Clinical trial NCT05609877: The NONA-LISA Trial
Official title: NON-pharmacological Approach Less Invasive Surfactant Administration (NONA-LISA) Trial: Protocol for a Randomised Controlled Trial
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Respiratory Distress Syndrome in Premature Infant
Lead sponsor: Rigshospitalet, Denmark
Sponsor class: OTHER
First posted: 2022-11-08
Enrollment: 324
Sex: ALL
Minimum age (years): 24
Maximum age (years): 30
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: 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 routine).
Primary purpose: TREATMENT

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.

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).

Primary outcomes:
measure: LISA failure within 24 hours.
timeFrame: 24 hours after procedure.
Secondary outcomes:
measure: Incidence of additional fentanyl administration
timeFrame: During the procedure, an average of 5-10 minutes.
measure: Pain or discomfort during the procedure (according to COMFORTneo score >14).
timeFrame: 24 hours after procedure
measure: Bradycardia <100 BPM for a minimum duration of 4 seconds.
timeFrame: 24 hours after procedure.
measure: Need for a second dose of surfactant
timeFrame: 24 hours after procedure.
measure: Escalation from LISA to INSURE in the same attempt
timeFrame: 24 hours after procedure.
measure: Apnoea that require bag and mask ventilation during the procedure
timeFrame: 24 hours after procedure.
measure: Observed surfactant reflux
timeFrame: 24 hours after procedure.
measure: Desaturation with SaO2 (right extremity measure) <85% during the procedure
timeFrame: 24 hours after procedure.
measure: Procedural time consumption from the introduction of the laryngoscope blade into the oral cavity to removal of the catheter.
timeFrame: 24 hours after procedure.
measure: Number of attempts of insertion of the catheter in the trachea.
timeFrame: 24 hours after procedure.
measure: Number of attempts of insertion of the laryngoscope in the oral cavity.
timeFrame: 24 hours after procedure.
measure: Time from meeting the criteria for surfactant treatment until surfactant administration
timeFrame: 24 hours after procedure.
measure: Incidence of endotracheal intubation.
timeFrame: 48 hours after procedure
measure: Incidence of pneumothorax within 48 hours after LISA.
timeFrame: 48 hours after procedure.
measure: 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).
timeFrame: 48 hours after procedure.
measure: Incidence of in-hospital mortality before discharge.
timeFrame: Through study completion, an average of 6 months.
measure: Cumulated duration of mechanical ventilation during hospitalisation.
timeFrame: Before discharge (through study completion, an average of 6 months).
measure: Cumulated duration of positive pressure ventilation during hospitalisation.
timeFrame: Before discharge (through study completion, an average of 6 months).
measure: Incidence of escalation of respiratory support from CPAP to other NIV modes during hospitalisation.
timeFrame: Before discharge (through study completion, an average of 6 months).
measure: Cumulated duration of all types of non-invasive respiratory support during hospitalisation.
timeFrame: Before discharge (through study completion, an average of 6 months).
measure: Cumulated duration of oxygen treatment with fraction of inspired oxygen (FiO2) >0.21.
timeFrame: Before discharge (through study completion, an average of 6 months).
measure: Cumulated duration of any repisratory support during hospitalisation.
timeFrame: Before discharge (through study completion, an average of 6 months).
measure: Duration of hospitalisation.
timeFrame: Before discharge (through study completion, an average of 6 months).
measure: Incidence of necrotising enterocolitis (according to Bell's Staging Criteria).
timeFrame: Before discharge (through study completion, an average of 6 months).
measure: Incidence of treatment-demanding retinopathy of prematurity.
timeFrame: Before discharge (through study completion, an average of 6 months).
measure: Incidence of intraventricular haemorrhage grade 3-4 and periventricular leukomalacia.
timeFrame: Before discharge (through study completion, an average of 6 months).
measure: Composite outcome of death or moderate/severe BPD at 36 weeks of corrected gestational age.
timeFrame: 36 weeks of corrected gestational age.
Other outcomes:
Locations:
city: Aalborg
country: Denmark
facility: Neonatalafsnittet, Børn- og Ungeafdelingen, Reberbansgade 15
city: Aarhus
country: Denmark
facility: Department of Paediatrics (Intensive Care Neonatology) and Perinatal Research Unit
city: Copenhagen
country: Denmark
facility: Department of Neonatal and Pediatric Intensive Care, Blegdamsvej 9
city: Odense
country: Denmark
facility: H.C. Andersen Børne- og Ungehospital, Kløvervænget 23C, Indgang 60
Study officials:
affiliation: Rigshospitalet, Denmark
name: Niklas Breindahl, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.