Inhaled Nitric Oxide and Neuroprotection in Premature Infants (NOVA2)

The purpose of this study is to determine whether inhaled nitric oxide improves the neurological outcome for premature infants.

Study Overview

• Status: Terminated
• Conditions: Intraventricular Hemorrhage; Bronchopulmonary Dysplasia; Prematurity; Periventricular Leukomalacia
• Intervention / Treatment: Drug: inhaled nitric oxide; Drug: oxygen

Detailed Description

With the advances in modern neonatal intensive care medicine in the last 20 years, survival of extremely preterm infants weighing less than 1500g (< 3 lbs, 5 oz) has risen markedly. However, with this increased survival has come a marked increase in the number of infants with serious neurodevelopmental disabilities: Premature infants with birth weights less than 1500g who survive to go home are at significant risk for serious neurodevelopmental problems: cognitive and motor delays, blindness, deafness, and cerebral palsy. In a recent randomized, placebo-controlled clinical trial, we assessed whether giving mechanically ventilated preterm infants inhaled nitric oxide gas (iNO) for 1 week after birth decreased the incidence of death and chronic lung disease. An unanticipated outcome of that study (Schreiber et. al. 2003) and a subsequent study of those infants at 2 years of age (Mestan et. al. 2005) was that premature infants treated with inhaled nitric oxide (iNO) have improved neurodevelopmental outcomes and physical growth at 2 years corrected age, compared with placebo-treated infants (Mestan et. al. 2005). INO therapy, therefore, appears to be a new treatment to protect the premature brain during development outside the womb. The overall goal of this application is understand the efficacy of iNO treatment in improving neurodevelopmental outcomes in at-risk premature infants.

• Study Type: Interventional
• Enrollment (Actual): 273
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• United States
  • Illinois
    • Chicago, Illinois, United States, 60637
      • The University of Chicago

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 2 hours to 3 days (Child)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Prematurity (birthweight ≤ 1500g, < 31 weeks gestation)
• Requiring respiratory support
• Admitted to the NICU at the University of Chicago

Exclusion Criteria:

• Severe congenital anomalies
• Genetic syndromes
• Extremely sick preterm infants requiring very high ventilatory pressures (OI ≥ 20)
• Premature infants judged by the physician as nonviable

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: INO Control (Short iNO); INO will be given to infants in the control group for the first 7 days of the study gas, then O2 or room air, as clinically appropriate, on the 8th day, until 33 weeks corrected age	Drug: inhaled nitric oxide; The amount of gas will be carefully controlled and adjusted to the level that best improves the function of subject's lungs. The subject will remain on inhaled nitric oxide until he/she reaches 33 weeks of gestation if assigned to the treatment arm, or until the 8th day of the study if he/she is assigned to the control arm.; Other Names: INO
Experimental: INO Treatment (Long iNO); The treatment group will receive iNO, combined with O2 or room air, until 33 weeks corrected age.	Drug: inhaled nitric oxide; The amount of gas will be carefully controlled and adjusted to the level that best improves the function of subject's lungs. The subject will remain on inhaled nitric oxide until he/she reaches 33 weeks of gestation if assigned to the treatment arm, or until the 8th day of the study if he/she is assigned to the control arm.; Other Names: INO; Drug: oxygen; The amount of gas will be carefully controlled and adjusted to the level that best improves the function of the subject's lungs. Subjects in the control arm of the study will receive oxygen beginning on the 8th day of the study until he/she reaches 33 weeks of gestation.; Other Names: O2

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Neurodevelopment		Two years
Bronchopulmonary Dysplasia (BPD) or Death	Need for respiratory support at 36 weeks post-menstrual age, either as positive pressure or supplemental oxygen to maintain oxygen saturations >90%, or death before discharge	36 weeks of age corrected (BPD) or before discharge (death)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Death	Death before discharge	through discharge (up to 400 days)
Bronchopulmonary Dysplasia	Need for respiratory support at 36 weeks post-menstrual age (PMA), either as positive pressure or supplemental oxygen to maintain oxygen saturations >90%	36 weeks of age corrected
Supplemental Oxygen Use		40 weeks PMA
BPD or Death in Infants Weighing < 750g	Need for respiratory support at 36 weeks post-menstrual age, either as positive pressure or supplemental oxygen to maintain oxygen saturations >90%, or death before discharge among infants < 750g	36 weeks of age corrected (BPD) or before discharge (death)
BPD or Death in Infants Weighing 750-999g	Need for respiratory support at 36 weeks post-menstrual age, either as positive pressure or supplemental oxygen to maintain oxygen saturations >90%, or death before discharge among infants 750-999g	36 weeks of age corrected (BPD) or before discharge (death)
BPD or Death in Black Infants	Need for respiratory support at 36 weeks post-menstrual age, either as positive pressure or supplemental oxygen to maintain oxygen saturations >90%, or death before discharge among Black infants	36 weeks of age corrected (BPD) or before discharge (death)

Collaborators and Investigators

• Sponsor: University of Chicago
• Investigators: Principal Investigator: Michael D. Schreiber, M.D., University of Chicago

Publications and helpful links

General Publications

• Schreiber MD, Gin-Mestan K, Marks JD, Huo D, Lee G, Srisuparp P. Inhaled nitric oxide in premature infants with the respiratory distress syndrome. N Engl J Med. 2003 Nov 27;349(22):2099-107. doi: 10.1056/NEJMoa031154.
• Mestan KK, Marks JD, Hecox K, Huo D, Schreiber MD. Neurodevelopmental outcomes of premature infants treated with inhaled nitric oxide. N Engl J Med. 2005 Jul 7;353(1):23-32. doi: 10.1056/NEJMoa043514.

Study record dates

Study Major Dates

• Study Start (Actual): May 1, 2008
• Primary Completion (Actual): June 7, 2023
• Study Completion (Actual): November 28, 2023

Study Registration Dates

• First Submitted: August 9, 2007
• First Submitted That Met QC Criteria: August 10, 2007
• First Posted (Estimated): August 13, 2007

Study Record Updates

• Last Update Posted (Actual): October 17, 2024
• Last Update Submitted That Met QC Criteria: October 15, 2024
• Last Verified: July 1, 2024

More Information

Terms related to this study

• Keywords: prematurity; bronchopulmonary dysplasia; nitric oxide; neurodevelopment; intraventricular hemorrhage; periventricular leukomalacia
• Additional Relevant MeSH Terms: Pathologic Processes; Cardiovascular Diseases; Vascular Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Respiratory Tract Diseases; Lung Diseases; Infant, Newborn, Diseases; Pregnancy Complications; Obstetric Labor Complications; Obstetric Labor, Premature; Lung Injury; Infant, Premature, Diseases; Ventilator-Induced Lung Injury; Encephalomalacia; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Hemorrhage; Premature Birth; Bronchopulmonary Dysplasia; Leukomalacia, Periventricular; 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: 15405A

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED