Clinical Trials Logo

Clinical Trial Details — Status: Active, not recruiting

Administrative data

NCT number NCT04419974
Other study ID # 20170014
Secondary ID
Status Active, not recruiting
Phase
First received
Last updated
Start date March 18, 2017
Est. completion date August 2021

Study information

Verified date June 2020
Source Hospital de Clinicas de Porto Alegre
Contact n/a
Is FDA regulated No
Health authority
Study type Observational

Clinical Trial Summary

The study will consist of a prospective observation of subjects in a natural history design. The investigators will monitor changes of clinical scales, quality of life, messenger ribonucleic acid (mRNA) of candidate genes (CCL11, TNFSF14, FCGR3B, CLC, and SLA) (and their peptide products, when possible), and eotaxin and S100B serum levels, in order to determine which of them is (are) the most sensitive. Participants will be stratified in three groups: ataxic carriers, pre-ataxic carriers and non-carriers (controls).


Description:

Spinocerebellar ataxia type 3, or Machado-Joseph disease (SCA3/MJD), is an autosomal dominant neurodegenerative disorder caused by a CAG expansion at ATXN3. The gene product is a 42kDa protein called ataxin-3, widely expressed in neurons and peripheral tissues. Physiological roles of ataxin-3 include, at least, ubiquitination and regulation of misfolded proteins, cytoskeletal organization and focal adhesions development, and transcriptional regulation, most often as a transcriptional corepressor. One purpose of the present study is to detect a possible association between altered transcription patterns of candidate genes and disease progression. On the other hand, previous evidences suggest that the disease process linked to polyQ aggregation in neuronal cell ("cell-autonomous process") might be worsened by what happens outside the neuronal cell ("non-cell-autonomous process"). Initial evidences lead to the role of astrocytes. This is a major depart from the traditional understanding of polyglutamine diseases, and comprises the main focus of the present study.

The main hypothesis of this study is that the SCA3/MJD clinical features may be in part associated to astrocytic processes. In order to test it, peripheral level of LIGHT protein (encoded by TNFSF14) and eotaxin (encoded by CCL11) - both expressed in astrocytes -, and of S100B (a myelin damage marker), will be measured. The investigators speculate if they can be biomarkers of disease progression and of pathological process, even before symptoms onset. In case this is positive, their responsiveness to change will be tested to check if it is better than those of clinical scales.

The second aim is to test if disease progression can be associated with changes in the transcriptional pattern of candidate genes FCGR3B, CLC and SLA.

"BIGPRO study - Astrocytes" intends to identify variations in these candidates and validate them as SCA3/MJD biomarkers. The study will consist of a prospective observation of subjects in a natural history design. Changes in clinical scales, quality of life, messenger ribonucleic acid (mRNA) of candidate genes (CCL11, TNFSF14, FCGR3B, CLC, and SLA) (and their peptide products, when possible), and eotaxin and S100B serum levels will be monitored in order to determine which of them is (are) the most sensitive. Participants will be stratified in three groups: ataxic carriers, pre-ataxic carriers and non-carriers (controls). For each asymptomatic carrier, the time until start of disease will be estimated according to the individual CAG expanded sequence (CAGexp) and subject's age. Clinical scales Scale for the Assessment and Rating of Ataxia (SARA), Neurological Examination Scale for SCA (NESSCA), International Co-operative Rating Scale (ICARS), Inventory of Non-ataxia Symptoms (INAS), SCA Functional Index (SCAFI), Composite Cerebellar Functional Severity Score (CCFS) and Quality of Life measurements (EQ-5D and SF-36), will be applied at baseline, at 12 months and at 24 months, in all subjects (all three groups). Eotaxin, TNFSF14, S100B and mRNAs, will be measured in the same moments. Progression rates of all these variables will be estimated through mixed-models, including, as covariates, age, group and their interactions.


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:

- Refusal to sign informed consent

- Other diagnosed neurological conditions;

- Diabetes Mellitus;

- Chronic allergy (asthma, eczema, urticaria)

- Eosinophilia on baseline

Study Design


Intervention

Diagnostic Test:
Molecular Diagnosis
Double-blind molecular diagnosis for the SCA3/MJD mutation.
Clinical Scales - Baseline
SARA, NESSCA, ICARS, INAS, SCAFI, CCFS will be applied on baseline.
Blood Draw - Baseline
Blood collection on baseline for evaluation of Candidate genes expression Serum proteins Lymphocytic proteins
Quality of Life Assessment - Baseline
Participants fill out 2 self-reported quality of life questionnaires.
Clinical Scales - Follow-up 12 months
SARA, NESSCA, ICARS, INAS, SCAFI, CCFS will be applied 12 months after baseline for prospective evaluation.
Blood Draw - Follow-up 12 months
Blood collection 12 months after baseline for prospective evaluation of Candidate genes expression Serum proteins Lymphocytic proteins
Quality of Life Assessment - Follow-up 12 months
Participants fill out 2 self-reported quality of life questionnaires for prospective evaluation.
Clinical Scales - Follow-up 24 months
SARA, NESSCA, ICARS, INAS, SCAFI, CCFS will be applied 24 months after baseline for prospective evaluation.
Blood Draw - Follow-up 24 months
Blood collection 24 months after baseline for prospective evaluation of Candidate genes expression Serum proteins Lymphocytic proteins
Quality of Life Assessment - Follow-up 24 months
Participants fill out 2 self-reported quality of life questionnaires for prospective evaluation.

Locations

Country Name City State
Brazil Hospital de Clinicas de Porto Alegre Porto Alegre Rio Grande Do Sul

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 serum concentrations of Eotaxin pg/ml 24 months
Primary Change in serum concentrations of S100B µg/l 24 months
Primary Change in expression of TNFSF14 Fold change (FC) 24 months
Primary Change in expression of CCL11 Fold change (FC) 24 months
Primary Change in EQ-5D-3L (EuroQoL 5 Domains evaluated in 3 levels) Quality of life scale evaluating 5 domains and a visual analog scale. Domain scores increase with worsening in quality of life. In the visual analog scale, worse scores mean decrease in quality of life. 24 months
Primary Change in SF-36 (Short-form 36) Quality of life scale evaluating 8 domains through 36 questions. Domain scores decrease with worsening in quality of life. 24 months
Secondary Change in expression of FCGR3B Fold change (FC) 24 months
Secondary Change in expression of CLC Fold change (FC) 24 months
Secondary Change in expression of SLA Fold change (FC) 24 months
See also
  Status Clinical Trial Phase
Completed NCT00992771 - Study to Determine the Safety and Tolerability of Varenicline (Chantix®) in Treating Spinocerebellar Ataxia Type 3 Phase 2
Completed NCT01096082 - Safety and Efficacy of Lithium Carbonate in Patients With Spinocerebellar Ataxia Type 3 Phase 2/Phase 3
Active, not recruiting NCT03701399 - Troriluzole in Adult Subjects With Spinocerebellar Ataxia Phase 3
Active, not recruiting NCT04229823 - Natural History of Oculomotor Neurophysiology in Ataxic and Pre-ataxic Carriers of SCA3/MJD
Terminated NCT05490563 - STRIDES - a Clinical Research Study of an Investigational New Drug to Treat Spinocerebellar Ataxia Phase 2/Phase 3
Withdrawn NCT04301284 - Study of CAD-1883 for Spinocerebellar Ataxia Phase 2
Withdrawn NCT01096095 - Pilot Study of Safety and Efficacy of Sodium Phenylbutyrate in Spinocerebellar Ataxia Type 3 Phase 2
Active, not recruiting NCT04268147 - Instrumented Data Exchange for Ataxia Study
Recruiting NCT01793168 - Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford
Active, not recruiting NCT05826171 - Priming Motor Learning Through Exercise in People With Spinocerebellar Ataxia N/A
Recruiting NCT04399265 - Efficacy Of Oral Trehalose In Spinocerebellar Ataxia 3 N/A
Completed NCT03885167 - Identification of Biomarkers in Spinocerebellar Ataxia 3
Terminated NCT05160558 - A Pharmacokinetics and Safety Study of BIIB132 in Adults With Spinocerebellar Ataxia 3 Phase 1
Recruiting NCT05822908 - A Safety and Pharmacokinetics Trial of VO659 in SCA1, SCA3 and HD Phase 1/Phase 2
Not yet recruiting NCT03378414 - Umbilical Cord Mesenchymal Stem Cells Therapy (19#iSCLife®-SA) for Patients With Spinocerebellar Ataxia Phase 2
Completed NCT05502432 - Repetitive Transcranial Magnetic Stimulation in SCA3 Patients N/A
Recruiting NCT04714307 - Neuropsychiatry and Cognition in SCA3/MJD
Recruiting NCT05557786 - Treatment of Transcranial Alternating Current Stimulation(tACS)on Cerebellar Ataxia
Recruiting NCT01060371 - Natural History Study of and Genetic Modifiers in Spinocerebellar Ataxias

External Links