The Diaphragmatic Initiated Ventilatory Assist (DIVA) Trial

Study Overview
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Brief Summary
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DIVA is a pragmatic randomized clinical trial (RCT) to determine: among (P) preterm infants born 24-27 6/7 weeks gestation undergoing extubation from mechanical ventilation, whether (I) Non-invasive neurally adjusted ventilatory assist (NIV-NAVA) (C) compared with Non-synchronized nasal intermittent positive pressure ventilation (NS-NIPPV), will reduce the incidence of (O) extubation failure within (T) 5 days (120 hours) of extubation.

Detailed Description
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Bronchopulmonary dysplasia (BPD) is the most common complication of prematurity and is the leading respiratory cause of childhood morbidity. Ventilator induced lung injury (VILI) an accepted and important contributor to BPD. Exposure to oxygen and positive pressure ventilation leads to developmental arrest and parenchymal injury in the immature preterm lung. Because even brief exposure to intubated positive pressure ventilation is injurious, avoiding invasive mechanical ventilation is the most widely acknowledged strategy to prevent VILI and the long-term sequela of BPD. Therefore, time on ventilators and rates of successful extubation are important endpoints of therapy. Non-invasive neurally adjusted ventilatory assist (NIV-NAVA) is an FDA approved technology that consistently synchronizes non-invasive respiratory support with infant respiratory drive. The Diaphragmatic Initiated Ventilatory Assist (DIVA) trial is an unblinded, pragmatic, multicenter phase III randomized clinical trial in extremely preterm infants 240/7- 276/7 weeks gestational age to determine if NIV-NAVA, compared with non-synchronized nasal intermittent positive pressure ventilation (NS-NIPPV), prevents extubation failure within 5 days (120 hours) of extubation from mechanical ventilation

Official Title
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The Diaphragmatic Initiated Ventilatory Assist (DIVA) Trial

Conditions
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Extubation Failure, Bronchopulmonary Dysplasia, Death

Intervention / Treatment
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* Device: NIV-NAVA
* Device: NS-NIPPV


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Gestational age of 24-27 6/7 weeks at birth Intubated in the first 7 days of life Undergoing extubation following at least 12 hours of invasive mechanical ventilation Post-natal age <28 days at time of extubation Exclusion Criteria: Major congenital anomalies, including pulmonary hypoplasia Neurologic disorders affecting respiratory drive (other than apnea of prematurity) Esophageal bleeding or other contraindication to NG/OG catheter placement Current weight <500 grams (based on Edi catheter approval) Study ventilator not available at time eligibility criteria are met Planned surgery or invasive procedure within 5 days of extubation Informed consent not provided

Ages Eligible for Study
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Minimum Age: 0 Days
Maximum Age: 28 Days

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
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: NIV-NAVA<br> | Device: NIV-NAVA<br>* Infants in the intervention arm will be managed with non-invasive neurally adjusted ventilatory assist (NIV-NAVA) using FDA-approved servos with associated FDA-approved Edi catheter.<br>* Other names: Non-invasive Neurally Adjusted Ventilatory Assist;|
| Active Comparator: NS- NIPPV<br> | Device: NS-NIPPV<br>* Infants in the active comparator arm will be treated with non-synchronized non-invasive positive pressure ventilation (NIPPV) through FDA-approved ventilators currently in use at each site.<br>* Other names: Non-synchronized Non-invasive Positive Pressure Ventilation;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Extubation failure | Extubation failure is defined when an infant is on the allocated mode of respiratory support and meets any of the following 4 criteria: (1) Rise in FiO2 at least 20% from pre-extubation value for >2 hours to maintain local SpO2 targets, (2) pH ≤7.20 or pCO2 ≥70mm Hg; (3) >1 apneic event requiring positive pressure ventilation (PPV) within 6 hours or ≥ 6 apneic events requiring stimulation within 6 hours (4) emergent intubation by the clinical team for cardiovascular instability or surgery. | within the first 5 days (120 hours) post extubation | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Bronchopulmonary Dysplasia (BPD) at 36 weeks PMA | BPD will be assessed as an ordinal outcome (none, grade 1, 2, 3), according to the NRN criteria. | 36 weeks PMA | 
| Death or BPD at 36 weeks PMA | Composite dichotomous (y/n) outcome of death or grade 2/3 BPD, using the NRN criteria | 36 weeks PMA | 
| Endotracheal intubation through 36 weeks PMA | Endotracheal intubation will be assessed 2 ways: As a dichotomous (y/n) outcome if it occurs at any time and also as days until endotracheal intubation (with censoring at 36 weeks PMA) | 36 weeks PMA | 
| Postmenstrual age at last invasive ventilation | Time to cessation of invasive ventilation, with censoring at 36 weeks PMA | 36 weeks PMA | 
| Postmenstrual age at last positive pressure support | Time to cessation of positive pressure respiratory support, with censoring at 36 weeks PMA | 36 weeks PMA | 
| Postmenstrual age at last supplemental oxygen | Time to cessation of supplemental oxygen, with censoring at 36 weeks PMA | 36 weeks PMA | 
| Prematurity-related morbidities through 36 weeks PMA | Brain injury (intraventricular hemorrhage and periventricular leukomalacia), patent ductus arteriosus requiring therapy, pulmonary hemorrhage, culture proven sepsis, necrotizing enterocolitis, retinopathy of prematurity | 36 weeks PMA |