Kidney Week

Abstract: SA-OR086

GFR Slope as a Surrogate End Point for Kidney Disease Progression – Individual Patient Meta-Analysis of RCTs: A Report from an NKF-FDA-EMA Workshop

Session Information

• New Considerations for Renoprotection Clinical Trials
  October 27, 2018 | Location: 1B, San Diego Convention Center
  Abstract Time: 06:06 PM - 06:18 PM

Category: CKD (Non-Dialysis)

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

Author

• Inker, Lesley, Tufts Medical Center, Boston, Massachusetts, United States

Lesley Inker, MD

Group or Team Name

• Chronic Kidney Disease-Epidemiology Collaboration

Background

A recent NKF-FDA-EMA Workshop evaluated candidate surrogate endpoints for clinical trials to slow kidney disease progression. GFR slope may provide an advantage over time to event endpoints by increasing power but has limitations, in particular when early acute changes differ from longer term changes.

Methods

Using a pooled dataset of 59074 participants from 47 studies, we computed GFR slope from randomization to 1, 2, and 3 years (total slope[TS]) as well as after excluding the initial 3 months after randomization (chronic slope[CS]). We performed Bayesian mixed models to relate the treatment effects on GFR slope to those on the clinical endpoint (CE), defined as ESKD, eGFR<15 or doubling of creatinine and to compute predicted hazard ratio (HR) for the clinical endpoint given a specified magnitude of treatment effect on slope.

Results

The figure shows associations of treatment effects on 3-year TS and CS compared to that of CE. For TS, associations weaken but persist at 2 years [R² 0.82 (0.46, 0.97)], and deteriorate at 1 year [R² 0.47 (0.09, 0.78)], likely related to presence of acute effects. For CS, sensitivity analyses using truncated data seem to show similar associations with follow-up time of 18-24 months. Results were consistent across eGFR, ACR and disease subgroups. For a 0.75 ml mean difference in 3-year TS and CS, predicted HR on the CE was 0.69 (0.59, 0.81) and 0.72 (0.60, 0.87), respectively.

Conclusion

Treatment effects on 3-year TS and CS have strong associations with those on the CE. TS over lesser time periods needs to consider presence of acute effect. These results, combined with analyses of epidemiological associations and simulation studies presented at the Workshop, support the use of GFR slope as a surrogate endpoint in clinical trials of kidney disease progression.

Colours represent different interventions. Size of the circle is proportional to number of events

Funding

• Private Foundation Support