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Clinical Trial Readiness for SCA1 and SCA3 (READISCA)

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ClinicalTrials.gov Identifier: NCT03487367
Recruitment Status : Recruiting
First Posted : April 4, 2018
Last Update Posted : September 7, 2018
Sponsor:
Collaborators:
University of Michigan
University of Minnesota - Clinical and Translational Science Institute
University of Utah
University of California, Los Angeles
University of Chicago
University of South Florida
Harvard University
Johns Hopkins University
University of Florida
Columbia University
Emory University
University of California, San Francisco
University of Alabama at Birmingham
University of Colorado, Denver
University of Rochester
Stanford University
Northwestern University
German Center for Neurodegenerative Diseases (DZNE)
Institut de Recherche sur la Moelle épinière et l'Encéphale
Information provided by (Responsible Party):
Tetsuo Ashizawa, MD, The Methodist Hospital System

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.

Condition or disease
Spinocerebellar Ataxia Type 1 Spinocerebellar Ataxia 3

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
Estimated Enrollment : 200 participants
Observational Model: Cohort
Time Perspective: Prospective
Official Title: Clinical Trial Readiness for SCA1 and SCA3
Actual Study Start Date : August 16, 2018
Estimated Primary Completion Date : December 31, 2022
Estimated Study Completion Date : December 31, 2022


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



Primary Outcome Measures :
  1. 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. [ Time Frame: Every 12 months for approximately 60 months ]
    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).

  2. Change in disease progression in SCA1 and SCA3 as determined by change in Composite Cerebellar Functional Severity Score (CCFS) total score over time. [ Time Frame: Every 12 months for approximately 60 months ]
    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.

  3. Change in disease progression in SCA1 and SCA3 as determined by change in timed 25 foot walk test (T25FW) over time. [ Time Frame: Every 12 months for approximately 60 months ]
    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.

  4. Change in disease progression in SCA1 and SCA3 as determined by change in Cerebellar Cognitive Affective Syndrome (CCAS) score over time. [ Time Frame: Every 12 months for approximately 60 months ]
    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.

  5. Change in disease progression in SCA1 and SCA3 as determined by change in Inventory of Non-ataxia Symptoms (INAS) total count over time. [ Time Frame: Every 12 months for approximately 60 months ]
    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.

  6. Change in disease progression in SCA1 and SCA3 as determined by change in Functional staging score over time. [ Time Frame: Every 12 months for approximately 60 months ]
    Functional staging is an instrument used to assess ambulatory capabilities of patients with cerebellar symptoms.

  7. Change in level of disease activity based on change in cerebellar and brainstem volumes since baseline imaging. (Aim 2) [ Time Frame: Every 12 months for approximately 36 months ]
    Change in level of disease activity based on change in cerebellar and brainstem volumes since baseline imaging.

  8. 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) [ Time Frame: Every 12 months for approximately 36 months ]
    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.

  9. Change in level of disease activity based on change in metabolite concentrations since baseline imaging. (Aim 2) [ Time Frame: Every 12 months for approximately 36 months ]
    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.

  10. Change in level of disease activity based on change in fractional isotropy since baseline imaging. (Aim 2) [ Time Frame: Every 12 months for approximately 36 months ]
    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.

  11. Change in level of disease activity based on change in mean diffusivity since baseline imaging. (Aim 2) [ Time Frame: Every 12 months for approximately 36 months ]
    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.

  12. Change in level of disease activity based on change in radial and axial diffusivity since baseline imaging. (Aim 2) [ Time Frame: Every 12 months for approximately 36 months ]
    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.

  13. Change in level of disease activity based on change in degree of co-activation within resting state networks since baseline imaging. (Aim 2) [ Time Frame: Every 12 months for approximately 36 months ]
    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.


Secondary Outcome Measures :
  1. Change in disease progression in SCA1 and SCA3 as determined by change in Friedreich's Ataxia Activities of Daily Living (FAA-ADL) over time. [ Time Frame: Every 12 months for approximately 60 months ]
    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.

  2. Change in disease progression in SCA1 and SCA3 as determined by change in Fatigue Severity Scale (FSS) over time. [ Time Frame: Every 12 months for approximately 60 months ]
    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.

  3. Change in disease progression in SCA1 and SCA3 as determined by change in Euro Qol-5D (EQ-5D) over time. [ Time Frame: Every 12 months for approximately 60 months ]
    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.

  4. Change in disease progression in SCA1 and SCA3 as determined by change in Patient Health Questionnaire (PHQ-9) over time. [ Time Frame: Every 12 months for approximately 60 months ]
    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.

  5. Change in disease progression in SCA1 and SCA3 as determined by change in Patient Global Impression (PGI) over time. [ Time Frame: Every 12 months for approximately 60 months ]
    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.

  6. Change in survival at 60 months between and within cohorts [ Time Frame: Baseline to 60 months ]
    To compare survival of patients between and within cohorts at 60 months


Biospecimen Retention:   Samples With DNA
Whole blood collected for DNA analysis


Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Ages Eligible for Study:   18 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
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.
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
  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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03487367


Contacts
Contact: Tetsuo Ashizawa, MD 346-238-5021 tashizawa@houstonmethodist.org
Contact: Chantel Potvin 346-238-5021 U01SCA1&3@houstonmethodist.org

Locations
United States, Texas
Houston Methodist Hospital Recruiting
Houston, Texas, United States, 77030
Contact: Tetsuo Ashizawa, MD    346-238-5021    U01SCA1&3@houstonmethodist.org   
Contact: Chantel Potvin    346-238-5021    cpotvin@houstonmethodist.org   
Sponsors and Collaborators
Tetsuo Ashizawa, MD
University of Michigan
University of Minnesota - Clinical and Translational Science Institute
University of Utah
University of California, Los Angeles
University of Chicago
University of South Florida
Harvard University
Johns Hopkins University
University of Florida
Columbia University
Emory University
University of California, San Francisco
University of Alabama at Birmingham
University of Colorado, Denver
University of Rochester
Stanford University
Northwestern 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 System
Study Director: Hank Paulson, MD, PhD University of Michigan
Study Director: Gulin Oz, MD University of Minnesota - Clinical and Translational Science Institute
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: Susan Perlman, MD University of California, Los Angeles
Principal Investigator: Michael Geschwind, MD,PhD University of California, San Francisco
Principal Investigator: Lauren Seeberger, MD University of Colorado, Denver
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 Michigan
Principal Investigator: Khalaf Bushara, MD University of Minnesota - Clinical and Translational Science Institute
Principal Investigator: Erika Augustine, MD University of Rochester
Principal Investigator: Alexander Paciorkowski, MD University of Rochester
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

Publications:

Responsible Party: Tetsuo Ashizawa, MD, HMRI Neurosciences Principal Investigator & Multicenter Lead Investigator, The Methodist Hospital System
ClinicalTrials.gov Identifier: NCT03487367     History of Changes
Other Study ID Numbers: Pro00017836
U01 - Ashizawa 2016 ( Other Identifier: HMRI )
First Posted: April 4, 2018    Key Record Dates
Last Update Posted: September 7, 2018
Last Verified: September 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Tetsuo Ashizawa, MD, The Methodist Hospital System:
spinocerebellar ataxia
ataxia
ataxias
SCA1
SCA3
spinocerebellar ataxia type 1
spinocerebellar ataxia type 3
READISCA

Additional relevant MeSH terms:
Ataxia
Cerebellar Ataxia
Spinocerebellar Ataxias
Spinocerebellar Degenerations
Machado-Joseph Disease
Dyskinesias
Neurologic Manifestations
Nervous System Diseases
Signs and Symptoms
Cerebellar Diseases
Brain Diseases
Central Nervous System Diseases
Spinal Cord Diseases
Heredodegenerative Disorders, Nervous System
Neurodegenerative Diseases
Genetic Diseases, Inborn