Evolution of Clinical Trial Design in ADPKD

Autosomal Dominant Polycystic Kidney Disease (ADPKD) is characterized by continuous growth in the size and number of kidney cysts during decades of relatively preserved renal function. Because of this slow progression, traditional clinical trial design, focused on kidney functional outcomes such as change in estimated glomerular filtration rate (eGFR) or time to kidney failure, requires significant investment of time and resources. This review examines the evolution of trial design to overcome these barriers, highlighting the pivotal shift to using total kidney volume (TKV) as a reasonably likely surrogate end point. Foundational studies such as the Consortium for Radiologic Imaging Studies in Polycystic Kidney Disease (CRISP) validated TKV as a prognostic biomarker, enabling a move away from functional end points. Subsequent interventional trials (e.g., HALT-PKD, TEMPO 3:4) further demonstrated the utility of TKV while revealing potential limitations in the relationship between kidney volume and function. Building on these lessons, the field could move to more sophisticated designs to improve efficiency and limit study size. Innovative approaches including adaptive methods, master protocols (i.e., platform and umbrella designs), and target trial emulation may reduce costs, enhance statistical power, and accelerate the development of therapeutic options for ADPKD.