Kidney Week

Abstract: TH-OR054

Acute Treatment Effects in Randomized Clinical Trials of CKD Progression

Session Information

• CKD: Clinical, Outcomes, and Trials
  November 07, 2019 | Location: 202, Walter E. Washington Convention Center
  Abstract Time: 05:42 PM - 05:54 PM

Category: CKD (Non-Dialysis)

• 2102 CKD (Non-Dialysis): Clinical, Outcomes, and Trials

Authors

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

Lesley Inker, MD



Dr. Inker is an attending physician and the director of the Kidney and Blood Pressure Center in the William B. Schwartz, M.D. Division of Nephrology at Tufts Medical Center, and an associate professor at Tufts University School of Medicine. Dr. Inker’s extensive research has established her as an expert in the implementation of estimated glomerular filtration rate by clinical laboratories, as well as an expert in estimating and measuring kidney function — including in specific populations such as the elderly and HIV-positive people. Dr. Inker, a leader in clinical trials end points research, also served as co-chair of the trial level analytical team for the recent joint workshop with NKF, the U.S. Food and Drug Administration and European Medicines Agency on End Points for Clinical Trials in Early Chronic Kidney Disease. The workshop was undertaken to review the results of a major, multi-year meta-analysis examining the largest compilation of data ever collected on chronic kidney disease.

• Tighiouart, Hocine, Tufts Medical Center, Boston, Massachusetts, United States

Hocine Tighiouart,

Group or Team Name

• Chronic Kidney Disease Epidemiology (CKD-EPI) Collaboration

Background

Interventions in CKD trials often produce early short-term treatment effects on GFR slope (i.e. acute effect) that differ from its late long-term effects. The presence of acute effects complicates the design, interpretation and reduces statistical power of randomized clinical trials (RCT) with GFR slope as endpoint.

Methods

We computed the acute effect in past RCTs included in Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) using repeated measures models (N RCTs 57; N participants 60620). For the 30 studies with sufficient measurements prior to 18 months we truncated the follow-up time to 18 months to ensure that the long term trajectory did not overly influence the acute effect. We estimated GFR using the CKD-EPI 2009 creatinine equation. We included time since baseline, treatment, time by treatment interaction and baseline GFR as covariates and used an unstructured variance-covariance matrix to account for the correlated longitudinal measurements within each patient. We modeled time as a fixed effect using restricted cubic splines and then as a categorical variable with follow-up times fixed at each study specific scheduled visits.

Results

In the total set of CKD-EPI RCTs, the overall mean (SD) acute effect of 0.19 (1.27) mL/min/1.73 m² over 3 months but both negative and positive acute effects were observed with 95% confidence intervals ranging from -2.3 to 2.7 mL/min/1.73 m²/3 months indicating large heterogeneity. The figure shows trajectories from baseline to 12 months for 6 example RCTs.

Conclusion

Acute effects are common but there is wide heterogeneity among RCTs. Understanding the timing, magnitude and nature of the acute effect of a specific intervention and population will inform optimal study design.

Smoothed trajectories of mean GFR differences from baseline by treatment group for 6 example RCTs. Dots show the observed means at the study-specific follow-up visit times. RASB, renin-angiotensin system blocker; BP, blood pressure; CCB, calcium channel blocker

Funding

• Private Foundation Support