Inhaled PGE1 in neonates with hypoxemic respiratory failure: Two pilot feasibility randomized clinical trials

Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

Background: Inhaled nitric oxide (INO), a selective pulmonary vasodilator, has revolutionized the treatment of neonatal hypoxemic respiratory failure (NHRF). However, there is lack of sustained improvement in 30 to 46% of infants. Aerosolized prostaglandins I2 (PGI2) and E1 (PGE1) have been reported to be effective selective pulmonary vasodilators. The objective of this study was to evaluate the feasibility of a randomized controlled trial (RCT) of inhaled PGE1 (IPGE1) in NHRF. Methods: Two pilot multicenter phase II RCTs are included in this report. In the first pilot, late preterm and term neonates with NHRF, who had an oxygenation index (OI) of ≥15 and <25 on two arterial blood gases and had not previously received INO, were randomly assigned to receive two doses of IPGE1 (300 and 150 ng/kg/min) or placebo. The primary outcome was the enrollment of 50 infants in six to nine months at 10 sites. The first pilot was halted after four months for failure to enroll a single infant. The most common cause for non-enrollment was prior initiation of INO. In a re-designed second pilot, co-administration of IPGE1 and INO was permitted. Infants with suboptimal response to INO received either aerosolized saline or IPGE1 at a low (150 ng/kg/min) or high dose (300 ng/kg/min) for a maximum duration of 72 hours. The primary outcome was the recruitment of an adequate number of patients (n = 50) in a nine-month-period, with fewer than 20% protocol violations. Results: No infants were enrolled in the first pilot. Seven patients were enrolled in the second pilot; three in the control, two in the low-dose IPGE1, and two in the high-dose IPGE1 groups. The study was halted for recruitment futility after approximately six months as enrollment targets were not met. No serious adverse events, one minor protocol deviation and one pharmacy protocol violation were reported. Conclusions: These two pilot RCTs failed to recruit adequate eligible newborns with NHRF. Complex management RCTs of novel therapies for persistent pulmonary hypertension of the newborn (PPHN) may require novel study designs and a longer period of time from study approval to commencement of enrollment. Trial registration: ClinicalTrials.gov: Pilot one: NCT number: 00598429. registered on 10 January 2008. Last updated: 3 February 2013.

Original languageEnglish (US)
Article number486
JournalTrials
Volume15
Issue number1
DOIs
StatePublished - Dec 12 2014
Externally publishedYes

Fingerprint

Alprostadil
Epoprostenol
Respiratory Insufficiency
Randomized Controlled Trials
Newborn Infant
Nitric Oxide
Vasodilator Agents
Persistent Fetal Circulation Syndrome
Medical Futility
Lung
Time and Motion Studies
Gases
Placebos
Therapeutics

Keywords

  • Aerosols
  • Clinical trial
  • Hypoxemic respiratory failure
  • Nebulizers
  • Neonatal
  • Prostaglandins
  • Pulmonary hypertension

ASJC Scopus subject areas

  • Medicine (miscellaneous)
  • Pharmacology (medical)

Cite this

Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network (2014). Inhaled PGE1 in neonates with hypoxemic respiratory failure: Two pilot feasibility randomized clinical trials. Trials, 15(1), [486]. https://doi.org/10.1186/1745-6215-15-486

Inhaled PGE1 in neonates with hypoxemic respiratory failure : Two pilot feasibility randomized clinical trials. / Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network.

In: Trials, Vol. 15, No. 1, 486, 12.12.2014.

Research output: Contribution to journalArticle

Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network 2014, 'Inhaled PGE1 in neonates with hypoxemic respiratory failure: Two pilot feasibility randomized clinical trials', Trials, vol. 15, no. 1, 486. https://doi.org/10.1186/1745-6215-15-486
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(1). 486. https://doi.org/10.1186/1745-6215-15-486
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. In: Trials. 2014 ; Vol. 15, No. 1.
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abstract = "Background: Inhaled nitric oxide (INO), a selective pulmonary vasodilator, has revolutionized the treatment of neonatal hypoxemic respiratory failure (NHRF). However, there is lack of sustained improvement in 30 to 46{\%} of infants. Aerosolized prostaglandins I2 (PGI2) and E1 (PGE1) have been reported to be effective selective pulmonary vasodilators. The objective of this study was to evaluate the feasibility of a randomized controlled trial (RCT) of inhaled PGE1 (IPGE1) in NHRF. Methods: Two pilot multicenter phase II RCTs are included in this report. In the first pilot, late preterm and term neonates with NHRF, who had an oxygenation index (OI) of ≥15 and <25 on two arterial blood gases and had not previously received INO, were randomly assigned to receive two doses of IPGE1 (300 and 150 ng/kg/min) or placebo. The primary outcome was the enrollment of 50 infants in six to nine months at 10 sites. The first pilot was halted after four months for failure to enroll a single infant. The most common cause for non-enrollment was prior initiation of INO. In a re-designed second pilot, co-administration of IPGE1 and INO was permitted. Infants with suboptimal response to INO received either aerosolized saline or IPGE1 at a low (150 ng/kg/min) or high dose (300 ng/kg/min) for a maximum duration of 72 hours. The primary outcome was the recruitment of an adequate number of patients (n = 50) in a nine-month-period, with fewer than 20{\%} protocol violations. Results: No infants were enrolled in the first pilot. Seven patients were enrolled in the second pilot; three in the control, two in the low-dose IPGE1, and two in the high-dose IPGE1 groups. The study was halted for recruitment futility after approximately six months as enrollment targets were not met. No serious adverse events, one minor protocol deviation and one pharmacy protocol violation were reported. Conclusions: These two pilot RCTs failed to recruit adequate eligible newborns with NHRF. Complex management RCTs of novel therapies for persistent pulmonary hypertension of the newborn (PPHN) may require novel study designs and a longer period of time from study approval to commencement of enrollment. Trial registration: ClinicalTrials.gov: Pilot one: NCT number: 00598429. registered on 10 January 2008. Last updated: 3 February 2013.",
keywords = "Aerosols, Clinical trial, Hypoxemic respiratory failure, Nebulizers, Neonatal, Prostaglandins, Pulmonary hypertension",
author = "{Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network} and Sood, {Beena G.} and Martin Keszler and Meena Garg and Klein, {Jonathan M.} and Robin Ohls and Namasivayam Ambalavanan and Cotten, {C. Michael} and Monica Malian and Sanchez, {Pablo J.} and Satyanarayana Lakshminrusimha and Nelin, {Leif D.} and {Van Meurs}, {Krisa P.} and Rebecca Bara and Shampa Saha and Abhik Das and Dennis Wallace and Higgins, {Rosemary D.} and Seetha Shankaran and Besner, {Gail E.} and Patricia Luzader and Chicoine, {Louis G.} and Jenna Gabrio and {O'Donnell Auman}, Jeanette and Zaterka-Baxter, {Kristin M.} and Stevenson, {David K.} and {Bethany Ball}, M. and Steven Chinn and Proud, {Melinda S.} and Carlo, {Waldemar A.} and Collins, {Monica V.} and Cosby, {Shirley S.} and Zahra Davis and Quinn, {Rebecca J.} and Denson, {Brenda Reed} and Uday Devaskar and Teresa Chanlaw and Rachel Geller and Bell, {Edward F.} and Widness, {John A.} and Johnson, {Karen J.} and Campbell, {Donia B.} and Colaizy, {Tarah T.} and Dagle, {John M.} and Ellsbury, {Dan L.} and Johnson, {Kristine M.} and Lynn Messina and Nohr, {Joanna L.} and Watterberg, {Kristi L.} and Lacy, {Conra Backstrom} and Morgan, {Nancy A.}",
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TY - JOUR

T1 - Inhaled PGE1 in neonates with hypoxemic respiratory failure

T2 - Two pilot feasibility randomized clinical trials

AU - Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network

AU - Sood, Beena G.

AU - Keszler, Martin

AU - Garg, Meena

AU - Klein, Jonathan M.

AU - Ohls, Robin

AU - Ambalavanan, Namasivayam

AU - Cotten, C. Michael

AU - Malian, Monica

AU - Sanchez, Pablo J.

AU - Lakshminrusimha, Satyanarayana

AU - Nelin, Leif D.

AU - Van Meurs, Krisa P.

AU - Bara, Rebecca

AU - Saha, Shampa

AU - Das, Abhik

AU - Wallace, Dennis

AU - Higgins, Rosemary D.

AU - Shankaran, Seetha

AU - Besner, Gail E.

AU - Luzader, Patricia

AU - Chicoine, Louis G.

AU - Gabrio, Jenna

AU - O'Donnell Auman, Jeanette

AU - Zaterka-Baxter, Kristin M.

AU - Stevenson, David K.

AU - Bethany Ball, M.

AU - Chinn, Steven

AU - Proud, Melinda S.

AU - Carlo, Waldemar A.

AU - Collins, Monica V.

AU - Cosby, Shirley S.

AU - Davis, Zahra

AU - Quinn, Rebecca J.

AU - Denson, Brenda Reed

AU - Devaskar, Uday

AU - Chanlaw, Teresa

AU - Geller, Rachel

AU - Bell, Edward F.

AU - Widness, John A.

AU - Johnson, Karen J.

AU - Campbell, Donia B.

AU - Colaizy, Tarah T.

AU - Dagle, John M.

AU - Ellsbury, Dan L.

AU - Johnson, Kristine M.

AU - Messina, Lynn

AU - Nohr, Joanna L.

AU - Watterberg, Kristi L.

AU - Lacy, Conra Backstrom

AU - Morgan, Nancy A.

PY - 2014/12/12

Y1 - 2014/12/12

N2 - Background: Inhaled nitric oxide (INO), a selective pulmonary vasodilator, has revolutionized the treatment of neonatal hypoxemic respiratory failure (NHRF). However, there is lack of sustained improvement in 30 to 46% of infants. Aerosolized prostaglandins I2 (PGI2) and E1 (PGE1) have been reported to be effective selective pulmonary vasodilators. The objective of this study was to evaluate the feasibility of a randomized controlled trial (RCT) of inhaled PGE1 (IPGE1) in NHRF. Methods: Two pilot multicenter phase II RCTs are included in this report. In the first pilot, late preterm and term neonates with NHRF, who had an oxygenation index (OI) of ≥15 and <25 on two arterial blood gases and had not previously received INO, were randomly assigned to receive two doses of IPGE1 (300 and 150 ng/kg/min) or placebo. The primary outcome was the enrollment of 50 infants in six to nine months at 10 sites. The first pilot was halted after four months for failure to enroll a single infant. The most common cause for non-enrollment was prior initiation of INO. In a re-designed second pilot, co-administration of IPGE1 and INO was permitted. Infants with suboptimal response to INO received either aerosolized saline or IPGE1 at a low (150 ng/kg/min) or high dose (300 ng/kg/min) for a maximum duration of 72 hours. The primary outcome was the recruitment of an adequate number of patients (n = 50) in a nine-month-period, with fewer than 20% protocol violations. Results: No infants were enrolled in the first pilot. Seven patients were enrolled in the second pilot; three in the control, two in the low-dose IPGE1, and two in the high-dose IPGE1 groups. The study was halted for recruitment futility after approximately six months as enrollment targets were not met. No serious adverse events, one minor protocol deviation and one pharmacy protocol violation were reported. Conclusions: These two pilot RCTs failed to recruit adequate eligible newborns with NHRF. Complex management RCTs of novel therapies for persistent pulmonary hypertension of the newborn (PPHN) may require novel study designs and a longer period of time from study approval to commencement of enrollment. Trial registration: ClinicalTrials.gov: Pilot one: NCT number: 00598429. registered on 10 January 2008. Last updated: 3 February 2013.

AB - Background: Inhaled nitric oxide (INO), a selective pulmonary vasodilator, has revolutionized the treatment of neonatal hypoxemic respiratory failure (NHRF). However, there is lack of sustained improvement in 30 to 46% of infants. Aerosolized prostaglandins I2 (PGI2) and E1 (PGE1) have been reported to be effective selective pulmonary vasodilators. The objective of this study was to evaluate the feasibility of a randomized controlled trial (RCT) of inhaled PGE1 (IPGE1) in NHRF. Methods: Two pilot multicenter phase II RCTs are included in this report. In the first pilot, late preterm and term neonates with NHRF, who had an oxygenation index (OI) of ≥15 and <25 on two arterial blood gases and had not previously received INO, were randomly assigned to receive two doses of IPGE1 (300 and 150 ng/kg/min) or placebo. The primary outcome was the enrollment of 50 infants in six to nine months at 10 sites. The first pilot was halted after four months for failure to enroll a single infant. The most common cause for non-enrollment was prior initiation of INO. In a re-designed second pilot, co-administration of IPGE1 and INO was permitted. Infants with suboptimal response to INO received either aerosolized saline or IPGE1 at a low (150 ng/kg/min) or high dose (300 ng/kg/min) for a maximum duration of 72 hours. The primary outcome was the recruitment of an adequate number of patients (n = 50) in a nine-month-period, with fewer than 20% protocol violations. Results: No infants were enrolled in the first pilot. Seven patients were enrolled in the second pilot; three in the control, two in the low-dose IPGE1, and two in the high-dose IPGE1 groups. The study was halted for recruitment futility after approximately six months as enrollment targets were not met. No serious adverse events, one minor protocol deviation and one pharmacy protocol violation were reported. Conclusions: These two pilot RCTs failed to recruit adequate eligible newborns with NHRF. Complex management RCTs of novel therapies for persistent pulmonary hypertension of the newborn (PPHN) may require novel study designs and a longer period of time from study approval to commencement of enrollment. Trial registration: ClinicalTrials.gov: Pilot one: NCT number: 00598429. registered on 10 January 2008. Last updated: 3 February 2013.

KW - Aerosols

KW - Clinical trial

KW - Hypoxemic respiratory failure

KW - Nebulizers

KW - Neonatal

KW - Prostaglandins

KW - Pulmonary hypertension

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DO - 10.1186/1745-6215-15-486

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