A Drug Development Tool for Trial Enrichment in Patients With Autosomal Dominant Polycystic Kidney Disease

INTRODUCTION: Total kidney volume (TKV) is a promising imaging biomarker for tracking and predicting the natural history of patients with autosomal dominant polycystic kidney disease. METHODS: A drug development tool was developed by linking longitudinal TKV measurements to the probability of a 30% decline of estimated glomerular filtration rate (eGFR) or end-stage renal disease. Drug development tools were developed based on observational data collected over multiple decades for an eGFR decline and end-stage renal disease in 641 and 866 patients with autosomal dominant polycystic kidney disease, respectively. RESULTS: The statistical association between predicted TKV at the time of a 30% decline of eGFR and that at the time of end-stage renal disease were both highly significant (P < 0.0001). The drug development tool was applied to demonstrate the utility of trial enrichment according to prespecified baseline TKV, age, and eGFR as enrollment criteria in hypothetical clinical trials. Patients with larger TKV (≥1000 ml) displayed steeper slopes of hazard, which translated into a higher risk of a 30% decline of eGFR within each baseline age (< or ≥40 years) or baseline eGFR (< or ≥50 ml/min per 1.73 m(2)) subgroups. DISCUSSION: These results suggest that, when eGFR is preserved, patients with larger TKV are more likely to progress to a 30% decline of eGFR within the course of a clinical trial, whereas eGFR and age displayed limited predictive value of disease progression in early disease. Pharmaceutical sponsors and academic investigators are encouraged to prospectively employ the above drug development tool to optimize trial designs in patients with autosomal dominant polycystic kidney disease.