Inhaled Nitric Oxide for Pulmonary Hypertension and Bronchopulmonary Dysplasia

Study Overview
=================
Brief Summary
-----------------
Inhaled nitric oxide (iNO) is an effective treatment for pulmonary hypertension (PH) in term and near-term infants. Preterm infants are at risk for early PH that is associated with high risk for bronchopulmonary dysplasia or death. In multiple clinical trials, iNO treatment was not effective for BPD prevention. However, infants were not screened for PH and iNO treatment was not targeted for PH. iNO treatment for PH in preterm infants is controversial due to lack of evidence. The study team hypothesizes that early diagnosis of PH (72-96 hours of life) and iNO treatment will decrease the incidence of death and bronchopulmonary dysplasia and improve oxygenation in extremely preterm infants. To determine if iNO treatment of extremely preterm infants with early pulmonary hypertension as established with echocardiographic evidence at 72-96 hours of age will decrease incidence of death or BPD. To determine if iNO treatment of extremely preterm infants with early PH will decrease the pulmonary artery pressure and improve oxygenation within 72 hours of intervention.

Detailed Description
-----------------
This is a single center, blinded, randomized control clinical trial to evaluate the effects of inhaled nitric oxide on the outcome of survival and incidence of bronchopulmonary dysplasia. This trial has a planned enrollment of 138 infants with 68 infants with delayed pulmonary transition assigned to either the treatment or placebo group. There is no enrollment restriction based on gender, ethnicity, or race. Enrollment is expected to take 36 months with an additional 12 months for data analysis.Infants with early pulmonary hypertension will be randomized to the treatment or placebo group. Treatment will continue until resolution of pulmonary hypertension or through Day 14, whichever comes first. Serial echocardiograms will be performed every 48 hours +/-12 hours until Day 14. Oxygen saturation levels will be averaged every 24 hour period following enrollment. This study will provide evidence for the beneficial effects of early diagnosis and treatment of pulmonary hypertension in preterm infants.

Official Title
-----------------
Treatment of Delayed Pulmonary Transition in Extremely Preterm Infants & Bronchopulmonary Dysplasia

Conditions
-----------------
Pulmonary Hypertension, Bronchopulmonary Dysplasia

Intervention / Treatment
-----------------
* Drug: inhaled nitric oxide
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Step 1: Birth between 23 weeks and 0 days and 29 weeks and 6 days. Positive pressure ventilation at 72-96 hours of age Step 2: Early pulmonary hypertension Exclusion Criteria: Step 1: Death prior to 12 hours of age or first echocardiogram Chromosomal anomalies Major congenital anomalies Myocardial dysfunction Complex cardiac defect Dependent on right to left shunting of blood Step 2: Excessive pulmonary blood flow (left to right shunt across PDA) Pulmonary blood flow obstruction secondary to pulmonary vein stenosis Mitral valve stenosis Cor triata Aortic valve atresia

Ages Eligible for Study
-----------------
Minimum Age: 23 Weeks
Maximum Age: 29 Weeks

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Masked randomized controlled trial
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Treatment group - active<br>inhaled nitric oxide treatment will start at 20 ppm and continue for 2 weeks or until resolution of pulmonary hypertension, whichever comes first. | Drug: inhaled nitric oxide<br>* inhaled nitric oxide will be administered starting at 20 ppm. Treatment will continue for 14 days or until resolution of pulmonary hypertension<br>* Other names: iNO;|
| Placebo Comparator: Treatment group - placebo<br>Placebo treatment will start at 20 ppm and continue for 2 weeks or until resolution of pulmonary hypertension, whichever comes first. | Drug: Placebo<br>* placebo will be administered starting at 20 ppm. Treatment will continue for 14 days or until resolution of pulmonary hypertension<br>|
| No Intervention: Control group<br>Enrolled infants with no evidence of pulmonary hypertension will serve as the control group for incidence of death or bronchopulmonary hypertension | |

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Death (yes/no) | Incidence of death | 36 weeks post menstrual age | 
| Bronchopulmonary (BPD) dysplasia (yes/no) | Incidence of bronchopulmonary dysplasia as determined by need for positive pressure ventilation or supplemental oxygen after room air challenge test | 36 weeks post menstrual age | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pulmonary arterial pressure (mmHg) | Pulmonary arterial pressure will be averaged for each 24-48 hour period after enrollment | Duration of treatment or up to Day 14 | 
| Oxygen saturation level percentage | Oxygen saturation level will be averaged for each 24 hour period after enrollment | Duration of treatment or up to Day 14 | 
| SF (SpO2/FiO2) ratio | Pulse oximetric saturation Spo2/Fio2 ratio | Duration of treatment or up to Day 14 |