Clinical Trial Readiness for SCA1 and SCA3

NCT03487367 | Unknown DMC

• 2 other identifiers: Pro00017836U01 - Ashizawa 2016
• Study Type: observational
• Target: 200
• Locations: 1 country
• Sites: 1

Brief Summary

The investigators plan to fill the gap between the current state of clinical trial readiness and the optimal one for SCA1 and SCA3, which are fatal rare diseases with no treatments. Through US-European collaborations, the investigators will establish the world's largest cohorts of subjects at the earliest disease stages, who will benefit most from treatments, validate an ability to detect disease onset and early progression by imaging markers, even prior to ataxia onset, and identify clinical trial designs that will generate the most conclusive results on treatment efficacy with small populations of patients.

Conditions

Spinocerebellar Ataxia Type 1; Spinocerebellar Ataxia 3

Keywords

spinocerebellar ataxia; ataxia; ataxias; SCA1; SCA3; spinocerebellar ataxia type 1; spinocerebellar ataxia type 3; READISCA; SCA; SCAs; clinical trial readiness

Outcome Measures

Primary Outcomes (13)

• Change in disease progression in SCA1 and SCA3 as determined by change in scale for the assessment and rating of ataxia (SARA) score over time.

  Scale for the assessment and rating of ataxia (SARA) was evaluated in two large validation trials performed by the EUROSCA clinical group and was found to be easy to use, reliable and valid. SARA has eight categories with accumulative score ranging from 0 (no ataxia) to 40 (most severe ataxia).

  Every 12 months for approximately 60 months

• Change in disease progression in SCA1 and SCA3 as determined by change in Composite Cerebellar Functional Severity Score (CCFS) total score over time.

  Composite Cerebellar Functional Severity Score (CCFS) is a validated quantitative scale used to evaluate cerebellar ataxia in adults and children. Total score calculation includes both the 9-hole pegboard test and the click test. A higher score indicates more severe cerebellar impairment.

  Every 12 months for approximately 60 months

• Change in disease progression in SCA1 and SCA3 as determined by change in timed 25 foot walk test (T25FW) over time.

  Timed 25 foot walk test (T25FW) is a quantitative mobility and leg function performance test based on a timed 25-walk. The T25FW has high inter-rater and test-retest reliability and shows evidence of good concurrent validity. Gait speed in general has been demonstrated to be a useful and reliable functional measure of walking ability.

  Every 12 months for approximately 60 months

• Change in disease progression in SCA1 and SCA3 as determined by change in Cerebellar Cognitive Affective Syndrome (CCAS) score over time.

  Cerebellar Cognitive Affective Syndrome Scale (CCAS Scale) is a battery of cognitive tasks used for determining the role of the cerebellum in the regulation of cognitive functions and present the procedure of neuropsychological diagnosis useful in indicating the specific cognitive and emotional problems in patients with cerebellar damage.

  Every 12 months for approximately 60 months

• Change in disease progression in SCA1 and SCA3 as determined by change in Inventory of Non-ataxia Symptoms (INAS) total count over time.

  Inventory of Non-ataxia Symptoms (INAS) is a scale utilized in recording the occurrence of accompanying non-ataxia symptoms. In the SARA validation trials, INAS was applied to a large number of SCA patients. Statistical evaluation showed good reliability.

  Every 12 months for approximately 60 months

• Change in disease progression in SCA1 and SCA3 as determined by change in Functional staging score over time.

  Functional staging is an instrument used to assess ambulatory capabilities of patients with cerebellar symptoms.

  Every 12 months for approximately 60 months

• Change in level of disease activity based on change in cerebellar and brainstem volumes since baseline imaging. (Aim 2)

  Change in level of disease activity based on change in cerebellar and brainstem volumes since baseline imaging.

  Every 12 months for approximately 36 months

• Change in level of disease activity based on grey matter (GM) and white matter (WM) loss metrics from voxel-based morphometric (VBM) since baseline imaging. (Aim 2)

  Change in level of disease activity as defined by change in grey matter volume and white matter volume from voxel-based morphometric data since baseline imaging.

  Every 12 months for approximately 36 months

• Change in level of disease activity based on change in metabolite concentrations since baseline imaging. (Aim 2)

  Change in level of disease activity on MR morphological, biochemical (MRS) and functional (resting-state fMRI) as defined by change in metabolite concentrations since baseline imaging.

  Every 12 months for approximately 36 months

• Change in level of disease activity based on change in fractional isotropy since baseline imaging. (Aim 2)

  Change in level of disease activity on MR morphological, biochemical (MRS) and functional (resting-state fMRI) as defined by change in mean diffusivity since baseline imaging.

  Every 12 months for approximately 36 months

• Change in level of disease activity based on change in mean diffusivity since baseline imaging. (Aim 2)

  Change in level of disease activity on MR morphological, biochemical (MRS) and functional (resting-state fMRI) as defined by change in mean diffusivity since baseline imaging.

  Every 12 months for approximately 36 months

• Change in level of disease activity based on change in radial and axial diffusivity since baseline imaging. (Aim 2)

  Change in level of disease activity on MR morphological, biochemical (MRS) and functional (resting-state fMRI) as defined by change in radial and axial diffusivity since baseline imaging.

  Every 12 months for approximately 36 months

• Change in level of disease activity based on change in degree of co-activation within resting state networks since baseline imaging. (Aim 2)

  Change in level of disease activity on MR morphological, biochemical (MRS) and functional (resting-state fMRI) as defined by change in degree of co-activation within resting state network since baseline imaging.

  Every 12 months for approximately 36 months

Secondary Outcomes (6)

• Change in disease progression in SCA1 and SCA3 as determined by change in Friedreich's Ataxia Activities of Daily Living (FAA-ADL) over time.

  Every 12 months for approximately 60 months

• Change in disease progression in SCA1 and SCA3 as determined by change in Fatigue Severity Scale (FSS) over time.

  Every 12 months for approximately 60 months

• Change in disease progression in SCA1 and SCA3 as determined by change in Euro Qol-5D (EQ-5D) over time.

  Every 12 months for approximately 60 months

• Change in disease progression in SCA1 and SCA3 as determined by change in Patient Health Questionnaire (PHQ-9) over time.

  Every 12 months for approximately 60 months

• Change in disease progression in SCA1 and SCA3 as determined by change in Patient Global Impression (PGI) over time.

  Every 12 months for approximately 60 months

Study Arms (4)

Early stage subjects

This cohort is defined by individuals with a total SARA score of less than or equal to 9.5

Premanifest mutation carriers

This cohort is defined by the presence of positive genetic diagnosis but no signs of ataxia and total SARA score of less than or equal to 2.5

50%-at-risk subjects

This cohort is defined by individuals who are at risk for SCA1 or SCA3 because they have a family member who tested positive for SCA1 or SCA3. Total SARA score is less than or equal to 2.5

Previously diagnosed early stage

This cohort is defined by individuals who were included in prior CRC-SCA, EUROSCA, ESMI or SPATAX studies who had a total SARA score of less than or equal to 10 in 2009-2012

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Probability Sample

Study Population

1. Early stage subjects refer to individuals who tested positive for the SCA1 or SCA3 gene mutation but show signs of ataxia 2. Premanifest mutation carriers refer to individuals who who tested positive for the SCA1 or SCA3 gene mutation but do not show signs of ataxia 3. 50%-at-Risk subjects refer to individuals who are at risk for developing SCA1 or SCA3 because they have an affected family member who tested positive for the gene mutation. 4. Previously diagnosed early stage patients refer to individuals who previously participated between 2009-2012 in the CRC-SCA, ESMI, EUROSCA, or SPATAX studies. At time of previous participation total SARA score must be less than or equal to 10.

You may qualify if:

• Signed informed consent (no study-related procedures may be performed before the subject has signed the consent form).
• Subjects of either sex aged 18 to 65 with presence of symptomatic ataxic disease or asymptomatic mutation carrier or
• Subjects with definite molecular diagnosis of SCA1 or SCA3 or another affected family member
• Subjects of any age with previous diagnosis of Early stage SCA1 and SCA3
• Subjects capable of understanding and complying with protocol requirements
• No changes in physical/occupational therapy status within two months prior to enrollment

You may not qualify if:

• Subjects currently receiving, or having received within 2 months prior to enrollment into this study, any investigational drug.
• Subjects who do not wish to or cannot comply with study procedures.
• Genotype consistent with other inherited ataxias
• Changes in coordinative physical and occupational therapy for ataxia 2 months prior to study participation
• Concomitant disorder(s) or condition(s) that affects assessment of ataxia or severity of ataxia during this study

Sponsors & Collaborators

• The Methodist Hospital Research Institute: lead
• University of Michigan: collaborator
• University of Minnesota: collaborator
• University of Utah: collaborator
• University of California, Los Angeles: collaborator
• University of Chicago: collaborator
• University of South Florida: collaborator
• Harvard University: collaborator
• Johns Hopkins University: collaborator
• University of Florida: collaborator
• Columbia University: collaborator
• Emory University: collaborator
• University of California, San Francisco: collaborator
• University of Alabama at Birmingham: collaborator
• University of Colorado, Denver: collaborator
• University of Rochester: collaborator
• Stanford University: collaborator
• Northwestern University: collaborator
• German Center for Neurodegenerative Diseases (DZNE): collaborator
• Institut de Recherche sur la Moelle épinière et l'Encéphale: collaborator
• University of Pennsylvania: collaborator
• Ohio State University: collaborator
• University of Iowa: collaborator

Study Sites (1)

Houston Methodist Hospital

Houston, Texas, 77030, United States

Location

Related Publications (6)

• Paulson HL, Shakkottai VG, Clark HB, Orr HT. Polyglutamine spinocerebellar ataxias - from genes to potential treatments. Nat Rev Neurosci. 2017 Oct;18(10):613-626. doi: 10.1038/nrn.2017.92. Epub 2017 Aug 17.

  PMID: 28855740 BACKGROUND

• Ashizawa T, Figueroa KP, Perlman SL, Gomez CM, Wilmot GR, Schmahmann JD, Ying SH, Zesiewicz TA, Paulson HL, Shakkottai VG, Bushara KO, Kuo SH, Geschwind MD, Xia G, Mazzoni P, Krischer JP, Cuthbertson D, Holbert AR, Ferguson JH, Pulst SM, Subramony SH. Clinical characteristics of patients with spinocerebellar ataxias 1, 2, 3 and 6 in the US; a prospective observational study. Orphanet J Rare Dis. 2013 Nov 13;8:177. doi: 10.1186/1750-1172-8-177.

  PMID: 24225362 BACKGROUND

• Oz G, Hutter D, Tkac I, Clark HB, Gross MD, Jiang H, Eberly LE, Bushara KO, Gomez CM. Neurochemical alterations in spinocerebellar ataxia type 1 and their correlations with clinical status. Mov Disord. 2010 Jul 15;25(9):1253-61. doi: 10.1002/mds.23067.

  PMID: 20310029 BACKGROUND

• Tezenas du Montcel S, Durr A, Rakowicz M, Nanetti L, Charles P, Sulek A, Mariotti C, Rola R, Schols L, Bauer P, Dufaure-Gare I, Jacobi H, Forlani S, Schmitz-Hubsch T, Filla A, Timmann D, van de Warrenburg BP, Marelli C, Kang JS, Giunti P, Cook A, Baliko L, Melegh B, Boesch S, Szymanski S, Berciano J, Infante J, Buerk K, Masciullo M, Di Fabio R, Depondt C, Ratka S, Stevanin G, Klockgether T, Brice A, Golmard JL. Prediction of the age at onset in spinocerebellar ataxia type 1, 2, 3 and 6. J Med Genet. 2014 Jul;51(7):479-86. doi: 10.1136/jmedgenet-2013-102200. Epub 2014 Apr 29.

  PMID: 24780882 BACKGROUND

• Arpin DJ, Subramony SH; READISCA Consortium; Vaillancourt DE, Ashizawa T, Durr A, Mareci T, Klockgether T, Faber J, Paulson HL, Oz G, Burns MR. Fixel-Based Analysis of Diffusion Imaging as a Quantitative Marker of Disease State in Spinocerebellar Ataxia. Ann Clin Transl Neurol. 2025 Sep;12(9):1846-1857. doi: 10.1002/acn3.70116. Epub 2025 Jul 15.

  PMID: 40665587 DERIVED

• Tezenas du Montcel S, Petit E, Olubajo T, Faber J, Lallemant-Dudek P, Bushara K, Perlman S, Subramony SH, Morgan D, Jackman B, Figueroa KP, Pulst SM, Fauret-Amsellem AL, Dufke C, Paulson HL, Oz G, Klockgether T, Durr A, Ashizawa T; READISCA Consortium Collaborators. Baseline Clinical and Blood Biomarkers in Patients With Preataxic and Early-Stage Disease Spinocerebellar Ataxia 1 and 3. Neurology. 2023 Apr 25;100(17):e1836-e1848. doi: 10.1212/WNL.0000000000207088. Epub 2023 Feb 16.

  PMID: 36797067 DERIVED

Biospecimen

Retention: SAMPLES WITH DNA

Whole blood collected for DNA analysis

MeSH Terms

Conditions

Spinocerebellar Ataxias; Machado-Joseph Disease; Ataxia

Condition Hierarchy (Ancestors)

Cerebellar Ataxia; Cerebellar Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Spinocerebellar Degenerations; Spinal Cord Diseases; Heredodegenerative Disorders, Nervous System; Neurodegenerative Diseases; Dyskinesias; Neurologic Manifestations; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Study Officials

• Tetsuo Ashizawa, MD

  The Methodist Hospital Research Institute

  STUDY CHAIR

• Hank Paulson, MD, PhD

  University of Michigan

  STUDY DIRECTOR

• Gulin Oz, MD

  University of Minnesota

  STUDY DIRECTOR

• Thomas Klockgether, MD

  University Hospital Bonn - DZNE

  STUDY DIRECTOR

• Alexandra Durr, MD, PhD

  Hôpital Universitaire Pitié-Salpêtrière - ICM/SPATAX

  STUDY DIRECTOR

• Sheng Han Kuo, MD

  Columbia University

  PRINCIPAL INVESTIGATOR

• George Wilmot, MD, PhD

  Emory University

  PRINCIPAL INVESTIGATOR

• Liana Rosenthal, MD

  Johns Hopkins University

  PRINCIPAL INVESTIGATOR

• Chiadikaobi Onyike, MD

  Johns Hopkins University

  PRINCIPAL INVESTIGATOR

• Puneet Opal, MD, PhD

  Northwestern University

  PRINCIPAL INVESTIGATOR

• Sharon Sha

  Stanford University

  PRINCIPAL INVESTIGATOR

• Talene Yacoubian, MD, PhD

  University of Alabama at Birmingham

  PRINCIPAL INVESTIGATOR

• Susan Perlman, MD

  University of California, Los Angeles

  PRINCIPAL INVESTIGATOR

• Michael Geschwind, MD,PhD

  University of California, San Francisco

  PRINCIPAL INVESTIGATOR

• Trevor Hawkins, MD

  University of Colorado, Denver

  PRINCIPAL INVESTIGATOR

• Christopher Gomez, MD, PhD

  University of Chicago

  PRINCIPAL INVESTIGATOR

• SH Subramony, MD

  University of Florida

  PRINCIPAL INVESTIGATOR

• Vikram Shakkottai, MD, PhD

  University of Texas

  PRINCIPAL INVESTIGATOR

• Khalaf Bushara, MD

  University of Minnesota

  PRINCIPAL INVESTIGATOR

• Theresa Zesiewicz, MD

  University of South Florida

  PRINCIPAL INVESTIGATOR

• Stefan Pulst, MD, PhD

  University of Utah

  PRINCIPAL INVESTIGATOR

• Jeremy Schmahmann, MD, PhD

  Harvard University

  PRINCIPAL INVESTIGATOR

• Peter Barker, MD

  Johns Hopkins University

  PRINCIPAL INVESTIGATOR

• Haris I Sair, MD

  Johns Hopkins University

  PRINCIPAL INVESTIGATOR

• Veronica Santini, MD

  Stanford University

  PRINCIPAL INVESTIGATOR

• Eva-Maria Ratai, MD

  Harvard University

  PRINCIPAL INVESTIGATOR

• Thomas Mareci, MD

  Universtiy of Florida, Gainesville

  PRINCIPAL INVESTIGATOR

• Laura Scorr, MD

  Emory University

  PRINCIPAL INVESTIGATOR

• Peggy C Nopoulos, MD

  University of Iowa

  PRINCIPAL INVESTIGATOR

• Ali G Hamedani, MD, PhD

  University of Pennsylvania

  PRINCIPAL INVESTIGATOR

• Yaz Y Kisanuki, MD, FAAN

  Ohio State University

  PRINCIPAL INVESTIGATOR

• Peter Morrison, DO

  University of Rochester

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: HMRI Neurosciences Principal Investigator & Multicenter Lead Investigator

Study Record Dates

• First Submitted: March 1, 2018
• First Posted: April 4, 2018
• Study Start: August 16, 2018
• Primary Completion: December 31, 2023
• Study Completion: December 31, 2023
• Last Updated: January 19, 2022

Record last verified: 2022-01

Locations

US (1)