Natural History of Oculomotor Neurophysiology in Ataxic and Pre-ataxic Carriers of SCA3/MJD

NCT04229823 | Unknown

• 1 other identifier: 2017-0015
• Study Type: observational
• Target: 95
• Locations: 1 country
• Sites: 1

Brief 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). 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.

Conditions

Spinocerebellar Ataxia Type 3; Machado-Joseph Disease

Keywords

Machado-Joseph Disease; Spinocerebellar Ataxia Type 3; SCA3; Biomarker; Natural history; Video-oculography; Eye movement; Surrogate biomarker; Oculomotor neurophysiology

Outcome Measures

Primary Outcomes (11)

• Change in vestibulo-ocular reflex gain regression slope (VORr)

  Gain (Eye velocity/Head velocity)

  24 months

• Change in vertical smooth pursuit gain

  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)

  Degrees/second

  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

  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

  24 months

• Change in slow-phase velocity of central nystagmus (SPV-C)

  Degrees/second

  24 months

• Change in Neurological Examination Score for Spinocerebellar Ataxia (NESSCA)

  Neurological examination score, varying between 0 and 40. Score increases with disease severity.

  24 months

• Change in SCA Functional Index (SCAFI)

  Composite score. Score decreases with disease severity.

  24 months

• Change in International Cooperative Ataxia Rating Scale (ICARS)

  Absolute score, varying between 0 and 100. Score increases with disease severity.

  24 months

• Change in Inventory of Non-Ataxia Symptoms (INAS) count

  Scale varying between 0 and 16. Score increases with disease severity.

  24 months

• Change in Composite Cerebellar Functional Severity Score (CCFS)

  Composite score. Score increases with disease severity.

  24 months

Secondary Outcomes (3)

• Change in horizontal smooth pursuit gain

  24 months

• Change in reflexive vertical saccade velocity (RVSV)

  24 months

• Change in volitional vertical saccade velocity (VVSV)

  24 months

Study Arms (3)

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; 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.

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.

Diagnostic Test: Video-oculography; Diagnostic Test: Clinical Scales; Diagnostic Test: Genotyping

Interventions

Video-oculography DIAGNOSTIC_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.

Ataxic carriers; Pre-ataxic carriers; Related controls

Clinical Scales DIAGNOSTIC_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).

Ataxic carriers; Pre-ataxic carriers; Related controls

Genotyping DIAGNOSTIC_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)

Pre-ataxic carriers; Related controls

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)
• 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.

You may qualify if:

• Individuals with molecular diagnosis of SCA3/MJD
• Individuals at 50% risk of inheriting SCA3/MJD mutation without any clinical manifestation

You may not qualify if:

• Other diagnosed neurological or vestibular condition
• Dyschromatopsia
• Refusal to sign informed consent

Sponsors & Collaborators

• Hospital de Clinicas de Porto Alegre: lead

Study Sites (1)

Universidade Federal do Rio Grande do Sul

Porto Alegre, Brazil

Location

Related Links

• BIGPRO study website

Biospecimen

Retention: SAMPLES WITH DNA

Whole blood, serum

MeSH Terms

Conditions

Machado-Joseph Disease

Interventions

Genotype

Condition Hierarchy (Ancestors)

Spinocerebellar Ataxias; Cerebellar Ataxia; Cerebellar Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Spinocerebellar Degenerations; Spinal Cord Diseases; Heredodegenerative Disorders, Nervous System; Neurodegenerative Diseases; Ataxia; Dyskinesias; Neurologic Manifestations; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities

Intervention Hierarchy (Ancestors)

Genetic Phenomena

Study Officials

• Laura Jardim

  Federal University of Rio Grande do Sul

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 7, 2020
• First Posted: January 18, 2020
• Study Start: March 28, 2017
• Primary Completion: December 1, 2020
• Study Completion: August 1, 2021
• Last Updated: July 9, 2020

Record last verified: 2020-07

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, ICF, CSR
• Time Frame: Data will become available after final statistical analysis and data publishing via direct contact with principal investigator
• Access Criteria: Investigators and researchers of the area

Locations

BR (1)