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

Phase 2

Terminated

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

Interventions: Drug: Aerosolized Normal Saline
Drug: Inhaled PGE1

Registration Number: NCT01467076

Lead Sponsor: NICHD Neonatal Research Network

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.

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 7

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.

Study & Design

Study Type: INTERVENTIONAL

Study Design: FACTORIAL

Arm && Interventions

Group	Intervention	Description
Aerosolized Normal Saline	Aerosolized Normal Saline	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.
Inhaled PGE1 (300 ng/kg/min)	Inhaled PGE1	300 ng/kg/min of Inhaled PGE1
Inhaled PGE1 (150 ng/kg/min)	Inhaled PGE1	150 ng/kg/min Inhaled PGE1

Primary Outcome Measures

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

Secondary Outcome Measures

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

Trial Locations

Locations (11): University of New Mexico
🇺🇸
Albuquerque, New Mexico, United States
University of Rochester
🇺🇸
Rochester, New York, United States
Stanford University
🇺🇸
Palo Alto, California, United States
University of Iowa
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Iowa City, Iowa, United States
Brown University, Women & Infants Hospital of Rhode Island
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Providence, Rhode Island, United States
University of California - Los Angeles
🇺🇸
Los Angeles, California, United States
Duke University
🇺🇸
Durham, North Carolina, United States
Research Institute at Nationwide Children's Hospital
🇺🇸
Columbus, Ohio, United States
University of Alabama at Birmingham
🇺🇸
Birmingham, Alabama, United States
Wayne State University
🇺🇸
Detroit, Michigan, United States
University of Texas Southwestern Medical Center at Dallas
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Dallas, Texas, United States