An observational study in Hereditary Spastic Paraplegia and Spastic Ataxia, sponsored by Heidelberg University. Recruiting at 30 sites in 9 countries. Open to participants aged 5 Years and older, including healthy volunteers. Per ClinicalTrials.gov, last updated 2026-09-01.
Sponsored by Heidelberg University · Observational
Ataxias, hereditary spastic paraplegias (HSP), and spastic ataxias (collectively referred to as SPAX diseases) are rare neurological conditions that cause progressive problems with walking, balance, coordination, and daily activities. Although many SPAX diseases are caused by specific genetic changes, there is still limited knowledge about how symptoms develop over time, how fast the diseases progress, and which clinical or biological measures best reflect meaningful changes for patients.
The TreatHSP Master Protocol establishes an adaptive natural history study platform designed to improve the understanding of SPAX diseases across all ages and disease stages. Within this platform, the TreatHSP/SPAX study serves as the core natural history study, providing a shared framework for long-term clinical follow-up, standardized outcome assessments, and biosample collection.
Participants enrolled in TreatHSP/SPAX are followed over time to document disease progression using clinical examinations, patient- and caregiver-reported outcomes, digital movement measures, imaging, and biological samples. In addition to this core dataset, the TreatHSP Platform allows optional, disease- or hypothesis-specific substudies to be added over time in selected participant groups. These additional assessments are introduced under the same master protocol, without creating separate stand-alone studies.
The overall goal of the TreatHSP Master Protocol is to generate high-quality natural history data, identify sensitive and patient-relevant outcome measures, and support the development of future therapies for ataxias, hereditary spastic paraplegias, and spastic ataxias.
Overview and Objectives: The TreatHSP Protocol defines an adaptive observational study platform for natural history research, outcome development, and biomarker discovery in ataxias, hereditary spastic paraplegias (HSP), and spastic ataxias (SPAX diseases). The platform is designed to support longitudinal, regulatory-grade data collection across genetically and clinically heterogeneous rare neurological disorders.
Within the TreatHSP platform, TreatHSP/SPAX represents the core natural history study. All participants are enrolled into TreatHSP/SPAX and undergo a standardized set of core assessments, forming the backbone of the platform. Additional disease- or hypothesis-specific investigations may be conducted within the same platform framework.
The primary objectives of the TreatHSP platform are to:
Characterize the longitudinal clinical course of SPAX diseases across genotypes, ages, and disease stages.
Identify, develop, and validate patient-relevant clinical outcome assessments. Discover and validate molecular, imaging, digital, and functional biomarkers relevant for disease progression, prognosis, and therapy development.
Establish a harmonized data and biosample resource to support clinical trial readiness and secondary research.
Adaptive Platform Design: The TreatHSP Master Protocol follows design principles analogous to interventional platform trials, adapted for observational research. A single master protocol governs all study activities, including governance, ethics, consent, data protection, and quality assurance.
The TreatHSP/SPAX core natural history study defines:
Core eligibility principles Mandatory clinical, functional, and patient-reported assessments Standardized biosample collection Common data elements and anchor outcome measures
Within this framework, additional adaptive Natural History Study appendices may be introduced as protocol amendments. These appendices add optional assessments (e.g. digital mobility monitoring, advanced imaging, biomarker studies) in predefined participant subsets, while preserving the integrity of the core cohort and dataset.
This adaptive design enables parallel investigation of multiple disease subgroups and research questions under a single, continuously evolving protocol.
Study Population:
The platform includes:
Individuals of all ages with a clinical or genetic diagnosis of an ataxia, hereditary spastic paraplegia, or spastic ataxia, including presymptomatic mutation carriers.
Selected affected or unaffected family members. Healthy unrelated control participants for selected analyses.
Registry Procedures and Quality Assurance:
The TreatHSP/SPAX core study functions as a structured patient registry within the TreatHSP Platform and follows predefined quality standards.
Data Collection and Validation:
Data are collected using standardized electronic case report forms. Automated data checks are applied to ensure validity, plausibility, and internal consistency. Queries are generated and resolved by trained study personnel.
Source Data Verification:
Data entered into the registry may be verified against source documents (e.g. medical records, imaging reports, laboratory data) using a risk-based and sample-based approach.
Data Dictionary:
A comprehensive data dictionary defines all variables collected within the platform, including variable definitions, data sources, coding standards (e.g. Human Phenotype Ontology, MedDRA where applicable), and reference ranges when relevant.
Standard Operating Procedures:
Standard Operating Procedures govern patient recruitment, informed consent, data collection, data management, biosample handling, quality control, statistical analysis, reporting, and change management for adaptive protocol amendments.
Monitoring and Auditing:
Central data monitoring and periodic site-level reviews are conducted to ensure data quality, protocol adherence, and compliance with ethical and regulatory requirements.
Sample Size and Statistical Considerations:
Due to the rarity and heterogeneity of SPAX diseases, the TreatHSP Platform does not define a fixed sample size. Enrollment is open-ended to ensure broad representation across disease subtypes. Statistical analyses are primarily longitudinal and descriptive, with detailed analysis plans defined for specific substudies as needed.
Handling of Missing Data:
Missing data are explicitly documented and categorized. Statistical analyses account for missing data using appropriate longitudinal methods and sensitivity analyses, depending on the research question.
Data Protection and Governance:
All data are pseudonymized and handled in accordance with applicable data protection regulations. Access to identifiable information is restricted to authorized personnel. Data sharing for secondary research is governed by defined access procedures and ethical approvals.
50 studies on the registry are indexed under Spastic Paraplegia, Hereditary; 19 are open to participants now.
This study's planned enrollment of 4,000 is above the median of 100 across 25 observational studies indexed under Spastic Paraplegia, Hereditary.
Browse Spastic Paraplegia, Hereditary studies →Heidelberg University is the lead sponsor of 287 studies on the registry; 19 are open to participants now.
Counted across the registry records on this site, refreshed daily.
Children, adolescents, and adults aged 5 years and older are recruited through multicenter, international participation from specialized neurology and genetics clinics, patient registries, affected families, and the general community. The study includes individuals with ataxia, spastic ataxia, hereditary spastic paraplegia, or related phenotypes; presymptomatic mutation carriers; first- or second-degree relatives of affected individuals; and neurologically healthy community controls.
Go through the criteria one by one — yes, no or not sure — and take the list to your doctor or the study team. Kept in this browser only.
General inclusion criteria:
- Age 5 or older
Cohort 1: Affected
Cohort 2: Presymptomatic mutation carriers
- Premanifest mutation carrier of (likely) pathogenic variant(s) in a disease gene associated with ataxia, spastic ataxia, HSP or related phenotype
Cohort 3: Family controls - 1st or 2nd degree relative of a person with a clinical or genetic diagnosis of ataxia, spastic ataxia, HSP or related phenotype
Cohort 4: Community controls
- Healthy individual unrelated to a person with neurodevelopmental or neurodegenerative ataxia, spastic ataxia, HSP or related phenotype
Exclusion Criteria:
Underlined terms in the criteria open these too. Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Before you join, the study team explains what taking part involves — its purpose, what happens, the risks and possible benefits — and answers your questions, so you can decide freely. Consent is usually recorded on a form (the informed consent form, ICF) signed by you or, where the law allows, by someone legally authorised to decide for you.
You can keep asking questions during the study, you are told of new information that matters, and you can choose to leave at any time.
Informed consent
Before you join, the study team explains what taking part involves — its purpose, what happens, the risks and possible benefits — and answers your questions, so you can decide freely. Consent is usually recorded on a form (the informed consent form, ICF) signed by you or, where the law allows, by someone legally authorised to decide for you.
You can keep asking questions during the study, you are told of new information that matters, and you can choose to leave at any time.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Clinical diagnosis of neurodevelopmental or neurodegenerative ataxia, spastic ataxia, HSP and alternative cause of phenotype excluded
Premanifest mutation carrier of (likely) pathogenic variant(s) in a disease gene associated with ataxia, spastic ataxia, HSP or related phenotype
1st or 2nd degree relative of a person with a clinical or genetic diagnosis of ataxia, spastic ataxia, HSP or related phenotype (group: Affected)
Healthy individual unrelated to a person with neurodevelopmental or neurodegenerative ataxia, spastic ataxia, HSP or related phenotype
Modified Spastic Paraplegia Rating Scale
The modified Spastic Paraplegia Rating Scale (mSPRS) is a clinician-reported outcome measure assessing disease severity in hereditary spastic paraplegia and related spastic movement disorders. It evaluates functional mobility, spasticity, muscle strength, pain and bladder function. The mSPRS is adapted from the original Spastic Paraplegia Rating Scale to improve feasibility and sensitivity to change in longitudinal studies. It can be applied in individuals aged 5 years and older, with higher scores indicating greater disease severity. The mSPRS serves as the primary outcome measure for the assessment of disease severity in all participants with hereditary spastic paraplegia.
Time frame: Through study completion, an average of 5 years, measured annually
Scale for the Assessment and Rating of Ataxia (SARA)
The Scale for the Assessment and Rating of Ataxia (SARA) is a standardized clinician-reported outcome measure used to quantify the severity of ataxia. It assesses key domains including gait, stance, sitting, speech disturbance, limb coordination, and fine motor control. The SARA provides a global measure of ataxia-related motor impairment and is widely used in both clinical practice and longitudinal research studies. The SARA is applied in study participants aged 8 years and older, with higher scores indicating greater ataxia severity. The SARA serves as the primary outcome measure for the assessment of disease severity in all participants with ataxia.
Time frame: Through study completion, an average of 5 years, measured annually
SPAX Composite Scale (SPAXCOM)
SPAXCOM is a clinician-reported composite outcome measure developed to assess disease severity in individuals with spastic ataxia. It integrates key motor and functional domains relevant to spastic-ataxic phenotypes, including gait and balance, coordination, spasticity, and functional mobility. SPAXCOM is designed to capture the combined contribution of pyramidal and cerebellar dysfunction and to provide a sensitive measure of disease severity and progression in spastic ataxia. Higher scores indicate greater disease severity. SPAXCOM serves as the primary outcome measure for participants with spastic ataxia.
Time frame: Through study completion, an average of 5 years, measured annually
Friedreich Ataxia Rating Scale - Activities of Daily Living (FARS-ADL)
The Friedreich Ataxia Rating Scale - Activities of Daily Living (FARS-ADL) assesses the impact of neurological impairment on everyday functioning, including walking, balance, speech, hand function, and self-care. In this study, both a clinician-reported (ClinRO) version and a patient-reported (PROM) version of the FARS-ADL are used to capture functional limitations from complementary perspectives and are applied in study participants aged 8 years and older. Although originally developed for Friedreich ataxia, the FARS-ADL is applicable across a range of ataxic and spastic movement disorders. Higher scores indicate greater functional impairment and reduced independence in daily activities.
Time frame: Through study completion, an average of 5 years, measured annually
Inventory of Non-Ataxia Signs - PLUS (INAS-PLUS)
INAS-PLUS is a clinician-reported inventory, derived from the original Inventory of Non-Ataxia Signs (INAS) and expanded by additional items, used to quantify the burden of neurological signs beyond core ataxia features in spastic and spastic-ataxic disorders.
Time frame: Through study completion, an average of 5 years, measured annually
MRC Sum Score for Muscle Strength
The Medical Research Council (MRC) Sum Score is a clinician-reported measure of global muscle strength based on standardized manual muscle testing across selected muscle groups. Individual muscle grades are summed to provide an overall estimate of muscle strength, with lower scores indicating greater weakness.
Time frame: Through study completion, an average of 5 years, measured annually
TreatHSP Quality of Life (TreatHSP-QoL)
The TreatHSP Quality of Life (TreatHSP-QoL) questionnaire is a disease-specific patient-reported outcome measure assessing health-related quality of life, including physical, functional, and psychosocial aspects, and is used in adults aged 18 years and older with hereditary spastic paraplegia and spastic ataxia.
Time frame: Through study completion, an average of 5 years, measured annually
Caregiver Priorities and Child Health Index of Life with Disabilities (CPCHILD)
The Caregiver Priorities and Child Health Index of Life with Disabilities (CPCHILD) is a caregiver-reported outcome measure developed for children and adolescents with motor disabilities. In this study, the CPCHILD is applied in all children aged 5 to 12 years, as well as in older individuals with cognitive impairment who are unable to reliably complete self-reported questionnaires.
Time frame: Through study completion, an average of 5 years, measured annually
FARS Functional Staging
The Friedreich Ataxia Rating Scale - Functional Staging (FARS-FS) is an ordinal measure of functional disease severity based on mobility and independence in activities of daily living. In this study, both a clinician-reported (ClinRO) version and a patient-reported (PROM) version of the FARS-FS are used to capture functional status from complementary perspectives. The FARS-FS serves as an anchor measure to support the determination and interpretation of clinically meaningful change in primary and secondary outcome measures over time.
Time frame: Through study completion, an average of 5 years, measured annually
SPATAX Disability Stage
SPATAX Disability Stage is a clinician-reported ordinal staging system that categorizes overall disability based on mobility and functional dependence. It provides a global measure of disease severity and is used in this study as an anchor measure to support the interpretation of clinically meaningful change in primary and secondary outcomes.
Time frame: Through study completion, an average of 5 years, measured annually
Clinical Global and Domain-Specific Impression of Severity and Change (CGI-S/CGI-C)
Clinical Global and Domain-Specific Impression of Severity and Change are clinician-reported assessments capturing overall disease severity and longitudinal change, as well as change within specific functional domains. The selected domains reflect disease impacts prioritized by individuals with SPAX diseases for their relevance to everyday life. These measures are used as anchor measures to contextualize and determine meaningful change in primary and secondary outcome measures.
Time frame: Through study completion, an average of 5 years, measured annually
Patient-reported Global and Domain-Specific Impression of Severity and Change (PGI-S / PGI-C)
Patient-reported Global and Domain-Specific Impression of Severity and Change are self-reported assessments capturing overall disease severity and longitudinal change, as well as change within specific functional domains. The selected domains reflect disease impacts prioritized by individuals with SPAX diseases for their relevance to everyday life. These patient-reported measures are used as anchor measures to support the interpretation and determination of clinically meaningful change in primary and secondary outcome measures.
Time frame: Through study completion, an average of 5 years, measured annually
Functional Mobility Scale (FMS)
The Functional Mobility Scale (FMS) is a clinician-reported measure of functional walking ability that classifies mobility across different distances and everyday environments. It provides an ordinal assessment of functional mobility and is used in this study as an anchor measure to support the interpretation of clinically meaningful change in primary and secondary outcome measures.
Time frame: Through study completion, an average of 5 years, measured annually
The Gross Motor Function Classification - MLD (GMFC-MLD)
The Gross Motor Function Classification - MLD (GMFC-MLD) is a clinician-reported ordinal classification system used to describe gross motor function and mobility limitations in children. It categorizes functional abilities based on age-appropriate motor skills and need for assistance. In this study, the GMFC-MLD is used as an anchor measure to support the interpretation of clinically meaningful change in outcome measures in children aged 5 to 12 years.
Time frame: Through study completion, an average of 5 years, measured annually
TreatHSP Mobility Questionnaire
The Mobility Change Questionnaire is a patient- or observer-reported anchor measure assessing perceived change in walking ability over the preceding week compared with the previous study visit. It captures mobility-related domains including walking distance and speed, effort, balance confidence, fear of falling, and overall walking ability. Depending on age and cognitive status, the questionnaire is completed by the participant or an observer and is used to support the interpretation of clinically meaningful change in primary and secondary outcome measures.
Time frame: Through study completion, an average of 5 years, measured annually
Achievement of developmental milestones
Achievement of key developmental motor milestones (unsupported sitting, unsupported standing, assisted walking, unsupported walking) will be assessed via caregiver/patient report. For each milestone, achievement status will be recorded as yes/no/unknown. Age at achievement will be reported in months for milestones confirmed as achieved. Where an exact age cannot be recalled, this will be noted as either delayed-but-unrecalled or achieved-at-normal-age-but-unrecalled.
Time frame: Through study completion, an average of 5 years, measured annually
Milestone regression
Loss of previously achieved motor function will be assessed via caregiver/patient report across four regression milestones: new requirement for sitting support, new requirement for standing support, new requirement for a walking aid (used for \>50% of walking activity), and new requirement for a wheelchair (used for \>50% of locomotion). For each milestone, status will be recorded as yes/no/unknown, with the calendar year of onset documented where applicable.
Time frame: Through study completion, an average of 5 years, measured annually
Plan to share: Yes — De-identified individual participant data collected within the TreatHSP Master Protocol may be shared for secondary research purposes. Data eligible for sharing include selected clinical, functional, patient-reported, digital, imaging, and biomarker data generated within the TreatHSP/SPAX core study and approved adaptive substudies. Data sharing is subject to approval through the TreatHSP governance framework and requires submission of a scientific proposal, review by the Steering Committee, and execution of a data use agreement. Only pseudonymized data will be shared, and access will be limited to the minimum dataset necessary to address the approved research question. Data sharing will occur in compliance with applicable data protection regulations and participant consent.
Supporting information: Study protocol
Time frame: Beginning January 2026 with no end date.
Access criteria: Access requests must be submitted as a research proposal describing the planned analyses and required data elements. Requests are reviewed by the TreatHSP Steering Committee or a delegated data access body based on scientific merit, feasibility, and compliance with ethical and data protection requirements. Approved requests require a data use agreement, and access is limited to the minimum dataset necessary for the approved analyses.
Started Jul 2024 (actual). Primary completion is estimated for Dec 2035, 137 months after the start.
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