Mixed‐effects models for slope‐based endpoints in clinical trials of chronic kidney disease

Abstract

US Food and Drug Administration and the European Medicines Agency, sponsored a workshop in which surrogate endpoints other than currently established event-time endpoints for clinical trials in chronic kidney disease (CKD) were presented and discussed. One such endpoint is a slope-based parameter describing the rate of decline in the estimated glomerular filtration rate (eGFR) over time. There are a number of challenges that can complicate such slope-based analyses in CKD trials. These include the possibility of an early but short-term acute treatment effect on the slope, both within-subject and between-subject heteroscedasticity, and informative censoring resulting from patient dropout due to death or onset of end-stage kidney disease. To address these issues, we first consider a class of mixed-effects models for eGFR that are linear in the parameters describing the mean eGFR trajectory but which are intrinsically nonlinear when a power-of-mean variance structure is used to model within-subject heteroscedasticity. We then combine the model for eGFR with a model for time to dropout to form a class of shared parameter models which, under the right specification of shared random effects, can minimize bias due to informative censoring. The models and methods of analysis are described and illustrated using data from two CKD studies one of which was one of 56 studies made available to the workshop analytical team. Lastly, methodology and accompanying software for prospectively determining sample size/power estimates are presented. KEYWORDSacute and chronic slopes, informative censoring, linear spline mixed-effects models, power-of-mean, shared parameter models 4218

Assessment of Acute Kidney Injury and Longitudinal Kidney Function After Hospital Discharge Among Patients With and Without COVID-19

“…In the absence of long-term follow-up data for patients with COVID-19-associated AKI, measuring the eGFR slope post hospitalization may inform prediction of future kidney disease progression. 14 Owing to their more severe AKI, we hypothesized that patients with COVID-19-associated AKI are at increased risk for eGFR decrease or worsening CKD after discharge compared with patients with AKI who did not have COVID-19.…”

GFR Slope as a Surrogate End Point for Kidney Disease Progression in Clinical Trials: A Meta-Analysis of Treatment Effects of Randomized Controlled Trials

“…34,38 Second, because we used the same slope model for each RCT, somewhat different results might be obtained if the model for slope were tailored to each RCT, including trial-specific strategies for informative censoring and designating the timing of the acute effect. 39 Third, because most included trials were not designed as short trials we cannot be certain about the effect of lesser follow-up time on the results, nor could we consider the effect of increased measurement frequencies on such shorter trials. Fourth, our results are dependent on the specific RCTs available to us.…”

Change in Albuminuria and GFR as End Points for Clinical Trials in Early Stages of CKD: A Scientific Workshop Sponsored by the National Kidney Foundation in Collaboration With the US Food and Drug Administration and European Medicines Agency

“…For clinical trials, we computed acute slope (from randomization to w3 months in follow-up), chronic slope (from 3 months to end of the trial), and total slope (from randomization to 1, 2, 3, or 4 years) using a simplified linear mixed-effects model based on a single slope starting at 3 months followup while adjusting for BL eGFR. 15 Additional methods were used to account for between-participant variability in eGFR trajectories, variability in individual eGFR assessments, informative censoring by ESKD and death, and uniform versus proportional long-term treatment effects (defined as treatment effects that are independent or proportional to the underlying rate of progression, eg, similar for fast and slow progressors or larger in fast progressors than in slow progressors). We also conducted preliminary analyses using combinations of UACR change and eGFR slope as a candidate surrogate end point, but these are not reported here.…”

“…Detail for the data analyses is provided in separate publications. [10][11][12][13][14][15] Perspectives from the FDA, EMA, and patient representatives are provided in accompanying editorials. [16][17][18] Additional information about the workshop is included in Item S1.…”