Analytic Challenges in Clinical Trials in Early Alzheimers Disease

The present investigation assessed how the heavily right-skewed data seen in recently reported results in Alzheimers Disease (AD) clinical trials influenced treatment contrasts when data were analyzed via the typical mixed-effects model for repeated measures (MMRM) versus robust regression (RR) and the non-parametric Hodges-Lehman estimator (HL). Results in simulated data patterned after AD trials showed that imbalance across treatment arms in the number of patients in the extreme right tail (those with rapid disease progression) frequently occurred by chance alone. Each analysis method controlled Type I error at or below the nominal level. The RR analysis yielded smaller standard errors, and more power than MMRM and HL. In datasets with appreciable imbalance in the number of rapid progressing patients, MMRM results favored the treatment arm with fewer rapid progressors. Results from HL showed the same trend, but to a lesser degree. Robust regression yielded similar results regardless of the ratio of rapid progressors. Although more research is needed over a wider range of scenarios, it should not be assumed that MMRM is the optimal approach for trials in early Alzheimers Disease. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This study did not receive any funding ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors