Examining the Use of Non-Invasive Inhaled Nitric Oxide to Reduce Chronic Lung Disease in Premature Newborns

Bronchopulmonary dysplasia (BPD) is a serious lung condition that affects premature newborns. The condition involves abnormal development of lung tissue and is characterized by inflammation and scarring in the lungs. Treatment with inhaled nitric oxide (iNO) may reduce the incidence of BPD and another commonly associated condition called pulmonary hypertension, which is high blood pressure in the vessels carrying blood to the lungs.. This study will determine if early treatment with low-dose iNO reduces the incidence of BPD, pulmonary hypertension, and death in premature newborns.

Study Overview

• Status: Completed
• Conditions: Bronchopulmonary Dysplasia
• Intervention / Treatment: Drug: Inhaled Nitric Oxide (iNO); Drug: Nitrogen (placebo)

Detailed Description

BPD is a serious lung condition that primarily affects premature newborns and newborns with low birth weights. iNO has been proven to be a safe and effective treatment for pulmonary hypertension and hypoxemic respiratory failure-both of which are abnormal lung conditions-in full-term newborns. However, in babies born prematurely, the effects of iNO on lung function are not well defined. Also, previous studies have mainly examined whether iNO reduces the incidence of BPD in newborns who are on mechanical ventilation. However, intubation and mechanical ventilation of premature newborns is now increasingly being avoided, and non-invasive support, including the use of nasal continuous positive airway pressure (NCPAP), is being used. Early treatment with low-dose iNO may reduce the incidence of BPD in premature newborns who do not require mechanical ventilation and intubation after delivery. The purpose of this study is to determine if low-dose, non-invasive iNO reduces the risk of BPD, pulmonary hypertension, and death in premature newborns who do not require mechanical ventilation.

This study will enroll premature newborns who require extra oxygen but do not require intubation or mechanical ventilation for respiratory failure in the first 72 hours of life. Participants will be randomly assigned to receive low-dose, non-invasive iNO or nitrogen (placebo) during their hospital stay. While hospitalized, participants' heart rate, blood oxygen level breathing rate, blood pressure, and medications will be monitored, and blood collection will occur at various times. Monitoring will continue until participants are 30 weeks corrected gestational age or for at least 14 days if participants are born at 29 weeks or more. All participants will undergo an ultrasound of the head when they are 7 days, 28 days, and 36 weeks of age. They will undergo an echocardiogram, which is an ultrasound of the heart, at 7 and 21 days of age and 4 weeks before the original expected due date. A chest x-ray will be performed before hospital discharge, and a breathing status test will be performed either 4 weeks before participants' original expected due date or before hospital discharge. Follow-up study visits will occur at Years 1 and 2, and will include a physical examination and developmental and behavioral testing. Another echocardiogram will also be performed at the Year 1 visit.

• Study Type: Interventional
• Enrollment (Actual): 124
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35242
      • University of Alabama at Birmingham
  • California
    • San Diego, California, United States, 92123
      • University of California San Diego
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Children's Hospital and University Colorado Hospital
  • Illinois
    • Chicago, Illinois, United States, 60614
      • Anne and Robert H. Lurie Children's Hospital of Chicago and Northwestern Memorial Hospital
  • Ohio
    • Columbus, Ohio, United States, 43205
      • Nationwide Children's Hospital
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt Children's Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 3 days (CHILD)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Birth weight of 500-1250 grams and gestational age of less than 34 weeks
• Age at enrollment is less than 72 hours
• Supplemental oxygen or 21% requirement by nasal cannula or NCPAP only

Exclusion Criteria:

• Presence of structural heart disease (other than patent ductus arteriosus, atrial septal defect less than 1 cm, or muscular ventricular septal defect less than 2 mm)
• Presence of lethal congenital anomaly
• Participating in another concurrent experimental study
• Requires mechanical ventilation in the first 72 hours of life (patients are not excluded if they are intubated briefly but they must be extubated at the time of consent and study entry prior to 72 hours of life)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: PREVENTION
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: TRIPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Inhaled Nitric Oxide (iNO); Participants will receive a low concentration of iNO until they are 30 weeks corrected gestational age or for 14 days if they were born at 29 weeks or more.	Drug: Inhaled Nitric Oxide (iNO); iNO will be delivered using the iNOVent device to provide 10 ppm proximally (yielding approximately 5 ppm to the posterior pharynx).
PLACEBO_COMPARATOR: Nitrogen (placebo); Participants will receive nitrogen (placebo) while in the hospital.	Drug: Nitrogen (placebo); Nitrogen will be delivered using the iNOVent device to provide 10 ppm proximally (yielding approximately 5 ppm to the posterior pharynx).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Combined Endpoint of Bronchopulmonary Dysplasia (BPD) or Mortality	Number of participants that developed bronchopulmonary dysplasia and/or that died	Week 36 or earlier, if participants are discharged from the hospital
Combined Endpoint of Bronchopulmonary Dysplasia (BPD) or Mortality Stratified by Birth Weight	Number of participants that developed bronchopulmonary dysplasia and/or that died, stratified by birth weight (grams)	Randomization to discharge

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Severity of Bronchopulmonary Dysplasia (BPD)	Assessment of the severity of BPD as defined by the oxygen reduction test	36 weeks corrected gestational age
Need for Mechanical Ventilation	Number of participants who required endotracheal intubation and mechanical ventilation	Anytime after randomization up to 36 weeks corrected gestational age
Total Ventilation Days	Of those participants who required mechanical ventilation, the total number of days receiving ventilation	After randomization up until hospital discharge
Necrotizing Enterocolitis (NEC)	Number of participants diagnosed with necrotizing enterocolitis	After randomization through hospital discharge
Symptomatic PDA Requiring Medical Treatment	Number of participants with a symptomatic PDA that required medical treatment	From randomization until discharge
Symptomatic PDA Requiring Surgical Ligation	Number of participants with symptomatic PDA that required surgical ligation	Randomization through discharge
Threshold Retinopathy of Prematurity (ROP)	Threshold ROP defined as requiring interventional therapy	Randomization to discharge
Severe Intracranial Hemorrhage	Number of participants that developed severe intracranial hemorrhage (grade 3-4)	Randomization to discharge
Sepsis	Number of participants that developed sepsis	Randomization to discharge

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Days in Hospital	Length of stay of participants	From birth to hospital discharge

Collaborators and Investigators

• Sponsor: University of Colorado, Denver
• Collaborators: National Heart, Lung, and Blood Institute (NHLBI)
• Investigators: Principal Investigator: John Kinsella, MD, Chidlren's Hospital and University of Colorado Hospital

Publications and helpful links

General Publications

• Kinsella JP, Cutter GR, Steinhorn RH, Nelin LD, Walsh WF, Finer NN, Abman SH. Noninvasive inhaled nitric oxide does not prevent bronchopulmonary dysplasia in premature newborns. J Pediatr. 2014 Dec;165(6):1104-1108.e1. doi: 10.1016/j.jpeds.2014.06.018. Epub 2014 Jul 22.

Study record dates

Study Major Dates

• Study Start: January 1, 2007
• Primary Completion (ACTUAL): July 1, 2014
• Study Completion (ACTUAL): December 1, 2014

Study Registration Dates

• First Submitted: August 6, 2009
• First Submitted That Met QC Criteria: August 6, 2009
• First Posted (ESTIMATE): August 10, 2009

Study Record Updates

• Last Update Posted (ACTUAL): June 15, 2017
• Last Update Submitted That Met QC Criteria: May 22, 2017
• Last Verified: May 1, 2017

More Information

Terms related to this study

• Keywords: Inhaled Nitric Oxide; Premature Newborns
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Infant, Newborn, Diseases; Pregnancy Complications; Obstetric Labor Complications; Obstetric Labor, Premature; Lung Injury; Infant, Premature, Diseases; Ventilator-Induced Lung Injury; Lung Diseases; Premature Birth; Bronchopulmonary Dysplasia; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Vasodilator Agents; Autonomic Agents; Peripheral Nervous System Agents; Protective Agents; Bronchodilator Agents; Anti-Asthmatic Agents; Respiratory System Agents; Antioxidants; Free Radical Scavengers; Endothelium-Dependent Relaxing Factors; Gasotransmitters; Nitric Oxide
• Other Study ID Numbers: 06-0124; 5P50HL084923 (NIH); 5 P50 HL084923-030001