Bosentan as Adjunctive Therapy for Persistent Pulmonary Hypertension of the Newborn: Results of the Randomized Multicenter Placebo-Controlled Exploratory Trial - 23/09/16
, Jeffrey Fineman, MD 2, Andjela Kusic-Pajic, MD 3, Peter Cornelisse, MSc 4, Martine Gehin, PhD 5, Pegah Nowbakht, MSc, Pharm, PhD 3, Christine M. Pierce, MD 6, Maurice Beghetti, MD 7on behalf of the
FUTURE-4 study investigators*
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).
Study design |
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.
Conclusion |
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.
Trial registration |
ClinicalTrials.gov: NCT01389856
Le texte complet de cet article est disponible en PDF.Keywords : pediatrics, endothelin, hypertension, pulmonary, pharmacology
Abbreviations : AE, ALT, AST, AUC, CmaxC, DOL, ECMO, ET, FiO2, iNO, PAH, PK, PPHN, SAE, tmax, ULN
Plan
| Funded by Actelion Pharmaceuticals Ltd, which also provided the trial drug, financial support for costs of conducting the trial at each site, and performed site monitoring and data analysis. R.S. is an Associate Editor of The Journal of Pediatrics, and has served as a consultant to Ikaria, Inc. J.F. has served as an Advisory Board member and Steering Committee member for Actelion Pharmaceuticals Ltd. A.K.-P., P.N., and M.G. are employees of and hold stock options for Actelion Pharmaceuticals Ltd. P.C. provided statistical analysis funded by Actelion Pharmaceuticals Ltd. C.P. has received consultancy fees from Actelion Pharmaceuticals Ltd. M.B. has served as a consultant, steering committee member, and/or advisory board member for Actelion Pharmaceuticals Ltd., Bayer-Healthcare, Eli Lilly, GlaxoSmithKline, and Pfizer. |
Vol 177
P. 90 - octobre 2016 Retour au numéro
Article précédent
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