Riluzole in patients with hereditary cerebellar ataxia – Authors' reply

Abstract

I read with interest Rhonda Voskuhl and colleagues’ report of a phase 2 trial of the combination of estriol and glatiramer acetate for women with relapsing-remitting multiple sclerosis, and Annette Langer-Gould’s Commentary on the Article. Ho wever, the authors did not seem to be aware Authors’ reply We thank Rick Brandsma and colleagues for their comments on our choice of a 1-point reduction in the Scale for the Assessment and Rating of Ataxia (SARA) as a cutoff for ataxia improvement. As discussed in the Article, this option was largely justifi ed by the yearly progression reported for the patients we included in the study (mainly with spinocerebellar ataxia types 1 and 2, or Friedreich’s ataxia). Long-term disease progression in spinocerebellar ataxia types 1, 2, 3, and 6 was reported in The Lancet Neurology shortly after the publication of our Article; the increases in SARA score per year were 2·11 for type 1, 1·49 for type 2, 1·56 for type 3, and 0·80 for type 6. These increases suggest that a one-point reduction in the SARA score after 1 year for patients with spinocerebellar ataxia type 1 represents a gain of three points with respect to the expected progression of disease. If we had analysed our data with a reduction cutoff of two points at 12 months, we would still have noted a signifi cant diff erence in favour of riluzole treatment (nine of 28 cases vs zero of 27 cases; p=0·001). We thank Jonas Alex Morales Saute and Laura Bannach Jardim for their comments about the possibility that riluzole works as a diseasemodifying therapy and on the design of randomised clinical trials in rare orphan diseases such as the hereditary ataxias. Overall, we endorse their suggestions, especially the usefulness of a delayed start design and the need for open-label phases in which all patients would receive the active drug for longer periods after a positive short-duration randomised trial. Because of regulatory and economic hurdles, open-label phases were diffi cult to plan in our populations of patients: only three patients remained on riluzole therapy from the fi rst trial (one died from multisystem atrophy, but two patients are doing well, without adverse eff ects or progression, after 5 years of follow-up). The future plan for the therapeutic development of riluzole should take into account three points: fi rst, that the drug seems to be effective in different forms of cerebellar ataxia; second, Alexandra Durr’s suggestion of aiming for a large sample size of patients with homogeneous forms of ataxias; and third, the usefulness of designing a randomised clinical trial with a long follow-up and planning an open-label phase for the placebo group.