PMID- 26386921
OWN - NLM
STAT- MEDLINE
DCOM- 20160915
LR  - 20181202
IS  - 1874-1754 (Electronic)
IS  - 0167-5273 (Linking)
VI  - 202
DP  - 2016 Jan 1
TI  - FUTURE-2: Results from an open-label, long-term safety and tolerability extension 
      study using the pediatric FormUlation of bosenTan in pUlmonary arterial 
      hypeRtEnsion.
PG  - 52-8
LID - S0167-5273(15)30309-0 [pii]
LID - 10.1016/j.ijcard.2015.08.080 [doi]
AB  - 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.
CI  - Copyright (c) 2015. Published by Elsevier Ireland Ltd.
FAU - Berger, Rolf M F
AU  - Berger RM
AD  - 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.
FAU - Haworth, Sheila G
AU  - Haworth SG
AD  - Institute of Child Health, University College, London, UK.
FAU - Bonnet, Damien
AU  - Bonnet D
AD  - M3C-Hospital Necker Enfants Malades, Department of Paediatric Cardiology, 
      Universite Paris Descartes, Paris, France.
FAU - Dulac, Yves
AU  - Dulac Y
AD  - Department of Paediatric Cardiology, Children's Hospital, Toulouse, France.
FAU - Fraisse, Alain
AU  - Fraisse A
AD  - La Timone Children's Hospital, Department of Paediatric Cardiology, Marseille, 
      France.
FAU - Galie, Nazzareno
AU  - Galie N
AD  - Institute of Cardiology, University of Bologna, Bologna, Italy.
FAU - Ivy, D Dunbar
AU  - Ivy DD
AD  - Children's Hospital Colorado, Department of Pediatric Cardiology, Denver, CO, 
      USA.
FAU - Jais, Xavier
AU  - Jais X
AD  - Bicetre Hospital, Department of Pneumology, Le Kremlin-Bicetre, France.
FAU - Miera, Oliver
AU  - Miera O
AD  - Deutsches Herzzentrum Berlin, Berlin, Germany.
FAU - Rosenzweig, Erika B
AU  - Rosenzweig EB
AD  - Columbia University, New York, NY, USA.
FAU - Efficace, Michela
AU  - Efficace M
AD  - Actelion Pharmaceuticals srl, Department of Biostatistics, Imperia, Italy.
FAU - Kusic-Pajic, Andjela
AU  - Kusic-Pajic A
AD  - Actelion Pharmaceuticals Ltd., Department of Clinical Science, Allschwil, 
      Switzerland.
FAU - Beghetti, Maurice
AU  - Beghetti M
AD  - Children's Hospital, Paediatric Cardiology Unit, University of Geneva, Geneva, 
      Switzerland.
LA  - eng
PT  - Clinical Trial, Phase III
PT  - Journal Article
PT  - Multicenter Study
PT  - Randomized Controlled Trial
PT  - Research Support, Non-U.S. Gov't
DEP - 20150809
PL  - Netherlands
TA  - Int J Cardiol
JT  - International journal of cardiology
JID - 8200291
RN  - 0 (Biomarkers, Pharmacological)
RN  - 0 (Endothelin Receptor Antagonists)
RN  - 0 (Sulfonamides)
RN  - Q326023R30 (Bosentan)
SB  - IM
EIN - Int J Cardiol. 2016 Nov 15;223:1072-1073. PMID: 27623401
MH  - Administration, Oral
MH  - Adult
MH  - Biomarkers, Pharmacological/metabolism
MH  - Bosentan
MH  - Dose-Response Relationship, Drug
MH  - Drug Tolerance
MH  - Endothelin Receptor Antagonists/administration & dosage/pharmacokinetics
MH  - Familial Primary Pulmonary Hypertension/*drug therapy/metabolism/mortality
MH  - Female
MH  - Follow-Up Studies
MH  - Global Health
MH  - Humans
MH  - Male
MH  - Sulfonamides/*administration & dosage/pharmacokinetics
MH  - Survival Rate/trends
MH  - Time Factors
MH  - Treatment Outcome
OTO - NOTNLM
OT  - Bosentan
OT  - Pediatric
OT  - Pulmonary arterial hypertension
OT  - Safety
EDAT- 2015/09/21 06:00
MHDA- 2016/09/16 06:00
CRDT- 2015/09/21 06:00
PHST- 2015/02/19 00:00 [received]
PHST- 2015/06/15 00:00 [revised]
PHST- 2015/08/06 00:00 [accepted]
PHST- 2015/09/21 06:00 [entrez]
PHST- 2015/09/21 06:00 [pubmed]
PHST- 2016/09/16 06:00 [medline]
AID - S0167-5273(15)30309-0 [pii]
AID - 10.1016/j.ijcard.2015.08.080 [doi]
PST - ppublish
SO  - Int J Cardiol. 2016 Jan 1;202:52-8. doi: 10.1016/j.ijcard.2015.08.080. Epub 2015 
      Aug 9.