• Jonas Alex Morales Saute, Carlos R M Rieder, Raphael Machado Castilhos, Thais Lampert Monte, Artur Francisco Schumacher-Schuh, Karina Carvalho Donis, Rui D'Ávila, Gabriele Nunes Souza, Aline Dutra Russo, Gabriel Vasata Furtado, Tailise Conte Gheno, Diogo Onofre Gomes Souza, Maria Luiza Saraiva-Pereira, Luis Valmor Cruz Portela, Suzi Camey, Vanessa Bielefeld Leotti Torman, and Laura Bannach Jardim.
• Post-Graduation Program in Medical Sciences, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil; Medical Genetics Service, Hospital de Clínicas de Porto Alegre (HCPA), Porto Alegre, RS, Brazil.
• J. Neurol. Sci. 2015 Nov 15; 358 (1-2): 72-6.

BackgroundIn a recent phase 2 clinical trial in spinocerebellar ataxia type 3/Machado Joseph disease (SCA3/MJD), a neurogenetic disorder without specific therapy, benefits of lithium carbonate were found only on secondary efficacy outcomes, all related to ataxic features. In order to help designing future studies, we further analyzed the trial data searching for treatment response modifiers and metric properties of spinocerebellar ataxia (SCA) scales.MethodsEfficacy analysis was performed with the Neurological Examination Score for the Assessment of Spinocerebellar Ataxia (NESSCA) and the Scale for the Assessment and Rating of Ataxia (SARA) subscores and with the subgroup of patients with independent gait according to the 8-meter walking-time (8MW). Interactions of clinical/molecular findings with treatment response, minimally important differences (MIDs), and sample size estimations for NESSCA, SARA, Spinocerebellar Ataxia Functional Index (SCAFI) and Composite Cerebellar Functional Score (CCFS) were evaluated.Results62 SCA3/MJD patients had been randomly assigned (1:1) for the double-blind, placebo-controlled trial. While cerebellar NESSCA (range: 0-7 points) differed between groups 0.64 points (95% CI 0.23 to 1.05, p<0.001) over the whole 48weeks of study, favoring lithium, no effect was found on non-ataxia subscores. Among patients able to perform the 8MW on baseline, NESSCA (p=0.010) and SCAFI (p=0.015) differed between groups favoring lithium. Finally, estimated sample sizes for the scales were provided.ConclusionLithium efficacy on cerebellar NESSCA, and on SCAFI and CCFS in the primary analysis, together with the lack of effect on non-ataxia features suggests that lithium should be tested in phase 3 trials in SCA3/MJD and that ataxia scales should be preferred to multisystem neurological instruments as the primary outcome. The inclusion of early stage patients is advisable in future clinical trials in SCA3/MJD.Trial Registrationclinicaltrials.gov identifier: NCT01096082.Copyright © 2015 Elsevier B.V. All rights reserved.

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