Neonatal and Pediatric Intensive Care, Blegdamsvej 9
    • Contact: Lise Aunsholt, MD, PhD; Email: lise.aunsholt@regionh.dk
    • Contact: Niklas Breindahl, MD
  • Odense, Denmark, 5000
    • Not yet recruiting
    • H.C. Andersen Børne- og Ungehospital, Kløvervænget 23C, Indgang 60
    • Contact: Gitte Zachariassen, MD, PhD; Email: Gitte.Zachariassen@rsyd.dk
    • Contact: Stine Lund, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 5 months to 6 months (Child)
• Accepts Healthy Volunteers: No

Description

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.

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).

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: Fentanyl group; 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.	Procedure: Less Invasive Surfactant Administration (LISA); All infants will be treated with the Less Invasive Surfactant Administration (LISA) procedure; Drug: Fentanyl; Fentanyl 0.5-1.0 mcg/kg will be administered intravenously as pre-procedure analgesia; Behavioral: Non-pharmacological standard operating procedure; All infants will receive the same non-pharmacological standard operating procedure.
Sham Comparator: Saline group; 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.	Procedure: Less Invasive Surfactant Administration (LISA); All infants will be treated with the Less Invasive Surfactant Administration (LISA) procedure; Behavioral: Non-pharmacological standard operating procedure; All infants will receive the same non-pharmacological standard operating procedure.; Drug: Isotonic saline; Isotonic saline will be administered intravenously instead of pre-procedure analgesia.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
LISA failure within 24 hours.	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.	24 hours after procedure.

Secondary Outcome Measures

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

Collaborators and Investigators

• Sponsor: Rigshospitalet, Denmark
• Investigators: Principal Investigator: Niklas Breindahl, MD, Rigshospitalet, Denmark

Publications and helpful links

General Publications

• Breindahl N, Henriksen TB, Heiring C, Bay ET, Haaber J, Salmonsen TG, Carlsen ELM, Zachariassen G, Agergaard P, Viuff AF, Bender L, Gronnebaek Tolsgaard M, Aunsholt L. NON-pharmacological Approach Less Invasive Surfactant Administration (NONA-LISA) trial: protocol for a randomised controlled trial. Pediatr Res. 2024 Jan 11. doi: 10.1038/s41390-023-02998-0. Online ahead of print.
• Breindahl N, Tolsgaard MG, Henriksen TB, Roehr CC, Szczapa T, Gagliardi L, Vento M, Stoen R, Bohlin K, van Kaam AH, Klotz D, Durrmeyer X, Han T, Katheria AC, Dargaville PA, Aunsholt L. Curriculum and assessment tool for less invasive surfactant administration: an international Delphi consensus study. Pediatr Res. 2023 Sep;94(3):1216-1224. doi: 10.1038/s41390-023-02621-2. Epub 2023 May 4.

Study record dates

Study Major Dates

• Study Start (Actual): June 1, 2024
• Primary Completion (Estimated): May 31, 2028
• Study Completion (Estimated): May 31, 2029

Study Registration Dates

• First Submitted: October 18, 2022
• First Submitted That Met QC Criteria: November 1, 2022
• First Posted (Actual): November 8, 2022

Study Record Updates

• Last Update Posted (Actual): September 20, 2024
• Last Update Submitted That Met QC Criteria: September 18, 2024
• Last Verified: July 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Respiration Disorders; Lung Diseases; Infant, Newborn, Diseases; Infant, Premature, Diseases; Respiratory Distress Syndrome; Respiratory Distress Syndrome, Newborn; Physiological Effects of Drugs; Central Nervous System Depressants; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Anesthetics, Intravenous; Anesthetics, General; Anesthetics; Analgesics, Opioid; Narcotics; Adjuvants, Anesthesia; Respiratory System Agents; Fentanyl; Pulmonary Surfactants
• Other Study ID Numbers: The NONA-LISA trial

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: The datasets used and/or analysed during the current study will be available from the principal investigator on reasonable request after publication of results.

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