Lithium carbonate in amyotrophic lateral sclerosis patients homozygous for the C-allele at SNP rs12608932 in UNC13A: protocol for a confirmatory, randomized, group-sequential, event-driven, double-blind, placebo-controlled trial

BackgroundGiven the large genetic heterogeneity in amyotrophic lateral sclerosis (ALS), it seems likely that genetic subgroups may benefit differently from treatment. An exploratory meta-analysis identified that patients homozygous for the C-allele at SNP rs12608932, a single nucleotide polymorphism...

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Autores: Willemse, Sean W., Roes, Kit C. B., Van Damme, Philip, Hardiman, Orla, Ingre, Caroline, Povedano Panades, Mónica, Wray, Naomi R., Gijzen, Marleen, De Pagter, Mirjam S., Demaegd, Koen C., Janse, Annemarie F. C., Vink, Roel G., Sleutjes, Boudewijn T. H. M., Chiò, Adriano, Corcia, Philippe, Reviers, Evy, Al-Chalabi, Ammar, Kiernan, Matthew C., Van Den Berg, Leonard H., Van Es, Michael A., Van Eijk, Ruben P. A.
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2022
País:España
Institución:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
Repositorio:Recercat. Dipósit de la Recerca de Catalunya
OAI Identifier:oai:recercat.cat:2445/192187
Acceso en línea:https://hdl.handle.net/2445/192187
Access Level:acceso abierto
Palabra clave:Esclerosi lateral amiotròfica
Assaigs clínics
Amyotrophic lateral sclerosis
Clinical trials
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spelling Lithium carbonate in amyotrophic lateral sclerosis patients homozygous for the C-allele at SNP rs12608932 in UNC13A: protocol for a confirmatory, randomized, group-sequential, event-driven, double-blind, placebo-controlled trialWillemse, Sean W.Roes, Kit C. B.Van Damme, PhilipHardiman, OrlaIngre, CarolinePovedano Panades, MónicaWray, Naomi R.Gijzen, MarleenDe Pagter, Mirjam S.Demaegd, Koen C.Janse, Annemarie F. C.Vink, Roel G.Sleutjes, Boudewijn T. H. M.Chiò, AdrianoCorcia, PhilippeReviers, EvyAl-Chalabi, AmmarKiernan, Matthew C.Van Den Berg, Leonard H.Van Es, Michael A.Van Eijk, Ruben P. A.Esclerosi lateral amiotròficaAssaigs clínicsAmyotrophic lateral sclerosisClinical trialsBackgroundGiven the large genetic heterogeneity in amyotrophic lateral sclerosis (ALS), it seems likely that genetic subgroups may benefit differently from treatment. An exploratory meta-analysis identified that patients homozygous for the C-allele at SNP rs12608932, a single nucleotide polymorphism in the gene UNC13A, had a statistically significant survival benefit when treated with lithium carbonate. We aim to confirm the efficacy of lithium carbonate on the time to death or respiratory insufficiency in patients with ALS homozygous for the C-allele at SNP rs12608932 in UNC13A. MethodsA randomized, group-sequential, event-driven, double-blind, placebo-controlled trial will be conducted in 15 sites across Europe and Australia. Patients will be genotyped for UNC13A; those homozygous for the C-allele at SNP rs12608932 will be eligible. Patients must have a diagnosis of ALS according to the revised El Escorial criteria, and a TRICALS risk-profile score between -6.0 and -2.0. An expected number of 1200 patients will be screened in order to enroll a target sample size of 171 patients. Patients will be randomly allocated in a 2:1 ratio to lithium carbonate or matching placebo, and treated for a maximum duration of 24 months. The primary endpoint is the time to death or respiratory insufficiency, whichever occurs first. Key secondary endpoints include functional decline, respiratory function, quality of life, tolerability, and safety. An interim analysis for futility and efficacy will be conducted after the occurrence of 41 events. DiscussionLithium carbonate has been proven to be safe and well-tolerated in patients with ALS. Given the favorable safety profile, the potential benefits are considered to outweigh the burden and risks associated with study participation. This study may provide conclusive evidence about the life-prolonging potential of lithium carbonate in a genetic ALS subgroup.Springer Science and Business Media LLC2023202320222023info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersion18 p.application/pdfhttps://hdl.handle.net/2445/192187Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))reponame:Recercat. Dipósit de la Recerca de Catalunyainstname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)InglésReproducció del document publicat a: https://doi.org/10.1186/s13063-022-06906-5Trials, 2022, vol. 23, num. 1, p. 978https://doi.org/10.1186/s13063-022-06906-5cc by (c) Willemse, Sean W. et al., 2022http://creativecommons.org/licenses/by/3.0/es/info:eu-repo/semantics/openAccessoai:recercat.cat:2445/1921872026-05-29T05:05:01Z
dc.title.none.fl_str_mv Lithium carbonate in amyotrophic lateral sclerosis patients homozygous for the C-allele at SNP rs12608932 in UNC13A: protocol for a confirmatory, randomized, group-sequential, event-driven, double-blind, placebo-controlled trial
title Lithium carbonate in amyotrophic lateral sclerosis patients homozygous for the C-allele at SNP rs12608932 in UNC13A: protocol for a confirmatory, randomized, group-sequential, event-driven, double-blind, placebo-controlled trial
spellingShingle Lithium carbonate in amyotrophic lateral sclerosis patients homozygous for the C-allele at SNP rs12608932 in UNC13A: protocol for a confirmatory, randomized, group-sequential, event-driven, double-blind, placebo-controlled trial
Willemse, Sean W.
Esclerosi lateral amiotròfica
Assaigs clínics
Amyotrophic lateral sclerosis
Clinical trials
title_short Lithium carbonate in amyotrophic lateral sclerosis patients homozygous for the C-allele at SNP rs12608932 in UNC13A: protocol for a confirmatory, randomized, group-sequential, event-driven, double-blind, placebo-controlled trial
title_full Lithium carbonate in amyotrophic lateral sclerosis patients homozygous for the C-allele at SNP rs12608932 in UNC13A: protocol for a confirmatory, randomized, group-sequential, event-driven, double-blind, placebo-controlled trial
title_fullStr Lithium carbonate in amyotrophic lateral sclerosis patients homozygous for the C-allele at SNP rs12608932 in UNC13A: protocol for a confirmatory, randomized, group-sequential, event-driven, double-blind, placebo-controlled trial
title_full_unstemmed Lithium carbonate in amyotrophic lateral sclerosis patients homozygous for the C-allele at SNP rs12608932 in UNC13A: protocol for a confirmatory, randomized, group-sequential, event-driven, double-blind, placebo-controlled trial
title_sort Lithium carbonate in amyotrophic lateral sclerosis patients homozygous for the C-allele at SNP rs12608932 in UNC13A: protocol for a confirmatory, randomized, group-sequential, event-driven, double-blind, placebo-controlled trial
dc.creator.none.fl_str_mv Willemse, Sean W.
Roes, Kit C. B.
Van Damme, Philip
Hardiman, Orla
Ingre, Caroline
Povedano Panades, Mónica
Wray, Naomi R.
Gijzen, Marleen
De Pagter, Mirjam S.
Demaegd, Koen C.
Janse, Annemarie F. C.
Vink, Roel G.
Sleutjes, Boudewijn T. H. M.
Chiò, Adriano
Corcia, Philippe
Reviers, Evy
Al-Chalabi, Ammar
Kiernan, Matthew C.
Van Den Berg, Leonard H.
Van Es, Michael A.
Van Eijk, Ruben P. A.
author Willemse, Sean W.
author_facet Willemse, Sean W.
Roes, Kit C. B.
Van Damme, Philip
Hardiman, Orla
Ingre, Caroline
Povedano Panades, Mónica
Wray, Naomi R.
Gijzen, Marleen
De Pagter, Mirjam S.
Demaegd, Koen C.
Janse, Annemarie F. C.
Vink, Roel G.
Sleutjes, Boudewijn T. H. M.
Chiò, Adriano
Corcia, Philippe
Reviers, Evy
Al-Chalabi, Ammar
Kiernan, Matthew C.
Van Den Berg, Leonard H.
Van Es, Michael A.
Van Eijk, Ruben P. A.
author_role author
author2 Roes, Kit C. B.
Van Damme, Philip
Hardiman, Orla
Ingre, Caroline
Povedano Panades, Mónica
Wray, Naomi R.
Gijzen, Marleen
De Pagter, Mirjam S.
Demaegd, Koen C.
Janse, Annemarie F. C.
Vink, Roel G.
Sleutjes, Boudewijn T. H. M.
Chiò, Adriano
Corcia, Philippe
Reviers, Evy
Al-Chalabi, Ammar
Kiernan, Matthew C.
Van Den Berg, Leonard H.
Van Es, Michael A.
Van Eijk, Ruben P. A.
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Esclerosi lateral amiotròfica
Assaigs clínics
Amyotrophic lateral sclerosis
Clinical trials
topic Esclerosi lateral amiotròfica
Assaigs clínics
Amyotrophic lateral sclerosis
Clinical trials
description BackgroundGiven the large genetic heterogeneity in amyotrophic lateral sclerosis (ALS), it seems likely that genetic subgroups may benefit differently from treatment. An exploratory meta-analysis identified that patients homozygous for the C-allele at SNP rs12608932, a single nucleotide polymorphism in the gene UNC13A, had a statistically significant survival benefit when treated with lithium carbonate. We aim to confirm the efficacy of lithium carbonate on the time to death or respiratory insufficiency in patients with ALS homozygous for the C-allele at SNP rs12608932 in UNC13A. MethodsA randomized, group-sequential, event-driven, double-blind, placebo-controlled trial will be conducted in 15 sites across Europe and Australia. Patients will be genotyped for UNC13A; those homozygous for the C-allele at SNP rs12608932 will be eligible. Patients must have a diagnosis of ALS according to the revised El Escorial criteria, and a TRICALS risk-profile score between -6.0 and -2.0. An expected number of 1200 patients will be screened in order to enroll a target sample size of 171 patients. Patients will be randomly allocated in a 2:1 ratio to lithium carbonate or matching placebo, and treated for a maximum duration of 24 months. The primary endpoint is the time to death or respiratory insufficiency, whichever occurs first. Key secondary endpoints include functional decline, respiratory function, quality of life, tolerability, and safety. An interim analysis for futility and efficacy will be conducted after the occurrence of 41 events. DiscussionLithium carbonate has been proven to be safe and well-tolerated in patients with ALS. Given the favorable safety profile, the potential benefits are considered to outweigh the burden and risks associated with study participation. This study may provide conclusive evidence about the life-prolonging potential of lithium carbonate in a genetic ALS subgroup.
publishDate 2022
dc.date.none.fl_str_mv 2022
2023
2023
2023
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://hdl.handle.net/2445/192187
url https://hdl.handle.net/2445/192187
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Reproducció del document publicat a: https://doi.org/10.1186/s13063-022-06906-5
Trials, 2022, vol. 23, num. 1, p. 978
https://doi.org/10.1186/s13063-022-06906-5
dc.rights.none.fl_str_mv cc by (c) Willemse, Sean W. et al., 2022
http://creativecommons.org/licenses/by/3.0/es/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv cc by (c) Willemse, Sean W. et al., 2022
http://creativecommons.org/licenses/by/3.0/es/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv 18 p.
application/pdf
dc.publisher.none.fl_str_mv Springer Science and Business Media LLC
publisher.none.fl_str_mv Springer Science and Business Media LLC
dc.source.none.fl_str_mv Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))
reponame:Recercat. Dipósit de la Recerca de Catalunya
instname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
instname_str Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
reponame_str Recercat. Dipósit de la Recerca de Catalunya
collection Recercat. Dipósit de la Recerca de Catalunya
repository.name.fl_str_mv
repository.mail.fl_str_mv
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