REAL-MS: Observational Database Study of AHSCT and MS Therapies

REAL-MS is a multicentre, observational, longitudinal, database-based cohort study designed to evaluate the comparative effectiveness and safety of AHSCT and high-efficacy disease-modifying therapies (H-DMTs) in adults with multiple sclerosis (MS) treated in routine clinical practice. The principal comparison is AHSCT versus H-DMTs; clinically relevant comparisons between individual H-DMTs may also be undertaken where data quality, follow-up duration, and sample size are sufficient. The study addresses the need for longer-term comparative evidence from real-world clinical settings. Treatment allocation is not determined by the protocol. Decisions about treatment initiation, discontinuation, switching, and other aspects of clinical management remain the responsibility of the treating clinical team and patient as part of usual care. No additional treatment, investigations, or clinical visits are required solely for research purposes. The registry includes retrospective and prospective components. The retrospective component includes eligible patients treated between 1 January 2008 and 31 January 2025 whose information is available in authorised local clinical audit datasets or previously approved research datasets. Relevant data are extracted locally by authorised staff and transferred in anonymised form to the central study database. The prospective component is planned to begin in October 2026 and will collect longitudinal information from eligible participants during routine clinical follow-up. Prospective participants will provide written informed consent before study-specific data collection where required by applicable local regulations and ethics approvals. Data for the prospective component are pseudonymised before central entry; the key linking the study identifier to an individual's identity is retained securely at the local participating site and is not transferred to the coordinating centre. Data are collected from routine clinical records using a standardised electronic case report form implemented in REDCap and hosted by Imperial College London. Data may include demographic and clinical characteristics, MS phenotype, treatment history, relapse history, disability assessments, MRI findings, routine laboratory results where available, treatment discontinuation or switching, and safety-related clinical events. Definitions for collected variables and outcomes are specified in the study case report form and associated data dictionary. The data dictionary provides variable-level definitions, coding formats, and permitted values to support consistent data collection across centres. The registry incorporates quality-assurance measures to promote accuracy, completeness, and consistency of data. REDCap provides role-based access controls, audit trails, and data-validation functionality. Standardised data definitions and built-in validation rules are used where feasible to identify missing, inconsistent, or implausible entries. Data quality will also be supported through central review of data completeness and consistency, with queries issued to participating sites when clarification or correction is needed. Participating site investigators are responsible for local study conduct, compliance with governance requirements, and the accuracy and completeness of data submitted to the registry. The coordinating centre oversees site communication, study administration, data-collection procedures, and central data-quality processes. The study may be subject to audit by Imperial College London or relevant regulatory bodies. As this is an observational registry, it does not undertake systematic adverse-event reporting as would be required in an interventional trial. However, safety outcomes of interest-including serious adverse events, infections or viral reactivations, hospitalisations, malignancies, secondary autoimmune diseases, treatment discontinuation due to adverse events, and mortality-will be identified from routine clinical data where available. Analyses will follow a prespecified statistical analysis plan. Descriptive analyses will summarise baseline demographic, clinical, radiological, and treatment-related characteristics overall and by treatment group. Comparative analyses will account for the non-randomised nature of treatment allocation and the potential for baseline imbalance and confounding. Depending on the comparison and outcome, methods may include multivariable regression adjustment, propensity score matching, inverse probability of treatment weighting, propensity score stratification, and sensitivity analyses using alternative adjustment approaches. Time-to-event outcomes will generally be analysed using Kaplan-Meier methods and Cox proportional-hazards models; other outcomes will use appropriate regression methods. Prespecified subgroup analyses may examine whether comparative outcomes differ according to factors such as MS phenotype, age, sex, baseline disability, disease duration, prior treatment exposure, baseline MRI activity, and treatment era. The extent and pattern of missing data will be described. Missing data will be addressed according to their amount, nature, and likely mechanism, using approaches such as complete-case analysis, multiple imputation, and sensitivity analyses as appropriate. Additional sensitivity analyses may assess the effect of missing MRI or disability data on outcome ascertainment. As a multicentre registry study, the final sample size will depend on the number of eligible participants identified and enrolled across participating centres during the study period. Analyses of individual H-DMT comparisons will be performed only where there is sufficient sample size, follow-up duration, and data completeness to support reliable interpretation. Study data will be stored securely with appropriate technical and organisational safeguards. Access is restricted to authorised personnel. Results will be reported in aggregate or otherwise non-identifiable form and may be disseminated through scientific publications, conference presentations, and, where feasible, summaries for participants, patients, and the wider public.