Chronic Kidney Disease Epidemiology – Clinical Trials Consortium (CKD-EPI CT)

Chronic kidney disease (CKD) is any condition that causes reduced kidney function over a period of time. CKD is common and harmful, but with few therapies. Conduct of randomized clinical trials (RCTs) in CKD is hampered, in part, because CKD often progresses slowly, with insufficient clinical endpoints (i.e., kidney failure or doubling of serum creatinine) in feasible time frames. In addition, there is insufficient data to guide sponsors or investigators in design of new RCTs.

The Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) was established in 2003 to address fundamental questions in CKD epidemiology using individual patient data and rigorous methods in clinical chemistry and statistics to create useful tools for research, patient care, and public health (1-3).

Proteinuria, or the occurrence of abnormal amounts of protein in urine, and decline in glomerular filtration rate (GFR), or the rate at which kidneys filter blood, are signs of kidney disease. A critical focus of CKD-EPI has been evaluation of surrogate endpoints for kidney disease progression, focusing on early changes in proteinuria (albuminuria) and GFR decline (time to 30% and 40% decline in eGFR and eGFR slope) as the key endpoints of interest, using individual patient meta-analysis of RCTs (4-9). The RCTs included in CKD-EPI Clinical Trials Consortium (CKD-EPI CT) have been identified through systematic literature searches with the goal to include all available studies, thereby decreasing potential bias of the analyses. The systematic search was initially conducted in 2007, then updated for the more recent analyses and was last performed in 2017 (7). To our knowledge, this is the largest and most diverse collection of RCTs for CKD progression. This work was presented at a series of workshops (May 2008, December 2012, March 2018) sponsored by the National Kidney Foundation (NKF) in collaboration with the Food and Drug Administration (FDA) and European Medicines Agency (EMA) (4, 5, 10).

Results to date were able to comment on the general validity of these endpoints, but were not able to make specific recommendations for how to select specific endpoints in specific trials and populations. The overall goal of our next phase is to develop evidence-based tools to rigorously evaluate trade-offs between alternative design strategies, including requirements for sample size and study duration, thereby improving feasibility and decreasing cost without inflating the risk of false positive conclusions. We anticipate that such tools could facilitate drug development even at the earlier stages as it enables sponsors to make calculations as to the optimal path from early phase investigations to regulatory approval. More efficient trials should spur an increased number of RCTs, speeding development of effective therapies for CKD.
References:
1. Chronic Kidney Disease Epidemiology Collaboration. http://ckdepi.org; 2016.
2. Inker LA, Schmid CH, Tighiouart H, Eckfeldt JH, Feldman HI, Greene T, et al. Estimating glomerular filtration rate from serum creatinine and cystatin C. N Engl J Med 2012;367(1):20-9.
3. Levey AS, Stevens LA, Schmid CH, Zhang YL, Castro AF, 3rd, Feldman HI, et al. A new equation to estimate glomerular filtration rate. Ann Intern Med 2009;150(9):604-12.
4. Levey AS, Cattran D, Friedman A, Miller WG, Sedor J, Tuttle K, et al. Proteinuria as a surrogate outcome in CKD: report of a scientific workshop sponsored by the National Kidney Foundation and the US Food and Drug Administration. Am J Kidney Dis 2009;54(2):205-26.
5. Levey AS, Inker LA, Matsushita K, Greene T, Willis K, Lewis E, et al. GFR decline as an end point for clinical trials in CKD: a scientific workshop sponsored by the National Kidney Foundation and the US Food and Drug Administration. American Journal of Kidney Diseases 2014;64(6):821-35.
6. Inker LA, Lambers Heerspink HJ, Mondal H, Schmid CH, Tighiouart H, Noubary F, et al. GFR decline as an alternative end point to kidney failure in clinical trials: a meta-analysis of treatment effects from 37 randomized trials. American Journal of Kidney Diseases 2014;64(6):848-59.
7. Inker LA, Levey AS, Pandya K, Stoycheff N, Okparavero A, Greene T. Early Change in Proteinuria as a Surrogate End Point for Kidney Disease Progression: An Individual Patient Meta-analysis. Am J Kidney Dis 2014;64(1):74-85.
8. Inker LA, Mondal H, Greene T, Masaschi T, Locatelli F, Schena FP, et al. Early Change in Urine Protein as a Surrogate End Point in Studies of IgA Nephropathy: An Individual-Patient Meta-analysis. Am J Kidney Dis 2016;68(3):392-401.
9. Greene T, Teng CC, Inker LA, Redd A, Ying J, Woodward M, et al. Utility and validity of estimated GFR-based surrogate time-to-event end points in CKD: a simulation study. American Journal of Kidney Diseases 2014;64(6):867-79.
10. National Kidney Foundation. Accelerating New Clinical Trials and Treatments for Kidney Disease. https://www.kidney.org/news/accelerating-new-clinical-trials-and-treatments-kidney-disease; 2018.