Pharm Stat. 2024 Apr 3. doi: 10.1002/pst.2381. Online ahead of print.
ABSTRACT
In several therapeutic areas, including chronic kidney disease (CKD) and immunoglobulin A nephropathy (IgAN), there is a growing interest in how best to analyze estimated glomerular filtration rate (eGFR) data over time in randomized clinical trials including how to best accommodate situations where the rate of change is not anticipated to be linear over time, often due to possible short term hemodynamic effects of certain classes of interventions. In such situations, concerns have been expressed by regulatory authorities that the common application of single slope analysis models may induce Type I error inflation. This article aims to offer practical advice and guidance, including SAS codes, on the statistical methodology to be employed in an eGFR rate of change analysis and offers guidance on trial design considerations for eGFR endpoints. A two-slope statistical model for eGFR data over time is proposed allowing for an analysis to simultaneously evaluate short term acute effects and long term chronic effects. A simulation study was conducted under a range of credible null and alternative hypotheses to evaluate the performance of the two-slope model in comparison to commonly used single slope random coefficients models as well as to non-slope based analyses of change from baseline or time normalized area under the curve (TAUC). Importantly, and contrary to preexisting concerns, these simulations demonstrate the absence of alpha inflation associated with the use of single or two-slope random coefficient models, even when such models are misspecified, and highlight that any concern regarding model misspecification relates to power and not to lack of Type I error control.
PMID:38568372 | DOI:10.1002/pst.2381
