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Orodispersible minitablets of enalapril for use in children with heart failure (LENA): Rationale and protocol for a multicentre pharmacokinetic bridging study and follow-up safety study

INTRODUCTION: Treatment of paediatric heart failure is based on paradigms extensively tested in the adult population assuming similar underlying pathophysiological mechanisms. Angiotensin converting enzyme inhibitors (ACEI) like enalapril are one of the cornerstones of treatment and commonly used of...

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Autores principales: Bajcetic, Milica, de Wildt, Saskia N., Dalinghaus, Michiel, Breitkreutz, Jörg, Klingmann, Ingrid, Lagler, Florian B., Keatley-Clarke, Anne, Breur, Johannes MPJ., Male, Christoph, Jovanovic, Ida, Szatmári, Andras, Ablonczy, László, Burckhardt, Bjoern B., Cawello, Willi, Kleine, Karl, Obarcanin, Emina, Spatenkova, Lucie, Swoboda, Vanessa, van der Meulen, Marijke, Wagner, Peter, Walsh, Jennifer, Läer, Stephanie
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6586986/
https://www.ncbi.nlm.nih.gov/pubmed/31249901
http://dx.doi.org/10.1016/j.conctc.2019.100393
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author Bajcetic, Milica
de Wildt, Saskia N.
Dalinghaus, Michiel
Breitkreutz, Jörg
Klingmann, Ingrid
Lagler, Florian B.
Keatley-Clarke, Anne
Breur, Johannes MPJ.
Male, Christoph
Jovanovic, Ida
Szatmári, Andras
Ablonczy, László
Burckhardt, Bjoern B.
Cawello, Willi
Kleine, Karl
Obarcanin, Emina
Spatenkova, Lucie
Swoboda, Vanessa
van der Meulen, Marijke
Wagner, Peter
Walsh, Jennifer
Läer, Stephanie
author_facet Bajcetic, Milica
de Wildt, Saskia N.
Dalinghaus, Michiel
Breitkreutz, Jörg
Klingmann, Ingrid
Lagler, Florian B.
Keatley-Clarke, Anne
Breur, Johannes MPJ.
Male, Christoph
Jovanovic, Ida
Szatmári, Andras
Ablonczy, László
Burckhardt, Bjoern B.
Cawello, Willi
Kleine, Karl
Obarcanin, Emina
Spatenkova, Lucie
Swoboda, Vanessa
van der Meulen, Marijke
Wagner, Peter
Walsh, Jennifer
Läer, Stephanie
author_sort Bajcetic, Milica
collection PubMed
description INTRODUCTION: Treatment of paediatric heart failure is based on paradigms extensively tested in the adult population assuming similar underlying pathophysiological mechanisms. Angiotensin converting enzyme inhibitors (ACEI) like enalapril are one of the cornerstones of treatment and commonly used off-label in children. Dose recommendations have been extrapolated from adult experience, but the relationship between dose and pharmacokinetics (PK) in (young) children is insufficiently studied. Furthermore, appropriate paediatric formulations are lacking. Within the European collaborative project LENA, a novel formulation of enalapril orodispersible minitablets (ODMT), suitable for paediatric administration, will be tested in (young) children with heart failure due to either dilated cardiomyopathy or congenital heart disease in two pharmacokinetic bridging studies. Paediatric PK data of enalapril and its active metabolite enalaprilat will be obtained. In a follow-up study, the safety of enalapril ODMTs will be demonstrated in patients on long-term treatment of up to 10 months. Furthermore, additional information about pharmacodynamics (PD) and ODMT acceptability will be collected in all three studies. METHODS AND ANALYSIS: Phase II/III, open-label, multicentre study. Children with dilated cardiomyopathy (DCM) (n = 25; 1 month to less than 12 years) or congenital heart disease (CHD) (n = 60; 0 to less than 6 years) requiring or already on ACEI will be included. Exclusion criteria include severe heart failure precluding ACEI use, hypotension, renal impairment, hypersensitivity to ACEI. For those naïve to ACEI up-titration to an optimal dose will be performed, those already on ACEI will be switched to an expected equivalent dose of enalapril ODMT and optimised. In the first 8 weeks of treatment, a PK profile will be obtained at the first dose (ACEI naïve patients) or when an optimal dose is reached. Furthermore, population PK will be done with concentrations detected over the whole treatment period. PD and safety data will be obtained at least at 2-weeks intervals. Subsequently, an intended number of 85 patients will be followed-up up to 10 months to demonstrate long-term safety, based on the occurrence of (severe) adverse events and monitoring of vital signs and renal function. ETHICS AND DISSEMINATION: Clinical Trial Authorisation and a favourable ethics committee opinion were obtained in all five participating countries. Results of the studies will be submitted for publication in a peer-reviewed journal. TRIAL REGISTRATION NUMBERS: EudraCT 2015-002335-17, EudraCT 2015-002396-18, EudraCT 2015-002397-21.
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spelling pubmed-65869862019-06-27 Orodispersible minitablets of enalapril for use in children with heart failure (LENA): Rationale and protocol for a multicentre pharmacokinetic bridging study and follow-up safety study Bajcetic, Milica de Wildt, Saskia N. Dalinghaus, Michiel Breitkreutz, Jörg Klingmann, Ingrid Lagler, Florian B. Keatley-Clarke, Anne Breur, Johannes MPJ. Male, Christoph Jovanovic, Ida Szatmári, Andras Ablonczy, László Burckhardt, Bjoern B. Cawello, Willi Kleine, Karl Obarcanin, Emina Spatenkova, Lucie Swoboda, Vanessa van der Meulen, Marijke Wagner, Peter Walsh, Jennifer Läer, Stephanie Contemp Clin Trials Commun Article INTRODUCTION: Treatment of paediatric heart failure is based on paradigms extensively tested in the adult population assuming similar underlying pathophysiological mechanisms. Angiotensin converting enzyme inhibitors (ACEI) like enalapril are one of the cornerstones of treatment and commonly used off-label in children. Dose recommendations have been extrapolated from adult experience, but the relationship between dose and pharmacokinetics (PK) in (young) children is insufficiently studied. Furthermore, appropriate paediatric formulations are lacking. Within the European collaborative project LENA, a novel formulation of enalapril orodispersible minitablets (ODMT), suitable for paediatric administration, will be tested in (young) children with heart failure due to either dilated cardiomyopathy or congenital heart disease in two pharmacokinetic bridging studies. Paediatric PK data of enalapril and its active metabolite enalaprilat will be obtained. In a follow-up study, the safety of enalapril ODMTs will be demonstrated in patients on long-term treatment of up to 10 months. Furthermore, additional information about pharmacodynamics (PD) and ODMT acceptability will be collected in all three studies. METHODS AND ANALYSIS: Phase II/III, open-label, multicentre study. Children with dilated cardiomyopathy (DCM) (n = 25; 1 month to less than 12 years) or congenital heart disease (CHD) (n = 60; 0 to less than 6 years) requiring or already on ACEI will be included. Exclusion criteria include severe heart failure precluding ACEI use, hypotension, renal impairment, hypersensitivity to ACEI. For those naïve to ACEI up-titration to an optimal dose will be performed, those already on ACEI will be switched to an expected equivalent dose of enalapril ODMT and optimised. In the first 8 weeks of treatment, a PK profile will be obtained at the first dose (ACEI naïve patients) or when an optimal dose is reached. Furthermore, population PK will be done with concentrations detected over the whole treatment period. PD and safety data will be obtained at least at 2-weeks intervals. Subsequently, an intended number of 85 patients will be followed-up up to 10 months to demonstrate long-term safety, based on the occurrence of (severe) adverse events and monitoring of vital signs and renal function. ETHICS AND DISSEMINATION: Clinical Trial Authorisation and a favourable ethics committee opinion were obtained in all five participating countries. Results of the studies will be submitted for publication in a peer-reviewed journal. TRIAL REGISTRATION NUMBERS: EudraCT 2015-002335-17, EudraCT 2015-002396-18, EudraCT 2015-002397-21. Elsevier 2019-06-08 /pmc/articles/PMC6586986/ /pubmed/31249901 http://dx.doi.org/10.1016/j.conctc.2019.100393 Text en © 2019 Published by Elsevier Inc. http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Article
Bajcetic, Milica
de Wildt, Saskia N.
Dalinghaus, Michiel
Breitkreutz, Jörg
Klingmann, Ingrid
Lagler, Florian B.
Keatley-Clarke, Anne
Breur, Johannes MPJ.
Male, Christoph
Jovanovic, Ida
Szatmári, Andras
Ablonczy, László
Burckhardt, Bjoern B.
Cawello, Willi
Kleine, Karl
Obarcanin, Emina
Spatenkova, Lucie
Swoboda, Vanessa
van der Meulen, Marijke
Wagner, Peter
Walsh, Jennifer
Läer, Stephanie
Orodispersible minitablets of enalapril for use in children with heart failure (LENA): Rationale and protocol for a multicentre pharmacokinetic bridging study and follow-up safety study
title Orodispersible minitablets of enalapril for use in children with heart failure (LENA): Rationale and protocol for a multicentre pharmacokinetic bridging study and follow-up safety study
title_full Orodispersible minitablets of enalapril for use in children with heart failure (LENA): Rationale and protocol for a multicentre pharmacokinetic bridging study and follow-up safety study
title_fullStr Orodispersible minitablets of enalapril for use in children with heart failure (LENA): Rationale and protocol for a multicentre pharmacokinetic bridging study and follow-up safety study
title_full_unstemmed Orodispersible minitablets of enalapril for use in children with heart failure (LENA): Rationale and protocol for a multicentre pharmacokinetic bridging study and follow-up safety study
title_short Orodispersible minitablets of enalapril for use in children with heart failure (LENA): Rationale and protocol for a multicentre pharmacokinetic bridging study and follow-up safety study
title_sort orodispersible minitablets of enalapril for use in children with heart failure (lena): rationale and protocol for a multicentre pharmacokinetic bridging study and follow-up safety study
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6586986/
https://www.ncbi.nlm.nih.gov/pubmed/31249901
http://dx.doi.org/10.1016/j.conctc.2019.100393
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