Phenotypes, Biomarkers and Pathophysiology in Spastic Ataxias

Spastic Ataxia Clinical Trial

— SPAX-PBP  

Official title:

Phenotypes, Biomarkers and Pathophysiology in Spastic Ataxias

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04297891
• Other study ID #: SPAX-PBP
• Secondary ID: 441409627
• Status: Recruiting
• Start date: September 1, 2020
• Est. completion date: June 2025

Study information

• Verified date: May 2022
• Source: University Hospital Tuebingen
• Contact: Rebecca Schüle, PD Dr.
• Phone: +49 7071 29
• Email: rebecca.schuele-freyer[@]uni-tuebingen.de
• Is FDA regulated: No
• Study type: Observational [Patient Registry]

Clinical Trial Summary

The aim of this study is to determine the clinical spectrum and natural progression of Spastic Ataxias (SPAX) and related disorders in a prospective multicenter natural history study, identify digital, imaging and molecular biomarkers that can assist in diagnosis and therapy development and study the genetic etiology and molecular mechanisms of these diseases.

Description:

The investigators will perform a registry-based standardized prospective Natural History Study (NHS) in SPAX and related disorders. Participants will be seen annually. At study visits a standardized clinical examination will be performed including application of clinical rating scales (selection of rating scales may vary depending on the individual phenotype and specific genotype); data will be entered into a clinical database (HSP Registry; https://www.hsp-registry.net and ARCA Registry; www.ARCA-registry.org). At all study visits, patients will be asked to donate biosamples; biomaterial collection is optional and participants can elect to participate in sampling of blood, urine, CSF, and/or a skin biopsy. Optionally, additional examinations may be performed including imaging, quantitative movement analysis, neuropsychological examinations, analysis of patient or observer reported outcomes and OMICS analysis to characterize molecular biomarkers. In participants without a genetic diagnosis, next generation sequencing may be performed. Thus this study will establish a model of disease progression and mechanistic evolution in SPAX, which will allow to track and understand selective as well as overlapping dysfunction of the cerebellum and corticospinal tract. In a transatlantic natural history study we will longitudinally validate clinician- and patient-reported, digital and molecular outcomes. In addition, we will improve on existing and develop new outcome parameters that show superior sensitivity to change. These include a novel clinical SPAX composite score, a smartphone mHealth toolbox combining remote assessment of daily living by wearable sensors with app-based patient-entered outcomes (SPAX.app), and multimodal MRI radiomics with an innovative machine learning approach for multisite MRI analysis, including in particular the infratentorial space. Longitudinal validation of targeted fluid biomarker candidates will aslo be an important part.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 250
• Est. completion date: June 2025
• Est. primary completion date: June 2024
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: N/A and older

Eligibility

Inclusion Criteria:

• ARSACS cohort: genetic diagnosis of ARSACS and clinically manifest disease
• SPG7 cohort: genetic diagnosis of SPG7 and clinically manifest disease
• Unrelated healthy controls: no signs or history of neurological or psychiatric disease AND
• written informed consent provided AND
• Participants are willing and able to comply with study procedures

Exclusion Criteria:

• Missing informed consent
• For controls: evidence of a neurodegenerative disease or movement disorders; inability to give informed consent

Related Conditions & MeSH terms

• Ataxia
• Cerebellar Ataxia
• Intellectual Disability
• Muscle Spasticity
• Optic Atrophy
• Spastic Ataxia
• Spinocerebellar Ataxias

Intervention

Other:
• Clinical rating scale to measure Ataxia disease severity and progression
SARA is a clinical scale developed by Schmitz-Hübsch et al which assesses a range of different impairments in cerebellar ataxia. The scale is made up of 8 items related to gait, stance, sitting, speech, finger-chase test, nose-finger test, fast alternating movements and heel-shin test.
• Clinical rating scale to measure spastic paraplegia disease severity and progression
A 13-item scale to rate functional impairment occurring in pure forms of spastic paraplegia (SP). Additional symptoms constituting a complicated form of SP are recorded in an inventory.
• Disease-specific severity index for adults with autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS)
The DSI-ARSACS is a valid measure of disease severity for the adult ARSACS population that is able to distinguish between patients with different clinical profiles. It considers the 3 components (pyramidal, cerebellar, neuropathic) of the disease, and documents its content validity, internal consistency, and construct validity.

Diagnostic Test:
• Next-Gen Sequencing (NGS)
Whole Genome Sequencing, Whole Exome Sequencing, Transcriptomics, Proteomics, Metabolomics

Locations

Country	Name	City	State
Canada	Montreal Neurological Institute of McGill University, Department of Neurology and Neurosurgery and Human Genetics	Montreal,	Quebec
Canada	Université de Sherbrooke	Saguenay	Quebec
France	Département d'information médicale (DIM); Département de Biostatistique, Santn 3emé Publique et Information Médicale (BIOSPIM)- Bâtiment Mazarie étage; Hôpitaux Universitaires Pitié Salpêtrière	Paris
Germany	University Hospital Essen (AöR)	Essen
Germany	Center for Neurology & Hertie-Institute for Clinical Brain Research, Dept. for Neurodegenerative Diseases	Tübingen	Baden-Württemberg
Italy	IRCCS Fondazione Stella Maris	Pisa
Netherlands	Radboud University Medical Center; Department of Neurology & Donders Institute for Brain, Cognition, and Behaviour	Nijmegen
Turkey	Koç Univ. Hospital, KUTTAMNDAL	Istanbul
United Kingdom	Department of Clinical Neurosciences, University of Cambridge; John Van Geest Cambridge Centre for Brain Repair	Cambridge

Sponsors (3)

Lead Sponsor	Collaborator
Dr. Rebecca Schule	German Center for Neurodegenerative Diseases (DZNE), German Research Foundation

Countries where clinical trial is conducted

Canada,  France,  Germany,  Italy,  Netherlands,  Turkey,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Change of the Patient-Reported Outcomes Measurement Information System (PROMIS) short form "physical function" 12a from baseline to 2-year follow-up	Self-report questionnaire comprising 12 questions. All PROMIS scores are standardized (item-level calibration) and expressed as T-scores with a population mean of 50 and a Standard Deviation (SD) of 10. Higher T-scores hereby indicate a higher physical function level.	24 months
Other	Change of the Patient-Reported Outcomes Measurement Information System (PROMIS) short form "social roles and activities" 8a from baseline to 2-year follow-up	Self-report questionnaire comprising 8 questions. All PROMIS scores are standardized (item-level calibration) and expressed as T-scores with a population mean of 50 and a Standard Deviation (SD) of 10. Higher T-scores hereby indicate a higher degree of social participation.	24 months
Primary	Change of Scale for the Assessment and Rating of Ataxia (SARA) from baseline to 2-year follow-up	Severity of the ataxia component of the disease will be assessed by application of the Scale for the Assessment and Rating of Ataxia (SARA). The total score is calculated as the sum of al items, yielding a total score between 0 and 38. Hereby, higher SARA scores indicate more severe disease.	24 months
Primary	Change of Spastic Paraplegia Rating Scale (SPRS) from baseline to 2-year follow-up	Severity of the spasticity component of the disease will be assessed by application of the Spastic Paraplegia Rating Scale. The total score is calculated as the sum of al items, yielding a total score between 0 and 52. Hereby, higher SPRS scores indicate more severe disease.	24 months
Secondary	Change of Disease severity index - Autosomal recessive spastic ataxia of Charlevoix-Saguenay(DSI-ARSACS) from baseline to 2-year follow-up	The DSI-ARSACS is a clinical rating scale consisting of 8 items reflecting the 3 main components of the disease (pyramidal, cerebellar, and neuropath systems) specifically developed to measure disease progression in ARSACs. The DSI-ARSACS total score can range from 0 to 38. Hereby, higher DSI-ARSACS scores indicate more severe disease.	24 months

External Links

•   Website of the ARCA Registry
•   Website of the HSP Registry