Inhaled Prostaglandin E1 (IPGE1) for Hypoxemic Respiratory Failure (NHRF)

Study Overview
=================
Brief Summary
-----------------
This is a randomized controlled trial (RCT) on the use of Inhaled prostaglandin E1 (IPGE1) in Neonatal Hypoxemic Respiratory Failure (NHRF). Fifty patients recruited at 10 high volume sites within the NICHD Neonatal Research Network will constitute a pilot sample to evaluate the feasibility and safety of prolonged IPGE1 administration and determination of optimal dose. In this Pilot RCT, two doses of IPGE1 (300 and 150 ng/kg/min) will be administered over a maximum duration of 72 hours and compared with placebo. Once feasibility and safety of IPGE1 administered over 72 hours has been demonstrated in the pilot trial, a full scale randomized controlled trial will be planned.

Detailed Description
-----------------
Hypoxemic respiratory failure in the newborn (NHRF) is usually associated with widespread vasoconstriction of the pulmonary microvasculature giving rise to intra- and extra-pulmonary shunts and profound hypoxemia. The goal of therapy is to decrease the regional pulmonary vascular resistance of ventilated lung areas thus decreasing intrapulmonary shunting and selectively reducing the pulmonary-artery pressure without causing systemic vasodilation. Intravenously administered vasodilators lack pulmonary selectivity leading to systemic side effects. Inhaled nitric oxide (INO), a selective pulmonary vasodilator, has revolutionized the treatment of respiratory failure in the newborn. However, there is lack of sustained improvement in 30-46% of infants; moreover, INO requires specialized systems for administration, making the treatment expensive. Aerosolized prostaglandins I2 and E1 have been reported to be effective selective pulmonary vasodilators in animals and human adults. In addition, inhaled prostaglandin I2 (IPGI2) has also been reported to be effective in preterm and term newborns, and children with pulmonary hypertension. Although intravenous PGE1 is widely used in neonates, the use of the inhaled form has not been reported in newborns with pulmonary hypertension. Compared to PGI2, PGE1 has a shorter half-life, lower acidity constant (pKa) (6.3 versus 10.5), bronchodilator action, anti-proliferative and anti-inflammatory effects on the alveolar, interstitial and vascular spaces of the lung. Prostaglandin nebulization can be used without the sophisticated technical equipment needed for controlled NO inhalation and hence is less expensive. It has no known toxic metabolites or toxic effects. Prostaglandins and nitric oxide (NO) relax the vascular smooth muscles through two different second-messenger systems; therefore, in combination, INO and IPGE1 may have synergistic effect. The existing literature suggests that inhaled PGE1 is a potential effective vasodilator in the treatment of NHRF . We have reported the safety and feasibility of short-term administration of inhaled PGE1 in an un-blinded Phase I/II dose-escalation study. Four doses ranging from 25 to 300 ng/kg/min were tested for a maximum duration of 3 hours. We have also reported the stability of IPGE1, its emitted dose and aerosol particle size distribution (APSD) in a neonatal ventilator circuit. In addition we have demonstrated the safety of high dose IPGE1 (1200 ng/kg/min) over 24 hours in ventilated piglets. In the current protocol, we propose a pilot to evaluate the feasibility and safety of prolonged IPGE1 in NHRF. Two doses of IPGE1 (300 and 150 ng/kg/min) will be tested followed by weaning for a maximum duration of 72 hours to determine feasibility, safety, optimal dose and duration of therapy in 50 patients in ten NICHD NRN sites. An IND status has been approved by the FDA for this trial.

Official Title
-----------------
Pilot Randomized Clinical Trial of Inhaled PGE1 in Neonates With Sub-Optimal Response to Inhaled Nitric Oxide

Conditions
-----------------
Prematurity, Respiratory Insufficiency, Pulmonary Hypertension, Respiratory Distress Syndrome, Newborn

Intervention / Treatment
-----------------
* Drug: Aerosolized Normal Saline
* Drug: Inhaled PGE1


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Gestational age less than or equal to 34 weeks Postnatal age less than or equal to 7 days (168 hours). Assisted ventilation for hypoxemic respiratory failure. Diagnosis of NHRF including perinatal aspiration syndrome (meconium, blood, or amniotic fluid), suspected/proven pneumonia/sepsis, respiratory distress syndrome, idiopathic persistent pulmonary hypertension of the newborn (PPHN) or suspected pulmonary hypoplasia. Receiving INO for at least 1 hour and not >72 hours. Oxygenation Index (OI ) ≥ 15 on any 2 arterial blood gases 15 minutes to 12 hours apart while on INO. An indwelling arterial line is present Exclusion Criteria: Any infant in whom a decision has been made not to provide full treatment (e.g. chromosomal anomalies, severe birth asphyxia). Known structural congenital heart disease except patent ductus arteriosus and atrial/ventricular level shunts. Congenital diaphragmatic hernia. Thrombocytopenia unresponsive to platelet transfusion. Enrollment in a conflicting and/or Investigational New Drug (IND) clinical trial.

Ages Eligible for Study
-----------------
Maximum Age: 7 Days

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

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

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

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Factorial Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Inhaled PGE1 (150 ng/kg/min)<br>150 ng/kg/min Inhaled PGE1 | Drug: Inhaled PGE1<br>* Two initial doses of IPGE1 will be tested - 150 and 300 ng/kg/min. Thus, there will be three arms to the study - IPGE1 [150], IPGE1 [300], and placebo (normal saline). This design will allow comparison of the two doses of IPGE1 with each other and controls; and also allow comparison of any IPGE1 with controls. In this Pilot RCT, two doses of IPGE1 (300 and 150 ng/kg/min) will be administered over a maximum duration of 72 hours to determine the optimal dose and duration of therapy.<br>* Other names: Inhaled Prostaglandin E1;|
| Placebo Comparator: Aerosolized Normal Saline<br>Eligible infants will be randomly assigned to either IPGE1 [150ng/kg/min], IPGE1 [300ng/kg/min] or control group. Infants in the control group will receive the same volume of aerosolized saline and oxygen from the respirator. | Drug: Aerosolized Normal Saline<br>* Two initial doses of IPGE1 will be tested - 150 and 300 ng/kg/min. Thus, there will be three arms to the study - IPGE1 [150], IPGE1 [300], and placebo (normal saline). This design will allow comparison of the two doses of IPGE1 with each other and controls; and also allow comparison of any IPGE1 with controls. Placebo will be administered over a maximum duration of 72 hours.<br>* Other names: Normal Saline;|
| Active Comparator: Inhaled PGE1 (300 ng/kg/min)<br>300 ng/kg/min of Inhaled PGE1 | Drug: Inhaled PGE1<br>* Two initial doses of IPGE1 will be tested - 150 and 300 ng/kg/min. Thus, there will be three arms to the study - IPGE1 [150], IPGE1 [300], and placebo (normal saline). This design will allow comparison of the two doses of IPGE1 with each other and controls; and also allow comparison of any IPGE1 with controls. In this Pilot RCT, two doses of IPGE1 (300 and 150 ng/kg/min) will be administered over a maximum duration of 72 hours to determine the optimal dose and duration of therapy.<br>* Other names: Inhaled Prostaglandin E1;|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Feasibility Assessed as the Number of Participants Who Were Enrolled in the Study | The primary outcome is the ability to recruit adequate number of infants (n=50) in a 9 month period without excessive (>20%) protocol violations. | From study start through 9 months after 75% of the participating sites are enrolling | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Partial Pressure of Oxygen in the Blood (PaO2) | Changes in PaO2 based on the arterial blood gases (ABG) measurements obtained after 60 minutes and ABG obtained 4 hours after start of study aerosol. | Measurement of ABG at 60±15 minutes and 4±2 hours after start of study aerosol. | 
| Change in Oxygenation Index (OI) | Change in OI based on the arterial blood gases (ABG) measurements obtained at 60±15 minutes and ABG obtained 4±2 hours after start of study aerosol. | Measurement of ABG at 60±15 minutes and 4±2 hours after start of study aerosol. | 
| Need for Inhaled Nitric Oxide (INO) 72 Hours After INO | Administration of INO continued after the Infant was on INO for 72 hours | Date of first administration of INO to date of final discontinuation of INO | 
| Duration of iNO Therapy | Duration the infant is on INO from initial administration of INO to final discontinuation of INO. | From date of first administration of INO to date of final discontinuation of INO. | 
| Death | Deaths prior to discharge home. | From birth through status (death, transfer, or discharge). | 
| Need for Extracorporeal Membrane Oxygenation (ECMO) | ECMO provided at the institution for the infant after discontinuation of study aerosol. | From after discontinuation of study aerosol through status (death, transfer, or discharge). | 
| Duration of Mechanical Ventilation | Duration the infant is on Mechanical Ventilation from birth through status (death, transfer or discharge) | From birth through status (death, transfer or discharge) | 
| Number of Days of Supplemental Oxygen (O2) Used | Number of days from birth during which the FiO2 at some point was > 0.21. | From birth through status (death, transfer or discharge) | 
| Length of Hospital Stay | Length of stay in hospital from birth to discharge home. | From birth to discharge home |