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

Trials

Study Protocol

Philippe Corcia¹  Ammar Al-Chalabi²  Caroline Ingre³  Mirjam S. de Pagter⁴  Marleen Gijzen⁴  Kit C. B. Roes⁵  Orla Hardiman⁶  Matthew C. Kiernan⁷  Sean W. Willemse⁸  Leonard H. van den Berg⁸  Koen C. Demaegd⁸  Michael A. van Es⁸  Boudewijn T. H. M. Sleutjes⁸  Ruben P. A. van Eijk⁹  Philip Van Damme^1,10  Evy Reviers^1,11  Monica Povedano^1,12  Naomi R. Wray^1,13  Annemarie F. C. Janse^1,14  Roel G. Vink^1,14  Adriano Chiò^1,15 

[1] Centre Constitutif SLA, CHRU de Tours - Fédération des centres SLA Tours-Limoges, LitORALS, Tours, France;Department of Basic and Clinical Neuroscience, King’s College London, Maurice Wohl Clinical Neuroscience Institute, London, UK;Department of Neurology, King’s College Hospital, London, UK;Department of Clinical Neuroscience, Karolinska Institute, Stockholm, Sweden;Department of Genetics, UMC Utrecht, Utrecht, The Netherlands;Department of Health Evidence, Radboud UMC, Nijmegen, The Netherlands;Department of Neurology, National Neuroscience Centre, Beaumont Hospital, Dublin, Ireland;FutureNeuro SFI Research Centre, Royal College of Surgeons in Ireland, Dublin, Ireland;Department of Neurology, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia;Brain and Mind Centre, University of Sydney, Sydney, New South Wales, Australia;Department of Neurology, UMC Utrecht, Utrecht, The Netherlands;Department of Neurology, UMC Utrecht, Utrecht, The Netherlands;Biostatistics and Research Support, Julius Centre for Health Sciences and Primary Care, Utrecht University, Utrecht, Netherlands;Department of Neurology, University Hospitals Leuven, Leuven, Belgium;European Organization for Professionals and Patients with ALS (EUpALS) & ALS Liga Belgium, Leuven, Belgium;Functional Unit of Amyotrophic Lateral Sclerosis (UFELA), Service of Neurology, Bellvitge University Hospital, Hospitalet de Llobregat, Spain;Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia;TRICALS, Utrecht, The Netherlands;‘Rita Levi Montalcini’ Department of Neuroscience, University of Turin, Turin, Italy;Neurology, AOU Città della Salute e della Scienza Hospital of Turin, Turin, Italy;

关键词: Amyotrophic lateral sclerosis;    Lithium carbonate;    UNC13A;    SNP rs12608932;    Randomized controlled trial;   

DOI  :  10.1186/s13063-022-06906-5

 received in 2022-10-05, accepted in 2022-11-03,  发布年份 2022

来源: Springer

【 摘 要 】

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.Trial registrationEudraCT number 2020-000579-19. Registered on 29 March 2021.

【 授权许可】

CC BY   
© The Author(s) 2022

【 图 表 】

Fig. 1