READYCOM: protocol for a 2-year prospective natural history and cross-sectional muscle-fatigability study for improving trial readiness in congenital myopathies.

introductionCongenital myopathies (CMYO) are a group of rare hereditary muscle diseases defined by characteristic abnormalities on muscle biopsy. Several types, including the core myopathies central core disease and multi-minicore disease, nemaline myopathy and centronuclear myopathy, have been identified based on the characteristic histopathological changes and attributed to various genetic backgrounds. The most prominent clinical features are generalised muscle weakness often pronounced axially, variable cardiorespiratory and bulbar impairment, and skeletal and joint involvement. Currently, no curative therapies are available for CMYOs; however, a few phase I and II trials have been performed or are expected in the near future. To reach trial readiness, an informed understanding of the disease course and a selection of relevant and sensitive clinical and functional outcome measures, and blood and imaging biomarkers is necessary. Furthermore, additional symptoms such as muscle fatigability have been recognised but not investigated systematically yet. The lack of understanding muscle fatigability in CMYO in particular calls for a cross-sectional study as this feature may be a treatment target. METHODS AND ANALYSIS: In collaboration with patient representatives, two studies have been designed: (1) a prospective cohort study with five 6-monthly visits over a 2-year period; and (2) a cross-sectional study on muscle fatigability. For both studies, patients from the same study population will be included. We aim to include 45 patients in study 1 and 75 in study 2. Patients are invited to participate in both studies. In study 1, we will perform a range of assessments covering patient-reported outcomes, clinical and functional outcome measures, and blood and imaging biomarkers. For study 2, we will assess the muscle fatigability and neuromuscular junction transmission. Baseline data will be analysed using descriptive statistics and correlation analysis. To assess disease progression, mixed models will be used. Multiple linear regressions will be used to explore the relationship between potential disease-modifying variables and disease severity. ETHICS AND DISSEMINATION: This study was approved by the Central Committee on Research Involving Human Subjects (CCMO, registration number NL83069.000.23). Findings will be shared with the participating patients and the funder. It will be presented at conferences and shared through peer-reviewed publications. TRIAL REGISTRATION NUMBER: NCT06157268.