Utility and Validity of Estimated GFR–Based Surrogate Time-to-Event End Points in CKD: A Simulation Study Tom Greene, PhD, Chia-Chen Teng, MS, Lesley.

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Presentation transcript:

Utility and Validity of Estimated GFR–Based Surrogate Time-to-Event End Points in CKD: A Simulation Study Tom Greene, PhD, Chia-Chen Teng, MS, Lesley A. Inker, MD, MS, Andrew Redd, PhD, Jian Ying, PhD, Mark Woodward, PhD, Josef Coresh, MD, PhD, Andrew S. Levey, MD American Journal of Kidney Diseases Volume 64, Issue 6, Pages 867-879 (December 2014) DOI: 10.1053/j.ajkd.2014.08.019 Copyright © 2014 National Kidney Foundation, Inc. Terms and Conditions

Figure 1 (Top row) Log hazard ratios (HRs), (middle row) percentage of patients with events, and (bottom row) the required N for end points defined by end-stage renal disease (ESRD) alone or composites of designated estimated glomerular filtration rate (eGFR) declines and ESRD (horizontal axis) with and without confirmation of eGFR events (solid and dashed curves) for trials with a short, medium, and long median planned follow-up of 2, 3, or 5 years (green, blue, or red curves) for 3 scenarios for the acute effect and long-term treatment effect: (1) no acute effect and a 25% uniform long term treatment effect (left), (2) no acute effect and a 25% proportional long-term treatment effect, and (3) a negative 1.25mL/min/1.73m2 acute effect of the treatment and a 25% proportional long-term treatment effect. Mean baseline eGFR was 42.5mL/min/1.73m2 for each scenario, with all other input parameters in the simulations set to their base-case value. The required Ns are provided on the square root scale. In some cases, curves fail to display fully due to overlap. American Journal of Kidney Diseases 2014 64, 867-879DOI: (10.1053/j.ajkd.2014.08.019) Copyright © 2014 National Kidney Foundation, Inc. Terms and Conditions

Figure 2 (Top row) Log hazard ratios (HRs), (middle row) percentage of patients with events, and (bottom row) the required N for end points defined by end-stage renal disease (ESRD) alone or composites of designated estimated glomerular filtration rate (eGFR) declines and ESRD (horizontal axis) with and without confirmation of eGFR events (solid and dashed curves) for trials with a short, medium, and long median planned follow-up of 2, 3, or 5 years (green, blue, or red curves) and with a (left) low mean baseline eGFR of 27.5mL/min/1.73m2, (middle) intermediate mean baseline eGFR of 42.5mL/min/1.73m2, or (right) high mean baseline eGFR of 67.5mL/min/1.73m2. All other input parameters in the simulations were set to their base-case value including the assumption of a mixed proportional/additive model for the long-term treatment effect. The required Ns are provided on the square root scale. In some cases, curves fail to display fully due to overlap. American Journal of Kidney Diseases 2014 64, 867-879DOI: (10.1053/j.ajkd.2014.08.019) Copyright © 2014 National Kidney Foundation, Inc. Terms and Conditions

Figure 3 Type 1 error of composite end points based on end-stage renal disease (ESRD) and either a 57% estimated glomerular filtration rate (eGFR) decline (red curve), 40% eGFR decline (blue curve), or 30% eGFR decline (green curve) with or without confirmation (solid or dashed curves) relative to the clinical end point of ESRD when there are varying acute effects of the treatment (horizontal axis), but no treatment effect on time to ESRD. The targeted type 1 error is 5%, so deviations of the curves above 5% represent inflated risk of a false conclusion of treatment harm for negative acute effects or inflated risk of a false conclusion of treatment effect for positive acute effects. The rows reflect different levels of baseline eGFR and the columns represent mean planned trial durations of 2, 3, or 5 years. All other input parameters in the simulations were set to their base-case value. In general, in this surrogate end point setting, we expect that a small inflation of type 1 error relative to the clinical end point may be acceptable in certain circumstances, but that large increases in type 1 error to levels close to 10% or higher are unacceptable. In regulatory settings, the consequences of a false-positive conclusion of treatment benefit may be more severe than for a false-positive conclusion of treatment harm. Abbreviation: Fup, follow-up. American Journal of Kidney Diseases 2014 64, 867-879DOI: (10.1053/j.ajkd.2014.08.019) Copyright © 2014 National Kidney Foundation, Inc. Terms and Conditions