Rolf M F Berger1, Sheila G Haworth2, Damien Bonnet3, Yves Dulac4, Alain Fraisse5, Nazzareno Galiè6, D Dunbar Ivy7, Xavier Jaïs8, Oliver Miera9, Erika B Rosenzweig10, Michela Efficace11, Andjela Kusic-Pajic12, Maurice Beghetti13. 1. 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. 2. Institute of Child Health, University College, London, UK. 3. M3C-Hospital Necker Enfants Malades, Department of Paediatric Cardiology, Université Paris Descartes, Paris, France. 4. Department of Paediatric Cardiology, Children's Hospital, Toulouse, France. 5. La Timone Children's Hospital, Department of Paediatric Cardiology, Marseille, France. 6. Institute of Cardiology, University of Bologna, Bologna, Italy. 7. Children's Hospital Colorado, Department of Pediatric Cardiology, Denver, CO, USA. 8. Bicêtre Hospital, Department of Pneumology, Le Kremlin-Bicêtre, France. 9. Deutsches Herzzentrum Berlin, Berlin, Germany. 10. Columbia University, New York, NY, USA. 11. Actelion Pharmaceuticals srl, Department of Biostatistics, Imperia, Italy. 12. Actelion Pharmaceuticals Ltd., Department of Clinical Science, Allschwil, Switzerland. 13. Children's Hospital, Paediatric Cardiology Unit, University of Geneva, Geneva, Switzerland.
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.
RCT Entities:
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: Erika B Rosenzweig; Steven H Abman; Ian Adatia; Maurice Beghetti; Damien Bonnet; Sheila Haworth; D Dunbar Ivy; Rolf M F Berger Journal: Eur Respir J Date: 2019-01-24 Impact factor: 16.671
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