The NONA-LISA Trial

NCT ID: NCT05609877

Last Updated: 2024-09-20

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: NA
• Total Enrollment: 324 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2024-06-01
• Study Completion Date: 2029-05-31

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.

Conditions

Respiratory Distress Syndrome in Premature Infant

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

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.

Group Type: ACTIVE_COMPARATOR

Less Invasive Surfactant Administration (LISA)

Intervention Type: PROCEDURE

All infants will be treated with the Less Invasive Surfactant Administration (LISA) procedure

Fentanyl

Intervention Type: DRUG

Fentanyl 0.5-1.0 mcg/kg will be administered intravenously as pre-procedure analgesia

Non-pharmacological standard operating procedure

Intervention Type: BEHAVIORAL

All infants will receive the same non-pharmacological standard operating procedure.

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.

Group Type: SHAM_COMPARATOR

Isotonic saline

Intervention Type: DRUG

Isotonic saline will be administered intravenously instead of pre-procedure analgesia.

Less Invasive Surfactant Administration (LISA)

Intervention Type: PROCEDURE

All infants will be treated with the Less Invasive Surfactant Administration (LISA) procedure

Non-pharmacological standard operating procedure

Intervention Type: BEHAVIORAL

All infants will receive the same non-pharmacological standard operating procedure.

Interventions

Isotonic saline

Isotonic saline will be administered intravenously instead of pre-procedure analgesia.

Intervention Type: DRUG

Less Invasive Surfactant Administration (LISA)

All infants will be treated with the Less Invasive Surfactant Administration (LISA) procedure

Intervention Type: PROCEDURE

Fentanyl

Fentanyl 0.5-1.0 mcg/kg will be administered intravenously as pre-procedure analgesia

Intervention Type: DRUG

Non-pharmacological standard operating procedure

All infants will receive the same non-pharmacological standard operating procedure.

Intervention Type: BEHAVIORAL

Eligibility Criteria

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).

• Minimum Eligible Age: 24 Weeks
• Maximum Eligible Age: 30 Weeks
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Rigshospitalet, Denmark

OTHER

Sponsor Role: lead

Responsible Party

Lise Aunsholt

MD, PhD, associate professor

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Niklas Breindahl, MD

Role: PRINCIPAL_INVESTIGATOR

Rigshospitalet, Denmark

Locations

Neonatalafsnittet, Børn- og Ungeafdelingen, Reberbansgade 15

Aalborg, , Denmark

Site Status: WITHDRAWN

Department of Paediatrics (Intensive Care Neonatology) and Perinatal Research Unit

Aarhus, , Denmark

Site Status: RECRUITING

Department of Neonatal and Pediatric Intensive Care, Blegdamsvej 9

Copenhagen, , Denmark

Site Status: RECRUITING

H.C. Andersen Børne- og Ungehospital, Kløvervænget 23C, Indgang 60

Odense, , Denmark

Site Status: NOT_YET_RECRUITING

Countries

Denmark

Central Contacts

Lise Aunsholt, MD, PhD

Role: CONTACT

lise.aunsholt@regionh.dk

+4561991137

Niklas Breindahl, MD

Role: CONTACT

niklas.breindahl@regionh.dk

+4528566410

Facility Contacts

Tine B Henriksen, MD, PhD

Role: primary

tine.brink.henriksen@clin.au.dk

Peter Agergaard, MD

Role: backup

Lise Aunsholt, MD, PhD

Role: primary

lise.aunsholt@regionh.dk

Niklas Breindahl, MD

Role: backup

Gitte Zachariassen, MD, PhD

Role: primary

Gitte.Zachariassen@rsyd.dk

Stine Lund, MD

Role: backup

References

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 Sep;96(4):1084-1089. doi: 10.1038/s41390-023-02998-0. Epub 2024 Jan 11.

Reference Type: BACKGROUND

PMID: 38200325 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 37142651 (View on PubMed)

Breindahl N, Henriksen TB, Heiring C, Bay ET, Haaber J, Salmonsen TG, Agergaard P, Carlsen ELM, Tolsgaard MG, Aunsholt L. Can non-pharmacological comfort care replace fentanyl in LISA? The NONA-LISA feasibility study. Pediatr Res. 2025 Aug 2. doi: 10.1038/s41390-025-04310-8. Online ahead of print.

Reference Type: DERIVED

PMID: 40753114 (View on PubMed)

Other Identifiers

The NONA-LISA trial

Identifier Type: -

Identifier Source: org_study_id