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Public Release Type:
Journal
Publication Year: 2023
Affiliation: Division of Nephrology, Tufts Medical Center, Boston, MA USA
Population Health Sciences, University of Utah School of Medicine, UT, USA
Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands
Renal and Metabolic Division, the George Institute for Global Health, NSW, Australia
Instituto de Investigación Hospital 12 de octubre (i+12), Madrid, Spain
Division of Nephrology, RWTH Aachen University, Aachen, Germany
Department of Nephrology, Hospital General Universitario Gregorio Marañón, Madrid, Spain
Clinical Trial Service Unit and Epidemiological Studies Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK
Nakayamadera Imai Clinic, Takarazuka, Japan
Program in Health Services and Systems Research, Duke-NUS Medical School, Singapore
Division of Nephrology, Vanderbilt University, Nashville, TN, USA
Division of Nephrology, Prince of Wales Hospital, Chinese University of Hong Kong, Shatin, Hong Kong
Department of Nephrology, AZ Delta, Roeselare, Belgium
Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy
Renal, Dialysis and Transplant Unit, Department of Emergency and Organ Transplantation, University of Bari, Bari, Italy
Department of Internal Medicine, UT Southwestern Medical Center, Dallas, TX, USA
Department of Nephrology and Dialysis, Sant’Anna Hospital, ASST Lariana, 22042 Como, Italy
Division of Nephrology, University Hospital of Würzburg, Würzburg, Germany
The George Institute for Global Health, University of New South Wales, Sydney, Australia
Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China
Request IDs:
22864
Studies:
FONT 2 Study: Novel Therapies for Resistant FSGS Phase II Clinical Trials
,
Novel Therapies to Treat Resistant Focal Segmental Glomerulosclerosis: Phase II Clinical Trial
Background: GFR decline is on the causal pathway to kidney failure, and has been proposed as a surrogate endpoint in clinical trials of CKD progression. Evidence was lacking as to the applicability across diseases. Methods: We estimated treatment effects on GFR slope (mean difference in GFR slope between the randomized groups), for the total slope starting at baseline and chronic slope starting at 3-months after randomization, and on the clinical endpoint (doubling of serum creatinine, GFR < 15 mL/min per 1.73 m2 or kidney failure with replacement therapy) for each of 66 treatment comparisons in an individual-level analysis of CKD trials (total N = 170,071). We used a Bayesian mixed effects model to relate treatment effects on GFR slope with those on the clinical endpoint, and predict the treatment effects on the clinical endpoint from that on GFR slope in future trials. Findings: Across all studies, treatment effects on the clinical endpoint were strongly associated with treatment effects on total slope computed over 3 years (median R2=0.98 [95% Bayesian Confidence Interval [BCI] 0.85-1.00]) with a moderate association with treatment effects on the chronic slope (R2 =0.56 [95% BCI 0.25, 0.79]). For future trials, the model predicts that with sufficient sample size, an observed treatment effect of 0.75 mL/min per 1.73 m2/year or greater on total slope over 3 years or chronic slope predicts HR for the clinical endpoint 0.74 (0.61, 0.89) and 0.78 (0.52, 1.17) , respectively. There was no evidence of heterogeneity across disease groups in this association for the total slope, with a suggestion of modest heterogeneity for the chronic slope. Interpretation: Our results confirm total GFR slope a valid surrogate endpoint for CKD progression. The chronic slope may be useful in some situations. These results will be presented to support qualification of GFR slope as a surrogate endpoint to the European Medicines Agency. Funding The study was funded by the National Kidney Foundation (NKF). NKF has received consortium support from the following companies: AstraZeneca, Bayer, Cerium, Chinook, Boehringer Ingelheim, CSL Behring, Novartis and Travere. A variety of sources have supported the RCTs included in the CKD-EPI CT. These funding sources include government agencies such as national institutes of health and medical research councils as well as foundations and industry sponsors listed in Appendix 2 in the supplement. ?
