%0 Journal Article
%A Hendrickx, Niels
%A Mentré, France
%A Hamdan, Alzahra
%A Karlsson, Mats O
%A Hooker, Andrew C
%A Traschütz, Andreas
%A Gagnon, Cynthia
%A Schüle-Freyer, Rebecca
%A Synofzik, Matthis
%A Comets, Emmanuelle
%T Comparing randomized trial designs to estimate treatment effect in rare diseases with longitudinal models: a simulation study showcased by Autosomal Recessive Cerebellar Ataxias using the SARA score.
%J BMC medical research methodology
%V 25
%N 1
%@ 1471-2288
%C London
%I BioMed Central
%M DZNE-2025-00920
%P 179
%D 2025
%X Parallel designs with an end-of-treatment analysis are commonly used for randomised trials, but they remain challenging to conduct in rare diseases due to small sample size and heterogeneity. A more powerful alternative could be to use model-based approaches. We investigated the performance of longitudinal modelling to evaluate disease-modifying treatments in rare diseases using simulations. Our setting was based on a model describing the progression of the standard clinician-reported outcome SARA score in patients with ARCA (Autosomal Recessive Cerebellar Ataxia), a group of ultra-rare, genetically defined, neurodegenerative diseases. We performed a simulation study to evaluate the influence of trials settings on their ability to detect a treatment effect slowing disease progression, using a previously published non-linear mixed effect logistic model. We compared the power of parallel, crossover and delayed start designs, investigating several trial settings: trial duration (2 or 5 years); disease progression rate (slower or faster); magnitude of residual error (σ=2 or σ=0.5); number of patients (100 or 40); method of statistical analysis (longitudinal analysis with non-linear or linear models; standard statistical analysis), and we investigated their influence on the type 1 error and corrected power of randomised trials. In all settings, using non-linear mixed effect models resulted in controlled type 1 error and higher power (88
%K Humans
%K Randomized Controlled Trials as Topic: methods
%K Cerebellar Ataxia: therapy
%K Cerebellar Ataxia: genetics
%K Computer Simulation
%K Longitudinal Studies
%K Disease Progression
%K Research Design
%K Rare Diseases: therapy
%K Treatment Outcome
%K Clinical trial design (Other)
%K Model-based analysis (Other)
%K Non-linear Mixed effect models (Other)
%K Rare disease (Other)
%K Simulation study (Other)
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:40739200
%2 pmc:PMC12309037
%R 10.1186/s12874-025-02626-x
%U https://pub.dzne.de/record/280242