title: FUTURE-2: Results from an open-label, long-term safety and tolerability extension study using the pediatric FormUlation of bosenTan in pUlmonary arterial hypeRtEnsion.
abstract: BACKGROUND
  A novel formulation of bosentan was evaluated in children with pulmonary arterial hypertension (PAH) in FUTURE-1, which characterized its pharmacokinetic and clinical profile. The subsequent phase III, open-label, long-term extension study, FUTURE-2, aimed to provide long-term tolerability, safety and exploratory efficacy data.
  
  
  METHODS
  Children (≥2 and <12 years) with idiopathic or heritable PAH, who completed 12-week treatment in FUTURE-1 and for whom bosentan was considered beneficial were enrolled, and continued to receive bosentan 4 mg/kg twice-daily, which could be down-titrated to 2mg/kg if not tolerated. Safety and tolerability were evaluated via treatment-emergent adverse events (AEs), serious AEs, growth, and laboratory measurements. Exploratory efficacy endpoints included time to PAH worsening and long-term survival. All analyses were conducted on pooled data of both studies.
  
  
  RESULTS
  36 patients were enrolled in FUTURE-1 and 33 continued in FUTURE-2. The overall median duration of exposure to bosentan was 27.7 (range 1.9-59.6) months. Treatment-emergent AEs occurred in 32 (88.9%) patients; AEs considered treatment-related in 15 (41.7%) patients. Of 51 serious AEs, three were considered treatment-related: two incidences of reported PAH worsening and one of autoimmune hepatitis. Six deaths occurred; none were considered treatment-related. Kaplan-Meier event-free estimates of PAH worsening were 78.9% and 73.6% at 2 and 4 years, respectively.
  
  
  CONCLUSIONS
  The pediatric bosentan formulation was generally well tolerated, its safety profile comparable to that of the adult formulation when used in children. The results are in line with the efficacy profile of bosentan in previous pediatric and adult PAH studies of shorter duration.
authors.affiliation: Center for Congenital Heart Diseases, Department of Paediatric Cardiology, Beatrix Children's Hospital, University Medical Centre, Groningen, The Netherlands. Electronic address: r.m.f.berger@umcg.nl.
authors.forename: Rolf M F
authors.initials: RM
authors.lastname: Berger
authors.affiliation: Institute of Child Health, University College, London, UK.
authors.forename: Sheila G
authors.initials: SG
authors.lastname: Haworth
authors.affiliation: M3C-Hospital Necker Enfants Malades, Department of Paediatric Cardiology, Université Paris Descartes, Paris, France.
authors.forename: Damien
authors.initials: D
authors.lastname: Bonnet
authors.affiliation: Department of Paediatric Cardiology, Children's Hospital, Toulouse, France.
authors.forename: Yves
authors.initials: Y
authors.lastname: Dulac
authors.affiliation: La Timone Children's Hospital, Department of Paediatric Cardiology, Marseille, France.
authors.forename: Alain
authors.initials: A
authors.lastname: Fraisse
authors.affiliation: Institute of Cardiology, University of Bologna, Bologna, Italy.
authors.forename: Nazzareno
authors.initials: N
authors.lastname: Galiè
authors.affiliation: Children's Hospital Colorado, Department of Pediatric Cardiology, Denver, CO, USA.
authors.forename: D Dunbar
authors.initials: DD
authors.lastname: Ivy
authors.affiliation: Bicêtre Hospital, Department of Pneumology, Le Kremlin-Bicêtre, France.
authors.forename: Xavier
authors.initials: X
authors.lastname: Jaïs
authors.affiliation: Deutsches Herzzentrum Berlin, Berlin, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Miera
authors.affiliation: Columbia University, New York, NY, USA.
authors.forename: Erika B
authors.initials: EB
authors.lastname: Rosenzweig
authors.affiliation: Actelion Pharmaceuticals srl, Department of Biostatistics, Imperia, Italy.
authors.forename: Michela
authors.initials: M
authors.lastname: Efficace
authors.affiliation: Actelion Pharmaceuticals Ltd., Department of Clinical Science, Allschwil, Switzerland.
authors.forename: Andjela
authors.initials: A
authors.lastname: Kusic-Pajic
authors.affiliation: Children's Hospital, Paediatric Cardiology Unit, University of Geneva, Geneva, Switzerland.
authors.forename: Maurice
authors.initials: M
authors.lastname: Beghetti
mesh_terms: D000284:Administration, Oral; D000328:Adult; D054316:Biomarkers, Pharmacological / Q000378:metabolism; D000077300:Bosentan; D004305:Dose-Response Relationship, Drug; D004361:Drug Tolerance; D065128:Endothelin Receptor Antagonists / Q000008:administration & dosage / Q000493:pharmacokinetics; D065627:Familial Primary Pulmonary Hypertension / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality; D005260:Female; D005500:Follow-Up Studies; D014943:Global Health; D006801:Humans; D008297:Male; D013449:Sulfonamides / Q000008:administration & dosage* / Q000493:pharmacokinetics; D015996:Survival Rate / Q000639:trends; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D054316:Biomarkers, Pharmacological; D065128:Endothelin Receptor Antagonists; D013449:Sulfonamides; D000077300:Bosentan
keywords: Bosentan; Pediatric; Pulmonary arterial hypertension; Safety