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H Subramony Completed/ Unpublished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Completed/ Unpublished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Phase I NIH Completed/ Unpublished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