Abstract: FR-PO1136
Application of eGFR Thresholds as End Point Components in a Kidney Hierarchical Composite End Point
Session Information
- CKD: Kidney Function and Extrarenal Complications
October 25, 2024 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: CKD (Non-Dialysis)
- 2302 CKD (Non-Dialysis): Clinical, Outcomes, and Trials
Authors
- Jongs, Niels, Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, University of Groningen, Groningen, Netherlands
- Gasparyan, Samvel B., Late Stage Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
- Frison, Lars, Late Stage Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
- Schloemer, Patrick, Pharmaceuticals, Research and Development, Bayer AG, Berlin, Germany
- Brinker, Meike Daniela, Pharmaceuticals, Research and Development, Bayer AG, Wuppertal, Germany
- Rossert, Jerome A., Late Stage Development, Cardiovascular, Renal and Metabolism (CVRM), Biopharmaceuticals R&D, AstraZeneca, Gaithersburg, Maryland, United States
- Little, Dustin J., Late Stage Development, Cardiovascular, Renal and Metabolism (CVRM), Biopharmaceuticals R&D, AstraZeneca, Gaithersburg, Maryland, United States
- Heerspink, Hiddo Jan L., Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, University of Groningen, Groningen, Netherlands
Background
We developed and validated a kidney hierarchical composite endpoint (HCE) combining time-to-event endpoints with the rate of estimated glomerular filtration rate (eGFR) decline (eGFR slope) as a continuous endpoint. An alternative to this continuous endpoint is to apply thresholds on an absolute scale for the pairwise comparisons in the eGFR slope component. We assessed the impact of different thresholds on the treatment effects and statistical power on the kidney HCE analysed using win odds.
Methods
We calculated the win-odds in the DAPA-CKD trial and compared treatment effects for the original HCE versus HCEs with different eGFR thresholds (0.5, 0.75, or 1.0 mL/min/1.73m2/year eGFR slope difference; Table). We estimated the statistical power for these thresholds using a bootstrap sampling procedure and replicated these analyses in the RENAAL, IDNT, ALTITUDE, SONAR, CREDENCE, and FIDELIO-DKD trials.
Results
In DAPA-CKD, the win-odds and statistical power were consistent regardless of which eGFR thresholds were included (Table). Results were similar in all the six kidney outcome trials.
Conclusion
Our findings indicate that application of eGFR thresholds in the kidney HCE does not alter treatment effects or compromise statistical power and may facilitate clinical interpretation of trial results.
Table. Pairwise comparisons per component of the HCE and win-odds
| Dapagliflozin 10 mg | Placebo | Win-odds | Power* | |||
| Wins (%) | Wins (%) | Ties (%) | (95% CI) | % | ||
| Kidney HCE eGFR (continuous) | All-cause death | 247971 (5.4) | 171435 (3.7) | 0 | ||
| End-stage kidney disease | 124658 (2.7) | 85196 (1.8) | 0 | |||
| Sustained decline of eGFR <15 | 83467 (1.8) | 61327 (1.3) | 0 | |||
| 57% eGFR decline from baseline | 62964 (1.4) | 24776 (0.5) | 0 | |||
| 50% eGFR decline from baseline | 62138 (1.3) | 26080 (0.6) | 0 | |||
| 40% eGFR decline from baseline | 160461 (3.5) | 118693 (2.6) | 0 | |||
| eGFR slope | 1975543 (42.7) | 1426395 (30.8) | 0 | |||
| Total | 2717202 (58.7) | 1913902 (41.3) | 0 | 1.42 (1.32, 1.52) | 97.4 | |
| Kidney HCE with eGFR threshold of >0.5 mL/min | eGFR slope | 1794224 (38.7) | 1252131 (27.0) | 355583 (7.7) | ||
| Total | 2535883 (54.8) | 1739638 (37.6) | 355583 (7.7) | 1.42 (1.32, 1.52) | 92.4 | |
| Kidney HCE with eGFR threshold of >0.75 mL/min | eGFR slope | 1702693 (36.8) | 1168907 (25.2) | 530338 (11.5) | ||
| Total | 2444352 (52.8) | 1656414 (35.8) | 530338 (11.5) | 1.41 (1.32, 1.51) | 91.8 | |
| Kidney HCE with eGFR threshold of >1.0 mL/min | eGFR slope | 1611160 (34.8) | 1088509 (23.5) | 702269 (15.2) | ||
| Total | 2352819 (50.8) | 1576016 (34.0) | 702269 (15.2) | 1.40 (1.31, 1.50) | 92.9 | |
*Statistical power for a simulated trial of 500 participants is shown
Funding
- Commercial Support – AstraZeneca