Early iNO for Oxidative Stress, Vascular Tone and Inflammation in Babies With Hypoxic Respiratory Failure

Effect of Early iNO on Oxidative Stress, Vascular Tone and Inflammation in Term and Late-Preterm Infants With Hypoxic Respiratory Failure

The investigators in this study are concerned about the harmful effects of oxygen exposure in newborn infants, particularly at high concentrations. Inhaled nitric oxide (iNO) is an FDA approved drug for the treatment of hypoxic respiratory failure (HRF) in term and late-preterm babies greater than 34 weeks gestation. Hypoxic respiratory failure occurs when a patient's lungs cannot get enough oxygen into their bloodstream. This condition is traditionally treated with high concentrations of oxygen and most often requires the patient be placed on a ventilator (breathing machine). The administration of inhaled nitric oxygen directly into the lungs often improves blood oxygen levels and allows caretakers to reduce the amount of oxygen given to the baby. The purpose of this research study is to evaluate if giving the inhaled nitric oxide earlier in the course of disease improves the effectiveness of the drug, reduces the amount of cellular injury from oxygen exposure, and decreases the total amount of time a patient requires supplemental oxygen. This study uses an FDA approved drug in a new manner.

Study Overview

• Status: Withdrawn
• Conditions: Persistent Fetal Circulation Syndrome; Persistent Pulmonary Hypertension of Newborn; Hypertension, Pulmonary, of Newborn, Persistent
• Intervention / Treatment: Drug: Inhaled nitric oxide; Drug: Nitrogen Gas; Drug: Crossover iNO

• Study Type: Interventional
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • Florida
    • Gainesville, Florida, United States, 32610
      • Shands Hospital at the University of Florida

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 year to 1 year (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Gestational age ≥ 35 weeks gestation
• Age of life ≤ 48 hours
• Diagnosis of hypoxic respiratory failure (HRF) as defined by a post-ductal SaO2 ≤90% in ≥50% oxygen with a PEEP of ≥ 6cm or an oxygenation index (OI) ≥ 10 but ≤ 15 when mean airway pressure and PaO2 are known.
• Mothers (ages 18 - 65) of eligible subjects for additional data collection

Exclusion Criteria:

• Gestational age < 35 weeks gestation.
• Post-natal age > 48 hours.
• Previous treatment with 100% oxygen for longer than 4 hours.
• Confirmed congenital diaphragmatic hernia.
• Suspected or confirmed congenital airway or pulmonary anomaly.
• Suspected or confirmed chromosomal anomaly or genetic aberration, with the exception of patients with trisomy 21 who do not have complex congenital heart disease.
• Infants with pneumothorax as the primary cause of their HRF.
• Infants with confirmed complex congenital heart disease.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Early inhaled nitric oxide; Patients randomized to receive iNO at OI 10-15.	Drug: Inhaled nitric oxide; Drug is initiated at 20ppm. Patients randomized to receive iNO at OI 10-15.; Other Names: INOmax
Placebo Comparator: Bioinert inhaled gas (nitrogen gas); Patients randomized to bioinert inhaled gas at OI 10-15.	Drug: Nitrogen Gas; Placebo gas (bioinert), Patients randomized to bioinert inhaled gas at OI 10-15.; Other Names: bioinert
Active Comparator: Crossover iNO; Patients who deteriorate (OI >20 on two consecutive blood gases) will be unblinded. If they are receiving placebo gas, they will be started on iNO and make up the crossover cohort.	Drug: Crossover iNO; Patients who deteriorate (OI >20 on two consecutive blood gases) will be unblinded. If they are receiving placebo gas, they will be started on iNO and make up the crossover cohort.; Other Names: INOmax; bioinert

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Biomarkers of oxidative injury.	Early administration of iNO to infants with HRF will result in reduced hyperoxia-mediated oxidative injury as measured by known biomarkers of oxygen free radical injury, including malondialdehyde and 8-hydroxy-2'-deoxyguanosine.	Urine samples will be collected upon enrollment and then at specific time points within the first 48 hours of study intervention to compare the change in biomarker concentrations from baseline up to hour 48.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Responsiveness to study treatment.	Earlier administration of iNO to infants with HRF/PPHN (persistent pulmonary hypertension of the newborn) will lessen reactive oxygen species formation resulting in improved responsiveness to the drug as measured by the initial changes in arterial oxygen concentration after administration of the drug.	Arterial oxygen concentration will be measured upon enrollment and at specific time points in the first 36 hours of study intervention to compare the change in arterial oxygen concentration from baseline up to hour 36.
Expression of endothelin-1.	Earlier treatment with iNO may potentiate pulmonary vasodilation by modulating endothelin-1 expression.	Concentration of endothelin-1 will be measured upon enrollment and at specific time points in the first 36 hours of study intervention to compare the change in concentration from baseline up to hour 36.
Markers of inflammation.	Early iNO may up-regulate production of endogenous anti-inflammatory eicosanoids such as PGE2 (prostaglandin E2). Additionally, avoidance of hyperoxia in these patients may mitigate pro-inflammatory cytokines known to potentiate lung injury.	Concentrations of pro and anti-inflammatory markers will be measured upon enrollment and at specific time points in the first 36 hours of study intervention to compare the change in concentrations from baseline up to hour 36.
Duration of oxygen treatment.	Early administration of iNO to infants with HRF will result in at least a 15% reduction in total days of oxygen therapy.	Participants will be followed for the duration of their hospital stay, with an expected average stay of 4 weeks.
Expression of VEGF (vascular endothelial growth factor).	Earlier treatment with iNO may potentiate pulmonary vasodilation by preventing hyperoxic down regulation of VEGF.	Concentration of VEGF will be measured upon enrollment and at specific time points in the first 36 hours of study intervention to compare the change in concentration from baseline up to hour 36.

Collaborators and Investigators

• Sponsor: University of Florida
• Collaborators: Mallinckrodt
• Investigators: Principal Investigator: Catalina Bazacliu, MD, University of Florida

Study record dates

Study Major Dates

• Study Start (Actual): May 1, 2016
• Primary Completion (Actual): September 18, 2019
• Study Completion (Actual): September 19, 2019

Study Registration Dates

• First Submitted: June 19, 2013
• First Submitted That Met QC Criteria: June 28, 2013
• First Posted (Estimate): July 3, 2013

Study Record Updates

• Last Update Posted (Actual): January 7, 2020
• Last Update Submitted That Met QC Criteria: January 5, 2020
• Last Verified: January 1, 2020

More Information

Terms related to this study

• Keywords: Oxidative Stress; Infant, Newborn; Nitric Oxide; Vascular Endothelial Growth Factor; Persistent Fetal Circulation Syndrome; Endothelin 1
• Additional Relevant MeSH Terms: Pathologic Processes; Cardiovascular Diseases; Vascular Diseases; Respiratory Tract Diseases; Respiration Disorders; Lung Diseases; Infant, Newborn, Diseases; Hypertension; Inflammation; Respiratory Insufficiency; Hypertension, Pulmonary; Persistent Fetal Circulation Syndrome; 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: IRB201400791; 00089105 (Other Identifier: RAC); OCR17867 (Other Identifier: Universiy of Florida)

Drug and device information, study documents

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