Inhaled PGE(1) in neonates with hypoxemic respiratory failure: two pilot feasibility randomized clinical trials

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 I(2) (PGI(2)) and E(1) (PGE(1)) 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 PGE(1) (IPGE(1)) 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 IPGE(1) (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 IPGE(1) and INO was permitted. Infants with suboptimal response to INO received either aerosolized saline or IPGE(1) 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 IPGE(1), and two in the high-dose IPGE(1) 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. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/1745-6215-15-486) contains supplementary material, which is available to authorized users.