A randomized, phase 2 clinical trial of lithium carbonate in Machado-Joseph disease

Authors

  • Jonas Alex Morales Saute MD, PhD,

    1. Postgraduate Program in Medical Sciences, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil
    2. Medical Genetics, Hospital de Clínicas de Porto Alegre (HCPA), Porto Alegre, Rio Grande do Sul, Brazil
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  • Raphael Machado de Castilhos MD, MsC,

    1. Medical Genetics, Hospital de Clínicas de Porto Alegre (HCPA), Porto Alegre, Rio Grande do Sul, Brazil
    2. Instituto Nacional de Genética Médica Populacional (INAGEMP), Porto Alegre, Rio Grande do Sul, Brazil
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  • Thais Lampert Monte MD, MsC,

    1. Postgraduate Program in Medical Sciences, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil
    2. Neurology Services, Porto Alegre, Rio Grande do Sul, Brazil
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  • Artur Francisco Schumacher-Schuh MD, MsC,

    1. Neurology Services, Porto Alegre, Rio Grande do Sul, Brazil
    2. Postgraduate Program in Genetics and Molecular Biology, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil
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  • Karina Carvalho Donis MD,

    1. Medical Genetics, Hospital de Clínicas de Porto Alegre (HCPA), Porto Alegre, Rio Grande do Sul, Brazil
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  • Rui D'Ávila MD,

    1. Medical Genetics, Hospital de Clínicas de Porto Alegre (HCPA), Porto Alegre, Rio Grande do Sul, Brazil
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  • Gabriele Nunes Souza,

    1. Medical Genetics, Hospital de Clínicas de Porto Alegre (HCPA), Porto Alegre, Rio Grande do Sul, Brazil
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  • Aline Dutra Russo,

    1. Postgraduate Program in Genetics and Molecular Biology, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil
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  • Gabriel Vasata Furtado MsC,

    1. Postgraduate Program in Genetics and Molecular Biology, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil
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  • Tailise Conte Gheno MsC,

    1. Postgraduate Program in Genetics and Molecular Biology, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil
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  • Diogo Onofre Gomes de Souza MD, PhD,

    1. Department of Biochemistry, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil
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  • Luis Valmor Cruz Portela PhD,

    1. Department of Biochemistry, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil
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  • Maria-Luiza Saraiva-Pereira PhD,

    1. Medical Genetics, Hospital de Clínicas de Porto Alegre (HCPA), Porto Alegre, Rio Grande do Sul, Brazil
    2. Instituto Nacional de Genética Médica Populacional (INAGEMP), Porto Alegre, Rio Grande do Sul, Brazil
    3. Postgraduate Program in Genetics and Molecular Biology, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil
    4. Department of Biochemistry, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil
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  • Suzi Alvez Camey PhD,

    1. Postgraduate Program in Epidemiology. Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil
    2. Department of Statistics, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil
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  • Vanessa Bielefeld Leotti Torman MsC,

    1. Department of Statistics, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil
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  • Carlos Roberto de Mello Rieder MD, PhD,

    1. Postgraduate Program in Medical Sciences, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil
    2. Neurology Services, Porto Alegre, Rio Grande do Sul, Brazil
    3. Neurology Department, Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA), Porto Alegre, Rio Grande do Sul, Brazil
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  • Laura Bannach Jardim MD, PhD

    Corresponding author
    1. Postgraduate Program in Medical Sciences, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil
    2. Medical Genetics, Hospital de Clínicas de Porto Alegre (HCPA), Porto Alegre, Rio Grande do Sul, Brazil
    3. Instituto Nacional de Genética Médica Populacional (INAGEMP), Porto Alegre, Rio Grande do Sul, Brazil
    4. Department of Internal Medicine, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil
    • Correspondence to: Dr. Laura Bannach Jardim, Medical Genetics Service, Hospital de Clínicas de Porto Alegre, Rua Ramiro Barcelos 2350, 90.035-903, Porto Alegre, Brazil; ljardim@hcpa.ufrgs.br

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  • Funding agencies: This academic clinical trial was supported by Fundação de Amparo à Pesquisa do Estado do Rio Grande do Sul (FAPERGS) (09/0078-5), Conselho Nacional de Desenvolvimento Cientifico e Tecnológico (CNPq) (478888/2010-4 and Instituto Nacional de Ciência e Tecnologia em Excitotoxicidade e Neuroproteção), and Fundo de Incentivo à Pesquisa e Eventos-Hospital de Clínicas de Porto Alegre (FIPE-HCPA) (09-418).

  • Relevant conflicts of interest/financial disclosures: The Brazilian pharmaceutical company Eurofarma donated lithium carbonate tablets only and provided no further support to the study.

  • Full financial disclosures and author roles may be found in the online version of this article.

ABSTRACT

Background

Because lithium exerts neuroprotective effects in preclinical models of polyglutamine disorders, our objective was to assess the safety and efficacy of lithium carbonate (0.5-0.8 milliequivalents per liter) in patients with Machado-Joseph disease (spinocerebellar ataxia type 3 [MJD/SCA3]).

Methods

For this phase 2, single-center, double-blind, parallel, placebo-controlled trial (ClinicalTrials.gov identifier NCT01096082), 62 patients who had MJD/SCA3 with a disease duration ≤10 years and an independent gait were randomly assigned (1:1) to receive either lithium or placebo.

Results

After 24 weeks, 169 adverse events were reported, including 50.3% in the lithium group (P = 1.00; primary safety outcome). Sixty patients (31 in the placebo group and 29 in the lithium group) were analyzed for efficacy (intention-to-treat analysis). Mean progression between groups did not differ according to scores on the Neurological Examination Score for the Assessment of Spinocerebellar Ataxia (NESSCA) after 48 weeks (−0.35; 95% confidence interval, −1.7 to 1.0; primary efficacy outcome). The lithium group exhibited minor progression on the PATA speech-rate (P = 0.002), the nondominant Click Test (P = 0.023), the Spinocerebellar Ataxia Functional Index (P = 0.003), and the Composite Cerebellar Functional Score (P = 0.029).

Conclusions

Lithium was safe and well tolerated, but it had no effect on progression when measured using the NESSCA in patients with MJD/SCA3. This slowdown in secondary outcomes deserves further clarification. © 2014 International Parkinson and Movement Disorder Society

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