TY  - JOUR
AU  - Hendrickx, Niels
AU  - Mentré, France
AU  - Hamdan, Alzahra
AU  - Karlsson, Mats O
AU  - Hooker, Andrew C
AU  - Traschütz, Andreas
AU  - Gagnon, Cynthia
AU  - Schüle-Freyer, Rebecca
AU  - Synofzik, Matthis
AU  - Comets, Emmanuelle
TI  - 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.
JO  - BMC medical research methodology
VL  - 25
IS  - 1
SN  - 1471-2288
CY  - London
PB  - BioMed Central
M1  - DZNE-2025-00920
SP  - 179
PY  - 2025
AB  - 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
KW  - Humans
KW  - Randomized Controlled Trials as Topic: methods
KW  - Cerebellar Ataxia: therapy
KW  - Cerebellar Ataxia: genetics
KW  - Computer Simulation
KW  - Longitudinal Studies
KW  - Disease Progression
KW  - Research Design
KW  - Rare Diseases: therapy
KW  - Treatment Outcome
KW  - Clinical trial design (Other)
KW  - Model-based analysis (Other)
KW  - Non-linear Mixed effect models (Other)
KW  - Rare disease (Other)
KW  - Simulation study (Other)
LB  - PUB:(DE-HGF)16
C6  - pmid:40739200
C2  - pmc:PMC12309037
DO  - DOI:10.1186/s12874-025-02626-x
UR  - https://pub.dzne.de/record/280242
ER  -