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Abstract: SA-OR082

Change in Albuminuria and GFR as End Points for Clinical Trials in Early Stages of CKD: A Scientific Workshop Collaboration by the NKF, EMA, and FDA

Session Information

Category: CKD (Non-Dialysis)

  • 1902 CKD (Non-Dialysis): Clinical, Outcomes, and Trials

Author

  • Levey, Andrew S., Tufts Medical Center, Boston, Massachusetts, United States

Group or Team Name

  • Planning and Operations Committees and Analytic Group
Background

The workshop was held on March 15-16, 2018. We used observational studies, clinical trials and simulations to address the research aims (Table). At the ASN meeting, we will present updated and more detailed results.

Methods

For observational studies, we included 20 studies comprising 585,723 participants with 7047 clinical endpoints (ESKD) for ACR change (or equivalent PCR change) and 14 studies, 3,373,368 participants, 14348 endpoints for eGFR slope. For clinical trials, we included 43 trials comprising 30,078 participants with 3939 clinical endpoints (ESKD, eGFR <15 and Scr doubling) for ACR change and 47 trials, 59,074 participants, 6883 endpoints for eGFR slope. For simulations, we performed 1000 independent simulations for >1200 scenarios for parameters related to eGFR trajectories and study design to compare power and type 1 error for eGFR slope with the clinical endpoint (ESKD or Scr doubling).

Results

For observational studies, after adjustment for measurement error, relationships between change in ACR or eGFR slope and the clinical endpoint were strong and consistent. For clinical trials, relationships of treatment effects on change in ACR and eGFR slopes with the clinical endpoint were moderately strong and strong, respectively. The magnitude of relationships was similar across cohorts and trials for both ACR change and eGFR slope (30% ACR reduction or eGFR slope improvement by 0.5-1.0 ml/min/1.73 m2 per year were associated with a HR of approximately 0.7 for the clinical endpoint). For simulations, eGFR slope can substantially reduce the required sample size and duration of followup compared to the clinical endpoint in some circumstances, particularly when baseline eGFR is high.

Conclusion

These analyses suggest that both change in albuminuria and GFR slope can fulfill criteria for surrogacy for use as endpoints in clinical trials for CKD progression under some conditions (characteristics of the clinical population, intervention and trial design), with stronger support for GFR slope than for albuminuria change. Implementation requires understanding conditions under which one or the other surrogate is likely to perform well and restricting its use to those settings.

NKF-EMA-FDA Workshop Research Aims
1. Examine associations of changes in ACR with subsequent adverse outcomes (ESRD and mortality), and examine consistency of associations across subgroups (level of ACR and GFR, disease, and interventions) as well as implications of measurement error.
2. Examine associations of slope of GFR with subsequent adverse outcomes (ESRD and mortality), and examine consistency of associations across subgroups (level of ACR and GFR disease, intervention) as well as implications of measurement error.
3. Examine associations of treatment effects on early change in ACR with treatment effects on established endpoints, and consistency across subgroups (level of ACR and GFR, disease, and intervention)
4. Examine associations of treatment effects on GFR slope (acute, chronic and total slope) with treatment effects on established endpoints, and consistency across subgroups (level of ACR and GFR, disease, and intervention).
5. Develop methods to combine early change in ACR and GFR for combined endpoint

Funding

  • Private Foundation Support