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

Tracking Information
First Submitted Date ICMJE	October 17, 2011
First Posted Date ICMJE	November 8, 2011
Results First Submitted Date	November 3, 2016
Results First Posted Date	December 30, 2016
Last Update Posted Date	December 30, 2016
Study Start Date ICMJE	November 2011
Actual Primary Completion Date	May 2012 (Final data collection date for primary outcome measure)
Current Primary Outcome Measures ICMJE; (submitted: November 3, 2016)	Assess Feasibility to Recruit at Least 50 Infants [ Time Frame: 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.
Original Primary Outcome Measures ICMJE; (submitted: November 7, 2011)	Assess Feasibility [ Time Frame: 9 months after 75% of the participating sites are enrolling ]; The primary outcome is the ability to recruit adequate number of patients (50) in a 9 month period without excessive (>20%) protocol violations
Change History	Complete list of historical versions of study NCT01467076 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures ICMJE; (submitted: February 9, 2012)	Improvement in Partial Pressure of Oxygen in the Blood (PaO2) [ Time Frame: 72 hours ]; Improvement in Oxygenation Index (OI) [ Time Frame: 72 Hours ]; Need for INO 72 Hours After INO [ Time Frame: 72 hours after INO ]; Duration of iNO Therapy [ Time Frame: Until death or hospital discharge, up to one year ]; Death [ Time Frame: Up to one year ]; Need for Extracorporeal Membrane Oxygenation (ECMO) [ Time Frame: Until death or hospital discharge, up to one year ]; Duration of Mechanical Ventilation [ Time Frame: Until death or hospital discharge, up to on year ]; Number of Days of Oxygen (O2) Used, and Need for Supplemental Oxygen (O2) [ Time Frame: 28 Days of LIfe ]; Length of Hospital Stay [ Time Frame: Up to one year ]
Original Secondary Outcome Measures ICMJE; (submitted: November 7, 2011)	Improvement in PaO2 [ Time Frame: 72 hours ]; Improvement in Oxygenation index [ Time Frame: 72 Hours ]; Need for INO 72 Hours After INO [ Time Frame: 72 hours after INO ]; Duration of iNO Therapy [ Time Frame: Until death or hospital discharge, up to one year ]; Death [ Time Frame: Up to one year ]; Need for ECMO [ Time Frame: Until death or hospital discharge, up to one year ]; Duration of Mechanical Ventilation [ Time Frame: Until death or hospital discharge, up to on year ]; Number of days of O2 used, and need for supplemental O2 [ Time Frame: 28 Days of LIfe ]; Length of Hospital Stay [ Time Frame: Up to one year ]
Current Other Outcome Measures ICMJE	Not Provided
Original Other Outcome Measures ICMJE	Not Provided
Descriptive Information
Brief Title ICMJE	Inhaled Prostaglandin E1 (IPGE1) for Hypoxemic Respiratory Failure (NHRF)
Official Title ICMJE	Pilot Randomized Clinical Trial of Inhaled PGE1 in Neonates With Sub-Optimal Response to Inhaled Nitric Oxide
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.
Study Type ICMJE	Interventional
Study Phase	Phase 2
Study Design ICMJE	Allocation: Randomized; Intervention Model: Factorial Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
Condition ICMJE	Prematurity; Respiratory Insufficiency; Pulmonary Hypertension; Respiratory Distress Syndrome, Newborn
Intervention ICMJE	Drug: Aerosolized 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. Other Name: Normal Saline; Drug: Inhaled PGE1 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. Other Name: Inhaled Prostaglandin E1
Study Arms	Active Comparator: Inhaled PGE1 (150 ng/kg/min) 150 ng/kg/min Inhaled PGE1 Intervention: Drug: Inhaled PGE1; Placebo Comparator: 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. Intervention: Drug: Aerosolized Normal Saline; Active Comparator: Inhaled PGE1 (300 ng/kg/min) 300 ng/kg/min of Inhaled PGE1 Intervention: Drug: Inhaled PGE1
Publications *	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.
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
Recruitment Information
Recruitment Status ICMJE	Terminated
Actual Enrollment ICMJE; (submitted: July 16, 2012)	7
Original Estimated Enrollment ICMJE; (submitted: November 7, 2011)	50
Actual Study Completion Date	June 2012
Actual Primary Completion Date	May 2012 (Final data collection date for primary outcome measure)
Eligibility Criteria ICMJE	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.
Sex/Gender	Sexes Eligible for Study: All
Ages	up to 7 Days (Child)
Accepts Healthy Volunteers	No
Contacts ICMJE	Contact information is only displayed when the study is recruiting subjects
Listed Location Countries ICMJE	United States
Removed Location Countries
Administrative Information
NCT Number ICMJE	NCT01467076
Other Study ID Numbers ICMJE	NICHD-NRN-0046; U10HD040689 ( U.S. NIH Grant/Contract ); U10HD021385 ( U.S. NIH Grant/Contract ); U10HD027904 ( U.S. NIH Grant/Contract ); U10HD027880 ( U.S. NIH Grant/Contract ); U10HD034216 ( U.S. NIH Grant/Contract ); U10HD040492 ( U.S. NIH Grant/Contract ); U10HD053109 ( U.S. NIH Grant/Contract ); U10HD040461 ( U.S. NIH Grant/Contract ); U10HD068263 ( U.S. NIH Grant/Contract ); U10HD068270 ( U.S. NIH Grant/Contract ); U10HD068278 ( U.S. NIH Grant/Contract ); U10HD036790 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee	Yes
U.S. FDA-regulated Product	Not Provided
IPD Sharing Statement	Not Provided
Responsible Party	NICHD Neonatal Research Network
Study Sponsor ICMJE	NICHD Neonatal Research Network
Collaborators ICMJE	National Center for Research Resources (NCRR); Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Investigators ICMJE	Principal Investigator: Beena Sood, MD Wayne State University Principal Investigator: Martin Keszler, MD Brown University, Women & Infants Hospital of Rhode Island Principal Investigator: C. Michael Cotten, MD Duke University Principal Investigator: Abhik Das, PhD RTI International Principal Investigator: Krisa P Van Meurs, MD Stanford University Principal Investigator: Namasivayam Ambalavanan, MD University of Alabama at Birmingham Principal Investigator: Jonathan M Klein, MD University of Iowa Principal Investigator: Robin Ohls, MD University of New Mexico Principal Investigator: Pablo J Sanchez, MD University of Texas, Southwestern Medical Center at Dallas Principal Investigator: Satyan Lakshminrusimha, MD University of Rochester Principal Investigator: Uday Devaskar, MD University of California, Los Angeles Principal Investigator: Leif Nelin, MD Research Institute at Nationwide Children's Hospital
PRS Account	NICHD Neonatal Research Network
Verification Date	November 2016
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP