title: Inhaled PGE1 in neonates with hypoxemic respiratory failure: two pilot feasibility randomized clinical trials.
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.
  
  
  BACKGROUND
  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.
authors.affiliation: Department of Pediatrics, Children's Hospital of Michigan, 3901 Beaubien Blvd., 4H42, Detroit, MI, 48201, USA. bsood@med.wayne.edu.
authors.forename: Beena G
authors.initials: BG
authors.lastname: Sood
authors.affiliation: Department of Pediatrics, Women and Infants Hospital, Brown University, 101 Dudley Street, Providence, RI, 0290, USA. mkeszler@wihri.org.
authors.forename: Martin
authors.initials: M
authors.lastname: Keszler
authors.affiliation: Department of Pediatrics, University of California, 10833 Le Conte Avenue, Room B2-375 MDCC, Los Angeles, CA, 90095, USA. MGarg@mednet.ucla.edu.
authors.forename: Meena
authors.initials: M
authors.lastname: Garg
authors.affiliation: Department of Pediatrics, University of Iowa, 200 Hawkins Drive, Iowa City, IA, 52242, USA. jonathan-klein@uiowa.edu.
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Klein
authors.affiliation: MSC10 5590 1, University of New Mexico Health Sciences Center, Albuquerque, NM, 87131-0001, USA. ROhls@salud.unm.edu.
authors.forename: Robin
authors.initials: R
authors.lastname: Ohls
authors.affiliation: Division of Neonatology, University of Alabama at Birmingham, 176F Suite 9380 619 South 19th St, Birmingham, AL, 35249-7335, UK. nambalavanan@peds.uab.edu.
authors.forename: Namasivayam
authors.initials: N
authors.lastname: Ambalavanan
authors.affiliation: Department of Pediatrics, Duke University, 2424 Erwin Road Suite 504, Durham, NC, 27705, USA. cotte010@mc.duke.edu.
authors.forename: C Michael
authors.initials: CM
authors.lastname: Cotten
authors.affiliation: Department of Pediatrics, Children's Hospital of Michigan, 3901 Beaubien Blvd., 4H42, Detroit, MI, 48201, USA. mmalian@dmc.org.
authors.forename: Monica
authors.initials: M
authors.lastname: Malian
authors.affiliation: Department of Pediatrics, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX, 75390, USA. pablo.sanchez@nationwidechildrens.org.
authors.forename: Pablo J
authors.initials: PJ
authors.lastname: Sanchez
authors.affiliation: Department of Pediatrics, University of Buffalo, 219 Bryant Street, Buffalo, NY, 14222, USA. slakshmi@buffalo.edu.
authors.forename: Satyan
authors.initials: S
authors.lastname: Lakshminrusimha
authors.affiliation: Department of Pediatrics, The Ohio State University and Nationwide Children's Hospital, 700 Children's Drive, W203, Columbus, OH, 43205, USA. Leif.Nelin@nationwidechildrens.org.
authors.forename: Leif D
authors.initials: LD
authors.lastname: Nelin
authors.affiliation: Department of Pediatrics, Division of Neonatal and Developmental Medicine, Stanford University School of Medicine and Lucile Packard Children's Hospital, 750 Welch Road, Suite 315, Palo Alto, CA, 94304, USA. vanmeurs@stanford.edu.
authors.forename: Krisa P
authors.initials: KP
authors.lastname: Van Meurs
authors.affiliation: Department of Pediatrics, Children's Hospital of Michigan, 3901 Beaubien Blvd., 4H42, Detroit, MI, 48201, USA. bara@med.wayne.edu.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Bara
authors.affiliation: Social, Statistical and Environmental Sciences Unit, RTI International, Research Triangle Park, NC, USA. saha@rti.org.
authors.forename: Shampa
authors.initials: S
authors.lastname: Saha
authors.affiliation: Social, Statistical and Environmental Sciences Unit, RTI International, 6110 Executive Blvd., Suite 902, Rockville, MD, 20852-3903, USA. adas@rti.org.
authors.forename: Abhik
authors.initials: A
authors.lastname: Das
authors.affiliation: Social, Statistical and Environmental Sciences Unit, RTI International, 6110 Executive Blvd., Suite 902, Rockville, MD, 20852-3903, USA. dwallace@rti.org.
authors.forename: Dennis
authors.initials: D
authors.lastname: Wallace
authors.affiliation: Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Rm 4B03, 6100 Executive Blvd., MSC 7510, Bethesda, MD, 20892-7510, USA. higginsr@mail.nih.gov.
authors.forename: Rosemary D
authors.initials: RD
authors.lastname: Higgins
authors.affiliation: Department of Pediatrics, Children's Hospital of Michigan, 3901 Beaubien Blvd., 4H42, Detroit, MI, 48201, USA. sshankar@med.wayne.edu.
authors.forename: Seetha
authors.initials: S
authors.lastname: Shankaran
mesh_terms: D000280:Administration, Inhalation; D000336:Aerosols; D000527:Alprostadil / Q000008:administration & dosage*; D057239:Early Termination of Clinical Trials; D005240:Feasibility Studies; D006801:Humans; D000860:Hypoxia / Q000175:diagnosis / Q000188:drug therapy* / Q000503:physiopathology; D007231:Infant, Newborn; D018579:Patient Selection; D010547:Persistent Fetal Circulation Syndrome / Q000175:diagnosis / Q000188:drug therapy* / Q000503:physiopathology; D010865:Pilot Projects; D012131:Respiratory Insufficiency / Q000175:diagnosis / Q000188:drug therapy* / Q000503:physiopathology; D018401:Sample Size; D013997:Time Factors; D016896:Treatment Outcome; D014481:United States; D014665:Vasodilator Agents / Q000008:administration & dosage*
chemical_list: D000336:Aerosols; D014665:Vasodilator Agents; D000527:Alprostadil