Planning future clinical trials in Machado Joseph disease: Lessons from a phase 2 trial

Abstract Background In 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...

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Veröffentlicht in:Journal of the neurological sciences 2015-11, Vol.358 (1), p.72-76
Hauptverfasser: Saute, Jonas Alex Morales, Rieder, Carlos R.M, Castilhos, Raphael Machado, Monte, Thais Lampert, Schumacher-Schuh, Artur Francisco, Donis, Karina Carvalho, D'Ávila, Rui, Souza, Gabriele Nunes, Russo, Aline Dutra, Furtado, Gabriel Vasata, Gheno, Tailise Conte, Souza, Diogo Onofre Gomes, Saraiva-Pereira, Maria Luiza, Portela, Luis Valmor Cruz, Camey, Suzi, Torman, Vanessa Bielefeld Leotti, Jardim, Laura Bannach
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Sprache:eng
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Zusammenfassung:Abstract Background In 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. Methods Efficacy 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. Results 62 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 48 weeks 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. Conclusion Lithium 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 registration clinicaltrials.gov identifier: NCT01096082.
ISSN:0022-510X
1878-5883
DOI:10.1016/j.jns.2015.08.019