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2017 ; 2
(3
): 451-460
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A Drug Development Tool for Trial Enrichment in Patients With Autosomal Dominant
Polycystic Kidney Disease
#MMPMID29142972
Perrone RD
; Mouksassi MS
; Romero K
; Czerwiec FS
; Chapman AB
; Gitomer BY
; Torres VE
; Miskulin DC
; Broadbent S
; Marier JF
Kidney Int Rep
2017[May]; 2
(3
): 451-460
PMID29142972
show ga
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.