Elsevier

The Lancet Neurology

Volume 21, Issue 3, March 2022, Pages 225-233
The Lancet Neurology

Articles
Safety and efficacy of riluzole in spinocerebellar ataxia type 2 in France (ATRIL): a multicentre, randomised, double-blind, placebo-controlled trial

https://doi.org/10.1016/S1474-4422(21)00457-9Get rights and content

Summary

Background

Riluzole has been reported to be beneficial in patients with cerebellar ataxia; however, effectiveness in individual subtypes of disease is unclear due to heterogeneity in participants' causes and stages of disease. Our aim was to test riluzole in a single genetic disease, spinocerebellar ataxia type 2.

Methods

We did a randomised, double-blind, placebo-controlled, multicentre trial (the ATRIL study) at eight national reference centres for rare diseases in France that were part of the Neurogene National Reference Centre for Rare Diseases. Participants were patients with spinocerebellar ataxia type 2 with an age at disease onset of up to 50 years and a scale for the assessment and rating of ataxia (SARA) score of at least 5 and up to 26. Patients were randomly assigned centrally (1:1) to receive either riluzole 50 mg orally or placebo twice per day for 12 months. Two visits, at baseline and at 12 months, included clinical measures and 3T brain MRI. The primary endpoint was the proportion of patients whose SARA score improved by at least 1 point. Analyses were done in the intention-to-treat population (all participants who were randomly assigned) and were done with only the observed data (complete case analysis). This trial is registered at ClinicalTrials.gov (NCT03347344) and has been completed.

Findings

Between Jan 18, 2018, and June 14, 2019, we enrolled 45 patients. 22 patients were randomly assigned to receive riluzole and 23 to receive placebo. Median age was 42 years (IQR 36–57) in the riluzole group and 49 years (40–56) in the placebo group and 23 (51%) participants were women. All participants presented with moderate-stage disease, characterised by a median SARA score of 13·5 (IQR 9·5–16·5). The primary endpoint, SARA score improvement of at least 1 point after 12 months, was observed in seven patients (32%) in the treated group versus nine patients (39%) in the placebo group, with a mean difference of −10·3% (95% CI −37·4% to 19·2%; p=0·75). SARA score showed a median increase (ie, worsening) of 0·5 points (IQR −1·5 to 1·5) in the riluzole group versus 0·3 points (−1·0 to 2·5) in the placebo group (p=0·70). No serious adverse event was reported in the riluzole-treated group whereas four patients in placebo group had a serious adverse event (hepatic enzyme increase, fracture of external malleolus, rectorrhagia, and depression). The number of patients with adverse events was similar in both groups (riluzole 16 [73%] patients vs placebo 19 [83%] patients; p=0·49).

Interpretation

We were able to recruit 45 patients moderately affected by spinocerebellar ataxia type 2 for this trial. Riluzole did not improve clinical or radiological outcomes in these patients. However, our findings provide data on progression of spinocerebellar ataxia type 2 that might prove to be valuable for the design of other clinical trials.

Funding

French Ministry of Health.

Introduction

Spinocerebellar ataxias are a group of autosomal dominantly inherited progressive neurological diseases that are clinically and genetically heterogeneous,1 with 48 subtypes. A subgroup of seven subtypes is caused by pathological expansions of a polymorphic CAG repeat and most commonly affects adults in midlife. These seven subtypes are spinocerebellar ataxia type 1 (associated with pathogenic variants in ATXN1), spinocerebellar ataxia type 2 (ATXN2), spinocerebellar ataxia type 3 (ATXN3), spinocerebellar ataxia type 6 (CACNA1A), spinocerebellar ataxia type 7 (ATXN7), spinocerebellar ataxia type 17 (TBP), and dentatorubral pallidoluysian atrophy (ATN1). For these seven subtypes, mean age at onset and severity are closely and negatively correlated with the expanded CAG repeat size: the longer the pathological repeat, the earlier the age at onset. Paediatric and juvenile forms of the disease can also occur, especially for spinocerebellar ataxia type 2 and spinocerebellar ataxia type 7. The natural history of the disease for subtypes 1, 2, and 3 is well established, including the annual progression rate of the scale for the assessment and rating of ataxia (SARA) score.2 No curative treatment exists for these diseases, although antisense oligonucleotides have produced encouraging results in several mouse models.3, 4

Research in context

Evidence before this study

We searched PubMed from inception to Nov 23, 2021, for the following terms without language restriction: “cerebellar ataxia”, “spinocerebellar ataxias (SCAs)”, “riluzole”, and “clinical trials”. We found two clinical trials with evidence of clinical improvement after riluzole treatment. The first, a pilot study, included 40 patients affected by genetic and other forms of ataxias with a treatment duration of 8 weeks (NCT00202397), and the second trial included 60 patients with different causes of inherited cerebellar ataxias and disease stages treated for 12 months (NCT01104649) .

Added value of this study

The ATRIL study assessed the safety and efficacy of riluzole in patients with spinocerebellar ataxia type 2. We enrolled a homogeneous cohort of patients with spinocerebellar ataxia type 2 recruited by the French network of rare neurogenetic diseases. This choice for replication was justified by three facts: patients with spinocerebellar ataxia type 2 are among those included in previous ataxia studies; spinocerebellar ataxia type 2 can present an amyotrophic lateral sclerosis-like phenotype, and riluzole is widely used to treat amyotrophic lateral sclerosis; and intermediate ATXN2 alleles (27–32 CAG repeats) are a risk factor for amyotrophic lateral sclerosis. In addition, we used pretrial cerebral MRI scans (cerebellum and brainstem volumes), added a quantitative measure of ataxia (the composite cerebellar functional severity score), and carefully analysed motor neuron involvement and quality-of-life measures. The ATRIL results showed no clinical or radiological improvement after riluzole treatment in patients with spinocerebellar ataxia type 2. However, we were able to measure significant volume loss over 12 months for specific brain regions in these patients.

Implications of all the available evidence

We report the absence of improvement of clinical or radiological outcomes under riluzole treatment, despite satisfactory treatment compliance and absence of serious adverse events. However, our longitudinal imaging results might provide valuable biomarkers for upcoming clinical trials.

Several disease-modifying treatments have been tested in hereditary ataxias, such as valproic acid or lithium, without demonstrated efficacy to support their clinical use. However, the effect of riluzole has been reported as beneficial in two trials. The first trial, which was a pilot study with 40 patients affected by genetic and other forms of ataxia,5 showed a decrease of 5 points on the international cooperative ataxia rating scale score after 4 weeks and 8 weeks of treatment with riluzole (100 mg/day) compared with placebo. The second trial, which was a placebo-controlled, randomised, double-blind study included 40 patients with spinocerebellar ataxias (spinocerebellar ataxia types 1, 2, 6, 8, or 10) and 20 patients with Friedreich ataxia, treated for 12 months.6 That study confirmed the beneficial effect of riluzole with a 1 point decrease on the SARA score after 1 year. However, these two studies included patients with different forms of disease-causing variants and different disease stages, as well as presymptomatic carriers. This heterogeneity makes the generalisability of the positive effect unclear in individual disease subgroups. For this reason, we decided to do a trial in a population that was homogeneous in terms of genotype. Riluzole is widely used in amyotrophic lateral sclerosis with beneficial effects on survival,7 patients with spinocerebellar ataxia type 2 frequently present with involvement of motor neurons,8 and intermediate ATXN2 alleles (27–32 CAG repeat expansion) are a risk factor for amyotrophic lateral sclerosis,9 predisposing patients to more rapid progression.10 We therefore did a placebo-controlled trial with riluzole for 12 months in patients with spinocerebellar ataxia type 2, the same primary clinical endpoint as the previously reported 1 year trial.6

Section snippets

Study design and participants

For this multicentre, double-blind, randomised, placebo-controlled study (the ATRIL study), patients were recruited from eight national reference centres for rare diseases in France. Eligible patients were aged at least 18 years, with a genetically confirmed diagnosis of spinocerebellar ataxia type 2 (CAG repeat lengths ≥33 in the ATNX2 gene), a SARA score of at least 5 and up to 26, and an age at onset of up to 50 years. Patients received physiotherapy as standard care before and during the

Results

Between Jan 18, 2018, and June 14, 2019, we enrolled 45 patients with spinocerebellar ataxia type 2 recruited in eight national reference centres for rare disease: the Pitié-Salpêtrière University Hospital in Paris (n=26), the Purpan University Hospital in Toulouse (n=5), the Pellegrin University Hospital in Bordeaux (n=3), the Pierre Wertheimer Neurological Hospital in Bron (n=3), the University Hospital of Angers (n=2), the University Hospital of Lille (n=2), the La Timone Hospital in

Discussion

A regimen of 50 mg of riluzole twice per day for 12 months in adults with spinocerebellar ataxia type 2 did not result in a 1 point decrease of the SARA score at month 12 more often than did placebo. Therefore, we could not confirm a beneficial effect of riluzole, as has been previously reported.6

The mechanism of action of riluzole is not yet clear. This molecule has a pleiotropic effect on several ion channels and neurotransmitters. Riluzole seems to have a neuroprotective action enhancing the

Data sharing

Individual anonymised participant data and relevant clinical study documents (study protocol, statistical analysis plan, informed consent form, and clinical study report) will be available for qualified scientific and medical researchers as necessary for doing legitimate research. To request access to the data and submit a research proposal, please send a request to [email protected].

Declaration of interests

We declare no competing interests.

References (26)

  • DR Scoles et al.

    Antisense oligonucleotide therapy for spinocerebellar ataxia type 2

    Nature

    (2017)
  • G Ristori et al.

    Riluzole in cerebellar ataxia: a randomized, double-blind, placebo-controlled pilot trial

    Neurology

    (2010)
  • SM Pulst

    Degenerative ataxias, from genes to therapies: the 2015 Cotzias Lecture

    Neurology

    (2016)
  • Cited by (0)

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