Prematurity, Pulmonary Hypertension, Respiratory Distress Syndrome, Newborn, Respiratory Insufficiency
Conditions
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.
Interventions
DRUGAerosolized 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.
DRUGInhaled 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.
Sponsors
National Center for Research Resources (NCRR)
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
NICHD Neonatal Research Network
Study design
Allocation
RANDOMIZED
Intervention model
FACTORIAL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
No minimum to 7 Days
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Feasibility Assessed as the Number of Participants Who Were Enrolled in the Study | From study start through 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Oxygenation Index (OI) | Measurement of ABG at 60±15 minutes and 4±2 hours after start of study aerosol. | Change in OI based on the arterial blood gases (ABG) measurements obtained at 60±15 minutes and ABG obtained 4±2 hours after start of study aerosol. |
| Need for Inhaled Nitric Oxide (INO) 72 Hours After INO | Date of first administration of INO to date of final discontinuation of INO | Administration of INO continued after the Infant was on INO for 72 hours |
| Duration of iNO Therapy | From date of first administration of INO to date of final discontinuation of INO. | Duration the infant is on INO from initial administration of INO to final discontinuation of INO. |
| Death | From birth through status (death, transfer, or discharge). | Deaths prior to discharge home. |
| Change in Partial Pressure of Oxygen in the Blood (PaO2) | Measurement of ABG at 60±15 minutes and 4±2 hours after start of study aerosol. | Changes in PaO2 based on the arterial blood gases (ABG) measurements obtained after 60 minutes and ABG obtained 4 hours after start of study aerosol. |
| Duration of Mechanical Ventilation | From birth through status (death, transfer or discharge) | Duration the infant is on Mechanical Ventilation from birth through status (death, transfer or discharge) |
| Number of Days of Supplemental Oxygen (O2) Used | From birth through status (death, transfer or discharge) | Number of days from birth during which the FiO2 at some point was \> 0.21. |
| Length of Hospital Stay | From birth to discharge home | Length of stay in hospital from birth to discharge home. |
| Need for Extracorporeal Membrane Oxygenation (ECMO) | From after discontinuation of study aerosol through status (death, transfer, or discharge). | ECMO provided at the institution for the infant after discontinuation of study aerosol. |
Countries
United States
Participant flow
Recruitment details
Opened for recruitment on 10/20/2011. There was a lag of 33 to 90 days between IRB approval and site readiness to enroll patients. 46 infants were screened at 8 sites, 14 met eligibility criteria, and 7 were randomized. Enrollment was halted for lack of feasibility in mid-May 2012; at that time, only 7 patients had been enrolled.
Pre-assignment details
Seven eligible infants were not enrolled because parents were unavailable or refused consent for 3 of the infants, 3 infants met ECMO criteria, and 1 had cardio-respiratory arrest.
Participants by arm
| Arm | Count |
|---|---|
| Control Aerosolized saline | 3 |
| Low Dose IPGE1 150 ng/kg/min | 2 |
| High Dose IPGE1 300 ng/kg/min | 2 |
| Total | 7 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Lost to Follow-up | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | Control | Low Dose IPGE1 | High Dose IPGE1 | Total |
|---|---|---|---|---|
| Age, Customized Age at Randomization | 41.75 hours | 11.30 hours | 26.65 hours | 28.73 hours |
| Birthweight | 3591 grams | 3530 grams | 3320 grams | 3496 grams |
| Delivery by Cesarean Section | 2 participants | 2 participants | 1 participants | 5 participants |
| Intubation in Delivery Room | 0 participants | 2 participants | 2 participants | 4 participants |
| Sex: Female, Male Female | 1 Participants | 1 Participants | 2 Participants | 4 Participants |
| Sex: Female, Male Male | 2 Participants | 1 Participants | 0 Participants | 3 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 0 / 3 | 0 / 2 | 0 / 2 |
| serious Total, serious adverse events | 2 / 3 | 0 / 2 | 0 / 2 |
Outcome results
Primary
Feasibility Assessed as the Number of Participants Who Were Enrolled in the Study
The primary outcome is the ability to recruit adequate number of infants (n=50) in a 9 month period without excessive (\>20%) protocol violations.
Time frame: From study start through 9 months after 75% of the participating sites are enrolling
Population: Late preterm \& term infants ≤ 7 days postnatal age undergoing conventional ventilation (CNV) or high frequency oscillatory ventilation (HFOV) for NHRF (including perinatal aspiration syndrome, suspected/proven pneumonia/sepsis, respiratory distress syndrome, idiopathic PPHN or suspected pulmonary hypoplasia) with suboptimal response to INO
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Control | Feasibility Assessed as the Number of Participants Who Were Enrolled in the Study | 3 participants |
| Low Dose IPGE1 | Feasibility Assessed as the Number of Participants Who Were Enrolled in the Study | 2 participants |
| High Dose IPGE1 | Feasibility Assessed as the Number of Participants Who Were Enrolled in the Study | 2 participants |
Secondary
Change in Oxygenation Index (OI)
Change in OI based on the arterial blood gases (ABG) measurements obtained at 60±15 minutes and ABG obtained 4±2 hours after start of study aerosol.
Time frame: Measurement of ABG at 60±15 minutes and 4±2 hours after start of study aerosol.
Population: To gauge change in OI for each group we present both the average and the range of the difference between the two OI ABG measurements (measurement at 4±2 hours - measurement at 60±15 minutes after start of study aerosol). A positive difference indicates an increase in OI measurement; a negative difference indicates a decrease in OI measurement.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Control | Change in Oxygenation Index (OI) | 4 oxygenation index |
| Low Dose IPGE1 | Change in Oxygenation Index (OI) | 14 oxygenation index |
| High Dose IPGE1 | Change in Oxygenation Index (OI) | 10 oxygenation index |
Secondary
Change in Partial Pressure of Oxygen in the Blood (PaO2)
Changes in PaO2 based on the arterial blood gases (ABG) measurements obtained after 60 minutes and ABG obtained 4 hours after start of study aerosol.
Time frame: Measurement of ABG at 60±15 minutes and 4±2 hours after start of study aerosol.
Population: To gauge the improvement in PaO2 for each group, the average of the difference between the two PaO2 ABG measurements (measurement at 4±2 hours-measurement at 60±15 minutes after start of study aerosol) and the range(minimum, maximum) of the differences between OI ABG measurements at the two time points within each group are presented here.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Control | Change in Partial Pressure of Oxygen in the Blood (PaO2) | 30 mmHg |
| Low Dose IPGE1 | Change in Partial Pressure of Oxygen in the Blood (PaO2) | 85 mmHg |
| High Dose IPGE1 | Change in Partial Pressure of Oxygen in the Blood (PaO2) | 48 mmHg |
Secondary
Death
Deaths prior to discharge home.
Time frame: From birth through status (death, transfer, or discharge).
Population: All 3 infants in the control group, 2 infant in the Low dose and 2 infants in the High dose IPGE1 groups have status data (death, transfer or discharge).
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Control | Death | 0 Participants |
| Low Dose IPGE1 | Death | 0 Participants |
| High Dose IPGE1 | Death | 0 Participants |
Secondary
Duration of iNO Therapy
Duration the infant is on INO from initial administration of INO to final discontinuation of INO.
Time frame: From date of first administration of INO to date of final discontinuation of INO.
Population: The date of final discontinuation of INO was recorded for 2 infants in the control group, 1 infant in the low dose and all 2 infants in the high dose group.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Control | Duration of iNO Therapy | 59.02 hours |
| Low Dose IPGE1 | Duration of iNO Therapy | 18.57 hours |
| High Dose IPGE1 | Duration of iNO Therapy | 56.22 hours |
Secondary
Duration of Mechanical Ventilation
Duration the infant is on Mechanical Ventilation from birth through status (death, transfer or discharge)
Time frame: From birth through status (death, transfer or discharge)
Population: All 3 infants in the aerosolized saline group, and the 2 infants in the lower dose IPGE1 group and high dose IPGE1 Group have the number of days on mechanical ventilation from birth to death, transfer or discharge.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Control | Duration of Mechanical Ventilation | 22 Days |
| Low Dose IPGE1 | Duration of Mechanical Ventilation | 8 Days |
| High Dose IPGE1 | Duration of Mechanical Ventilation | 16 Days |
Secondary
Length of Hospital Stay
Length of stay in hospital from birth to discharge home.
Time frame: From birth to discharge home
Population: Two infants in the aerosolized saline group, and 2 infants in the lowd ose IPGE1 group and high dose IPGE1 Group were discharged home/chronic care.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Control | Length of Hospital Stay | 64 Days |
| Low Dose IPGE1 | Length of Hospital Stay | 31 Days |
| High Dose IPGE1 | Length of Hospital Stay | 39 Days |
Secondary
Need for Extracorporeal Membrane Oxygenation (ECMO)
ECMO provided at the institution for the infant after discontinuation of study aerosol.
Time frame: From after discontinuation of study aerosol through status (death, transfer, or discharge).
Population: All 3 infants in the control group, 2 infant in the Low dose and 2 infants in the High dose IPGE1 groups have data on ECMO use at the institution after discontinuation of study aerosol.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Control | Need for Extracorporeal Membrane Oxygenation (ECMO) | 2 Participants |
| Low Dose IPGE1 | Need for Extracorporeal Membrane Oxygenation (ECMO) | 1 Participants |
| High Dose IPGE1 | Need for Extracorporeal Membrane Oxygenation (ECMO) | 2 Participants |
Secondary
Need for Inhaled Nitric Oxide (INO) 72 Hours After INO
Administration of INO continued after the Infant was on INO for 72 hours
Time frame: Date of first administration of INO to date of final discontinuation of INO
Population: Date of final discontinuation of INO was not available for 1 infant in the Control group and 1 infant in the LOW DOSE IPGE1 group
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Control | Need for Inhaled Nitric Oxide (INO) 72 Hours After INO | 1 Participants |
| Low Dose IPGE1 | Need for Inhaled Nitric Oxide (INO) 72 Hours After INO | 0 Participants |
| High Dose IPGE1 | Need for Inhaled Nitric Oxide (INO) 72 Hours After INO | 0 Participants |
Secondary
Number of Days of Supplemental Oxygen (O2) Used
Number of days from birth during which the FiO2 at some point was \> 0.21.
Time frame: From birth through status (death, transfer or discharge)
Population: All 3 infants in the aerosolized saline group, and the 2 infants in the lower dose IPGE1 group and high dose IPGE1 Group have the number of days on supplemental oxygen from birth to death, transfer or discharge.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Control | Number of Days of Supplemental Oxygen (O2) Used | 43 Days |
| Low Dose IPGE1 | Number of Days of Supplemental Oxygen (O2) Used | 8 Days |
| High Dose IPGE1 | Number of Days of Supplemental Oxygen (O2) Used | 11 Days |