PROSPAX: An integrated multimodal progression chart in spastic ataxias

Spastic ataxias (SPAX) represent a rapidly growing group of >100 rare
neurodegenerative genetic diseases (prevalence 10-15/100.000) with joined
affection of the cerebellum and corticospinal tract (CST), They often manifest
early in life, with devastating chronically progressive consequences on daily
life while treatment options are limited to symptom relief. The two most common
SPAX disease are Autosomal-recessive Spastic Ataxia Charlevoix Saguenay
(ARSACS) and SPG7, accounting for about 10-60% of all SPAX patients. Recent
genetic advances facilitate the development of targeted molecular therapies and
pave the way towards a precision medicine approach of SPAX.

However, effective trial-planning in SPAX diseases is hampered by several
challenges. First of all, SPAX patients and clinical data or biomarker
collections are fragmented. There are limited numbers of patients per center
and per disease, often scattered over large geographic areas. Besides, clinical
assessments are non-standardized and biomaterial or brain imaging collections
are small, decentralized and unconnected. Second, there is lack of
SPAX-specific, longitudinally validated outcome measures and a complete lack of
digital and patient-reported outcomes. Although PROSPAX partners have developed
and validated the two main clinical rating scales capturing ataxia and
spasticity (Scale for the Assessment and Rating of Ataxia (SARA) and Spastic
Paraplegia Rating Scale (SPRS), respectively, the sensitivity of these measures
to track and understand overlapping dysfunction of the cerebellum and CST can
be further increased. Besides, models of disease progression in SPAX, capturing
the relative dynamics of outcome measure changes over the course of the
disease, are lacking.

Therefore the aim of this study is to longitudinally validate existing disease
markers and develop novel clinical, digital, imaging and molecular outcome
measures specifically tailored to cerebellar and CST dysfunction, in a cohort
of ARSACS and SPG7 patients.

Primary Objective:
• To chart longitudinal disease progression rates for SPG7 and ARSACS by a
multisite, prospective natural history study.

Secondary Objective(s):
• Development of a new clinical SPAX composite scale.
• To identify (a combined set of) clinical and non-clinical markers (PROMs,
MRI, clinical assessments, biochemical markers) most sensitive to change over
time in SPAX patients in comparison with controls.
• To map the effects of disease progression during daily living with SPAX by
creating and validating a mobile toolbox (SPAX.app) of digital, smartphone and
wristband sensor-based performance measures of daily living that will capture
patient-centered outcomes (PCOM) of daily living with SPAX.

This prospective cohort study will capture the natural history of Dutch spastic
ataxia patients over the course of 4 years. We will include 15 SPAX patients
and 5 matched healthy controls. All study participants will undergo detailed
annual assessments at baseline, 1 year after baseline and 2 years after
baseline. After three and four years, the participants will have a telephone
consultation to administer a set of questionnaires. Besides, participant will
participate in the development of the SPAX.app. They will undergo an extra
assessment in the gait and balance lab of the Rehabilitation department and
will participate in self-assessment of the SPAX.app in their homesetting (6
weeks for healthy controls, +-30 weeks for SPAX patients)

Participants will visit the study centre once a year for two consecutive years.
These three visits include a clinical and motor assessment (validated ataxia
and spasticity-scales and sensor-based quantitive assessment of motor deficits)
MRI (60min) scans. Blood samples will be acquired at each visit. Besides
patients will complete questionnaires from PROMIS®, which stands for Patient
Reported Outcomes Measurement Information System. Measuring patient-reported
health status for physical, mental, and social well-being. After three and four
years, the participants will have a telephone consultation to administer a set
of questionnaires (FARS-ADL and PGI-C).

For development of SPAX.app, patients will visit the gait and balance lab of
the Rehabilitation department once, and will participate in self-assessment of
the SPAX.app in their homesetting (6 weeks for healthy controls, +-30 weeks for
SPAX patients)