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CLINICAL TRIALS AND NATURAL HISTORY STUDY Vikram Shakkottai, MD, PhDUniversity of Michigan
Ataxia trials
82 listed studies on www.clinicaltrials.gov
Phase I Small group (20-100). Assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of a drug
Phase II Larger group (20-300). Designed to assess efficacy, as well as to continue Phase I safety assessments
Phase III Randomized controlled multicenter trials on larger groups (300–3,000). Aimed at being the definitive assessment of how effective the drug is, in comparison with current 'gold standard' treatment.
Sporadic ataxia
Study Aim Location PI Results
Riluzole Phase II
S. Andrea Hospital (Italy)
Giovanni Ristori
Riluzole reduces ICARS score by > 5 points
Coenzyme Q10
Phase I
UT GalvestonUF
H Subramony Completed/ Unpublished
Rifampicin(MSA)
Phase III
Multi-center
Phillip LowDavid RobertsonSid Gilman
Not yet recruiting
Lithium(MSA)
Phase II
University Federico II (Italy)
Alessandro Filla
Ongoing
Friedreich Ataxia
20 studiesStudy Aim Location
PI Results
Idebenone Phase III
UCLACHOP
Susan PerlmanDavid Lynch
No significant alteration in neurological function at 6-months (Arch Neurol. 2010 67:941-7)
Deferiprone Phase II
BelgiumFrance ItalySpain
Massimo PandolfoArnold MunnichFranco TaroniJavier Arpa
Completed/ Unpublished
Epoetin alfa Phase II
Federico II University(Italy)
Alessandro Filla Ongoing
Carbamylated Erythropoietin
Phase II
AustriaGermanyItaly
H. Lundbeck A/S (company)
Ongoing
Dominant ataxias
Study Aim Location
PI Results
Lithium(SCA1)
Phase I NIH Completed/ Unpublished
Riluzole Phase II/III
S. Andrea Hospital
Silvia Romano Ongoing
Varenicline(SCA3)
Phase II
USFUCLA
Theresa Zesiewicz
Ongoing
Riluzole in ataxia
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.
Outcome measure: 5 points in the International Cooperative Ataxia Rating Scale (ICARS).
The number of patients with a 5-point ICARS drop was significantly higher in the riluzole group than in the placebo group after 8 weeks (13/19 vs 1/19). The mean change in the riluzole group ICARS after treatment revealed a decrease (p < 0.001) in the total score -7.05 vs 0.16.
Sporadic, mild adverse events occurred.
Ristori et. Al., Neurology. 2010;74:839-45.
Riluzole in ataxia
Ristori et. Al., Neurology. 2010;74:839-45.
Natural History Study of and Genetic Modifiers in Spinocerebellar Ataxias
To establish a new multidisciplinary consortium that provides the infrastructure for future clinical trials to test safety and efficacy of therapeutic interventions for spinocerebellar ataxias.
Rare Disease = # of Patient <200,000 in US
Participating Sites of SCA-CRC
Original Sites ( ) University of Florida: Ashizawa, Subramony UCLA: Perlman University of Chicago: Gomez Emory University: Wilmot University of Michigan: Paulson University of Minnesota: Bushara University of South Florida: Zesiewicz University of Utah: Pulst
Voluntary Participants ( ) Johns Hopkins University: Ying Harvard University: Schmarmann UCSF: Kang Columbia University: Kuo/Fahn NIH, NINDS: Galpern, ORDR: Ferguson EuroSCA, Brazil, Japan
Patient Support Organizations National Ataxia Foundation: S. Hagan Sparkman Fund
Specific Aims of SCA-CRC
Aim 1. Establish the organizational foundations for the CRC-SCA
Aim 2. Recruit patients, obtain longitudinal clinical data for future clinical trials, and develop novel methods for clinical trials for a small sample size.
Aim 3. Initiate a pilot study to determine genetic modifiers of SCA 1, 2, 3 and 6
Aim 4. Establish a training program for cultivating physician-scientist investigators for clinical and translational research of SCA
Current enrollment
Type of SCA N Mean age ± SD Age range Age at onsetSARA
SCA1 30 48.68 ± 13.2 1-65 47.68 14.87
SCA2 31 50.06 ± 12.04 26-71 49.06 15.81
SCA3 64 51.6 ± 12.63 1-74 50.93 17.03
SCA6 45 62.9 ± 14.71 1-91 61.95 15.26
Total 170 53.8 ± 14.1 1-91 52.91 15.97
Future directions
Spin-off clinical trials:
Varenicline for SCA3 Lithium for SCA1 CoQ10 for SAOA Riluzole for SCAs
Acknowledgements
Tetsuo Ashizawa H. Subramony
National Ataxia Foundation NIH 5RC1NS068897 (PI Ashizawa) Training component of the NIH
5RC1NS068897