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

Study Results

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Basic Information

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Recruitment Status

TERMINATED

Clinical Phase

PHASE2

Total Enrollment

7 participants

Study Classification

INTERVENTIONAL

Study Start Date

2011-11-30

Study Completion Date

2012-06-30

Brief Summary

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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.

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Detailed Description

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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.

Conditions

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Prematurity Respiratory Insufficiency Pulmonary Hypertension Respiratory Distress Syndrome, Newborn

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

FACTORIAL

Primary Study Purpose

TREATMENT

Blinding Strategy

QUADRUPLE

Participants Caregivers Investigators Outcome Assessors

Study Groups

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Inhaled PGE1 (150 ng/kg/min)

150 ng/kg/min Inhaled PGE1

Group Type ACTIVE_COMPARATOR

Inhaled PGE1

Intervention Type DRUG

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.

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.

Group Type PLACEBO_COMPARATOR

Aerosolized Normal Saline

Intervention Type DRUG

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 (300 ng/kg/min)

300 ng/kg/min of Inhaled PGE1

Group Type ACTIVE_COMPARATOR

Inhaled PGE1

Intervention Type DRUG

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.

Interventions

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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.

Intervention Type 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.

Intervention Type DRUG

Other Intervention Names

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Normal Saline Inhaled Prostaglandin E1

Eligibility Criteria

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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.

Maximum Eligible Age

7 Days

Eligible Sex

ALL

Accepts Healthy Volunteers

No