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

This study has been terminated.
(The study was halted due to futility concerns based on the unmet benchmarks as specified in the pilot study protocol.)
Sponsor:
Collaborator:
Information provided by (Responsible Party):
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
ClinicalTrials.gov Identifier:
NCT01467076
First received: October 17, 2011
Last updated: February 13, 2013
Last verified: January 2013
  Purpose

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.


Condition Intervention Phase
Prematurity
Respiratory Insufficiency
Pulmonary Hypertension
Respiratory Distress Syndrome, Newborn
Drug: Aerosolized Normal Saline
Drug: Inhaled PGE1
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Factorial Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Pilot Randomized Clinical Trial of Inhaled PGE1 in Neonates With Sub-Optimal Response to Inhaled Nitric Oxide

Resource links provided by NLM:


Further study details as provided by Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD):

Primary Outcome Measures:
  • Assess Feasibility [ Time Frame: 9 months after 75% of the participating sites are enrolling ] [ Designated as safety issue: No ]
    The primary outcome is the ability to recruit adequate number of patients (50) in a 9 month period without excessive (>20%) protocol violations


Secondary Outcome Measures:
  • Improvement in partial pressure of oxygen in the blood (PaO2) [ Time Frame: 72 hours ] [ Designated as safety issue: Yes ]
  • Improvement in Oxygenation Index (OI) [ Time Frame: 72 Hours ] [ Designated as safety issue: Yes ]
  • Need for INO 72 hours after INO [ Time Frame: 72 hours after INO ] [ Designated as safety issue: No ]
  • Duration of iNO Therapy [ Time Frame: Until death or hospital discharge, up to one year ] [ Designated as safety issue: Yes ]
  • Death [ Time Frame: Up to one year ] [ Designated as safety issue: Yes ]
  • Need for Extracorporeal membrane oxygenation (ECMO) [ Time Frame: Until death or hospital discharge, up to one year ] [ Designated as safety issue: Yes ]
  • Duration of mechanical ventilation [ Time Frame: Until death or hospital discharge, up to on year ] [ Designated as safety issue: Yes ]
  • Number of days of oxygen (O2) used, and need for supplemental oxygen (O2) [ Time Frame: 28 Days of LIfe ] [ Designated as safety issue: Yes ]
  • Length of Hospital Stay [ Time Frame: Up to one year ] [ Designated as safety issue: No ]

Enrollment: 7
Study Start Date: November 2011
Study Completion Date: June 2012
Primary Completion Date: May 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Inhaled PGE1 (150 ng/kg/min)
150 ng/kg/min Inhaled PGE1
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
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.
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
Active Comparator: Inhaled PGE1 (300 ng/kg/min)
300 ng/kg/min of Inhaled PGE1
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

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

Ages Eligible for Study:   up to 7 Days
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01467076

Locations
United States, Alabama
University of Alabama at Birmingham
Birmingham, Alabama, United States, 35233
United States, California
University of California - Los Angeles
Los Angeles, California, United States, 90025
Stanford University
Palo Alto, California, United States, 94304
United States, Iowa
University of Iowa
Iowa City, Iowa, United States, 52242
United States, Michigan
Wayne State University
Detroit, Michigan, United States, 48201
United States, New Mexico
University of New Mexico
Albuquerque, New Mexico, United States, 87131
United States, New York
University of Rochester
Rochester, New York, United States, 14642
United States, North Carolina
Duke University
Durham, North Carolina, United States, 27710
United States, Ohio
Research Institute at Nationwide Children's Hospital
Columbus, Ohio, United States, 43205
United States, Rhode Island
Brown University, Women & Infants Hospital of Rhode Island
Providence, Rhode Island, United States, 02905
United States, Texas
University of Texas Southwestern Medical Center at Dallas
Dallas, Texas, United States, 75235
Sponsors and Collaborators
Investigators
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
  More Information

Additional Information:
No publications provided

Responsible Party: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
ClinicalTrials.gov Identifier: NCT01467076     History of Changes
Other Study ID Numbers: NICHD-NRN-0046, U10HD040689, U10HD021385, U10HD027904, U10HD027880, U10HD034216, U10HD040492, U10HD053109, U10HD040461, U10HD068263, U10HD068270, U10HD068278, U10HD036790
Study First Received: October 17, 2011
Last Updated: February 13, 2013
Health Authority: United States: Food and Drug Administration
United States: Federal Government

Additional relevant MeSH terms:
Hypertension
Hypertension, Pulmonary
Respiratory Distress Syndrome, Newborn
Respiratory Insufficiency
Vascular Diseases
Cardiovascular Diseases
Lung Diseases
Respiratory Tract Diseases
Respiration Disorders
Infant, Premature, Diseases
Infant, Newborn, Diseases
Alprostadil
Platelet Aggregation Inhibitors
Hematologic Agents
Therapeutic Uses
Pharmacologic Actions
Vasodilator Agents
Cardiovascular Agents
Urological Agents

ClinicalTrials.gov processed this record on October 19, 2014