Lithium carbonate in amyotrophic lateral sclerosis: Lack of efficacy in a dose-finding trial
Open accessAbstract
BACKGROUND: A neuroprotective effect of lithium in amyotrophic lateral sclerosis (ALS) has been recently reported. We performed a multicenter trial with lithium carbonate to assess its tolerability, safety, and efficacy in patients with ALS, comparing 2 different target blood levels (0.4-0.8 mEq/L, therapeutic group [TG], vs 0.2-0.4 mEq/L, subtherapeutic group [STG]). METHODS: The study was a multicenter, single-blind, randomized, dose-finding trial, conducted from May 2008 to November 2009 in 21 Italian ALS centers. The trial was registered with the public database of the Italian Agency for Drugs (http://oss-sper-clin.agenziafarmaco.it/) (EudraCT number 2008-001094-15). RESULTS: As of October 2009, a total of 171 patients had been enrolled, 87 randomized to the TG and 84 to the STG. The interim data analysis, performed per protocol, showed that 117 patients (68.4%) discontinued the study because of death/tracheotomy/severe disability, adverse events (AEs)/serious AEs (SAEs), or lack of efficacy. The Data Monitoring Committee recommended stopping the trial on November 2, 2009. CONCLUSIONS: Lithium was not well-tolerated in this cohort of patients with ALS, even at subtherapeutic doses. The 2 doses were equivalent in terms of survival/severe disability and functional data. The relatively high frequency of AEs/SAEs and the reduced tolerability of lithium raised serious doubts about its safety in ALS. CLASSIFICATION OF EVIDENCE: The study provides Class II evidence that therapeutic (0.4-0.8 mEq/L) vs subtherapeutic (0.2-0.4 mEq/L) lithium carbonate did not differ in the primary outcome of efficacy (survival/loss of autonomy) in ALS. Both target levels led to dropouts in more than 30% of participants due to patient-perceived lack of efficacy and AEs.
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Despite early enthusiasm over lithium in patients and mouse models, five subsequent trials showed no clinical benefit in survival or neuromuscular outcomes for ALS patients.
“Despite early enthusiasm over lithium in patients and mouse models [505,506], five subsequent trials showed no clinical benefit in survival or neuromuscular outcomes for ALS patients [507–511].”
From Autophagy and ALS: mechanistic insights and therapeutic implications (2022) · cites this paper as [508]
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BackgroundLithium for treatment of amyotrophic lateral sclerosis: Much ado about nothing
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Amyotrofik Lateral Skleroz Patofizyolojisi ve Tedavi Yaklaşımları
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- Authors
- Chiò, A., Borghero, G., Calvo, A., Capasso, M., Caponnetto, C., Corbo, M., Giannini, F., Logroscino, G., Mandrioli, J., Marcello, N., Mazzini, L., Moglia, C., Monsurrò, M. R., Mora, G., Patti, F., Perini, M., Pietrini, V., Pisano, F., Pupillo, E., Sabatelli, M., Salvi, F., Silani, V., Simone, I. L., Sorarù, G., Tola, M. R., Volanti, P., & Beghi, E.
- Affiliations
- From the Dipartimento di Neuroscienze (A. Chio, A. Calvo, C.M.), AOU San Giovanni Battista & Università degli Studi di Torino, Torino; Clinica Neurologica (G.B.), AOU di Cagliari e Università degli Studi di Cagliari, Cagliari; Centro Regionale Malattie Neuromuscolari (M. Capasso), Università degli Studi “G. d'Annunzio” Chieti; Clinica Neurologica II (C.C.), Università degli Studi di Genova; NEuroMuscular Omnicentre (NEMO) (M. Corbo), Fondazione Serena, AO Niguarda Ca Granda, Milan;...
- University of Cagliari (IT)
- University of Siena (IT)
- University of Parma (IT)
- ORCID
- Venue
- Neurology
- Published
- 2010-08-17
- Volume
- 75
- Issue
- 7
- Pages
- 619-625
- ISSN
- 0028-3878 (ISSN-L)
- 1526-632X
- OpenAlex
- W1977669991
- Cited by
- 96
- References
- 21
- Citations by year
- 2024: 4 · 2023: 3 · 2022: 5 · 2021: 3 · 2020: 5 · 2019: 2 · 2018: 1 · 2017: 2 · 2016: 5 · 2015: 8 · 2014: 7 · 2013: 14 · 2012: 13
- FWCI
- 9.72
- Type
- journal article
- Language
- en
- Open access
- green
- hdl.handle.net
- Licence
- cc-by
- Locations
- Neurology (publishedVersion)
- PubMed (publishedVersion)
- IRIS UNIMORE (University of Modena and Reggio Emilia) (submittedVersion, cc-by)
- Institutional Research Information System University of Turin (University of Turin) (submittedVersion)
- CINECA IRIS Institutional Research Information System (University of Bari Aldo Moro) (submittedVersion)
- Use Siena air (University of Siena) (submittedVersion)
- Topics
- Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Amyloidosis: Diagnosis, Treatment, Outcomes
- Keywords
- lithium carbonate, amyotrophic lateral sclerosis, neuroprotection, lithium blood levels, tolerability, adverse events, survival, loss of autonomy, trial discontinuation
- MeSH terms
- Adolescent, Adult, Aged, Amyotrophic Lateral Sclerosis, Dose-Response Relationship, Drug, Enzyme Inhibitors, Female, Follow-Up Studies, Humans, Male, Middle Aged, Retrospective Studies, Time Factors, Single-Blind Method, Lithium Carbonate, Treatment Outcome, Kaplan-Meier Estimate, Young Adult
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