Heerspink, Hiddo L;
Jongs, Niels;
Schloemer, Patrick;
Little, Dustin J;
Brinker, Meike;
Tasto, Christoph;
Karpefors, Martin;
... Gasparyan, Samvel B; + view all
(2023)
Development and Validation of a New Hierarchical Composite End Point for Clinical Trials of Kidney Disease Progression.
Journal of the American Society of Nephrology
10.1681/ASN.0000000000000243.
(In press).
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Abstract
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.
| Type: | Article |
|---|---|
| Title: | Development and Validation of a New Hierarchical Composite End Point for Clinical Trials of Kidney Disease Progression |
| Location: | United States |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1681/ASN.0000000000000243 |
| Publisher version: | https://doi.org/10.1681/ASN.0000000000000243 |
| Language: | English |
| Additional information: | This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Renal Medicine |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10180720 |
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