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

Sean W Willemse¹, Kit C B Roes², Philip Van Damme³, Orla Hardiman^{4

5}, Caroline Ingre⁶, Monica Povedano⁷, Naomi R Wray⁸, Marleen Gijzen⁹, Mirjam S de Pagter⁹, Koen C Demaegd¹, Annemarie F C Janse¹⁰, Roel G Vink¹⁰, Boudewijn T H M Sleutjes¹, Adriano Chiò^{11

12}, Philippe Corcia¹³, Evy Reviers¹⁴, Ammar Al-Chalabi^{15

16}, Matthew C Kiernan^{17

18}, Leonard H van den Berg¹, Michael A van Es¹, Ruben P A van Eijk^{19

20}

Affiliations

¹ Department of Neurology, UMC Utrecht, Utrecht, The Netherlands.
² Department of Health Evidence, Radboud UMC, Nijmegen, The Netherlands.
³ Department of Neurology, University Hospitals Leuven, Leuven, Belgium.
⁴ Department of Neurology, National Neuroscience Centre, Beaumont Hospital, Dublin, Ireland.
⁵ FutureNeuro SFI Research Centre, Royal College of Surgeons in Ireland, Dublin, Ireland.
⁶ Department of Clinical Neuroscience, Karolinska Institute, Stockholm, Sweden.
⁷ Functional Unit of Amyotrophic Lateral Sclerosis (UFELA), Service of Neurology, Bellvitge University Hospital, Hospitalet de Llobregat, Spain.
⁸ Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia.
⁹ Department of Genetics, UMC Utrecht, Utrecht, The Netherlands.
¹⁰ TRICALS, Utrecht, The Netherlands.
¹¹ 'Rita Levi Montalcini' Department of Neuroscience, University of Turin, Turin, Italy.
¹² Neurology, AOU Città della Salute e della Scienza Hospital of Turin, Turin, Italy.
¹³ Centre Constitutif SLA, CHRU de Tours - Fédération des centres SLA Tours-Limoges, LitORALS, Tours, France.
¹⁴ European Organization for Professionals and Patients with ALS (EUpALS) & ALS Liga Belgium, Leuven, Belgium.
¹⁵ Department of Basic and Clinical Neuroscience, King's College London, Maurice Wohl Clinical Neuroscience Institute, London, UK.
¹⁶ Department of Neurology, King's College Hospital, London, UK.
¹⁷ Department of Neurology, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia.
¹⁸ Brain and Mind Centre, University of Sydney, Sydney, New South Wales, Australia.
¹⁹ Department of Neurology, UMC Utrecht, Utrecht, The Netherlands. R.P.A.vanEijk-2@umcutrecht.nl.
²⁰ Biostatistics and Research Support, Julius Centre for Health Sciences and Primary Care, Utrecht University, Utrecht, Netherlands. R.P.A.vanEijk-2@umcutrecht.nl.

PMID: 36471413
PMCID: PMC9721045
DOI: 10.1186/s13063-022-06906-5

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

Sean W Willemse et al. Trials. 2022.

. 2022 Dec 5;23(1):978.

doi: 10.1186/s13063-022-06906-5.

Authors

Affiliations

¹ Department of Neurology, UMC Utrecht, Utrecht, The Netherlands.
² Department of Health Evidence, Radboud UMC, Nijmegen, The Netherlands.
³ Department of Neurology, University Hospitals Leuven, Leuven, Belgium.
⁴ Department of Neurology, National Neuroscience Centre, Beaumont Hospital, Dublin, Ireland.
⁵ FutureNeuro SFI Research Centre, Royal College of Surgeons in Ireland, Dublin, Ireland.
⁶ Department of Clinical Neuroscience, Karolinska Institute, Stockholm, Sweden.
⁷ Functional Unit of Amyotrophic Lateral Sclerosis (UFELA), Service of Neurology, Bellvitge University Hospital, Hospitalet de Llobregat, Spain.
⁸ Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia.
⁹ Department of Genetics, UMC Utrecht, Utrecht, The Netherlands.
¹⁰ TRICALS, Utrecht, The Netherlands.
¹¹ 'Rita Levi Montalcini' Department of Neuroscience, University of Turin, Turin, Italy.
¹² Neurology, AOU Città della Salute e della Scienza Hospital of Turin, Turin, Italy.
¹³ Centre Constitutif SLA, CHRU de Tours - Fédération des centres SLA Tours-Limoges, LitORALS, Tours, France.
¹⁴ European Organization for Professionals and Patients with ALS (EUpALS) & ALS Liga Belgium, Leuven, Belgium.
¹⁵ Department of Basic and Clinical Neuroscience, King's College London, Maurice Wohl Clinical Neuroscience Institute, London, UK.
¹⁶ Department of Neurology, King's College Hospital, London, UK.
¹⁷ Department of Neurology, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia.
¹⁸ Brain and Mind Centre, University of Sydney, Sydney, New South Wales, Australia.
¹⁹ Department of Neurology, UMC Utrecht, Utrecht, The Netherlands. R.P.A.vanEijk-2@umcutrecht.nl.
²⁰ Biostatistics and Research Support, Julius Centre for Health Sciences and Primary Care, Utrecht University, Utrecht, Netherlands. R.P.A.vanEijk-2@umcutrecht.nl.

PMID: 36471413
PMCID: PMC9721045
DOI: 10.1186/s13063-022-06906-5

Abstract

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.

Keywords: Amyotrophic lateral sclerosis; Lithium carbonate; Randomized controlled trial; SNP rs12608932; UNC13A.

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Conflict of interest statement

SWW, KCBR, OH, CI, MP, NRW, MG, MdP, KCD, AFCJ, RGV, BTHMS, PC, ER, AAC, and RPAvE declare no competing interests. PVD has served in advisory boards for Biogen, CSL Behring, Alexion Pharmaceuticals, Ferrer, QurAlis, Cytokinetics, Argenx, UCB, Muna Therapeutics, Alector, Augustine Therapeutics, and VectorY (paid to institution). AC serves on scientific advisory boards for Mitsubishi Tanabe, Biogen, Roche, Denali Pharma, Cytokinetics, Lilly, and Amylyx Pharmaceuticals and has received a research grant from Biogen. MCK is funded by the National Health and Medical Research Council of Australia Program Grant (#1132524), Partnership Project (#1153439) and Practitioner Fellowship (1156093).LHvdB declares fees to his institution from Biogen, Wave, Amylyx, Ferrer, and Cytokinetics for being on a scientific advisory board; fees to his institution from Amylyx for a lecture; an unrestricted educational grant from Takeda; and is the Chair of ENCALS and TRICALS. MAvE has consulted for Biogen, and has received travel grants from Shire (formerly Baxalta) and serves as medical monitor for Ferrer in the ADORE trial (NCT05178810), other funding sources include the Netherlands Organization for Health Research and Development (Vidi scheme), The Thierry Latran Foundation, Motor Neurone Disease Association, FIGHT-MND and the ALS Foundation Netherlands. Several authors of this publication are member of the European Reference Network for Rare Neuromuscular Diseases (ERN-NMD).

References

1. van Es MA, Hardiman O, Chio A, Al-Chalabi A, Pasterkamp RJ, Veldink JH, et al. Amyotrophic lateral sclerosis. Lancet. 2017;390(10107):2084–2098. doi: 10.1016/S0140-6736(17)31287-4. - DOI - PubMed
1. Brown RH, Al-Chalabi A. Amyotrophic Lateral Sclerosis. N Engl J Med. 2017;377(2):162–172. doi: 10.1056/NEJMra1603471. - DOI - PubMed
1. Van Eijk RPA, Westeneng HJ, Nikolakopoulos S, Verhagen IE, Van Es MA, Eijkemans MJC, et al. Refining eligibility criteria for amyotrophic lateral sclerosis clinical trials. Neurology. 2019;92(5):E451–E460. doi: 10.1212/WNL.0000000000006855. - DOI - PMC - PubMed
1. Johnston CA, Stanton BR, Turner MR, Gray R, Blunt AHM, Butt D, et al. Amyotrophic lateral sclerosis in an urban setting: A population based study of inner city London. J Neurol. 2006;253(12):1642–1643. doi: 10.1007/s00415-006-0195-y. - DOI - PubMed
1. Lacomblez L, Bensimon G, Leigh PN, Guillet P, Meininger V. Dose-ranging study of riluzole in amyotrophic lateral sclerosis. Lancet. 1996;347(9013):1425–1431. doi: 10.1016/S0140-6736(96)91680-3. - DOI - PubMed

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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

Affiliations

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

Authors

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Abstract

Conflict of interest statement

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