Lesley A Inker1, Hiddo J L Heerspink2, Hocine Tighiouart3, Juhi Chaudhari4, Shiyuan Miao4, Ulysses Diva5, Alex Mercer6, Gerald B Appel7, James V Donadio8, Jürgen Floege9, Philip K T Li10, Bart D Maes11, Francesco Locatelli12, Manuel Praga13, Francesco P Schena14, Andrew S Levey4, Tom Greene15. 1. Division of Nephrology, Tufts Medical Center, Boston, MA. Electronic address: linker@tuftsmedicalcenter.org. 2. Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands. 3. Institute for Clinical Research and Health Policy Studies, Tufts Medical Center, Boston, MA; Tufts Clinical and Translational Science Institute, Tufts University, Boston, MA. 4. Division of Nephrology, Tufts Medical Center, Boston, MA. 5. Biometrics, Travere Therapeutics Inc, San Diego, CA. 6. Clinical Drug Development, JAMCO Pharma Consulting AB, Stockholm, Sweden. 7. Division of Nephrology, Columbia University Medical Center and the New York Presbyterian Hospital, New York, NY. 8. Emeritus Staff, Mayo Clinic, Rochester, MN. 9. Division of Nephrology and Immunology, RWTH Aachen University, Aachen, Germany. 10. Division of Nephrology, Prince of Wales Hospital, Chinese University of Hong Kong, Shatin, Hong Kong. 11. Department of Nephrology, AZ Delta, Roeselare, Belgium. 12. Department of Nephrology and Dialysis, Alessandro Manzoni Hospital, Lecco. 13. Instituto de Investigación Hospital Universitario 12 de Octubre, i+12, Complutense University, Madrid, Spain. 14. Renal, Dialysis and Transplant Unit, Department of Emergency and Organ Transplantation, University of Bari, Bari, Italy. 15. Departments of Population Health Sciences and Internal Medicine, University of Utah, Salt Lake City, UT.
Abstract
RATIONALE & OBJECTIVE: An early change in proteinuria is considered a reasonably likely surrogate end point in immunoglobulin A nephropathy (IgAN) and can be used as a basis for accelerated approval of therapies, with verification in a postmarketing confirmatory trial. Glomerular filtration rate (GFR) slope is a recently validated surrogate end point for chronic kidney disease progression and may be considered as the end point used for verification. We undertook a meta-analysis of clinical trials in IgAN to compare treatment effects on change in proteinuria versus change in estimated GFR (eGFR) slope. STUDY DESIGN: Individual patient-level meta-analysis. SETTING & STUDY POPULATIONS: Individual data of 1,037 patients from 12 randomized trials. SELECTION CRITERIA FOR STUDIES: Randomized trials of IgAN with proteinuria measurements at baseline and 6 (range, 2.5-14) months and at least a further 1 year of follow-up for the clinical outcome. ANALYTICAL APPROACH: For each trial, we estimated the treatment effects on proteinuria and on the eGFR slope, computed as the total slope starting at baseline or the chronic slope starting 3 months after randomization. We used a Bayesian mixed-effects analysis to relate the treatment effects on proteinuria to effects on GFR slope across these studies and developed a prediction model for the treatment effect on the GFR slope based on the effect on proteinuria. RESULTS: Across all studies, treatment effects on proteinuria accurately predicted treatment effects on the total slope at 3 years (median R2 = 0.88; 95% Bayesian credible interval [BCI], 0.06-1) and on the chronic slope (R2 = 0.98; 95% BCI, 0.29-1). For future trials, an observed treatment effect of approximately 30% reduction in proteinuria would confer probabilities of at least 90% for nonzero treatment benefits on the total and chronic slopes of eGFR. We obtained similar results for proteinuria at 9 and 12 months and total slope at 2 years. LIMITATIONS: Study population restricted to 12 trials of small sample size, leading to wide BCIs. There was heterogeneity among trials with respect to study design and interventions. CONCLUSIONS: These results provide new evidence supporting that early reduction in proteinuria can be used as a surrogate end point for studies of chronic kidney disease progression in IgAN.
RATIONALE & OBJECTIVE: An early change in proteinuria is considered a reasonably likely surrogate end point in immunoglobulin A nephropathy (IgAN) and can be used as a basis for accelerated approval of therapies, with verification in a postmarketing confirmatory trial. Glomerular filtration rate (GFR) slope is a recently validated surrogate end point for chronic kidney disease progression and may be considered as the end point used for verification. We undertook a meta-analysis of clinical trials in IgAN to compare treatment effects on change in proteinuria versus change in estimated GFR (eGFR) slope. STUDY DESIGN: Individual patient-level meta-analysis. SETTING & STUDY POPULATIONS: Individual data of 1,037 patients from 12 randomized trials. SELECTION CRITERIA FOR STUDIES: Randomized trials of IgAN with proteinuria measurements at baseline and 6 (range, 2.5-14) months and at least a further 1 year of follow-up for the clinical outcome. ANALYTICAL APPROACH: For each trial, we estimated the treatment effects on proteinuria and on the eGFR slope, computed as the total slope starting at baseline or the chronic slope starting 3 months after randomization. We used a Bayesian mixed-effects analysis to relate the treatment effects on proteinuria to effects on GFR slope across these studies and developed a prediction model for the treatment effect on the GFR slope based on the effect on proteinuria. RESULTS: Across all studies, treatment effects on proteinuria accurately predicted treatment effects on the total slope at 3 years (median R2 = 0.88; 95% Bayesian credible interval [BCI], 0.06-1) and on the chronic slope (R2 = 0.98; 95% BCI, 0.29-1). For future trials, an observed treatment effect of approximately 30% reduction in proteinuria would confer probabilities of at least 90% for nonzero treatment benefits on the total and chronic slopes of eGFR. We obtained similar results for proteinuria at 9 and 12 months and total slope at 2 years. LIMITATIONS: Study population restricted to 12 trials of small sample size, leading to wide BCIs. There was heterogeneity among trials with respect to study design and interventions. CONCLUSIONS: These results provide new evidence supporting that early reduction in proteinuria can be used as a surrogate end point for studies of chronic kidney disease progression in IgAN.
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Authors: Andrew S Levey; Lesley A Inker; Kunihiro Matsushita; Tom Greene; Kerry Willis; Edmund Lewis; Dick de Zeeuw; Alfred K Cheung; Josef Coresh Journal: Am J Kidney Dis Date: 2014-10-16 Impact factor: 8.860
Authors: Lesley A Inker; Hiddo J L Heerspink; Hocine Tighiouart; Andrew S Levey; Josef Coresh; Ron T Gansevoort; Andrew L Simon; Jian Ying; Gerald J Beck; Christoph Wanner; Jürgen Floege; Philip Kam-Tao Li; Vlado Perkovic; Edward F Vonesh; Tom Greene Journal: J Am Soc Nephrol Date: 2019-07-10 Impact factor: 10.121
Authors: Tom Greene; Jian Ying; Edward F Vonesh; Hocine Tighiouart; Andrew S Levey; Josef Coresh; Jennifer S Herrick; Enyu Imai; Tazeen H Jafar; Bart D Maes; Ronald D Perrone; Lucia Del Vecchio; Jack F M Wetzels; Hiddo J L Heerspink; Lesley A Inker Journal: J Am Soc Nephrol Date: 2019-07-10 Impact factor: 10.121
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