Inhaled PGE1 in Neonatal Hypoxemic Respiratory Failure

Study Overview
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Brief Summary
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This pilot study was a randomized, placebo-controlled, clinical trial to test the safety of using the intravenous form of Prostaglandin E1 (PGE1) in an inhaled form for treatment of hypoxemic respiratory failure in term newborns. The study planned to enroll 50 infants diagnosed with hypoxemic respiratory failure at nine NICHD Neonatal Research Network sites, and randomly assign them to receive one dose over a 72-hour period of either high concentration PGE1 (300 ng/kg/min), low concentration PGE1 (150 ng/kg/min), or placebo (normal saline, the diluent for the drug). In addition to determining the safety, optimal dose, and duration of the therapy, this pilot trial planned to evaluate the feasibility of conducting a larger, multi-center randomized, blinded placebo-controlled trial.

Detailed Description
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Hypoxemic respiratory failure (HRF), frequently associated with persistent pulmonary hypertension of the newborn (PPHN), is a rare, but life-threatening condition affecting approximately 2 to 9 percent of infants admitted to neonatal intensive care units and results in significant morbidity and mortality. It occurs more often in full- or post-term babies whose circulatory systems do not adapt well to breathing outside the womb. HRF may result from congenital hernia of the diaphragm, group B streptococcal infection, inhaling meconium in the womb, or respiratory distress syndrome. Medical treatments, such as high frequency ventilation, inhaled nitric oxide, and Extracorporeal Membrane Oxygenation (ECMO, a heart and lung support machine), have significantly increased survival of children with HRF. These therapies, while successful, however, have a variety of side effects and potential long-term disabilities. This feasibility trial was designed to test the safety of using the intravenous form of Prostaglandin E1 in an inhaled form (iPGE1) on infants born at 34 0/7ths weeks gestational age or greater diagnosed with hypoxemic respiratory failure and on assisted ventilation. The intravenous form of PGE1 was to be aerosolized and administered via a nebulizer attached to the infant's ventilator. The goal was to enroll 50 subjects within 6-9 months, in preparation for a larger, multi-center randomized control trial; however, the study was withdrawn for lack of recruitment.

Official Title
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Randomized Clinical Trial of Inhaled PGE1 (IPGE1) in Neonatal Hypoxemic Respiratory Failure. A Protocol for the NICHD Neonatal Research Network

Conditions
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Infant, Newborn, Respiratory Insufficiency, Pulmonary Hypertension, Respiratory Distress Syndrome, Newborn, Streptococcal Infections

Intervention / Treatment
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* Drug: Inhaled Prostaglandin E1


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Infants born at 34 0/7ths weeks gestational age or greater (by best obstetrical estimate) and at a postnatal age no greater than 7 days (168 hours) Infants diagnosed with hypoxemic respiratory failure (HRF), including perinatal aspiration syndrome (meconium, blood, or amniotic fluid), pneumonia/ sepsis, respiratory distress syndrome, or idiopathic respiratory failure Infants who will receive assisted ventilation for HRF Infants with an oxygenation index (MAP x FiO2 x 100/PaO2)(OI) of 15-25 on two arterial gases taken between 15 minutes and 12 hours apart An indwelling arterial line Infants whose parents/legal guardians have provided consent for enrollment Exclusion Criteria: Any infant in whom a decision has been made not to provide full treatment Known structural congenital heart disease, except patent ductus arteriosus and atrial/ventricular level shunts Congenital diaphragmatic hernia Preterm neonates less than 34 weeks Thrombocytopenia (platelet count < 80,000/μl) unresponsive to platelet transfusion Infants receiving hypothermia for hypoxic ischemic encephalopathy Previous treatment with inhaled nitric oxide Infants already enrolled in a conflicting and/or Investigational New Drug (IND) clinical trial Infants whose parents/legal guardians refuse consent

Ages Eligible for Study
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Maximum Age: 7 Days

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: High dose<br>PGE1 300 ng/kg/min via nebulizer over a 72-hour period | Drug: Inhaled Prostaglandin E1<br>* Delivery of one dose of either high dose PGE1 (300 ng/kg/min), low dose PGE1 (150 ng/kg/min), or placebo (normal saline, the diluent for the drug) via nebulizer over a 72-hour period<br>* Other names: Alprostadil;|
| Active Comparator: Low dose<br>PGE1 150 ng/kg/min via nebulizer over a 72-hour period | Drug: Inhaled Prostaglandin E1<br>* Delivery of one dose of either high dose PGE1 (300 ng/kg/min), low dose PGE1 (150 ng/kg/min), or placebo (normal saline, the diluent for the drug) via nebulizer over a 72-hour period<br>* Other names: Alprostadil;|
| Placebo Comparator: Placebo<br>Normal saline, the diluent for the drug, via nebulizer over a 72-hour period | Drug: Inhaled Prostaglandin E1<br>* Delivery of one dose of either high dose PGE1 (300 ng/kg/min), low dose PGE1 (150 ng/kg/min), or placebo (normal saline, the diluent for the drug) via nebulizer over a 72-hour period<br>* Other names: Alprostadil;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The ability to recruit an adequate number of patients (n = 50) in a 6-9 month period without excessive (>20%) protocol violations. |  | 6-9 months after trial begins recruitment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression to an OI greater than 25 |  | 72-hours after enrollment | 
| Improvement in partial pressure of oxygen (PaO2) in the blood gas |  | 72-hours after enrollment | 
| Change in OI |  | 72 hours after enrollment | 
| Death |  | 72-hours after intervention | 
| Need for inhaled nitric oxide or ECMO |  | 72-hours after enrollment | 
| Length of hospitalization |  |  | 
| Duration of mechanical ventilation |  |  | 
| Number of days of oxygen used and need for supplemental oxygen at 28 days of life |  |  | 
| Occurrence of grade III-IV intracranial hemorrhage and cystic leukomalacia |  |  | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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NICHD Neonatal Research Network, Hypoxemic respiratory failure (HRF), Persistent pulmonary hypertension of the newborn (PPHN), Prostaglandin E1 (PGE1), Mechanical ventilation, Meconium, aspiration