Clinical trial NCT01467076: Inhaled Prostaglandin E1 (IPGE1) for Hypoxemic Respiratory Failure (NHRF)
Official title: Pilot Randomized Clinical Trial of Inhaled PGE1 in Neonates With Sub-Optimal Response to Inhaled Nitric Oxide
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Prematurity
Respiratory Insufficiency
Pulmonary Hypertension
Respiratory Distress Syndrome, Newborn
Lead sponsor: NICHD Neonatal Research Network
Sponsor class: NETWORK
Collaborators: name: National Center for Research Resources (NCRR)
name: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
First posted: 2011-11-08
Enrollment: 7
Sex: ALL
Maximum age (years): 7
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: FACTORIAL
Primary purpose: TREATMENT

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.

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.

Primary outcomes:
measure: Feasibility Assessed as the Number of Participants Who Were Enrolled in the Study
timeFrame: From study start through 9 months after 75% of the participating sites are enrolling
Secondary outcomes:
measure: Change in Partial Pressure of Oxygen in the Blood (PaO2)
timeFrame: Measurement of ABG at 60±15 minutes and 4±2 hours after start of study aerosol.
measure: Change in Oxygenation Index (OI)
timeFrame: Measurement of ABG at 60±15 minutes and 4±2 hours after start of study aerosol.
measure: Need for Inhaled Nitric Oxide (INO) 72 Hours After INO
timeFrame: Date of first administration of INO to date of final discontinuation of INO
measure: Duration of iNO Therapy
timeFrame: From date of first administration of INO to date of final discontinuation of INO.
measure: Death
timeFrame: From birth through status (death, transfer, or discharge).
measure: Need for Extracorporeal Membrane Oxygenation (ECMO)
timeFrame: From after discontinuation of study aerosol through status (death, transfer, or discharge).
measure: Duration of Mechanical Ventilation
timeFrame: From birth through status (death, transfer or discharge)
measure: Number of Days of Supplemental Oxygen (O2) Used
timeFrame: From birth through status (death, transfer or discharge)
measure: Length of Hospital Stay
timeFrame: From birth to discharge home
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama at Birmingham
state: Alabama
city: Los Angeles
country: United States
facility: University of California - Los Angeles
state: California
city: Palo Alto
country: United States
facility: Stanford University
state: California
city: Iowa City
country: United States
facility: University of Iowa
state: Iowa
city: Detroit
country: United States
facility: Wayne State University
state: Michigan
city: Albuquerque
country: United States
facility: University of New Mexico
state: New Mexico
city: Rochester
country: United States
facility: University of Rochester
state: New York
city: Durham
country: United States
facility: Duke University
state: North Carolina
city: Columbus
country: United States
facility: Research Institute at Nationwide Children's Hospital
state: Ohio
city: Providence
country: United States
facility: Brown University, Women & Infants Hospital of Rhode Island
state: Rhode Island
city: Dallas
country: United States
facility: University of Texas Southwestern Medical Center at Dallas
state: Texas
Study officials:
affiliation: Wayne State University
name: Beena Sood, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Brown University, Women & Infants Hospital of Rhode Island
name: Martin Keszler, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Duke University
name: C. Michael Cotten, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: RTI International
name: Abhik Das, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Stanford University
name: Krisa P Van Meurs, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Alabama at Birmingham
name: Namasivayam Ambalavanan, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Iowa
name: Jonathan M Klein, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of New Mexico
name: Robin Ohls, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Texas, Southwestern Medical Center at Dallas
name: Pablo J Sanchez, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Rochester
name: Satyan Lakshminrusimha, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of California, Los Angeles
name: Uday Devaskar, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Research Institute at Nationwide Children's Hospital
name: Leif Nelin, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.