Methodological issues in clinical trials of polycystic kidney disease: a focused review

The field of therapeutics in autosomal dominant polycystic kidney disease (ADPKD) has seen a significant expansion recently, as major clinical trials have provided promising evidence in favor of new disease-modifying drugs. Though these trials are encouraging, limitations are noticeable in the form of methodological issues that restrict the interpretation of results. In this review, we discuss the methodological pitfalls of high-profile clinical interventional trials for ADPKD which have been published since 2009. Issues in study design, patient selection and follow-up, analyses and reporting of results are presented. From this review, we highlight a number of suggestions for future improvement including designs to enrich a more homogeneous patient population (i.e. based on their age-adjusted total kidney volume and/or underlying mutation class) at high-risk for disease progression, appropriate study duration and patient sample size that are matched to the disease severity of the study patients, and the use of baseline characteristics (i.e. renal function, TKV, and the proportion of PKD1 and PKD2 patients) of the analyzed patients as a quality control measure to assess any potential imbalance in randomization. Furthermore, the recognition that TKV change is not a linear trait is important in both the study design and interpretation. Implementing these lessons learned from the published trials will greatly enhance the robustness and validity of future clinical trials in ADPKD.