title: Bosentan as Adjunctive Therapy for Persistent Pulmonary Hypertension of the Newborn: Results of the Randomized Multicenter Placebo-Controlled Exploratory Trial.
abstract: OBJECTIVE
  To evaluate the efficacy, safety, and pharmacokinetics of the endothelin receptor antagonist bosentan as adjunctive therapy for neonates with persistent pulmonary hypertension of the newborn (PPHN).
  
  
  METHODS
  This was a phase 3, multicenter, randomized, placebo-controlled exploratory trial (FUTURE-4). Eligible patients were >34 weeks gestation, <7 days old, receiving inhaled nitric oxide (iNO) treatment (≥4 hours), and had persistent respiratory failure (oxygenation index [OI] ≥12). After 2:1 randomization, bosentan 2 mg/kg or placebo was given by nasogastric tube twice daily for ≥48 hours and up to 1 day after iNO weaning.
  
  
  RESULTS
  Twenty-one neonates received a study drug (13 bosentan, 8 placebo). Compared with the placebo group, the group treated with bosentan had a higher median baseline OI and greater need for vasoactive agents. One treatment failure (need for extracorporeal membrane oxygenation) occurred in the group treated with bosentan. The time to weaning from iNO or mechanical ventilation was not different between the groups. Bosentan was well tolerated and did not adversely affect systemic blood pressure or hepatic transaminase levels. Anemia and edema were more frequent in patients receiving bosentan. Blood concentrations of bosentan were low and variable on day 1, and achieved steady state on day 5.
  
  
  CONCLUSIONS
  Adjunctive bosentan was well tolerated, but did not improve oxygenation or other outcomes in our patients with PPHN. This effect may be related to delayed absorption of bosentan on treatment initiation in critically ill neonates or to more severe illness of the neonates who received bosentan.
  
  
  BACKGROUND
  ClinicalTrials.gov:NCT01389856.
authors: Children's National Health System, Department of Pediatrics, Washington, DC. Electronic address: rsteinhorn@childrensnational.org.
authors: Robin H
authors: RH
authors: Steinhorn
authors: Benioff Children's Hospital, Department of Pediatrics, University of California, San Francisco, CA.
authors: Jeffrey
authors: J
authors: Fineman
authors: Department of Clinical Development, Actelion Pharmaceuticals Ltd, Allschwil, Switzerland.
authors: Andjela
authors: A
authors: Kusic-Pajic
authors: Department of Biostatistics, Actelion Pharmaceuticals Ltd, Allschwil, Switzerland.
authors: Peter
authors: P
authors: Cornelisse
authors: Department of Clinical Pharmacology, Actelion Pharmaceuticals Ltd, Allschwil, Switzerland.
authors: Martine
authors: M
authors: Gehin
authors: Department of Clinical Development, Actelion Pharmaceuticals Ltd, Allschwil, Switzerland.
authors: Pegah
authors: P
authors: Nowbakht
authors: Pediatric and Neonatal Intensive Care Units, Great Ormond Street Hospital for Children, London, UK.
authors: Christine M
authors: CM
authors: Pierce
authors: Pediatric Cardiology Unit, Children's Hospital, University of Geneva, Geneva, Switzerland.
authors: Maurice
authors: M
authors: Beghetti
mesh_terms: D000077300:Bosentan; D004311:Double-Blind Method; D065128:Endothelin Receptor Antagonists / Q000009:adverse effects / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D009569:Nitric Oxide / Q000008:administration & dosage; D010547:Persistent Fetal Circulation Syndrome / Q000188:drug therapy*; D012121:Respiration, Artificial; D013449:Sulfonamides / Q000009:adverse effects / Q000627:therapeutic use*; D017211:Treatment Failure; D016896:Treatment Outcome
chemical_list: D065128:Endothelin Receptor Antagonists; D013449:Sulfonamides; D009569:Nitric Oxide; D000077300:Bosentan
keywords: endothelin; hypertension; pediatrics; pharmacology; pulmonary