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

Status

Indicates the current recruitment status or the expanded access status.
Unknown

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

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

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Observational

Enrollment (Actual)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
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

  • Brazil
      • 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

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

14 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

Group / Cohort

A group or subgroup of participants in an observational study that is assessed for biomedical or health outcomes.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
Ataxic carriers
Subjects with a CAG repeat expansion on ATXN3 and Scale for Assessment and Rating of Ataxia (SARA) of 3 points or more.
Diagnostic test: Video-oculography
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.
Diagnostic test: Clinical Scales
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.
Diagnostic test: Video-oculography
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.
Diagnostic test: Clinical Scales
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).
Diagnostic test: Genotyping
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.
Diagnostic test: Video-oculography
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.
Diagnostic test: Clinical Scales
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).
Diagnostic test: Genotyping
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

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
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

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
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.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
Hospital de Clinicas de Porto Alegre

Investigators

Investigators

A researcher involved in a clinical study. Related terms include site principal investigator, site sub-investigator, study chair, study director, and study principal investigator.
  • 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)

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
March 28, 2017

Primary Completion (Anticipated)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
December 1, 2020

Study Completion (Anticipated)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
August 1, 2021

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
January 7, 2020

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
January 14, 2020

First Posted (Actual)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
January 18, 2020

Study Record Updates

Last Update Posted (Actual)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
July 9, 2020

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
July 7, 2020

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
July 1, 2020

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant 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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