Clinical trial NCT04297891: Phenotypes, Biomarkers and Pathophysiology in Spastic Ataxias
Official title: Phenotypes, Biomarkers and Pathophysiology in Spastic Ataxias
Study type: OBSERVATIONAL
Overall status: UNKNOWN
Conditions: Spastic Ataxia
Keywords: Spastic Ataxia
Biomarker
Genetic etiology
Molecular mechanisms
Natural History Study
Lead sponsor: University Hospital Tuebingen
Sponsor class: OTHER
Collaborators: name: German Center for Neurodegenerative Diseases (DZNE)
name: German Research Foundation
First posted: 2020-03-06
Enrollment: 250
Sex: ALL
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Probands with clinically manifest and genetically confirmed spastic ataxia (genetic subtypes: ARSACS, SPG7) will be enrolled in this study. Additionally, healthy unrelated controls will be enrolled; these are necessary to contrast unspecific, gender- or age-related findings to disease specific findings.

Brief 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.

Detailed 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.

Eligibility criteria: 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

Primary outcomes:
measure: Change of Scale for the Assessment and Rating of Ataxia (SARA) from baseline to 2-year follow-up
timeFrame: 24 months
measure: Change of Spastic Paraplegia Rating Scale (SPRS) from baseline to 2-year follow-up
timeFrame: 24 months
Secondary outcomes:
measure: Change of Disease severity index - Autosomal recessive spastic ataxia of Charlevoix-Saguenay(DSI-ARSACS) from baseline to 2-year follow-up
timeFrame: 24 months
Other outcomes:
measure: Change of the Patient-Reported Outcomes Measurement Information System (PROMIS) short form "physical function" 12a from baseline to 2-year follow-up
timeFrame: 24 months
measure: Change of the Patient-Reported Outcomes Measurement Information System (PROMIS) short form "social roles and activities" 8a from baseline to 2-year follow-up
timeFrame: 24 months
Locations:
city: Montreal,
country: Canada
facility: Montreal Neurological Institute of McGill University, Department of Neurology and Neurosurgery and Human Genetics
state: Quebec
city: Saguenay
country: Canada
facility: Université de Sherbrooke
state: Quebec
city: Paris
country: France
facility: Département d'information médicale (DIM); Département de Biostatistique, Santn 3emé Publique et Information Médicale (BIOSPIM)- Bâtiment Mazarie étage; Hôpitaux Universitaires Pitié Salpêtrière
city: Tübingen
country: Germany
facility: Center for Neurology & Hertie-Institute for Clinical Brain Research, Dept. for Neurodegenerative Diseases
state: Baden-Württemberg
city: Essen
country: Germany
facility: University Hospital Essen (AöR)
city: Pisa
country: Italy
facility: IRCCS Fondazione Stella Maris
city: Nijmegen
country: Netherlands
facility: Radboud University Medical Center; Department of Neurology & Donders Institute for Brain, Cognition, and Behaviour
city: Istanbul
country: Turkey
facility: Koç Univ. Hospital, KUTTAMNDAL
city: Cambridge
country: United Kingdom
facility: Department of Clinical Neurosciences, University of Cambridge; John Van Geest Cambridge Centre for Brain Repair
Study officials:
affiliation: University Hospital Tübingen
name: Rebecca Schüle, PD Dr.
role: PRINCIPAL_INVESTIGATOR
affiliation: University Hospital Tübingen
name: Matthis Synofzik, Prof., Dr.
role: PRINCIPAL_INVESTIGATOR
References: