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