Clinical Trial Readiness for SCA1 and SCA3
| Status: | Recruiting |
|---|---|
| Conditions: | Neurology |
| Therapuetic Areas: | Neurology |
| Healthy: | No |
| Age Range: | 18 - 65 |
| Updated: | 9/9/2018 |
| Start Date: | August 16, 2018 |
| End Date: | December 31, 2022 |
| Contact: | Tetsuo Ashizawa, MD |
| Email: | tashizawa@houstonmethodist.org |
| Phone: | 346-238-5021 |
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.
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.
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.
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.
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.
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