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

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.

• Aerosolized Normal Saline (Drug), also known as Normal Saline: 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.
• Inhaled PGE1 (Drug), also known as Inhaled Prostaglandin E1: 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.

Primary outcomes

• 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 outcomes

• 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.

Sex: All, ages: any to 7 Days

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.

Participant flow

Outcome results

• Feasibility Assessed as the Number of Participants Who Were Enrolled in the Study (Primary), Number, participants: Control 3; Low Dose IPGE1 2; High Dose IPGE1 2
• Change in Partial Pressure of Oxygen in the Blood (PaO2) (Secondary), Mean, mmHg: Control 30 (-1 to 59); Low Dose IPGE1 85 (22 to 148); High Dose IPGE1 48 (-9 to 95)
• Change in Oxygenation Index (OI) (Secondary), Mean, oxygenation index: Control 4 (-1 to 9); Low Dose IPGE1 14 (6 to 21); High Dose IPGE1 10 (-5 to 25)
• Need for Inhaled Nitric Oxide (INO) 72 Hours After INO (Secondary), Count of participants, Participants: Control 1; Low Dose IPGE1 0; High Dose IPGE1 0
• Duration of iNO Therapy (Secondary), Mean, hours: Control 59.02 (44.95 to 73.08); Low Dose IPGE1 18.57 (18.57 to 18.57); High Dose IPGE1 56.22 (50.35 to 62.08)
• Death (Secondary), Count of participants, Participants: Control 0; Low Dose IPGE1 0; High Dose IPGE1 0
• Need for Extracorporeal Membrane Oxygenation (ECMO) (Secondary), Count of participants, Participants: Control 2; Low Dose IPGE1 1; High Dose IPGE1 2
• Duration of Mechanical Ventilation (Secondary), Mean, Days: Control 22 (17 to 30); Low Dose IPGE1 8 (4 to 11); High Dose IPGE1 16 (13 to 19)
• Number of Days of Supplemental Oxygen (O2) Used (Secondary), Mean, Days: Control 43 (24 to 79); Low Dose IPGE1 8 (4 to 12); High Dose IPGE1 11 (9 to 13)
• Length of Hospital Stay (Secondary), Mean, Days: Control 64 (27 to 81); Low Dose IPGE1 31 (21 to 40); High Dose IPGE1 39 (29 to 49)

Adverse events

Time frame: Enrolled infants were monitored continuously throughout study aerosol administration and through 48 hours post study aerosol discontinuation for possible adverse effects of PGE1.

Serious adverse events by term

• Results publication: Sood BG, Keszler M, Garg M, Klein JM, Ohls R, Ambalavanan N, Cotten CM, Malian M, Sanchez PJ, Lakshminrusimha S, Nelin LD, Van Meurs KP, Bara R, Saha S, Das A, Wallace D, Higgins RD, Shankaran S; Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Inhaled PGE1 in neonates with hypoxemic respiratory failure: two pilot feasibility randomized clinical trials. Trials. 2014 Dec 12;15:486. doi: 10.1186/1745-6215-15-486. PMID 25496504

• Beena Sood, MD, Principal investigator, Wayne State University
• Martin Keszler, MD, Principal investigator, Brown University, Women & Infants Hospital of Rhode Island
• C. Michael Cotten, MD, Principal investigator, Duke University
• Abhik Das, PhD, Principal investigator, RTI International
• Krisa P Van Meurs, MD, Principal investigator, Stanford University
• Namasivayam Ambalavanan, MD, Principal investigator, University of Alabama at Birmingham
• Jonathan M Klein, MD, Principal investigator, University of Iowa
• Robin Ohls, MD, Principal investigator, University of New Mexico
• Pablo J Sanchez, MD, Principal investigator, University of Texas, Southwestern Medical Center at Dallas
• Satyan Lakshminrusimha, MD, Principal investigator, University of Rochester
• Uday Devaskar, MD, Principal investigator, University of California, Los Angeles
• Leif Nelin, MD, Principal investigator, Research Institute at Nationwide Children's Hospital

NIH grants: U10HD040689, U10HD021385, U10HD027904, U10HD027880, U10HD034216, U10HD040492, U10HD053109, U10HD040461, U10HD068263, U10HD068270, U10HD068278, U10HD036790