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March 09, 2010; 74 (10) Articles

Riluzole in cerebellar ataxia

A randomized, double-blind, placebo-controlled pilot trial

G. Ristori, S. Romano, A. Visconti, S. Cannoni, M. Spadaro, M. Frontali, F. E. Pontieri, N. Vanacore, M. Salvetti
First published March 8, 2010, DOI: https://doi.org/10.1212/WNL.0b013e3181d31e23
G. Ristori
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S. Romano
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A. Visconti
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S. Cannoni
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M. Spadaro
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M. Frontali
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F. E. Pontieri
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N. Vanacore
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M. Salvetti
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Citation
Riluzole in cerebellar ataxia
A randomized, double-blind, placebo-controlled pilot trial
G. Ristori, S. Romano, A. Visconti, S. Cannoni, M. Spadaro, M. Frontali, F. E. Pontieri, N. Vanacore, M. Salvetti
Neurology Mar 2010, 74 (10) 839-845; DOI: 10.1212/WNL.0b013e3181d31e23

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Abstract

Background: The pleiotropic effects of riluzole may antagonize common mechanisms underlying chronic cerebellar ataxia, a debilitating and untreatable consequence of various diseases.

Methods: In a randomized, double-blind, placebo-controlled pilot trial, 40 patients presenting with cerebellar ataxias of different etiologies were randomly assigned to riluzole (100 mg/day) or placebo for 8 weeks. The following outcome measures were compared: proportion of patients with a decrease of at least 5 points in the International Cooperative Ataxia Rating Scale (ICARS) total score after 4 and 8 weeks compared with the baseline score; mean changes from the baseline to posttreatment ICARS (total score and subscores at 8 weeks); and occurrence of adverse events.

Results: Riluzole and placebo groups did not differ in baseline characteristics. The number of patients with a 5-point ICARS drop was significantly higher in the riluzole group than in the placebo group after 4 weeks (9/19 vs 1/19; odds ratio [OR] = 16.2; 95% confidence interval [CI ] 1.8–147.1) and 8 weeks (13/19 vs 1/19; OR = 39.0; 95% CI 4.2–364.2). The mean change in the riluzole group ICARS after treatment revealed a decrease (p < 0.001) in the total score (−7.05 [4.96] vs 0.16 [2.65]) and major 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 [0.40] for dysarthria). Sporadic, mild adverse events occurred.

Conclusions: These findings indicate the potential effectiveness of riluzole as symptomatic therapy in diverse forms of cerebellar ataxia.

Classification of evidence: This study provides Class I evidence that riluzole reduces, by at least 5 points, the ICARS score in patients with a wide range of disorders that cause cerebellar ataxia (risk difference 63.2%, 95% CI 33.5%–79.9%).

Glossary

ALS=
amyotrophic lateral sclerosis;
CI=
confidence interval;
FA=
Friedreich ataxia;
ICARS=
International Cooperative Ataxia Rating Scale;
MSA-C=
multiple system atrophy type C;
OR=
odds ratio;
SARA=
Scale for the Assessment and Rating of Ataxia;
SCA=
spinocerebellar ataxia.

Cerebellar ataxia, which often affects children and young adults, may be severely disabling, and its impact on caregivers and economic burden heavy (the mean annual cost per patient with spinocerebellar ataxia [SCA] was recently estimated to be 18,776 euros).1 No therapies of proven efficacy for cerebellar ataxia exist. Previous attempts based on the positive modulation of serotoninergic transmission yielded conflicting results, while recent studies have indicated that serotonin plays a secondary role in cerebellar neurotransmission.2 New approaches (GABAergic agents in cortical cerebellar atrophy and erythropoietin in Friedreich ataxia [FA])3,4 are in preliminary phases. Selective iron chelation and idebenone (a drug used for cardiac hypertrophy in FA, with recent reports of a presumed dose-related response in cerebellar ataxia)5–7 are currently being investigated in FA. It seems reasonable to state that additional therapies are needed. Our approach is aimed at antagonizing pathogenic mechanisms that may be shared by the many causes of cerebellar ataxia. Indeed, hyperexcitability of the neurons in the deep cerebellar nuclei due to reduced inhibitory input from Purkinje cells8,9 is believed to underlie different forms of cerebellar ataxia. Riluzole (Rilutek; Aventis Pharma, Cedex, France) opens small-conductance calcium-activated potassium channels,10 which have recently been shown to exert a critical regulatory effect on the firing rate of neurons in deep cerebellar nuclei (openers of these channels may reduce neuronal hyperexcitability and, consequently, therapeutically benefit cerebellar ataxia).11 We therefore hypothesized the use of riluzole, an approved therapy for amyotrophic lateral sclerosis (ALS), as a treatment for cerebella ataxia of different etiologies.

METHODS

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

RESULTS

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

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Table 1 Characteristics of the patients, ICARS score dynamics, and adverse events

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Table 2 Baseline characteristics of the 2 treatment groups

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.

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Table 3 Number of patients with a 5-point ICARS drop in the 2 groups

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.

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Table 4 Changes from the baseline to the posttreatment ICARS score (total score and subscores at 8 weeks) in the 2 treatment groups

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.

DISCUSSION

Riluzole proved to be safe in this brief trial: no adverse events were observed if we exclude the slight increase in alanine aminotransferase (which is sometimes known to occur), nor did cerebellar ataxia deteriorate in any of the treated patients. This, combined with its known safety profile in ALS,20 may warrant the long-term use of riluzole in chronic cerebellar ataxia. Moreover, riluzole at a dose of 50 mg twice daily resulted in a systematic and progressive drop in the patients' ICARS scores, notwithstanding the limitations of a trial that was conceived to be exploratory, i.e., the heterogeneity of the diseases included, the brief observation period, and the limited number of patients. One potential source of errors in this trial is the limitation of the scale we used to longitudinally evaluate cerebellar ataxia. As the Scale for the Assessment and Rating of Ataxia (SARA)21 had not yet been fully assessed when this study was designed, we decided to use the ICARS, which unlike the SARA is not linear. Another major advantage of using the SARA, as opposed to the ICARS, is that patients would have been assessed in a shorter time period22; other potential pitfalls that may have affected this trial would not, however, have been excluded: 1) patients' fatigue and psychological state were not evaluated (incidentally, riluzole is being tested as possible therapy for mood and anxiety disorders)23; 2) patient assessment included inherently subjective components, though the ICARS was found to satisfy accepted criteria for interrater reliability, test-retest reliability, and internal consistency.24 We used ICARS scores to obtain endpoints based on continuous and categorical variables. The categorical variable (proportion of patients with a 5-point ICARS drop) was based on the evidence available when the trial was designed (see Methods). Recent works on ICARS dynamics25,26 as well as the disability status of our patients at baseline (a 5-point drop in an ICARS baseline score of 39 corresponds to a 13% reduction) lend support to our choice. However, any methodologic limitations are unlikely to detract from the overall strength of our result (after 8 weeks a response was 39 times more frequent in the riluzole group than in the placebo group, the absolute risk difference was 63.2%, with a number needed to treat of 1.58, although wide confidence intervals suggest unstable estimates), which points to the possibility of effectively treating different forms of cerebellar ataxia with one drug. Riluzole seems to affect the heterogeneous pathophysiologic mechanisms that characterize our patient population (patients with presumptive dentate nucleus and spinal pathology, patients with more selective cerebellar involvement, and patients with presumptive severe brainstem pathology). Our findings warrant further studies that may help to better understand the mechanisms of action of riluzole in cerebellar ataxia (even by disclosing effects that may be different from those of our working hypothesis) and to provide a template for other, more potent, antiataxic drugs.

This study obviously leaves some questions regarding treatment duration, initiation, and dosage unanswered. Good tolerability with 100 mg twice daily was recently reported in patients with probable MSA-P27 and Parkinson plus disorders,28 though without significant antiparkinsonian effects. In our study, 2 of the 3 treated MSA-C patients improved (table 1). Whether this indicates that riluzole may effectively treat cerebellar dysfunction in MSA requires further investigation. Indeed, research is warranted to identify the extent to which different forms of cerebellar ataxia respond to riluzole. This pilot trial suggests that riluzole may be effective as symptomatic therapy, i.e., that it may be useful as a general front-line therapy while the diagnostic, often time-consuming, process is in progress, or even as add-on therapy in the curable forms of cerebellar ataxia. Further studies, involving large numbers of patients, for longer periods of time and using multiple outcome measures (our finding of a mean 20% drop in the ICARS baseline score, which points to a strong clinical effect, yields incomplete information on daily living function and life quality of patients), are needed to confirm this possible indication in clinical practice. Whether riluzole may also be effective as disease-modifying therapy in the incurable forms of cerebellar ataxia is an issue that requires studies on specific forms of cerebellar ataxia, in which particular attention would need to be paid to the dosage and timing of administration of the therapy.

AUTHOR CONTRIBUTIONS

Drs. Ristori and Romano were the principal investigators. Drs. Ristori, Romano, Pontieri, and Salvetti conceived and designed the study. Drs. Visconti, Romano, and Ristori followed up the patients and acquired the data. All the authors were involved in the assessment and interpretation of the data. The statistical analyses were conducted by Drs. Cannoni and Vanacore. Drs. Ristori, Romano, Pontieri, Vanacore, and Salvetti wrote the manuscript.

ACKNOWLEDGMENT

The authors thank the patients, their families, the doctors who referred some of the patients (Drs. C. Fieschi, S. Andrea Hospital, II Faculty of Medicine, “Sapienza” University of Rome; C. Mariotti, Unit of Biochemistry and Genetics, IRCCS Instituto Neurologico C. Besta, Milan; C. Colosimo, University Department of Neurosciences, “Sapienza” University of Rome; A. Filla, Department of Neurological Sciences, “Federico II,” University of Naples; and A. Pizzuti, CSS-Mendel Institute, Rome), and Dr. R. Boccia of the S. Andrea Hospital Pharmacy.

DISCLOSURE

Dr. Ristori, Dr. Romano, Dr. Visconti, Dr. Cannoni, Dr. Spadaro, and Dr. Frontali report no disclosures. Dr. Pontieri has received speaker honoraria from Novartis, Lundbeck Inc., Boehringer Ingelheim, and GlaxoSmithKline; and has received research support from MIUR, Ateneo, and Facoltà. Dr. Vanacore reports no disclosures. Dr. Salvetti serves as a consultant to Merck Serono and has received research support from Bayer Schering Pharma.

Footnotes

  • Embedded Image

  • Embedded Image

  • *These authors contributed equally to this work.

    Study funding: Supported by intramural research funds of the Center for Experimental Neurological Therapies (which in turn is also funded, as a special project, by the Associazione Italiana Sclerosi Multipla [Italian MS Association]), S. Andrea Hospital, II Faculty of Medicine, “Sapienza” University of Rome. Riluzole was provided free of charge by Sanofi-Aventis (Milan, Italy), which was not involved in the trial design, data collection, analysis and interpretation, or writing of this report.

    Disclosure: Author disclosures are provided at the end of the article.

    Received July 24, 2009. Accepted in final form December 14, 2009.

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    OpenUrlAbstract/FREE Full Text

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