Clinical Trial Readiness for SCA1 and SCA3

NCT ID: NCT03487367

Last Updated: 2022-01-19

Basic Information

• Recruitment Status: UNKNOWN
• Total Enrollment: 200 participants
• Study Classification: OBSERVATIONAL
• Study Start Date: 2018-08-16
• Study Completion Date: 2023-12-31

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.

Detailed Description

Spinocerebellar ataxia types 1 (SCA1) and 3 (SCA3) are rare, inherited neurodegenerative disorders that relentlessly progress to total disability and death. SCA1 is the fastest progressing SCA while SCA3 is the most common SCA in US and Europe. Expanded (CAG)n repeats encoding polyglutamines (polyQ) in the respective genes, Ataxin 1 (ATXN1) and Ataxin 3 (ATXN3), cause SCA1 and SCA3. Disease-modifying therapies that target the pathway upstream of the complex pathogenic cascade will offer ultimate treatment. Scientific premise and preclinical animal data strongly support MSK1 inhibitors for SCA1, citalopram for SCA3, and nucleotide-based gene silencing for both SCAs as drugs to be examined in clinical trials in five years. However, the challenge that investigators face in current clinical trial readiness for such disease-modifying therapies is that the modest effect size of candidate drugs as measured by the Scale for the Assessment and Rating of Ataxia (SARA; the most robust and well-validated clinical outcome assessment measure) requires large cohorts of study subjects to achieve sufficient statistical power. To accomplish the goal of establishing clinical trial readiness, the investigators propose to launch an international, multi-site effort focusing on premanifest mutation carriers and patients in an early disease stage, who are likely responders to the disease-modifying interventions prior to irreversible brain damage. Based on the investigators' studies funded by NIH and the National Ataxia Foundation (NAF), the US ataxia consortium has developed an unprecedented opportunity for tight collaborations with the European Ataxia Study Group to jointly address this challenge and establish clinical trial readiness for SCA1 and SCA3. To achieve this goal, the investigators propose the following specific aims:

Aim 1. Establish the world's largest cohorts of premanifest/early SCA1 and SCA3 by combining cohorts, clinical outcome assessment data and biofluid samples (blood, cerebrospinal fluid) from US and Europe Aim 2. Validate MR morphological, biochemical and functional biomarkers in premanifest and early SCA1 and SCA3 Aim 3. Adapt recent developments on statistical design and analysis of small population trials to SCAs.

Conditions

Spinocerebellar Ataxia Type 1; Spinocerebellar Ataxia 3

Study Design

• Observational Model Type: COHORT
• Study Time Perspective: PROSPECTIVE

Study Groups

Early stage subjects

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

No interventions assigned to this group

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

No interventions assigned to this group

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

No interventions assigned to this group

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

No interventions assigned to this group

Eligibility Criteria

Inclusion Criteria

1. Signed informed consent (no study-related procedures may be performed before the subject has signed the consent form).

2. Subjects of either sex aged 18 to 65 with presence of symptomatic ataxic disease or asymptomatic mutation carrier or

3. Subjects with definite molecular diagnosis of SCA1 or SCA3 or another affected family member

4. Subjects of any age with previous diagnosis of Early stage SCA1 and SCA3

5. Subjects capable of understanding and complying with protocol requirements

6. No changes in physical/occupational therapy status within two months prior to enrollment

Exclusion Criteria

1. Subjects currently receiving, or having received within 2 months prior to enrollment into this study, any investigational drug.

2. Subjects who do not wish to or cannot comply with study procedures.

3. Genotype consistent with other inherited ataxias

4. Changes in coordinative physical and occupational therapy for ataxia 2 months prior to study participation

5. Concomitant disorder(s) or condition(s) that affects assessment of ataxia or severity of ataxia during this study

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 65 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

University of Michigan

OTHER

Sponsor Role: collaborator

University of Minnesota

OTHER

Sponsor Role: collaborator

University of Utah

OTHER

Sponsor Role: collaborator

University of California, Los Angeles

OTHER

Sponsor Role: collaborator

University of Chicago

OTHER

Sponsor Role: collaborator

University of South Florida

OTHER

Sponsor Role: collaborator

Harvard University

OTHER

Sponsor Role: collaborator

Johns Hopkins University

OTHER

Sponsor Role: collaborator

University of Florida

OTHER

Sponsor Role: collaborator

Columbia University

OTHER

Sponsor Role: collaborator

Emory University

OTHER

Sponsor Role: collaborator

University of California, San Francisco

OTHER

Sponsor Role: collaborator

University of Alabama at Birmingham

OTHER

Sponsor Role: collaborator

University of Colorado, Denver

OTHER

Sponsor Role: collaborator

University of Rochester

OTHER

Sponsor Role: collaborator

Stanford University

OTHER

Sponsor Role: collaborator

Northwestern University

OTHER

Sponsor Role: collaborator

German Center for Neurodegenerative Diseases (DZNE)

OTHER

Sponsor Role: collaborator

Institut de Recherche sur la Moelle épinière et l'Encéphale

OTHER

Sponsor Role: collaborator

University of Pennsylvania

OTHER

Sponsor Role: collaborator

Ohio State University

OTHER

Sponsor Role: collaborator

University of Iowa

OTHER

Sponsor Role: collaborator

The Methodist Hospital Research Institute

OTHER

Sponsor Role: lead

Responsible Party

Tetsuo Ashizawa, MD

HMRI Neurosciences Principal Investigator & Multicenter Lead Investigator

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Tetsuo Ashizawa, MD

Role: STUDY_CHAIR

The Methodist Hospital Research Institute

Hank Paulson, MD, PhD

Role: STUDY_DIRECTOR

University of Michigan

Gulin Oz, MD

Role: STUDY_DIRECTOR

University of Minnesota

Thomas Klockgether, MD

Role: STUDY_DIRECTOR

University Hospital Bonn - DZNE

Alexandra Durr, MD, PhD

Role: STUDY_DIRECTOR

Hôpital Universitaire Pitié-Salpêtrière - ICM/SPATAX

Sheng Han Kuo, MD

Role: PRINCIPAL_INVESTIGATOR

Columbia University

George Wilmot, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

Emory University

Liana Rosenthal, MD

Role: PRINCIPAL_INVESTIGATOR

Johns Hopkins University

Chiadikaobi Onyike, MD

Role: PRINCIPAL_INVESTIGATOR

Johns Hopkins University

Puneet Opal, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

Northwestern University

Sharon Sha

Role: PRINCIPAL_INVESTIGATOR

Stanford University

Talene Yacoubian, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

University of Alabama at Birmingham

Susan Perlman, MD

Role: PRINCIPAL_INVESTIGATOR

University of California, Los Angeles

Michael Geschwind, MD,PhD

Role: PRINCIPAL_INVESTIGATOR

University of California, San Francisco

Trevor Hawkins, MD

Role: PRINCIPAL_INVESTIGATOR

University of Colorado, Denver

Christopher Gomez, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

University of Chicago

SH Subramony, MD

Role: PRINCIPAL_INVESTIGATOR

University of Florida

Vikram Shakkottai, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

University of Texas

Khalaf Bushara, MD

Role: PRINCIPAL_INVESTIGATOR

University of Minnesota

Theresa Zesiewicz, MD

Role: PRINCIPAL_INVESTIGATOR

University of South Florida

Stefan Pulst, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

University of Utah

Jeremy Schmahmann, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

Harvard University

Peter Barker, MD

Role: PRINCIPAL_INVESTIGATOR

Johns Hopkins University

Haris I Sair, MD

Role: PRINCIPAL_INVESTIGATOR

Johns Hopkins University

Veronica Santini, MD

Role: PRINCIPAL_INVESTIGATOR

Stanford University

Eva-Maria Ratai, MD

Role: PRINCIPAL_INVESTIGATOR

Harvard University

Thomas Mareci, MD

Role: PRINCIPAL_INVESTIGATOR

Universtiy of Florida, Gainesville

Laura Scorr, MD

Role: PRINCIPAL_INVESTIGATOR

Emory University

Peggy C Nopoulos, MD

Role: PRINCIPAL_INVESTIGATOR

University of Iowa

Ali G Hamedani, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

University of Pennsylvania

Yaz Y Kisanuki, MD, FAAN

Role: PRINCIPAL_INVESTIGATOR

Ohio State University

Peter Morrison, DO

Role: PRINCIPAL_INVESTIGATOR

University of Rochester

Locations

Houston Methodist Hospital

Houston, Texas, United States

Countries

United States

References

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.

Reference Type: BACKGROUND

PMID: 28855740 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 24225362 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 20310029 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 24780882 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 40665587 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 36797067 (View on PubMed)

Other Identifiers

U01 - Ashizawa 2016

Identifier Type: OTHER

Identifier Source: secondary_id

Pro00017836

Identifier Type: -

Identifier Source: org_study_id