S H Subramony M.D.

Professor of Neurology McKnight Brain Institute and University of Florida College of Medicine Gainesville, FL

NATIONAL ATAXIA REGISTRY AND NATURAL HISTORY STUDY

DISEASE REGISTRIES

    Special database containing information about persons with specific diseases Data is systematically collected and standardized Data entry  Patients  Physicians and health care providers  Researchers  EMR’s Usefulness  Promote research  Easier patient recruitment for studies and trials   Genotype/phenotype information Link repositories and other data resources  Therapy effectiveness  Knowledge dissemination

NATIONAL ATAXIA REGISTRY

    Database that collects basic information on patients with “degenerative” ataxia “Contact” registry: contact information and diagnosis “Curated”: we confirm the diagnosis as much as possible What type of patients can participate?

 Patients with ataxia not caused by an obvious and known disease like MS, strokes, tumors, infections etc  Patients with inherited and sporadic ataxias of all types  You don’t have to need a definite diagnosis of cause, only that you have ataxia

PURPOSE OF NAR

  Facilitate clinical research including drug trials in the field of ataxias Bring appropriate research groups in touch with the right group of patients  Caveats  Registry participation does not guarantee participation in a drug trial  You do not commit to participation in any trial or study

ELIGIBLE SUBJECTS

      Inherited ataxias  Dominant (SCA 1,2,3,5,6,7,8,10,12,13,14,17,DRPLA, other uncertain types)  Recessive (FA, AOA, POLG/MIRAS, AT, other types)  Mitochondrial, X-linked including FXTAS Sporadic ataxia (MSA, OPCA, idiopathic ataxia) Congenital ataxia Any other degenerative ataxias including gluten ataxia, GAD ataxia Subjects at risk for inherited ataxias(usually dominant) All inclusive

REGISTRY PROCESS

       Visit the web site (directly or through the NAF web site) www.nationalataxiaregistry.org

Click on new user log in on home page Enter essential contact information on page 2 Enter and confirm e mail address, choose a password and a security question on page 3 Print informed consent from page 4 Coordinator will contact you for telephonic consent before activating the account Once activated you will be able to log back and enter diagnostic details and basic information on “functional stage”

KEEP PASSWORD WRITTEN IN SECURE PLACE SEND COPY OF KEY DIAGNOSTIC DOCUMENT WITH CONSENT

NAR 2012

  1154 subjects have provided initial contact information 343 subjects have completed consent and submitted diagnostic information

NUMBER OF SUBJECTS WITH DIFFERENT DIAGNOSES

120 100 80 60 40 20 0

120% 100% 80% 60% 40% 20% 0% Gender ratios Male Female 120% 100% 80% 60% 40% 20% 0% Current age Less than 20 yrs 20-50 yrs More than 50 yrs

100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% Age at onset 80% 70% 60% 50% 40% 30% 20% 10% 0% Less than 20 yrs 20-50 yrs More than 50 yrs Not listed Functional stage 0 0.5

1 1.5

2 2.5

3 3.5

4 4.5

5

OBSTACLES AND COMING CHANGES

     Two step process, IRB mandated  Need for telephonic consent with each individual, return of singed paper consent Volunteer soft ware consultants E mail username Multiple diagnoses New ongoing initiatives  Back up compensated consultant  Negotiation with UF IRB for approving web based consent  Other necessary amendments to the protocol

THE CLINICAL RESEARCH CONSORTIUM FOR SPINOCEREBELLAR ATAXIA

  The CRC-SCA includes all the centers participating in the NIH funded natural history study of SCA 1,2,3 and 6 and all are members of the CAG The aim of this study is to collect information on US patients with SCA 1,2,3, and 6 regarding the natural progression of the disease, identify the best methods to assess disease progression and find any genetic markers that may influence the characteristics of the disease

PARTICIPATING SITES

NATURAL HISTORY DATABASE

       Natural History Database is important for understanding the disease progression, which will be critical in designing most clinical trials.

Only individuals with the diagnosis of SCA1, 2, 3 and 6 are included in the Natural History Database.

Visits occur every 6 month.

Each visit involves an interview, a physical examination, timed-measurement such as 25 meter (8 ft) walk and 9-hole peg board testing.

The first/baseline visit is used to consent the patient Blood is drawn once and tested for DNA modifiers at University of Utah lab.

A subset of patients will undergo home-based ataxia testing (gait monitor and computer on-line click test).

Ataxia patients SCA1,2,3&6 CRC-SCA Investigators National Ataxia Registry Blood samples RDCRN Website Clinical data collection NAF/UCLA Natural History Database DMCC Natural History Database Utah Genetic Modifier Database DMCC Genetic Modifier Database

NATURAL HISTORY STUDY

Female Male Total 300 200 100 0

Columns 1-6: American Indian, Asian, Pacific Islander, African American, White and other

AGE AT REGISTRATION AND DURATION OF DISEASE

30 20 10 0 80 70 60 50 40 SCA 1 SCA 2 SCA 3 SCA 6 25 20 15 10 5 0 SCA 1 SCA 2 SCA 3 SCA 6

140 120 100 80 60 40 20 0

NUMBER OF SUBECTS AND MEAN AGE AT ONSET

20 10 0 70 60 50 40 30 SCA 1 SCA 2 Number of subjects SCA 3 SCA 6 SCA 1 SCA 2 SCA 3 Mean age at onset SCA 6

MEAN SCORES AT BASELINE VISIT

80 60 40 20 0 SARA T25W 9HP SARA, walk test, peg board test 5 SCA 6 SCA 3 SCA 2 SCA 1 0 SCA 1 SCA 2 SCA 3 SCA 6 Series 1 Functional stage

SAMPLE SIZE ESTIMATES

 Number needed per arm to detect 50% reduction in disease progression in 1 year: 143 for 9HPT, 250 for SARA and 275 for SCAFI

Obs TYPE 1

One-arm efficacy

2

One-arm efficacy

3

One-arm efficacy

4

Two-arm efficacy

5

Two-arm efficacy

6

Two-arm efficacy

CHG18CON

3.3

3.3

3.3

3.3

3.3

3.3

CHG18LIT

2.31

1.98

1.65

2.31

1.98

1.65

P_REDUCTION Alpha Power

30 0.0492

0.806

NTotal

66 40 0.0492

50 0.0492

30 0.0492

40 0.0492

50 0.0492

0.806

0.805

0.803

0.800

0.805

38 25 256 144 94

SUMMARY

  NAR has continued to accrue subjects  Substantial number of subjects have no definite causative diagnosis  Issue of informed consent is a difficult one CRC-SCA  Has generated substantial natural history data  Sample size estimates still disappointingly large  International collaboration may be needed and is being initiated

AKNOWLEDGEMENTS

       Becca Beaulieu Tommy Zhu Sue Hagen Bill Hartnett Marty Ohmann Tee Ashizawa CRC- consortium investigators