TY - JOUR
T1 - Lithium carbonate in amyotrophic lateral sclerosis patients homozygous for the C-allele at SNP rs12608932 in UNC13A
T2 - protocol for a confirmatory, randomized, group-sequential, event-driven, double-blind, placebo-controlled trial
AU - Willemse, Sean W.
AU - Roes, Kit C.B.
AU - Van Damme, Philip
AU - Hardiman, Orla
AU - Ingre, Caroline
AU - Povedano, Monica
AU - Wray, Naomi R.
AU - Gijzen, Marleen
AU - de Pagter, Mirjam S.
AU - Demaegd, Koen C.
AU - Janse, Annemarie F.C.
AU - Vink, Roel G.
AU - Sleutjes, Boudewijn T.H.M.
AU - Chiò, Adriano
AU - Corcia, Philippe
AU - Reviers, Evy
AU - Al-Chalabi, Ammar
AU - Kiernan, Matthew C.
AU - van den Berg, Leonard H.
AU - van Es, Michael A.
AU - van Eijk, Ruben P.A.
N1 - Funding Information:
There are no acknowledgements.
Publisher Copyright:
© 2022, The Author(s).
PY - 2022/12
Y1 - 2022/12
N2 - Background: Given 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. Methods: A 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. Discussion: Lithium 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 registration: EudraCT number 2020-000579-19. Registered on 29 March 2021.
AB - Background: Given 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. Methods: A 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. Discussion: Lithium 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 registration: EudraCT number 2020-000579-19. Registered on 29 March 2021.
KW - Amyotrophic lateral sclerosis
KW - Lithium carbonate
KW - Randomized controlled trial
KW - SNP rs12608932
KW - UNC13A
UR - http://www.scopus.com/inward/record.url?scp=85143354745&partnerID=8YFLogxK
U2 - 10.1186/s13063-022-06906-5
DO - 10.1186/s13063-022-06906-5
M3 - Article
C2 - 36471413
AN - SCOPUS:85143354745
SN - 1745-6215
VL - 23
JO - Trials
JF - Trials
IS - 1
M1 - 978
ER -