Development and Validation of a New Hierarchical Composite End Point for Clinical Trials of Kidney Disease Progression.

Autor: Heerspink HJL; Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.; The George Institute for Global Health, Sydney, New South Wales, Australia., Jongs N; Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands., Schloemer P; Pharmaceuticals, Research and Development, Bayer AG, Berlin, Germany., Little DJ; Late Stage Development, Cardiovascular, Renal and Metabolism (CVRM), Biopharmaceuticals R&D, AstraZeneca, Gaithersburg, Maryland., Brinker M; Pharmaceuticals, Research and Development, Bayer AG, Wuppertal, Germany., Tasto C; Pharmaceuticals, Research and Development, Bayer AG, Wuppertal, Germany., Karpefors M; Late Stage Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden., Wheeler DC; The George Institute for Global Health, Sydney, New South Wales, Australia.; Department of Renal Medicine, University College London, London, United Kingdom., Bakris G; Department of Medicine, University of Chicago Medicine, Chicago, Illinois., Perkovic V; The George Institute for Global Health, Sydney, New South Wales, Australia.; Faculty of Medicine & Health, University New South Wales, Sydney, New South Wales, Australia., Nkulikiyinka R; Pharmaceuticals, Research and Development, Bayer AG, Berlin, Germany., Rossert J; Late Stage Development, Cardiovascular, Renal and Metabolism (CVRM), Biopharmaceuticals R&D, AstraZeneca, Gaithersburg, Maryland., Gasparyan SB; Late Stage Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.
Jazyk: angličtina
Zdroj: Journal of the American Society of Nephrology : JASN [J Am Soc Nephrol] 2023 Dec 01; Vol. 34 (12), pp. 2025-2038. Date of Electronic Publication: 2023 Oct 24.
DOI: 10.1681/ASN.0000000000000243
Abstrakt: Significance Statement: The established composite kidney end point in clinical trials combines clinical events with sustained large changes in GFR but does not weigh the relative clinical importance of the end point components. By contrast, a hierarchical composite end point (HCE) accounts for the clinical importance of the end point components. The authors developed and validated a kidney HCE that combines clinical kidney outcomes with longitudinal GFR changes (GFR slope). They demonstrate that in seven major placebo-controlled kidney outcome trials with different medications, treatment effect estimates on the HCE were consistently in similar directions and of similar magnitudes compared with treatment effects on the established kidney end point. The HCE's prioritization of clinical outcomes and ability to combine dichotomous outcomes with GFR slope make it an attractive alternative to the established kidney end point.
Background: The established composite kidney end point in clinical trials combines clinical events with sustained large changes in GFR. However, the statistical method does not weigh the relative clinical importance of the end point components. A HCE accounts for the clinical importance of the end point components and enables combining dichotomous outcomes with continuous measures.
Methods: We developed and validated a new HCE for kidney disease progression, performing post hoc analyses of seven major Phase 3 placebo-controlled trials that assessed the effects of canagliflozin, dapagliflozin, finerenone, atrasentan, losartan, irbesartan, and aliskiren in patients with CKD. We calculated the win odds (WOs) for treatment effects on a kidney HCE, defined as a hierarchical composite of all-cause mortality; kidney failure; sustained 57%, 50%, and 40% GFR declines from baseline; and GFR slope. The WO describes the odds of a more favorable outcome for receiving the active compared with the control. We compared the WO with the hazard ratio (HR) of the primary kidney outcome of the original trials.
Results: In all trials, treatment effects calculated with the WO reflected a similar direction and magnitude of the treatment effect compared with the HR. Clinical trials incorporating the HCE would achieve increased statistical power compared with the established composite end point at equivalent sample sizes.
Conclusions: In seven major kidney clinical trials, the WO and HR provided similar direction of treatment effect estimates with smaller HRs associated with larger WOs. The prioritization of clinical outcomes and inclusion of broader composite end points makes the HCE an attractive alternative to the established kidney end point.
(Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Society of Nephrology.)
Databáze: MEDLINE