Spinocerebellar Ataxia Type 3BIGPRONCT04229823
Natural History of Oculomotor Neurophysiology in Ataxic and Pre-ataxic Carriers of SCA3/MJD
An observational study of Spinocerebellar Ataxia Type 3 and Machado-Joseph Disease, run by Hospital de Clinicas de Porto Alegre at 1 site in Brazil.
Trial summary
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). Read more about this study
- Who is it for?
- Ages 18 years and olderHealthy volunteers can take part
- Conditions the study is for
- Spinocerebellar Ataxia Type 3, Machado-Joseph Disease
- What is being tested?
- Video-oculography, Clinical Scales and Genotyping
- How many people
- 95 participants
- Where
- 1 siteBrazil
- Study dates
- 28 Mar 2017to Aug 2021
- Phase
- Observational
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- Healthy volunteers accepted
- Adult, Older adult
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.
Who may be able to join
- Individuals with molecular diagnosis of SCA3/MJD
- Individuals at 50% risk of inheriting SCA3/MJD mutation without any clinical manifestation
Who cannot join
- Other diagnosed neurological or vestibular condition
- Dyschromatopsia
- Refusal to sign informed consent
Trial locations and contacts
1 site in 1 country.
About this study
Official title: 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.
Read the 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.
- Being tested
- Video-oculography, Clinical Scales, Genotyping
- Keywords
- Machado-Joseph Disease, Spinocerebellar Ataxia Type 3, SCA3, Biomarker, Natural history, Video-oculography, Eye movement, Surrogate biomarker, Oculomotor neurophysiology
- Medical subject headings
- Machado-Joseph Disease
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Video-oculographyDiagnostic test
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.
Clinical ScalesDiagnostic test
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).
GenotypingDiagnostic test
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)
| Study group | Role | What they receive |
|---|---|---|
| Ataxic carriers | Subjects with a CAG repeat expansion on ATXN3 and Scale for Assessment and Rating of Ataxia (SARA) of 3 points or more. Receives: Diagnostic Test: Video-oculography; Diagnostic Test: Clinical Scales | |
| 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. Receives: Diagnostic Test: Video-oculography; Diagnostic Test: Clinical Scales; Diagnostic Test: Genotyping | |
| Related controls | Subjects without a CAG repeat expansion on ATXN3, but with a first degree relative affected by the disease. Receives: Diagnostic Test: Video-oculography; Diagnostic Test: Clinical Scales; Diagnostic Test: Genotyping |
What is being measured
The primary outcome is the main question the study is designed to answer.
Change in vestibulo-ocular reflex gain regression slope (VORr)
Gain (Eye velocity/Head velocity)
Measured: 24 months
Change in vertical smooth pursuit gain
Regression slope of eye velocity versus target velocity during vertical smooth pursuit task
Measured: 24 months
Change in slow-phase velocity of gaze evoked nystagmus (SPV-GE)
Degrees/second
Measured: 24 months
Change in the slope of peak duration versus amplitude of volitional vertical saccades
egression slope between peak duration and saccade amplitude during volitional vertical saccades
Measured: 24 months
Change in the slope of peak duration versus amplitude of reflexive vertical saccades
Regression slope between peak duration and saccade amplitude during reflexive vertical saccades
Measured: 24 months
Change in slow-phase velocity of central nystagmus (SPV-C)
Degrees/second
Measured: 24 months
Change in Neurological Examination Score for Spinocerebellar Ataxia (NESSCA)
Neurological examination score, varying between 0 and 40. Score increases with disease severity.
Measured: 24 months
Change in SCA Functional Index (SCAFI)
Composite score. Score decreases with disease severity.
Measured: 24 months
Change in International Cooperative Ataxia Rating Scale (ICARS)
Absolute score, varying between 0 and 100. Score increases with disease severity.
Measured: 24 months
Change in Inventory of Non-Ataxia Symptoms (INAS) count
Scale varying between 0 and 16. Score increases with disease severity.
Measured: 24 months
Change in Composite Cerebellar Functional Severity Score (CCFS)
Composite score. Score increases with disease severity.
Measured: 24 months
Secondary outcomes (3)
Change in horizontal smooth pursuit gain
Gain (Eye velocity/Target velocity)
Measured: 24 months
Change in reflexive vertical saccade velocity (RVSV)
Degrees/second
Measured: 24 months
Change in volitional vertical saccade velocity (VVSV)
Degrees/second
Measured: 24 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted18 Jan 2020
- Study start28 Mar 2017
- Primary completionDec 2020 (estimated)
- Study completionAug 2021 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Spinocerebellar Ataxia Type 3Studies of the same condition, open and under way.
- More trials run by Hospital de Clinicas de Porto AlegreThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Observational
- Observational model
- Cohort
- Time perspective
- Prospective
- Enrolment
- 95 participants (actual)
Sponsor and investigators
- Lead sponsor
- Hospital de Clinicas de Porto Alegre
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Laura Jardim, Principal investigator, Federal University of Rio Grande do Sul
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04229823
- Sponsor's protocol ID
- 2017-0015
- Acronym
- BIGPRO
- Status last verified
- Jul 2020
- First submitted
- 7 Jan 2020
- Last updated
- 9 Jul 2020
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Yes: Data sharing will be done via direct contact with the Principal Investigator in order to preserve individual participants identities
Study at a glance
From the registry record, last updated by the sponsor on 9 Jul 2020. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Natural History of Oculomotor Neurophysiology in Ataxic and Pre-ataxic Carriers of Machado-Joseph Disease/Spinocerebellar Ataxia Type 3 (SCA3/MJD)
- ClinicalTrials.gov ID
- NCT04229823
- Acronym / sponsor ID
- BIGPRO / 2017-0015
- Keywords
- Machado-Joseph Disease, Spinocerebellar Ataxia Type 3, SCA3, Biomarker, Natural history, Video-oculography, Eye movement, Surrogate biomarker
- Study type
- Observational
- Recruitment status
- Unknown status
- Enrolment
- 95 participants (actual)
- Lead sponsor
- Hospital de Clinicas de Porto AlegreUniversity, hospital or other
- Study start
- 28 Mar 2017 (actual)
- Primary completion
- Dec 2020 (estimated)
- Study completion
- Aug 2021 (estimated)
- First posted
- 18 Jan 2020 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
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 design
- Observational model
- Cohort
- Time perspective
- Prospective
- Number of arms
- 3
| Arm | Type | Receives |
|---|---|---|
| Ataxic carriers | – | Diagnostic Test: Video-oculography, Diagnostic Test: Clinical ScalesSubjects with a CAG repeat expansion on ATXN3 and Scale for Assessment and Rating of Ataxia (SARA) of 3 points or more. |
| Pre-ataxic carriers | – | Diagnostic Test: Video-oculography, Diagnostic Test: Clinical Scales, Diagnostic Test: GenotypingSubjects with a CAG repeat expansion on ATXN3 and Scale for Assessment and Rating of Ataxia (SARA) of less than 3 points. |
| Related controls | – | Diagnostic Test: Video-oculography, Diagnostic Test: Clinical Scales, Diagnostic Test: GenotypingSubjects without a CAG repeat expansion on ATXN3, but with a first degree relative affected by the disease. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult, Older adult
- 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.
Key inclusion criteria (2 listed)
- Individuals with molecular diagnosis of SCA3/MJD
- Individuals at 50% risk of inheriting SCA3/MJD mutation without any clinical manifestation
Key exclusion criteria (3 listed)
- Other diagnosed neurological or vestibular condition
- Dyschromatopsia
- Refusal to sign informed consent
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Video-oculographyEye 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. | Diagnostic test | Ataxic carriers, Pre-ataxic carriers, Related controls |
| Clinical ScalesAll 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). | Diagnostic test | Ataxic carriers, Pre-ataxic carriers, Related controls |
| GenotypingIndividuals 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) | Diagnostic test | Pre-ataxic carriers, Related controls |
Primary outcome
Change in vestibulo-ocular reflex gain regression slope (VORr)
Time frame: 24 months
Gain (Eye velocity/Head velocity)
Change in vertical smooth pursuit gain
Time frame: 24 months
Regression slope of eye velocity versus target velocity during vertical smooth pursuit task
Change in slow-phase velocity of gaze evoked nystagmus (SPV-GE)
Time frame: 24 months
Degrees/second
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
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
Change in slow-phase velocity of central nystagmus (SPV-C)
Time frame: 24 months
Degrees/second
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.
Change in SCA Functional Index (SCAFI)
Time frame: 24 months
Composite score. Score decreases with disease severity.
Change in International Cooperative Ataxia Rating Scale (ICARS)
Time frame: 24 months
Absolute score, varying between 0 and 100. Score increases with disease severity.
Change in Inventory of Non-Ataxia Symptoms (INAS) count
Time frame: 24 months
Scale varying between 0 and 16. Score increases with disease severity.
Change in Composite Cerebellar Functional Severity Score (CCFS)
Time frame: 24 months
Composite score. Score increases with disease severity.
3 secondary outcomes
Change in horizontal smooth pursuit gain
Time frame: 24 months
Change in reflexive vertical saccade velocity (RVSV)
Time frame: 24 months
Change in volitional vertical saccade velocity (VVSV)
Time frame: 24 months
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 9 Jul 2020.
- BIGPRO study websiteLink provided by the sponsor.
- Individual participant dataSharing planned: Yes. Data sharing will be done via direct contact with the Principal Investigator in order to preserve individual participants identities
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Laura Jardim principal investigator
Federal University of Rio Grande do Sul
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of Spinocerebellar Ataxia Type 3 and Machado-Joseph Disease, run by Hospital de Clinicas de Porto Alegre at 1 site in Brazil.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 2 inclusion and 3 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: status not confirmed, as of the sponsor's last update on 9 Jul 2020. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Brazil. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Change in vestibulo-ocular reflex gain regression slope (VORr) (time frame: 24 months). The study lists 11 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 9 Jul 2020.