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

Tracking Information
First Submitted Date ICMJE	June 19, 2013
First Posted Date ICMJE	July 3, 2013
Last Update Posted Date	March 22, 2018
Actual Study Start Date ICMJE	May 2016
Estimated Primary Completion Date	November 2018 (Final data collection date for primary outcome measure)
Current Primary Outcome Measures ICMJE; (submitted: June 28, 2013)	Biomarkers of oxidative injury. [ Time Frame: 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. ]; 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.
Original Primary Outcome Measures ICMJE	Same as current
Change History	Complete list of historical versions of study NCT01891500 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures ICMJE; (submitted: March 13, 2015)	Responsiveness to study treatment. [ Time Frame: 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. ]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.; Expression of endothelin-1. [ Time Frame: 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. ]Earlier treatment with iNO may potentiate pulmonary vasodilation by modulating endothelin-1 expression.; Markers of inflammation. [ Time Frame: 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. ]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.; Duration of oxygen treatment. [ Time Frame: Participants will be followed for the duration of their hospital stay, with an expected average stay of 4 weeks. ]Early administration of iNO to infants with HRF will result in at least a 15% reduction in total days of oxygen therapy.; Expression of VEGF (vascular endothelial growth factor). [ Time Frame: 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. ]Earlier treatment with iNO may potentiate pulmonary vasodilation by preventing hyperoxic down regulation of VEGF.
Original Secondary Outcome Measures ICMJE; (submitted: June 28, 2013)	Responsiveness to study treatment. [ Time Frame: 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. ]Earlier administration of iNO to infants with HRF/PPHN 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.; Expression of endothelin-1. [ Time Frame: 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. ]Earlier treatment with iNO may potentiate pulmonary vasodilation by modulating endothelin-1 expression.; Markers of inflammation. [ Time Frame: 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. ]Early iNO may up-regulate production of endogenous anti-inflammatory eicosanoids such as PGE2. Additionally, avoidance of hyperoxia in these patients may mitigate pro-inflammatory cytokines known to potentiate lung injury.; Duration of oxygen treatment. [ Time Frame: Participants will be followed for the duration of their hospital stay, with an expected average stay of 4 weeks. ]Early administration of iNO to infants with HRF will result in at least a 15% reduction in total days of oxygen therapy.; Expression of VEGF (vascular endothelial growth factor). [ Time Frame: 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. ]Earlier treatment with iNO may potentiate pulmonary vasodilation by preventing hyperoxic down regulation of VEGF.
Current Other Outcome Measures ICMJE	Not Provided
Original Other Outcome Measures ICMJE	Not Provided
Descriptive Information
Brief Title ICMJE	Early iNO for Oxidative Stress, Vascular Tone and Inflammation in Babies With Hypoxic Respiratory Failure
Official Title ICMJE	Effect of Early iNO on Oxidative Stress, Vascular Tone and Inflammation in Term and Late-Preterm Infants With Hypoxic Respiratory Failure
Brief Summary	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.
Detailed Description	Not Provided
Study Type ICMJE	Interventional
Study Phase	Phase 4
Study Design ICMJE	Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Triple (Participant, Care Provider, Investigator); Primary Purpose: Treatment
Condition ICMJE	Persistent Fetal Circulation Syndrome; Hypertension, Pulmonary, of Newborn, Persistent; Persistent Pulmonary Hypertension of Newborn
Intervention ICMJE	Drug: Inhaled nitric oxide Drug is initiated at 20ppm. Patients randomized to receive iNO at OI 10-15. Other Name: INOmax; Drug: Nitrogen Gas Placebo gas (bioinert), Patients randomized to bioinert inhaled gas at OI 10-15. Other Name: bioinert; 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: bioinert INOmax
Study Arms	Experimental: Early inhaled nitric oxide Patients randomized to receive iNO at OI 10-15. Intervention: Drug: Inhaled nitric oxide; Placebo Comparator: Bioinert inhaled gas (nitrogen gas) Patients randomized to bioinert inhaled gas at OI 10-15. Intervention: Drug: Nitrogen Gas; 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. Intervention: Drug: Crossover iNO
Publications *	Not Provided
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
Recruitment Information
Recruitment Status ICMJE	Recruiting
Estimated Enrollment ICMJE; (submitted: March 21, 2018)	68
Original Estimated Enrollment ICMJE; (submitted: June 28, 2013)	24
Estimated Study Completion Date	December 2018
Estimated Primary Completion Date	November 2018 (Final data collection date for primary outcome measure)
Eligibility Criteria ICMJE	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.
Sex/Gender	Sexes Eligible for Study: All
Ages	up to 48 Hours (Child)
Accepts Healthy Volunteers	No
Contacts ICMJE	Contact: Catalina Bazacliu, MD 352-273-8985 cbazacliu@peds.ufl.edu Contact: Kelly D Curry, MSN 352 273 8979 hernack1@ufl.edu
Listed Location Countries ICMJE	United States
Removed Location Countries
Administrative Information
NCT Number ICMJE	NCT01891500
Other Study ID Numbers ICMJE	IRB201400791; 00089105 ( Other Identifier: RAC )
Has Data Monitoring Committee	Yes
U.S. FDA-regulated Product	Studies a U.S. FDA-regulated Drug Product: Yes Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement	Not Provided
Responsible Party	University of Florida
Study Sponsor ICMJE	University of Florida
Collaborators ICMJE	Mallinckrodt
Investigators ICMJE	Principal Investigator: Catalina Bazacliu, MD University of Florida
PRS Account	University of Florida
Verification Date	March 2018
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP