The NONA-LISA Trial

Study Overview
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Brief Summary
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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
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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 meeting the criteria for surfactant treatment by LISA and not meeting any of the exclusion criteria: PPROM >3 weeks and suspicion of oligohydramnion or lung hypoplasia Requiring intubation or mechanical ventilation at any time before randomisation Suspicion of pneumothorax or pulmonary haemorrhage or pleural effusion Major congenital malformation (e.g., congenital heart disease, oesophageal atresia, esophago-tracheal fistula, diaphragmatic hernia, abdominal wall defect) or chromosomal abnormality or inherited disorders of metabolism 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 routine). Additional analgesics will be provided at the discretion of the clinician. Patients will receive the unit's standard pre- 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 will be LISA failure in terms of the need for endotracheal intubation and mechanical ventilation more than 30 minutes (cumulated) within 24 hours after the procedure. Secondary outcomes are outlined in the Outcome section. 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.

Official Title
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The NON-pharmacological Approach Less Invasive Surfactant Administration Trial

Conditions
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Respiratory Distress Syndrome in Premature Infant

Intervention / Treatment
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* Procedure: NONA-LISA


Participation Criteria
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Eligibility Criteria
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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 surfactant treatment by LISA. Exclusion Criteria: prolonged premature rupture of membrane more than three weeks and suspicion of oligohydramnios or lung hypoplasia, endotracheal intubation at any time before LISA, suspicion of pneumothorax, pulmonary haemorrhage or pleural effusion, major congenital anatomical anomalies as described by the European Surveillance of Congenital Anomalies (EUROCAT).

Ages Eligible for Study
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Minimum Age: 24 Weeks
Maximum Age: 30 Weeks

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional 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).
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| No Intervention: Control group: LISA with analgesia combined with non-pharmacological approach as usual<br>The staff will perform Less Invasive Surfactant Administration using standard 0.5-1 mcg/kg fentanyl intravenously for LISA. In both groups, patients will receive the unit's standard pre- and post-procedure care including their non-pharmacological approach, use of atropine, caffeine, and naloxone at the discretion of the clinician based on local protocols and guidelines. All medications will be registered. | |
| Placebo Comparator: Intervention group: Non-pharmacological Approach LISA (NONA-LISA) alone<br>The staff will perform Less Invasive Surfactant Administration using the standard pre- and post-procedure care including non-pharmacological treatment. The patients will not receive pharmacological analgesic treatment routinely. In both groups, patients will receive the unit's standard pre- and post-procedure care including their non-pharmacological approach, use of atropine, caffeine, and naloxone at the discretion of the clinician based on local protocols and guidelines. All medications will be registered. | Procedure: NONA-LISA<br>* The staff will perform Less Invasive Surfactant Administration using the standard pre- and post-procedure care including non-pharmacological treatment. The patients will not receive pharmacological analgesic treatment routinely.<br>|

What is the study measuring?
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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 including 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). |  | 24 hours after procedure | 
| Bradycardia <100 BPM for a minimum duration of 4 seconds. |  | 24 hours after procedure. | 
| Apnoea that require bag and mask ventilation during the procedure |  | 24 hours after procedure. | 
| Desaturation with SaO2 (right extremity measure) <80% for a minimum duration of 10 seconds. |  | 24 hours after procedure. | 
| Procedural time consumption from the introduction of the laryngoscope blade into the oral cavity to removal of the catheter. |  | 24 hours after procedure. | 
| Number of attempts of insertion of the catheter in the trachea. |  | 24 hours after procedure. | 
| Time from meeting the criteria for surfactant treatment until the procedure starts. |  | 24 hours after procedure. | 
| Incidence of endotracheal intubation. |  | 48 hours after procedure | 
| Incidence of pneumothorax within 48 hours after LISA. |  | 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). |  | 48 hours after procedure. | 
| Incidence of in-hospital mortality before discharge. |  | Through study completion, an average of 6 months. | 
| Cumulated duration of mechanical ventilation during hospitalisation. |  | Before discharge (through study completion, an average of 6 months). | 
| Cumulated duration of positive pressure ventilation during hospitalisation. |  | Before discharge (through study completion, an average of 6 months). | 
| Cumulated duration of all types of non-invasive respiratory support during hospitalisation. |  | Before discharge (through study completion, an average of 6 months). | 
| Cumulated duration of oxygen treatment with fraction of inspired oxygen (FiO2) >0.21. |  | Before discharge (through study completion, an average of 6 months). | 
| Cumulated duration of any repisratory support during hospitalisation. |  | Before discharge (through study completion, an average of 6 months). | 
| Duration of hospitalisation. |  | Before discharge (through study completion, an average of 6 months). | 
| Incidence of necrotising enterocolitis (according to Bell's Staging Criteria). |  | Before discharge (through study completion, an average of 6 months). | 
| Incidence of treatment-demanding retinopathy of prematurity. |  | Before discharge (through study completion, an average of 6 months). | 
| Incidence of intraventricular haemorrhage grade 3-4 and periventricular leukomalacia. |  | 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. |  | 36 weeks of corrected gestational age. |