title: 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 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 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.
  
  
  CONCLUSIONS
  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.
  
  
  BACKGROUND
  clinicaltrials.gov identifier: NCT01096082.
authors: 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.
authors: Jonas Alex Morales
authors: JA
authors: Saute
authors: Post-Graduation Program in Medical Sciences, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil; Neurology Service, Hospital de Clínicas de Porto Alegre (HCPA), Porto Alegre, RS, Brazil.
authors: Carlos R M
authors: CR
authors: Rieder
authors: Post-Graduation Program in Genetics and Molecular Biology, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil; Instituto Nacional de Genética Médica Populacional (INAGEMP), Brazil.
authors: Raphael Machado
authors: RM
authors: Castilhos
authors: Post-Graduation Program in Medical Sciences, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil; Neurology Service, Hospital de Clínicas de Porto Alegre (HCPA), Porto Alegre, RS, Brazil.
authors: Thais Lampert
authors: TL
authors: Monte
authors: Neurology Service, Hospital de Clínicas de Porto Alegre (HCPA), Porto Alegre, RS, Brazil.
authors: Artur Francisco
authors: AF
authors: Schumacher-Schuh
authors: Medical Genetics Service, Hospital de Clínicas de Porto Alegre (HCPA), Porto Alegre, RS, Brazil.
authors: Karina Carvalho
authors: KC
authors: Donis
authors: Medical Genetics Service, Hospital de Clínicas de Porto Alegre (HCPA), Porto Alegre, RS, Brazil.
authors: Rui
authors: R
authors: D'Ávila
authors: 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.
authors: Gabriele Nunes
authors: GN
authors: Souza
authors: 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.
authors: Aline Dutra
authors: AD
authors: Russo
authors: Post-Graduation Program in Genetics and Molecular Biology, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil.
authors: Gabriel Vasata
authors: GV
authors: Furtado
authors: Post-Graduation Program in Genetics and Molecular Biology, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil.
authors: Tailise Conte
authors: TC
authors: Gheno
authors: Department of Biochemistry, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil; Instituto Nacional de Ciência e Tecnologia em Excitotoxicidade e Neuroproteção (INCTEN), Brazil.
authors: Diogo Onofre Gomes
authors: DO
authors: Souza
authors: Post-Graduation Program in Genetics and Molecular Biology, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil; Department of Biochemistry, 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.
authors: Maria Luiza
authors: ML
authors: Saraiva-Pereira
authors: Department of Biochemistry, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil; Instituto Nacional de Ciência e Tecnologia em Excitotoxicidade e Neuroproteção (INCTEN), Brazil.
authors: Luis Valmor Cruz
authors: LV
authors: Portela
authors: Post-Graduation Program in Epidemiology, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil; Department of Statistics, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil.
authors: Suzi
authors: S
authors: Camey
authors: Post-Graduation Program in Epidemiology, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil; Department of Statistics, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil.
authors: Vanessa Bielefeld Leotti
authors: VB
authors: Torman
authors: Post-Graduation Program in Medical Sciences, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil; Post-Graduation Program in Genetics and Molecular Biology, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil; Department of Internal Medicine, 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; Instituto Nacional de Genética Médica Populacional (INAGEMP), Brazil. Electronic address: ljardim@hcpa.edu.br.
authors: Laura Bannach
authors: LB
authors: Jardim
mesh_terms: D002986:Clinical Trials as Topic / Q000592:standards*; D017322:Clinical Trials, Phase II as Topic / Q000592:standards; D004311:Double-Blind Method; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D006801:Humans; D016651:Lithium Carbonate / Q000008:administration & dosage / Q000494:pharmacology*; D017827:Machado-Joseph Disease / Q000188:drug therapy*; D017063:Outcome Assessment, Health Care; D012107:Research Design / Q000592:standards*
chemical_list: D004791:Enzyme Inhibitors; D016651:Lithium Carbonate
keywords: Lithium; Machado Joseph disease; Polyglutamine disorders; Scales; Spinocerebellar ataxias; Treatment