TreatHSPTreatHSP/SPAX: Natural History Study for Ataxias, Hereditary Spastic Paraplegias and Spastic Ataxias Progression and Biomarkers

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.