Early Caffeine and LISA Compared to Caffeine and CPAP in Preterm Infants

Study Overview
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Brief Summary
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This study is being conducted to determine whether prophylactic administration of surfactant by the Less Invasive Surfactant Administration (LISA) method reduces the need for mechanical ventilation in the first 72 hours of life when compared to early Continuous Positive Airway Pressure (CPAP) alone.

Detailed Description
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In order to allow for initial stabilization on CPAP, infants will be randomized by 1 hour of life. Consented infants that are assessed by a provider as clinically stable (i.e. HR> 100 bpm) and spontaneously breathing on CPAP will be randomized by computer generated randomization cards placed in opaque envelopes. Randomization will be stratified by gestational age (24-26+6 weeks and 27-29+6 weeks) and labeled as such on each envelope. Multiples will be randomized to the same treatment group for ease of consent and family considerations. Infants randomized to LISA will receive surfactant (Curosurf 2.5 mL/kg, based on estimated fetal weight) and must be given in the first 2 hours of life using a conventional or video laryngoscope and a small flexible 16 gauge angiocatheter. All sites have agreed on using senior level physicians or practitioners that have prior experience with the LISA method. An orogastric tube will be placed into the stomach prior to laryngoscopy and the contents aspirated after the procedure to document any esophageal surfactant administration. Infants randomized to early CPAP will be managed according to unit practice for preterm infants on CPAP. Caffeine Administration: If randomized to LISA, caffeine will be given prior to the LISA procedure. In contrast, if randomized to CPAP, caffeine will be given soon after birth. If infants in the CPAP group meet intubation criteria, and the loading dose of caffeine has not been administered, to avoid delay in intubation, caffeine will be given no later than thirty minutes after intubation. As an unblinded trial it is critical that both groups are standardized to avoid bias towards one arm for intubation/treatment failure. Therefore, strict delivery room/NICU criteria will be used. In the Delivery Room, criteria for intubation will be as specified in the Neonatal Resuscitation Program guidelines (7th Ed) and will include: Chest compressions Ineffective respiration Prolonged positive pressure ventilation (PPV) Prolonged hypoxia In the Neonatal Intensive Care Unit (NICU), randomized infants in both groups will only be intubated if they meet strict failure criteria : CPAP level of 6-8 cmH2O and FiO2> 0.40 required to maintain oxygen saturation >90% for 2 hours after randomization pH of 7.15 or less OR a partial pCO2 >65 mmHg on any (2) blood gas (arterial/capillary/ or venous) at least 2 hours after randomization in the first 72 hours of life. Continued Apnea/Bradycardia/Desaturation events despite nasal intermittent minute ventilation (NIMV) mode of ventilation. Infants intubated prior to randomization will be excluded. Infants not consented prior to birth will also be excluded to avoid bias in patient selection. For pragmatic purposes sites will be able to use their standard approach for non-invasive ventilation (NCPAP or NIMV).

Official Title
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A Multicenter, Randomized Trial of Preterm Infants Receiving Caffeine and Less Invasive Surfactant Administration Compared to Caffeine and Early Continuous Positive Airway Pressure (CaLI Trial)

Conditions
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Premature Lungs, Respiratory Distress Syndrome, Surfactant Deficiency Syndrome Neonatal

Intervention / Treatment
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* Procedure: Less Invasive Surfactant Administration LISA
* Procedure: Continuous Positive Airway Pressure CPAP


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Premature infants born at 24 to 29+6 weeks gestation Informed consent obtained (antenatal) Infant is spontaneously breathing on CPAP of 5-8 cmH2O and maintaining a normal heart rate (HR>100 Bpm) Exclusion Criteria: Declined consent Infants with known congenital anomalies Unstable immediately after birth, requiring intubation in the delivery room

Ages Eligible for Study
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Minimum Age: 24 Weeks
Maximum Age: 29 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: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Less Invasive Surfactant Administration (LISA)<br>Infants that are spontaneously breathing with a normal heart rate will be randomized to receive prophylactic surfactant (Curosurf 2.5 mL/kg, based on estimated fetal weight) by the LISA procedure in the first 2 hours of life, using a conventional or video laryngoscope and a small flexible 16 gauge angiocatheter. Any repeat dosing for surfactant will be based on clinical indication at the physician discretion by the conventional endotracheal approach. | Procedure: Less Invasive Surfactant Administration LISA<br>* Laryngoscopy with insertion of a small 16 gauge angiocatheter to administer FDA approved Surfactant, during spontaneous respirations.<br>|
| Active Comparator: Continuous Positive Airway Pressure (CPAP)<br>Infants that are spontaneously breathing with a normal heart rate will be randomized to early Continuous Positive Airway Pressure (CPAP). | Procedure: Continuous Positive Airway Pressure CPAP<br>* Infant will remain on CPAP Therapy during spontaneous respirations<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Frequency of subjects requiring endotracheal intubation between the two groups (LISA vs CPAP) in the first 72 hours of life | Required intubation or meeting respiratory failure criteria of having a pCO2 greater than 65 mm Hg or an FiO2 greater than 0.4 for more than 2 hours in the first 72 hours of life | Within 72 hours of life | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of mechanical ventilation and/or CPAP | Number of days on mechanical ventilation and/or CPAP | Through study completion at discharge, up to 6 months of corrected gestational age | 
| Oxygen at 36 weeks corrected age | Requiring oxygen therapy greater than 0.21 at 36 weeks corrected age | Up to 40 weeks of corrected gestational age | 
| Frequency of Grade III and IV intraventricular hemorrhage | Intraventricular hemorrhage (grades 3-4) | Through study completion at discharge, up to 6 months of corrected gestational age | 
| Neurodevelopment outcome at 24 months of corrected gestational age | Neurodevelopmental assessments using the Bayley Scales of Infant Development 4th ed. will be done at 2 years of corrected corrected age (22-26 months) for subjects who were randomized at birth to receive surfactant by the LISA method versus CPAP alone. | Up to 2 years of corrected gestational age | 
| Neurodevelopment outcome at 2 Years of Age | Overall and Domain Scores- Ages and Stages, 3rd ed. Questionnaire | 22-26 months corrected gestational age | 
| Need for repeat surfactant dosing | Requiring more than one dose of surfactant | Up to 40 weeks of corrected gestational age | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Premature Infants, Respiratory Distress Syndrome, Less Invasive Surfactant administration, Continuous Positive Airway Pressure (CPAP)