Clinical trial NCT04229823: Natural History of Oculomotor Neurophysiology in Ataxic and Pre-ataxic Carriers of SCA3/MJD
Official title: Natural History of Oculomotor Neurophysiology in Ataxic and Pre-ataxic Carriers of Machado-Joseph Disease/Spinocerebellar Ataxia Type 3 (SCA3/MJD)
Study type: OBSERVATIONAL
Overall status: UNKNOWN
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
Lead sponsor: Hospital de Clinicas de Porto Alegre
Sponsor class: OTHER
First posted: 2020-01-18
Enrollment: 95
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Observational model: COHORT
Time perspective: PROSPECTIVE
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.

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.

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.

Eligibility criteria: 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

Primary outcomes:
measure: Change in vestibulo-ocular reflex gain regression slope (VORr)
timeFrame: 24 months
measure: Change in vertical smooth pursuit gain
timeFrame: 24 months
measure: Change in slow-phase velocity of gaze evoked nystagmus (SPV-GE)
timeFrame: 24 months
measure: Change in the slope of peak duration versus amplitude of volitional vertical saccades
timeFrame: 24 months
measure: Change in the slope of peak duration versus amplitude of reflexive vertical saccades
timeFrame: 24 months
measure: Change in slow-phase velocity of central nystagmus (SPV-C)
timeFrame: 24 months
measure: Change in Neurological Examination Score for Spinocerebellar Ataxia (NESSCA)
timeFrame: 24 months
measure: Change in SCA Functional Index (SCAFI)
timeFrame: 24 months
measure: Change in International Cooperative Ataxia Rating Scale (ICARS)
timeFrame: 24 months
measure: Change in Inventory of Non-Ataxia Symptoms (INAS) count
timeFrame: 24 months
measure: Change in Composite Cerebellar Functional Severity Score (CCFS)
timeFrame: 24 months
Secondary outcomes:
measure: Change in horizontal smooth pursuit gain
timeFrame: 24 months
measure: Change in reflexive vertical saccade velocity (RVSV)
timeFrame: 24 months
measure: Change in volitional vertical saccade velocity (VVSV)
timeFrame: 24 months
Other outcomes:
Locations:
city: Porto Alegre
country: Brazil
facility: Universidade Federal do Rio Grande do Sul
Study officials:
affiliation: Federal University of Rio Grande do Sul
name: Laura Jardim
role: PRINCIPAL_INVESTIGATOR
References: