Clinical trial NCT00202397: Effect of Riluzole as a Symptomatic Approach in Patients With Chronic Cerebellar Ataxia
Official title: Phase 2 Study of Riluzole Effects on Patients With Chronic Cerebellar Ataxia
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Hereditary Ataxia
Multiple Sclerosis
Cerebellar Ataxia
Keywords: cerebellar ataxia
deep cerebellar nuclei (DCN)
small-conductance calcium-activated potassium(SK)channels
riluzole
Sporadic ataxia
Multiple system atrophy type C
Lead sponsor: S. Andrea Hospital
Sponsor class: OTHER
First posted: 2005-09-20
Enrollment: 40
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Cerebellar disorders are often disabling and symptomatic therapies are limited to few options that are partially effective. It seems therefore appropriate to search for additional approaches.

Purkinje cells are the sole output of the cerebellar cortex: they project inhibitory signals to the deep cerebellar nuclei (DCN), which have a critical role in cerebellar function and motor performance. DCN neurons fire spontaneously in the absence of synaptic input from Purkinje neurons and modulation of the DCN response by Purkinje input is believed to be responsible for coordination of movement. Recent evidences support the notion that an increase in DCN excitability may be an important step in the development of cerebellar ataxia and point to the underlying molecular mechanisms: the inhibition of small-conductance calcium-activated potassium (SK) channels, that causes an increase of the firing frequency in DCN, correlates with cerebellar ataxia.

The rationale of the present project is that SK channel openers, such as riluzole, may have a beneficial effect on cerebellar ataxia.

The researchers propose to perform a pilot study investigating safety and efficacy of riluzole, an approved treatment for amyotrophic lateral sclerosis, as a symptomatic approach in patients with chronic cerebellar ataxia.

Detailed description: Forty patients with chronic cerebellar ataxia will be enrolled in a double-bind, randomized, placebo-controlled trial.

By central randomisation, patients will take 50 mg of riluzole or placebo twice daily for 8 weeks.

Electrocardiogram routine laboratory tests and pregnancy tests will be performed before drug administration, after 4 weeks of treatment and at the end of the study (after 8 weeks of treatment).

At the same time points the International Cooperative Ataxia Rating Scale (ICARS) for pharmacological assessment of the cerebellar syndrome will be administered to the two groups (riluzole and placebo) of patients. To guarantee the evaluation of the results in blind conditions, the neurologists who will evaluate the ICARS scores will be different from those who will deal with randomisation and follow-up of patients.

Eligibility criteria: Inclusion Criteria:

* Patients with cerebellar degeneration (heredoataxias, sporadic idiopathic ataxia, multiple system atrophy type C)
* Patients who meet McDonald criteria for probable or definite multiple sclerosis (MS) with chronic cerebellar ataxia (not acute cerebellar ataxia due to relapse)
* Age between 18 and 80 years

Exclusion Criteria:

* Ataxia due to other diseases
* Acute cerebellar ataxia
* Use of other drugs for chronic ataxia
* Serious concomitant illnesses (cardiac arrhythmias, haematological and hepatic diseases)
* Pregnancy or breast feeding

Primary outcomes:
measure: The International Cooperative Ataxia Rating Scale (ICARS) total scores and subscores (oculomotor, kinetic, postural, speech), comparing the three time points in the treated versus placebo group
timeFrame: pre-treatment, after 4 weeks of treatment and at the end of the study
Secondary outcomes:
Other outcomes:
Locations:
city: Rome
country: Italy
facility: S.Andrea Hospital - University of Rome "La Sapienza"
Study officials:
affiliation: S.Andrea Hospital, University of Rome "La Sapienza"
name: Marco Salvetti, Assoc. Prof
role: STUDY_DIRECTOR
affiliation: University of Roma La Sapienza
name: Giovanni Ristori, MD
role: PRINCIPAL_INVESTIGATOR
References:
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citation: Aizenman CD, Huang EJ, Linden DJ. Morphological correlates of intrinsic electrical excitability in neurons of the deep cerebellar nuclei. J Neurophysiol. 2003 Apr;89(4):1738-47. doi: 10.1152/jn.01043.2002.
citation: Raman IM, Gustafson AE, Padgett D. Ionic currents and spontaneous firing in neurons isolated from the cerebellar nuclei. J Neurosci. 2000 Dec 15;20(24):9004-16. doi: 10.1523/JNEUROSCI.20-24-09004.2000.
citation: Cao YJ, Dreixler JC, Couey JJ, Houamed KM. Modulation of recombinant and native neuronal SK channels by the neuroprotective drug riluzole. Eur J Pharmacol. 2002 Aug 2;449(1-2):47-54. doi: 10.1016/s0014-2999(02)01987-8.
citation: Doble A. The pharmacology and mechanism of action of riluzole. Neurology. 1996 Dec;47(6 Suppl 4):S233-41. doi: 10.1212/wnl.47.6_suppl_4.233s.
citation: Trouillas P, Takayanagi T, Hallett M, Currier RD, Subramony SH, Wessel K, Bryer A, Diener HC, Massaquoi S, Gomez CM, Coutinho P, Ben Hamida M, Campanella G, Filla A, Schut L, Timann D, Honnorat J, Nighoghossian N, Manyam B. International Cooperative Ataxia Rating Scale for pharmacological assessment of the cerebellar syndrome. The Ataxia Neuropharmacology Committee of the World Federation of Neurology. J Neurol Sci. 1997 Feb 12;145(2):205-11. doi: 10.1016/s0022-510x(96)00231-6.