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

Sood BG, Keszler M, Garg M, Klein JM, Ohls R, Ambalavanan N, Cotten CM, Malian M, Sanchez PJ, Lakshminrusimha S, Nelin LD, Van Meurs KP, Bara R, Saha S, Das A, Wallace D, Higgins RD, Shankaran S, Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Netwo - Trials (2014)

Bottom Line: Aerosolized prostaglandins I2 (PGI2) and E1 (PGE1) have been reported to be effective selective pulmonary vasodilators.No serious adverse events, one minor protocol deviation and one pharmacy protocol violation were reported.These two pilot RCTs failed to recruit adequate eligible newborns with NHRF.

View Article: PubMed Central - PubMed

Affiliation: Department of Pediatrics, Children's Hospital of Michigan, 3901 Beaubien Blvd., 4H42, Detroit, MI, 48201, USA. bsood@med.wayne.edu.

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 2011. Pilot two: NCT number: 01467076 17 October 2011. Last updated: 13 February 2013.

No MeSH data available.


Related in: MedlinePlus

Boxplots of timeline of events prior to initiation of study aerosol in control and combined IPGE1groups (low-dose and high-dose IPGE1). INO, inhaled nitric oxide; OI, oxygenation index. (a) Age at INO start (hours; (b) Age at randomization (hours); (c) Interval from 1st OI > 15 and start of study aerosol (hours); (d) Interval from randomization to start of study aerosol (hours).
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Fig4: Boxplots of timeline of events prior to initiation of study aerosol in control and combined IPGE1groups (low-dose and high-dose IPGE1). INO, inhaled nitric oxide; OI, oxygenation index. (a) Age at INO start (hours; (b) Age at randomization (hours); (c) Interval from 1st OI > 15 and start of study aerosol (hours); (d) Interval from randomization to start of study aerosol (hours).

Mentions: Of the seven infants randomized, three received aerosolized saline, and two each received high-dose and low-dose IPGE1. Aggregate data are presented for the control group and the two IPGE1 groups combined because of the small numbers of subjects in each group (Tables 1 and 2, Figures 4 and 5). The small numbers precluded formal statistical testing. Detailed individual patient data are presented in Table 3.Table 1


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

Sood BG, Keszler M, Garg M, Klein JM, Ohls R, Ambalavanan N, Cotten CM, Malian M, Sanchez PJ, Lakshminrusimha S, Nelin LD, Van Meurs KP, Bara R, Saha S, Das A, Wallace D, Higgins RD, Shankaran S, Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Netwo - Trials (2014)

Boxplots of timeline of events prior to initiation of study aerosol in control and combined IPGE1groups (low-dose and high-dose IPGE1). INO, inhaled nitric oxide; OI, oxygenation index. (a) Age at INO start (hours; (b) Age at randomization (hours); (c) Interval from 1st OI > 15 and start of study aerosol (hours); (d) Interval from randomization to start of study aerosol (hours).
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4414424&req=5

Fig4: Boxplots of timeline of events prior to initiation of study aerosol in control and combined IPGE1groups (low-dose and high-dose IPGE1). INO, inhaled nitric oxide; OI, oxygenation index. (a) Age at INO start (hours; (b) Age at randomization (hours); (c) Interval from 1st OI > 15 and start of study aerosol (hours); (d) Interval from randomization to start of study aerosol (hours).
Mentions: Of the seven infants randomized, three received aerosolized saline, and two each received high-dose and low-dose IPGE1. Aggregate data are presented for the control group and the two IPGE1 groups combined because of the small numbers of subjects in each group (Tables 1 and 2, Figures 4 and 5). The small numbers precluded formal statistical testing. Detailed individual patient data are presented in Table 3.Table 1

Bottom Line: Aerosolized prostaglandins I2 (PGI2) and E1 (PGE1) have been reported to be effective selective pulmonary vasodilators.No serious adverse events, one minor protocol deviation and one pharmacy protocol violation were reported.These two pilot RCTs failed to recruit adequate eligible newborns with NHRF.

View Article: PubMed Central - PubMed

Affiliation: Department of Pediatrics, Children's Hospital of Michigan, 3901 Beaubien Blvd., 4H42, Detroit, MI, 48201, USA. bsood@med.wayne.edu.

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 2011. Pilot two: NCT number: 01467076 17 October 2011. Last updated: 13 February 2013.

No MeSH data available.


Related in: MedlinePlus