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; Kit C B Roes; Philip Van Damme; Orla Hardiman; Caroline Ingre; Monica Povedano; Naomi R Wray; Marleen Gijzen; Mirjam S de Pagter; Koen C Demaegd; Annemarie F C Janse; Roel G Vink; Boudewijn T H M Sleutjes; Adriano Chiò; Philippe Corcia; Evy Reviers; Ammar Al-Chalabi; Matthew C Kiernan; Leonard H van den Berg; Michael A van Es; Ruben P A van Eijk

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

Trials. 2022 Dec 5;23(1):978. doi: 10.1186/s13063-022-06906-5.

Authors

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. [email protected].
²⁰ Biostatistics and Research Support, Julius Centre for Health Sciences and Primary Care, Utrecht University, Utrecht, Netherlands. [email protected].

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.

Publication types

Clinical Trial Protocol

MeSH terms

Alleles
Amyotrophic Lateral Sclerosis* / diagnosis
Amyotrophic Lateral Sclerosis* / drug therapy
Amyotrophic Lateral Sclerosis* / genetics
Humans
Lithium Carbonate / adverse effects
Meta-Analysis as Topic
Polymorphism, Single Nucleotide
Quality of Life
Randomized Controlled Trials as Topic
Respiratory Insufficiency* / drug therapy

Substances

Lithium Carbonate

Abstract

Publication types

MeSH terms

Substances

Grants and funding