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

Lead Investigator: Lesley Inker, Division of Nephrology, Tufts Medical Center

Title of Research Proposal: Chronic Kidney Disease Epidemiology – Clinical Trials Consortium (CKD-EPI CT).

Vivli Data Request: 4113

Funding Source: Additional Contracts or Consultancies – We have funding for this work from the National Kidney Foundation. We have submitted proposals to NIH for this work in the past but none are pending at present.

Potential Conflicts of Interest: LAI reports funding to Tufts Medical Center for research and contracts with the National Institutes of Health (NIH), National Kidney Foundation (NKF), Retrophin, Omeros and Reata Pharmaceuticals. She has consulting agreements with Tricida Inc. and Omeros Corp. Tufts Medical Center, John Hopkins University and Metabolon Inc. have a collaboration agreement to develop a product to estimate GFR from a panel of markers.

Summary of the Proposed Research:

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.

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. 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. 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).

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.

Requested Studies:

A Randomized, Double-Blind Study to Compare the Durability of Glucose Lowering and Preservation of Pancreatic Beta-Cell Function of Rosiglitazone Monotherapy Compared to Metformin or Glyburide/Glibenclamide in Patients With Drug-Naive, Recently Diagnosed Type 2 Diabetes Mellitus
Sponsor: GlaxoSmithKline
Study ID: NCT00279045
Sponsor ID: 49653/048

A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate Cardiovascular Outcomes Following Treatment With Alogliptin in Addition to Standard of Care in Subjects With Type 2 Diabetes and Acute Coronary Syndrome
Sponsor: Takeda
Study ID: NCT00968708
Sponsor ID: SYR-322_402

A Long Term, Randomised, Double Blind, Placebo-controlled Study to Determine the Effect of Albiglutide, When Added to Standard Blood Glucose Lowering Therapies, on Major Cardiovascular Events in Patients With Type 2 Diabetes Mellitus
Sponsor: GlaxoSmithKline
Study ID: NCT02465515
Sponsor ID: 116174