- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT04229823
Natural History of Oculomotor Neurophysiology in Ataxic and Pre-ataxic Carriers of SCA3/MJD (BIGPRO)
July 7, 2020 updated by: Hospital de Clinicas de Porto Alegre
Natural History of Oculomotor Neurophysiology in Ataxic and Pre-ataxic Carriers of Machado-Joseph Disease/Spinocerebellar Ataxia Type 3 (SCA3/MJD)
The study will consist of a prospective observation of subjects in a natural history design.
Disease progression will be monitored through clinical scales and video-oculography.
Participants will be stratified in three groups: ataxic carriers, pre-ataxic carriers and non-carriers (controls).
The following clinical scales will be applied in all subjects at baseline and at months 12 and 24: SARA, SCAFI, CCFS, NESSCA, INAS and ICARS.
Oculomotor function will be registered using video-oculography (EyeSeeCam, InterAcoustics) at the same time points.
Progression rates, effect sizes and responsiveness to change will be established for all parameters and results will be compared between candidate biomarkers.
Study Overview
Status
Unknown
Intervention / Treatment
Detailed Description
Spinocerebellar ataxia type 3, also called Machado-Joseph disease (SCA3/MJD), is an autosomal dominant neurodegenerative disorder caused by a CAG expansion (CAGexp) on ATXN3.
Over 20 years after the identification of the causal mutation, no form of prevention or treatment for this incapacitating condition was discovered.
Similarly to other polyglutamine (polyQ) diseases, SCA3/MJD has a slow progression.
Changes detected by clinical scales are small and, therefore, long intervals are needed to document disease progression.
Clinical trials using clinical scales as primary outcomes should be very long, what makes them hardly feasible.
In this context, the discovery of disease biomarkers is of utmost importance.
Biomarkers associated with disease progression and/or with therapeutic intervention might be more easily verified than the changes measured by clinical scales.
Seminal studies have demonstrated that oculomotor alterations and vestibulo-ocular reflex (VOR) impairment may be present even during presymptomatic periods.
Our primary hypothesis is eye movement parameters including VOR, saccades, smooth pursuit and fixation measured by video-oculography could be biomarkers of SCA3/MJD disease progression.
Besides that, the investigators aim to test if the candidate biomarkers present changes before disease-onset and if their responsiveness will be better than those of clinical scales, with more noticeable variations during a shorter period of time.
The study will consist of a prospective observation of subjects in a natural history design.
The investigators will monitor disease progression of the CAGexp carriers through clinical scales and video-oculography.
At least 75 adult subjects from Rio Grande do Sul will be invited to participate in the study, and at least 50 of the participants will be asymptomatic subjects, at 50% risk of carrying the mutation.
The study design will allow the subjects who wanted and the evaluators to stay blinded to subjects' genotypes.
Participants will be stratified in three groups: ataxic carriers, pre-ataxic carriers and non-carriers (controls).
Genotypes will be recorded separately to guarantee double blindness.
For every pre-ataxic carrier, time until the disease-onset will be estimated by an equation previously built, in which individual age and CAGexp are the determinants.
The following clinical scales will be applied in all subjects at baseline and at months 12 and 24: SARA, SCAFI, CCFS, NESSCA, INAS and ICARS.
Oculomotor function will be registered in video and analyzed using the EyeSeeCam device.
Progression rates of all variables will be estimated by mixed models, including as covariates age, groups and their interactions.
Progression rates, effect sizes and responsiveness to change will be established for all parameters and results will be compared between candidate biomarkers.
Study Type
Observational
Enrollment (Actual)
95
Contacts and Locations
This section provides the contact details for those conducting the study, and information on where this study is being conducted.
Study Locations
-
-
-
Porto Alegre, Brazil
- Universidade Federal do Rio Grande do Sul
-
-
Participation Criteria
Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.
Eligibility Criteria
Ages Eligible for Study
16 years and older (Adult, Older Adult)
Accepts Healthy Volunteers
No
Genders Eligible for Study
All
Sampling Method
Non-Probability Sample
Study Population
Individuals with molecular diagnosis of SCA3/MJD will be recruited from the Medical Genetics Service database of Hospital de Clínicas de Porto Alegre, Brazil, by telephone calls or by invitation in the outpatient clinic.
First degree relatives of these subjects at 50% risk of carrying the mutation will also be invited to participate.
Description
Inclusion Criteria:
- Individuals with molecular diagnosis of SCA3/MJD
- Individuals at 50% risk of inheriting SCA3/MJD mutation without any clinical manifestation
Exclusion Criteria:
- Other diagnosed neurological or vestibular condition
- Dyschromatopsia
- Refusal to sign informed consent
Study Plan
This section provides details of the study plan, including how the study is designed and what the study is measuring.
How is the study designed?
Design Details
- Observational Models: Cohort
- Time Perspectives: Prospective
Cohorts and Interventions
Group / Cohort |
Intervention / Treatment |
---|---|
Ataxic carriers
Subjects with a CAG repeat expansion on ATXN3 and Scale for Assessment and Rating of Ataxia (SARA) of 3 points or more.
|
Eye movement parameters will be measured in all of the subjects using video-oculography device (EyeSeeCam, InterAcoustics).
Measurement sessions consist of the study subject wearing a goggle attached to a camera that detects the pupil and eye position and velocity.
Evaluation start with vestibulo-ocular reflex testing, with video head impulse test.
Afterwards, saccades, smooth pursuit and fixation are evaluated.
All subjects are examined by an investigator in order to score clinical scales for ataxia, including Scale for the Assessment and Rating of Ataxia (SARA), International Co-operative Rating Scale (ICARS), Neurological Examination Scale for SCA (NESSCA), Inventory of Non-ataxia Symptoms (INAS), SCA Functional Index (SCAFI) and Composite Cerebellar Functional Severity Score (CCFS).
|
Pre-ataxic carriers
Subjects with a CAG repeat expansion on ATXN3 and Scale for Assessment and Rating of Ataxia (SARA) of less than 3 points.
|
Eye movement parameters will be measured in all of the subjects using video-oculography device (EyeSeeCam, InterAcoustics).
Measurement sessions consist of the study subject wearing a goggle attached to a camera that detects the pupil and eye position and velocity.
Evaluation start with vestibulo-ocular reflex testing, with video head impulse test.
Afterwards, saccades, smooth pursuit and fixation are evaluated.
All subjects are examined by an investigator in order to score clinical scales for ataxia, including Scale for the Assessment and Rating of Ataxia (SARA), International Co-operative Rating Scale (ICARS), Neurological Examination Scale for SCA (NESSCA), Inventory of Non-ataxia Symptoms (INAS), SCA Functional Index (SCAFI) and Composite Cerebellar Functional Severity Score (CCFS).
Individuals at 50% risk (offspring of subjects with molecular diagnosis of SCA3/MJD) will be genotyped in a double-blind manner so that they can be divided into pre-ataxic carriers and related controls (non carriers)
|
Related controls
Subjects without a CAG repeat expansion on ATXN3, but with a first degree relative affected by the disease.
|
Eye movement parameters will be measured in all of the subjects using video-oculography device (EyeSeeCam, InterAcoustics).
Measurement sessions consist of the study subject wearing a goggle attached to a camera that detects the pupil and eye position and velocity.
Evaluation start with vestibulo-ocular reflex testing, with video head impulse test.
Afterwards, saccades, smooth pursuit and fixation are evaluated.
All subjects are examined by an investigator in order to score clinical scales for ataxia, including Scale for the Assessment and Rating of Ataxia (SARA), International Co-operative Rating Scale (ICARS), Neurological Examination Scale for SCA (NESSCA), Inventory of Non-ataxia Symptoms (INAS), SCA Functional Index (SCAFI) and Composite Cerebellar Functional Severity Score (CCFS).
Individuals at 50% risk (offspring of subjects with molecular diagnosis of SCA3/MJD) will be genotyped in a double-blind manner so that they can be divided into pre-ataxic carriers and related controls (non carriers)
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Change in vestibulo-ocular reflex gain regression slope (VORr)
Time Frame: 24 months
|
Gain (Eye velocity/Head velocity)
|
24 months
|
Change in vertical smooth pursuit gain
Time Frame: 24 months
|
Regression slope of eye velocity versus target velocity during vertical smooth pursuit task
|
24 months
|
Change in slow-phase velocity of gaze evoked nystagmus (SPV-GE)
Time Frame: 24 months
|
Degrees/second
|
24 months
|
Change in the slope of peak duration versus amplitude of volitional vertical saccades
Time Frame: 24 months
|
egression slope between peak duration and saccade amplitude during volitional vertical saccades
|
24 months
|
Change in the slope of peak duration versus amplitude of reflexive vertical saccades
Time Frame: 24 months
|
Regression slope between peak duration and saccade amplitude during reflexive vertical saccades
|
24 months
|
Change in slow-phase velocity of central nystagmus (SPV-C)
Time Frame: 24 months
|
Degrees/second
|
24 months
|
Change in Neurological Examination Score for Spinocerebellar Ataxia (NESSCA)
Time Frame: 24 months
|
Neurological examination score, varying between 0 and 40.
Score increases with disease severity.
|
24 months
|
Change in SCA Functional Index (SCAFI)
Time Frame: 24 months
|
Composite score.
Score decreases with disease severity.
|
24 months
|
Change in International Cooperative Ataxia Rating Scale (ICARS)
Time Frame: 24 months
|
Absolute score, varying between 0 and 100.
Score increases with disease severity.
|
24 months
|
Change in Inventory of Non-Ataxia Symptoms (INAS) count
Time Frame: 24 months
|
Scale varying between 0 and 16.
Score increases with disease severity.
|
24 months
|
Change in Composite Cerebellar Functional Severity Score (CCFS)
Time Frame: 24 months
|
Composite score.
Score increases with disease severity.
|
24 months
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Change in horizontal smooth pursuit gain
Time Frame: 24 months
|
Gain (Eye velocity/Target velocity)
|
24 months
|
Change in reflexive vertical saccade velocity (RVSV)
Time Frame: 24 months
|
Degrees/second
|
24 months
|
Change in volitional vertical saccade velocity (VVSV)
Time Frame: 24 months
|
Degrees/second
|
24 months
|
Collaborators and Investigators
This is where you will find people and organizations involved with this study.
Investigators
- Principal Investigator: Laura Jardim, Federal University of Rio Grande do Sul
Publications and helpful links
The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.
Helpful Links
Study record dates
These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.
Study Major Dates
Study Start (Actual)
March 28, 2017
Primary Completion (Anticipated)
December 1, 2020
Study Completion (Anticipated)
August 1, 2021
Study Registration Dates
First Submitted
January 7, 2020
First Submitted That Met QC Criteria
January 14, 2020
First Posted (Actual)
January 18, 2020
Study Record Updates
Last Update Posted (Actual)
July 9, 2020
Last Update Submitted That Met QC Criteria
July 7, 2020
Last Verified
July 1, 2020
More Information
Terms related to this study
Keywords
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
- 2017-0015
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
Yes
IPD Plan Description
Data sharing will be done via direct contact with the Principal Investigator in order to preserve individual participants identities
IPD Sharing Time Frame
Data will become available after final statistical analysis and data publishing via direct contact with principal investigator
IPD Sharing Access Criteria
Investigators and researchers of the area
IPD Sharing Supporting Information Type
- Study Protocol
- Informed Consent Form (ICF)
- Clinical Study Report (CSR)
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
No
Studies a U.S. FDA-regulated device product
No
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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