Riluzole in cerebellar ataxia

Standard protocol approvals, registration, and patient consents.

This pilot trial was a randomized, double-blind comparison of riluzole (100 mg/day) and placebo, conducted between 2006 and 2008 at the Center for Experimental Neurological Therapies (Centers), S. Andrea Hospital, II Faculty of Medicine, “Sapienza” University of Rome, Italy. It is registered at the ClinicalTrial.gov Web site with the identifier NCT00202397. The trial was conducted according to Good Clinical Practice guidelines and the Declaration of Helsinki. The protocol was approved by the local ethics committee and each patient provided written informed consent. A local data and safety monitoring board oversaw the study conduct and possible safety issues.

Patient population.

The inclusion criteria were age between 18 and 80 years and chronic cerebellar ataxia (bilateral involvement of static and kinetic functions, as well as dysarthria and oculomotor dysfunction), irrespective of its etiology, disease duration, and disability status. The exclusion criteria were acute or noncerebellar ataxic syndromes, systemic illnesses (cardiac arrhythmias, hematologic diseases, and, in particular, hepatic disorders with serum values of alanine aminotransferase, aspartate aminotransferase, or bilirubin >1.5 times above normal limit), pregnancy (women of childbearing potential agreed to use contraception), or breastfeeding.

Protocol.

Eligible patients were evaluated for systemic illnesses and neurologic status. Cerebellar ataxia was assessed by means of the International Cooperative Ataxia Rating Scale (ICARS), a 100-point semiquantitative scale that provides a total score and subscores concerning static (0–34) and kinetic (0–52) cerebellar function, as well as dysarthria (0–8) and oculomotor dysfunction (0–6).¹² Increased or decreased scores indicate a worsening or improvement in cerebellar ataxia.

Patients who satisfied the inclusion criteria suspended any pharmacologic or physical therapy for ataxia for 2 weeks prior to enrolment and were randomly assigned, on a 1:1 ratio, to receive either riluzole (50 mg tablets twice daily) or placebo for 8 weeks. A list of randomization numbers and corresponding treatment numbers was computer-generated before the start of the study. This procedure was centrally (Centers) performed by personnel not involved in the study measurements. Eight-week supplies of the study drug were provided free of charge by Sanofi-Aventis (Milan, Italy) in prepackaged kits marked with the appropriate treatment number. The kits were kept and dispensed to eligible patients by the S. Andrea Hospital Pharmacy. The systemic and neurologic effects of riluzole were evaluated after 4 weeks of treatment and at the end of the trial (8 weeks). The following data were assessed at 3 time points (baseline and after 4 and 8 weeks of treatment): symptoms, physical and neurologic signs, ICARS score, electrocardiogram, and complete standard laboratory safety tests. At the same time points, any adverse event (any untoward medical occurrence, including an abnormal laboratory finding, regardless of its causal relationship to the study treatment) was recorded. The severity of the adverse events was graded as mild (minimal or no treatment required and no interference with the patient's daily activities); moderate (low level of inconvenience or concern; may require treatment and cause some interference with functioning); severe (patient's daily activities interrupted and systemic drug therapy or other treatment required; usually incapacitating); or life-threatening (immediate risk of death).

The treating investigator assessed the safety of riluzole and took all the medical decisions on the basis of the clinical and laboratory findings. The examining investigator assessed the treatment's efficacy and administered the ICARS; the examining investigator had access to the ICARS score but was unaware of the treatment groups until all the data had been collected and analyzed (data were first entered into a paper case report form, then into electronic databases for analysis). This prevented the blinding procedure from being broken as a result of observed efficacy, adverse events, or changes in laboratory tests.

Outcome measures.

The endpoints were as follows: differences between the riluzole and placebo groups in the proportion of patients who showed a decrease of at least 5 points in the ICARS total score after 4 and 8 weeks compared with the baseline score (a 5-point ICARS drop was considered clinically relevant on the basis of the reported dynamics of the ICARS at the time of the trial design; in particular, a study on progression of Friedreich ataxia reported a change of 0.3–3.0 points per year in the ICARS global score),¹³ differences in changes from the baseline to the posttreatment ICARS scores (total score and subscores at 8 weeks) between patients treated with riluzole and those receiving placebo, and differences between the 2 treatment arms in safety and tolerability (number, type, and severity of adverse events).

Statistical analyses.

Data were expressed as mean (SD) for continuous variables and as proportions for categorical variables. Comparisons between the riluzole and placebo groups were assessed using the t test for unpaired data and odds ratio (OR) with a relative confidence interval (CI) of 95% for categorical data. p Values <0.05 were considered significant. All the analyses were performed using the SPSS statistical package (version 15.0). The level of evidence was Class I, according to the classification scheme requirements of the American Academy of Neurology. Given the exploratory nature of this pilot trial and the fact that no clinical a priori hypothesis was available, no sample size analysis was performed. A sample size of 40 patients was selected on the basis of randomized therapeutic studies on cerebellar ataxia that had been conducted before the trial was designed.^14–18

Patient disposition and characteristics.

A total of 40 patients with cerebellar ataxia were enrolled at the Neurogenetic Unit of the S. Andrea Hospital, II Faculty of Medicine, “Sapienza” University of Rome: 20 were randomly assigned to receive riluzole and 20 to receive placebo (figure). The riluzole group consisted of 10 patients with hereditary ataxia (6 with SCA, 3 with FA, 1 with fragile X tremor/ataxia syndrome), 5 with sporadic ataxia (3 with probable multiple system atrophy type C [MSA-C],¹⁹ 1 with anti-GAD antibodies, 1 with anti-Yo antibodies), and 5 with ataxic syndromes of unknown origin. Placebo was administered to 7 patients with hereditary ataxia (2 with SCA, 5 with FA), 5 with sporadic ataxia (3 with probable MSA-C, 2 with multiple sclerosis), and 8 with ataxic syndromes of unknown origin (table 1). No significant difference was found between the 2 groups in the baseline characteristics (mean age, male/female ratio, disease duration, type of ataxic syndrome, and ICARS total scores and subscores) (table 2).

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Figure Flow diagram

Outcome measures.

Two subjects (one in the riluzole and the other in the placebo arm; table 1) withdrew their consent before receiving riluzole or placebo and were thus excluded from the ICARS score analysis. Table 3 shows the proportion of patients with a 5-point ICARS drop in the riluzole and placebo groups. The difference was already evident after 4 weeks (9/19 [47.4%] vs 1/19 [5.3%]; OR = 16.2; 95% CI 1.8–147.1) and became highly significant after 8 weeks (13/19 [68.4%] vs 1/19 [5.3%]; OR = 39.0; 95% CI 4.2–364.2). The absolute risk difference at 8 weeks was 63.2% (95% CI 33.5%–79.9%), with a number needed to treat of 1.58.

We also considered the mean change in the ICARS scores from baseline after 8 weeks of treatment as an endpoint based on continuous variables. We observed an improvement in the riluzole group, compared with the placebo group, in both the total score (−7.05 [4.96] vs 0.16 [2.65]; p < 0.001) and 3 subscores: −2.11 (2.75) vs 0.68 (1.94) for static function, −4.11 (2.96) vs 0.37 (2.0) for kinetic function, and −0.74 (0.81) vs 0.05 (0.4) for dysarthria; p < 0.001 for each. The oculomotor dysfunction subscore was the only score that did not contribute to the improvement observed in the riluzole group. The effects of riluzole, which are summarized in table 4, are due to the drop in the ICARS scores of 16 out of the 19 patients (table 1), who displayed a mean decrease of 8.6 points in the total score after 8 weeks (a 20% drop in the baseline score of 42.0, which implies a substantial clinical effect in such a short time window); by contrast, the 3 cases whose ICARS score dynamics were flat had higher (69/100 in patient 13 with MSA-C) and lower (21/100 in patient 28 with FA and 12/100 in patient 40 with SCA 2) baseline scores than the patients whose ICARS score dropped, which may point to a ceiling-floor effect.

With regard to safety (table 1), cerebellar ataxia deteriorated during the study period in only 2 patients, both of whom received placebo (ICARS total score increase after 8 weeks of 5 points in patient 11 and 7 points in patient 20). Four mild adverse events were observed during the trial: 2 patients treated with riluzole displayed an increase in alanine aminotransferase (<1.5 times above normal limit), while one patient in the riluzole group and another in the placebo group had transient vertigo.