Clinical trial NCT03487367: Clinical Trial Readiness for SCA1 and SCA3
Official title: Clinical Trial Readiness for SCA1 and SCA3
Study type: OBSERVATIONAL
Overall status: UNKNOWN
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
Lead sponsor: The Methodist Hospital Research Institute
Sponsor class: OTHER
Collaborators: name: University of Michigan
name: University of Minnesota
name: University of Utah
name: University of California, Los Angeles
name: University of Chicago
name: University of South Florida
name: Harvard University
name: Johns Hopkins University
name: University of Florida
name: Columbia University
name: Emory University
name: University of California, San Francisco
name: University of Alabama at Birmingham
name: University of Colorado, Denver
name: University of Rochester
name: Stanford University
name: Northwestern University
name: German Center for Neurodegenerative Diseases (DZNE)
name: Institut de Recherche sur la Moelle épinière et l'Encéphale
name: University of Pennsylvania
name: Ohio State University
name: University of Iowa
First posted: 2018-04-04
Enrollment: 200
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Observational model: COHORT
Time perspective: PROSPECTIVE
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.

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.

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
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.

Primary outcomes:
measure: 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.
timeFrame: Every 12 months for approximately 60 months
measure: Change in disease progression in SCA1 and SCA3 as determined by change in Composite Cerebellar Functional Severity Score (CCFS) total score over time.
timeFrame: Every 12 months for approximately 60 months
measure: Change in disease progression in SCA1 and SCA3 as determined by change in timed 25 foot walk test (T25FW) over time.
timeFrame: Every 12 months for approximately 60 months
measure: Change in disease progression in SCA1 and SCA3 as determined by change in Cerebellar Cognitive Affective Syndrome (CCAS) score over time.
timeFrame: Every 12 months for approximately 60 months
measure: Change in disease progression in SCA1 and SCA3 as determined by change in Inventory of Non-ataxia Symptoms (INAS) total count over time.
timeFrame: Every 12 months for approximately 60 months
measure: Change in disease progression in SCA1 and SCA3 as determined by change in Functional staging score over time.
timeFrame: Every 12 months for approximately 60 months
measure: Change in level of disease activity based on change in cerebellar and brainstem volumes since baseline imaging. (Aim 2)
timeFrame: Every 12 months for approximately 36 months
measure: 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)
timeFrame: Every 12 months for approximately 36 months
measure: Change in level of disease activity based on change in metabolite concentrations since baseline imaging. (Aim 2)
timeFrame: Every 12 months for approximately 36 months
measure: Change in level of disease activity based on change in fractional isotropy since baseline imaging. (Aim 2)
timeFrame: Every 12 months for approximately 36 months
measure: Change in level of disease activity based on change in mean diffusivity since baseline imaging. (Aim 2)
timeFrame: Every 12 months for approximately 36 months
measure: Change in level of disease activity based on change in radial and axial diffusivity since baseline imaging. (Aim 2)
timeFrame: Every 12 months for approximately 36 months
measure: Change in level of disease activity based on change in degree of co-activation within resting state networks since baseline imaging. (Aim 2)
timeFrame: Every 12 months for approximately 36 months
Secondary outcomes:
measure: Change in disease progression in SCA1 and SCA3 as determined by change in Friedreich's Ataxia Activities of Daily Living (FAA-ADL) over time.
timeFrame: Every 12 months for approximately 60 months
measure: Change in disease progression in SCA1 and SCA3 as determined by change in Fatigue Severity Scale (FSS) over time.
timeFrame: Every 12 months for approximately 60 months
measure: Change in disease progression in SCA1 and SCA3 as determined by change in Euro Qol-5D (EQ-5D) over time.
timeFrame: Every 12 months for approximately 60 months
measure: Change in disease progression in SCA1 and SCA3 as determined by change in Patient Health Questionnaire (PHQ-9) over time.
timeFrame: Every 12 months for approximately 60 months
measure: Change in disease progression in SCA1 and SCA3 as determined by change in Patient Global Impression (PGI) over time.
timeFrame: Every 12 months for approximately 60 months
measure: Change in survival at 60 months between and within cohorts
timeFrame: Baseline to 60 months
Other outcomes:
Locations:
city: Houston
country: United States
facility: Houston Methodist Hospital
state: Texas
Study officials:
affiliation: The Methodist Hospital Research Institute
name: Tetsuo Ashizawa, MD
role: STUDY_CHAIR
affiliation: University of Michigan
name: Hank Paulson, MD, PhD
role: STUDY_DIRECTOR
affiliation: University of Minnesota
name: Gulin Oz, MD
role: STUDY_DIRECTOR
affiliation: University Hospital Bonn - DZNE
name: Thomas Klockgether, MD
role: STUDY_DIRECTOR
affiliation: Hôpital Universitaire Pitié-Salpêtrière - ICM/SPATAX
name: Alexandra Durr, MD, PhD
role: STUDY_DIRECTOR
affiliation: Columbia University
name: Sheng Han Kuo, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Emory University
name: George Wilmot, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Johns Hopkins University
name: Liana Rosenthal, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Johns Hopkins University
name: Chiadikaobi Onyike, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Northwestern University
name: Puneet Opal, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Stanford University
name: Sharon Sha
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Alabama at Birmingham
name: Talene Yacoubian, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of California, Los Angeles
name: Susan Perlman, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of California, San Francisco
name: Michael Geschwind, MD,PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Colorado, Denver
name: Trevor Hawkins, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Chicago
name: Christopher Gomez, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Florida
name: SH Subramony, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Texas
name: Vikram Shakkottai, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Minnesota
name: Khalaf Bushara, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of South Florida
name: Theresa Zesiewicz, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Utah
name: Stefan Pulst, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Harvard University
name: Jeremy Schmahmann, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Johns Hopkins University
name: Peter Barker, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Johns Hopkins University
name: Haris I Sair, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Stanford University
name: Veronica Santini, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Harvard University
name: Eva-Maria Ratai, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Universtiy of Florida, Gainesville
name: Thomas Mareci, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Emory University
name: Laura Scorr, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Iowa
name: Peggy C Nopoulos, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Pennsylvania
name: Ali G Hamedani, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Ohio State University
name: Yaz Y Kisanuki, MD, FAAN
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Rochester
name: Peter Morrison, DO
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.