The Diaphragmatic Initiated Ventilatory Assist (DIVA) Trial (DIVA)

DIVA is a pragmatic randomized clinical trial (RCT) to determine: among (P) preterm infants born 23 0/7-28 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.

Study Overview

• Status: Recruiting
• Conditions: Death; Bronchopulmonary Dysplasia; Extubation Failure
• Intervention / Treatment: Device: NIV-NAVA; Device: NS-NIPPV

Detailed Description

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 23 0/7- 28 6/7 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

• Study Type: Interventional
• Enrollment (Estimated): 478
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Elizabeth Foglia; Phone Number: 267-441-7144; Email: FOGLIA@email.chop.edu
• Study Contact Backup: Name: Lisa Wesby, MS; Phone Number: 215-573-6318; Email: wesby@pennmedicine.upenn.edu

Study Locations

• Canada
  • Toronto, Canada, ON M5G 1X5
    • Recruiting
    • Mt Sinai Hospital
    • Contact: Amish Jain; Email: Amish.Jain@sinaihealth.ca
  • Vancouver, Canada, BC V6H 3N1
    • Recruiting
    • BC Children's and Women's Hospital
    • Contact: Jonathan Wong; Email: jonathan.wong@cw.bc.ca
  • Ontario
    • Toronto, Ontario, Canada, M4N3M5
      • Recruiting
      • Sunnybrook Health Sciences Centre
      • Contact: Maher Shahroor; Email: maher.shahroor@sunnybrook.ca
• United States
  • Arkansas
    • Little Rock, Arkansas, United States, 72202
      • Recruiting
      • Arkansas Children's Hospital
      • Contact: David Matlock; Email: DMatlock@uams.edu
  • California
    • Loma Linda, California, United States, 92350
      • Terminated
      • Loma Linda University
    • San Diego, California, United States, 92123
      • Recruiting
      • Sharp Mary Birch
      • Contact: Anup Katheria; Email: Anup.Katheria@sharp.com
  • Florida
    • Hollywood, Florida, United States, 33021
      • Recruiting
      • Joe DiMaggio Children's Hospital
      • Contact: Bruce Shulman; Email: brucesmd@icloud.com
    • Orlando, Florida, United States, 32803
      • Recruiting
      • AdventHealth
      • Contact: Samarth Shukla; Email: Samarth.Shukla.MD@AdventHealth.com
  • Indiana
    • Indianapolis, Indiana, United States, 46260
      • Recruiting
      • Peyton Manning Children's Hospital
      • Contact: Markus Tauscher; Email: mktausc1@ascension.org
  • Kentucky
    • Louisville, Kentucky, United States, 40202
      • Recruiting
      • Norton Children's Hospital
      • Contact: Dan Stewart; Email: dan.stewart@louisville.edu
  • Missouri
    • Kansas City, Missouri, United States, 64108
      • Recruiting
      • Children's Mercy Hospital
      • Contact: Christopher Nitkin; Email: crnitkin@cmh.edu
    • St Louis, Missouri, United States, 63110
      • Recruiting
      • Washington University in St.Louis
      • Contact: Roa Rakesh
      • Contact: Email: rao_r@wustl.edu
  • New Jersey
    • Voorhees Township, New Jersey, United States, 08043
      • Recruiting
      • Virtua Vorhees Hospital
      • Contact: Sarvin Ghavam
      • Contact: Email: ghavams@chop.edu
  • North Carolina
    • Charlotte, North Carolina, United States, 28203
      • Recruiting
      • Levine Children's Hospital
      • Contact: Eugenia Pallotto; Email: Eugenia.Pallotto@atriumhealth.org
    • Winston-Salem, North Carolina, United States, 27157
      • Recruiting
      • Atrial Health Brenner Children's Hospital( Wake Forest)
      • Contact: Ricardo J Rodriguez; Email: rjrodrig@wakehealth.edu
  • Ohio
    • Columbus, Ohio, United States, 43205
      • Recruiting
      • Nationwide Children's Hospital
      • Contact: Matthew Kielt
      • Contact: Email: Matthew.Kielt@nationwidechildrens.org
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Recruiting
      • Hospital of the University of Pennsylvania
      • Contact: Elizabeth Foglia; Email: FOGLIA@email.chop.edu
  • Utah
    • Murray, Utah, United States, 84107
      • Recruiting
      • Intermountain Medical Center
      • Contact: Bradley Yoder; Email: Bradley.Yoder@hsc.utah.edu
    • Provo, Utah, United States, 84604
      • Recruiting
      • Utah Valley Hospital
      • Contact: Bradley Yoder
      • Contact: Email: Bradley.Yoder@hsc.utah.edu
  • Virginia
    • Richmond, Virginia, United States, 23219
      • Recruiting
      • Children's Hospital of Richmond
      • Contact: Karen Hendrick-Munoz; Email: karen.hendricks-munoz@vcuhealth.org

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 second to 4 weeks (Child)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Gestational age of 23 0/7- 28 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 <32 weeks Post menstrual age 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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: NIV-NAVA	Device: NIV-NAVA; 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.; Other Names: Non-invasive Neurally Adjusted Ventilatory Assist
Active Comparator: NS- NIPPV	Device: NS-NIPPV; 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.; Other Names: Non-synchronized Non-invasive Positive Pressure Ventilation

What is the study measuring?

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Death	Death will be measured in two ways (1) as a dichotomous (y/n) outcome if death occurs prior to 36 weeks PMA, and (2) days until death (with censoring at 36 weeks PMA).	From randomization through 36 weeks PMA
Air Leaks	Air leaks will be measured as a dichotomous (y/n) outcome if a new pulmonary interstitial emphysema or pneumothorax occurs at any time after randomization until 36 weeks PMA.	From randomization through 36 weeks PMA
Gastrointestinal perforation or bleeding	This will be measured as a dichotomous (y/n) outcome if a new GI perforation or bleeding occurs at any time after randomization until 36 weeks PMA.	From randomization through 36 weeks PMA
Regional distribution of lung aeration	this will be measured with electrical impedance tomography in a subset of patients	From extubation through 5 days after extubation
Mean airway pressure	this will be measured from ventilator downloads for a subset of patients	From extubation through 5 days after extubation
peak inflation pressure	this will be measured from ventilator downloads for a subset of patients	From extubation through 5 days after extubation
Edi signal	this will be measured from ventilator downloads for a subset of patients	From extubation through 5 days after extubation
Fio2	this will be measured from ventilator downloads for a subset of patients	From extubation through 5 days after extubation

Collaborators and Investigators

• Sponsor: University of Pennsylvania
• Collaborators: National Heart, Lung, and Blood Institute (NHLBI)
• Investigators: Principal Investigator: Elizabeth Foglia, CHOP/UPENN

Publications and helpful links

General Publications

• Matlock DN, Ratcliffe SJ, Courtney SE, Kirpalani H, Firestone K, Stein H, Dysart K, Warren K, Goldstein MR, Lund KC, Natarajan A, Demissie E, Foglia EE. The Diaphragmatic Initiated Ventilatory Assist (DIVA) trial: study protocol for a randomized controlled trial comparing rates of extubation failure in extremely premature infants undergoing extubation to non-invasive neurally adjusted ventilatory assist versus non-synchronized nasal intermittent positive pressure ventilation. Trials. 2024 Mar 20;25(1):201. doi: 10.1186/s13063-024-08038-4.

Study record dates

Study Major Dates

• Study Start (Actual): August 3, 2022
• Primary Completion (Estimated): March 31, 2026
• Study Completion (Estimated): March 31, 2027

Study Registration Dates

• First Submitted: June 28, 2022
• First Submitted That Met QC Criteria: June 28, 2022
• First Posted (Actual): July 6, 2022

Study Record Updates

• Last Update Posted (Estimated): October 7, 2025
• Last Update Submitted That Met QC Criteria: October 6, 2025
• Last Verified: October 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Respiratory Tract Diseases; Lung Diseases; Infant, Premature, Diseases; Infant, Newborn, Diseases; Lung Injury; Ventilator-Induced Lung Injury; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Pathological Conditions, Signs and Symptoms; Death; Bronchopulmonary Dysplasia
• Other Study ID Numbers: 849912

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Research records will be retained at each study site, and at the DCC for 3 years after completion of the study. We will follow NIH sharing policies with regards to sharing of data and specimens to public repositories, where appropriate
• IPD Sharing Time Frame: 3 years after completion of the study
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: Yes