Clinical Trial Readiness for SCA1 and SCA3 (READISCA)

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Spinocerebellar Ataxia 3; Spinocerebellar Ataxia Type 1

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.

• Study Type: Observational
• Enrollment (Anticipated): 200

Contacts and Locations

Study Locations

• United States
  • Texas
    • Houston, Texas, United States, 77030
      • Houston Methodist Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• 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.

Description

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
6. AIM 2 exclusion criteria also includes the inability to undergo MRI scanning and weight over 300lbs, presence of structural abnormalities such as subdural hematoma or primary or metastatic neoplasms and concurrent illnesses or treatment interfering with cognitive function such as stroke or normal pressure hydrocephalus.

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

Number of groups / cohorts

4

Cohorts and Interventions

Group / Cohort
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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in disease progression in SCA1 and SCA3 as determined by change in Friedreich's Ataxia Activities of Daily Living (FAA-ADL) over time.	Friedreich's Ataxia Activities of Daily Living (FAA-ADL) is an instrument measuring patient reported activities of daily living such as speech, dressing, walking, etc. Activities of daily living can be scored from 0-4, with zero being normal and 4 being most severe.	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.	Fatigue Severity Scale (FSS) is a 9 item scale which measures the severity of fatigue and its effect on a person's activities and lifestyle in patients with a variety of disorders. Scale ranges from 1-7, where 1 indicates strongly disagree and 7 indicates strongly agree.	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.	Euro Qol-5D (EQ-5D), a measure developed by the EuroQol Group that generates a single index value for health status with considerable potential for use in health care evaluation.	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.	Patient Health Questionnaire (PHQ-9) is a 9-question instrument used to screen for depression. The total of all 9 responses from the PHQ-9 aims to predict the presence and severity of depression.	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.	Patient Global Impression (PGI) is patient reported measure of change in disease status, walking, hand function and speech since last visit or in the last 6 months. Changes can be reported as worse, stable/same, or improved/better.	Every 12 months for approximately 60 months
Change in survival at 60 months between and within cohorts	To compare survival of patients between and within cohorts at 60 months	Baseline to 60 months

Collaborators and Investigators

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

Publications and helpful links

General Publications

• 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.
• 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.
• 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.
• 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. Erratum In: J Med Genet. 2014 Sep;51(9):613. Bela, Melegh [corrected to Melegh, Bela].

Study record dates

Study Major Dates

• Study Start (Actual): August 16, 2018
• Primary Completion (Anticipated): December 31, 2023
• Study Completion (Anticipated): December 31, 2023

Study Registration Dates

• First Submitted: March 1, 2018
• First Submitted That Met QC Criteria: March 27, 2018
• First Posted (Actual): April 4, 2018

Study Record Updates

• Last Update Posted (Actual): January 19, 2022
• Last Update Submitted That Met QC Criteria: January 17, 2022
• Last Verified: January 1, 2022

More Information

Terms related to this study

• Keywords: SCA; ataxia; SCA3; spinocerebellar ataxia; ataxias; SCA1; spinocerebellar ataxia type 1; spinocerebellar ataxia type 3; READISCA; SCAs; clinical trial readiness
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neurologic Manifestations; Genetic Diseases, Inborn; Neurodegenerative Diseases; Dyskinesias; Spinal Cord Diseases; Heredodegenerative Disorders, Nervous System; Cerebellar Diseases; Ataxia; Cerebellar Ataxia; Spinocerebellar Ataxias; Spinocerebellar Degenerations; Machado-Joseph Disease
• Other Study ID Numbers: Pro00017836; U01 - Ashizawa 2016 (Other Identifier: HMRI)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No