Clinical Trial Readiness for SCA1 and SCA3
试验速览
- 阶段
- 不适用
- 入组人数
- 200
- 试验地点
- 1
- 主要终点
- 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.
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Observational
- 观察模型
- Cohort
- 时间视角
- Prospective
入排标准
- 年龄范围
- 18 Years 至 65 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •Signed informed consent (no study-related procedures may be performed before the subject has signed the consent form).
- •Subjects of either sex aged 18 to 65 with presence of symptomatic ataxic disease or asymptomatic mutation carrier or
- •Subjects with definite molecular diagnosis of SCA1 or SCA3 or another affected family member
- •Subjects of any age with previous diagnosis of Early stage SCA1 and SCA3
- •Subjects capable of understanding and complying with protocol requirements
- •No changes in physical/occupational therapy status within two months prior to enrollment
排除标准
- •Subjects currently receiving, or having received within 2 months prior to enrollment into this study, any investigational drug.
- •Subjects who do not wish to or cannot comply with study procedures.
- •Genotype consistent with other inherited ataxias
- •Changes in coordinative physical and occupational therapy for ataxia 2 months prior to study participation
- •Concomitant disorder(s) or condition(s) that affects assessment of ataxia or severity of ataxia during this study
- •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.
结局指标
主要结局
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.
时间窗: 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).
Change in disease progression in SCA1 and SCA3 as determined by change in Cerebellar Cognitive Affective Syndrome (CCAS) score over time.
时间窗: 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.
Change in disease progression in SCA1 and SCA3 as determined by change in Composite Cerebellar Functional Severity Score (CCFS) total score over time.
时间窗: 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.
Change in disease progression in SCA1 and SCA3 as determined by change in timed 25 foot walk test (T25FW) over time.
时间窗: 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.
Change in level of disease activity based on change in fractional isotropy since baseline imaging. (Aim 2)
时间窗: 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.
Change in disease progression in SCA1 and SCA3 as determined by change in Inventory of Non-ataxia Symptoms (INAS) total count over time.
时间窗: 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.
Change in disease progression in SCA1 and SCA3 as determined by change in Functional staging score over time.
时间窗: Every 12 months for approximately 60 months
Functional staging is an instrument used to assess ambulatory capabilities of patients with cerebellar symptoms.
Change in level of disease activity based on change in cerebellar and brainstem volumes since baseline imaging. (Aim 2)
时间窗: Every 12 months for approximately 36 months
Change in level of disease activity based on change in cerebellar and brainstem volumes since baseline imaging.
Change in level of disease activity based on change in metabolite concentrations since baseline imaging. (Aim 2)
时间窗: 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.
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)
时间窗: 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.
Change in level of disease activity based on change in mean diffusivity since baseline imaging. (Aim 2)
时间窗: 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.
Change in level of disease activity based on change in radial and axial diffusivity since baseline imaging. (Aim 2)
时间窗: 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.
Change in level of disease activity based on change in degree of co-activation within resting state networks since baseline imaging. (Aim 2)
时间窗: 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.
次要结局
- Change in disease progression in SCA1 and SCA3 as determined by change in Patient Health Questionnaire (PHQ-9) over time.(Every 12 months for approximately 60 months)
- Change in survival at 60 months between and within cohorts(Baseline to 60 months)
- Change in disease progression in SCA1 and SCA3 as determined by change in Patient Global Impression (PGI) over time.(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.(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.(Every 12 months for approximately 60 months)
- Change in disease progression in SCA1 and SCA3 as determined by change in Friedreich's Ataxia Activities of Daily Living (FAA-ADL) over time.(Every 12 months for approximately 60 months)
研究者
Tetsuo Ashizawa, MD
HMRI Neurosciences Principal Investigator & Multicenter Lead Investigator
The Methodist Hospital Research Institute