Kidney Week

Abstract: SA-OR084

Early Albuminuria Change as Surrogate End Point for Kidney Disease Progression – Individual Patient Meta-Analysis of Randomized Controlled Trials: 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: 05:42 PM - 05:54 PM

Category: CKD (Non-Dialysis)

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

Author

• Lambers Heerspink, Hiddo Jan, University Medical Center Groningen, Groningen, Netherlands

Hiddo Jan Lambers Heerspink, PhD

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. Change in albuminuria (UACR) may have advantages as it occurs earlier than kidney failure or GFR decline.

Methods

Using a pooled dataset including 30078 patients from 43 RCTs with UACR data at baseline and 6 months post-randomization, we estimated treatment effects on UACR and the composite clinical end point of ESRD, eGFR < 15 or doubling of serum creatinine using separate intent-to-treat analyses in each RCT. We then performed Bayesian mixed models to relate the treatment effects on UACR to treatment effects on the clinical endpoint and to compute the predicted hazard ratio for the clinical endpoint given a specified magnitude of treatment effect on UACR.

Results

Treatment reduced 6-month UACR by a geometric mean ratio (GMR) 22% (95%CI18-26). The figure shows a statistically significant association of treatment effects on change in UACR compared to that of the clinical endpoint. The association was strengthened when analyses were restricted to those with baseline UACR > 30mg/g [R² 47% (95%CI 2-96) vs 72% (5-99)]. For a 30% true change in UACR, the HR for the clinical endpoint was predicted to be 0.68 (95%CI 0.47-0.95) vs 0.93 (0.63-1.35) with no treatment effect on UACR. Results were consistent by subgroups of baseline eGFR, and disease.

Conclusion

In conjunction with results from epidemiological studies presented at the workshop, the moderately strong association between treatment effects on early changes in albuminuria and treatment effects on the clinical endpoint for UACR > 30mg/g supports the use of sufficiently large reductions (~> 30%) in albuminuria as a surrogate end point for kidney failure in clinical trials of kidney disease progression.

The colours represent different interventions. GMR, geometric mean ratio. HR, hazard ratio

Funding

• Private Foundation Support