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					CLINICAL TRIALS AND
NATURAL HISTORY STUDY
Vikram Shakkottai, MD, PhD
University 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      Giovanni Ristori   Riluzole reduces ICARS
                         Hospital                          score by > 5 points
                         (Italy)
Coenzyme     Phase I     UT Galveston   H Subramony        Completed/ Unpublished
Q10                      UF
Rifampicin   Phase III   Multi-center   Phillip Low        Not yet recruiting
(MSA)                                   David Robertson
                                        Sid Gilman
Lithium      Phase II    University     Alessandro Filla   Ongoing
(MSA)                    Federico II
                         (Italy)
   Friedreich Ataxia
Study
       20 studies
              Aim            Location      PI                 Results

Idebenone        Phase III   UCLA          Susan Perlman      No significant alteration in
                             CHOP          David Lynch        neurological function at 6-
                                                              months (Arch Neurol. 2010
                                                              67:941-7)
Deferiprone      Phase II    Belgium       Massimo Pandolfo   Completed/ Unpublished
                             France        Arnold Munnich
                             Italy         Franco Taroni
                             Spain         Javier Arpa
Epoetin alfa     Phase II    Federico II   Alessandro Filla   Ongoing
                             University
                             (Italy)
Carbamylated     Phase II    Austria       H. Lundbeck A/S    Ongoing
Erythropoietin               Germany       (company)
                             Italy
   Dominant ataxias

Study         Aim        Location    PI                  Results

Lithium       Phase I    NIH                             Completed/ Unpublished
(SCA1)
Riluzole      Phase      S. Andrea   Silvia Romano       Ongoing
              II/III     Hospital
Varenicline   Phase II   USF         Theresa Zesiewicz   Ongoing
(SCA3)                   UCLA
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



                                                               SARA
Type of SCA   N     Mean age ± SD   Age range   Age at onset
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

				
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