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

Spinocerebellar Ataxia Type 3 Clinical Trial

— BIGPRO  

Official title:

Natural History of Oculomotor Neurophysiology in Ataxic and Pre-ataxic Carriers of Machado-Joseph Disease/Spinocerebellar Ataxia Type 3 (SCA3/MJD)

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT04229823
• Other study ID #: 2017-0015
• Status: Active, not recruiting
• Start date: March 28, 2017
• Est. completion date: August 2021

Study information

• Verified date: July 2020
• Source: Hospital de Clinicas de Porto Alegre
• Contact: n/a
• Is FDA regulated: No
• Study type: Observational

Clinical 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). 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.

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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 95
• Est. completion date: August 2021
• Est. primary completion date: December 2020
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Ataxia
• Cerebellar Ataxia
• Machado-Joseph Disease
• Spinocerebellar Ataxia Type 3
• Spinocerebellar Ataxias
• Spinocerebellar Degenerations

Intervention

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.
• 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).
• 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)

Locations

Country	Name	City	State
Brazil	Universidade Federal do Rio Grande do Sul	Porto Alegre

Sponsors (1)

Lead Sponsor	Collaborator
Hospital de Clinicas de Porto Alegre

Country where clinical trial is conducted

Brazil, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change in vestibulo-ocular reflex gain regression slope (VORr)	Gain (Eye velocity/Head velocity)	24 months
Primary	Change in vertical smooth pursuit gain	Regression slope of eye velocity versus target velocity during vertical smooth pursuit task	24 months
Primary	Change in slow-phase velocity of gaze evoked nystagmus (SPV-GE)	Degrees/second	24 months
Primary	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
Primary	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
Primary	Change in slow-phase velocity of central nystagmus (SPV-C)	Degrees/second	24 months
Primary	Change in Neurological Examination Score for Spinocerebellar Ataxia (NESSCA)	Neurological examination score, varying between 0 and 40. Score increases with disease severity.	24 months
Primary	Change in SCA Functional Index (SCAFI)	Composite score. Score decreases with disease severity.	24 months
Primary	Change in International Cooperative Ataxia Rating Scale (ICARS)	Absolute score, varying between 0 and 100. Score increases with disease severity.	24 months
Primary	Change in Inventory of Non-Ataxia Symptoms (INAS) count	Scale varying between 0 and 16. Score increases with disease severity.	24 months
Primary	Change in Composite Cerebellar Functional Severity Score (CCFS)	Composite score. Score increases with disease severity.	24 months
Secondary	Change in horizontal smooth pursuit gain	Gain (Eye velocity/Target velocity)	24 months
Secondary	Change in reflexive vertical saccade velocity (RVSV)	Degrees/second	24 months
Secondary	Change in volitional vertical saccade velocity (VVSV)	Degrees/second	24 months

External Links

•   BIGPRO study website