Kidney Week

Abstract: PO1578

STAGED-PKD: Patient Enrichment and Modeling-Driven Efficient ADPKD Trial Design

Session Information

• Cystic Kidney Diseases: Emerging Concepts, Biomarkers, and Clinical Trials
  October 22, 2020 | Location: On-Demand
  Abstract Time: 10:00 AM - 12:00 PM

Category: Genetic Diseases of the Kidneys

• 1001 Genetic Diseases of the Kidneys: Cystic

Authors

• Perrone, Ronald D., Division of Nephrology, Tufts Medical Center, Tufts University School of Medicine, Boston, Massachusetts, United States

Ronald D. Perrone,

• Hariri, Ali, Sanofi Genzyme, Cambridge, Massachusetts, United States

Ali Hariri,

• Minini, Pascal, Sanofi, Chilly Mazarin, France

Pascal Minini,

• Chapman, Arlene B., Department of Medicine, University of Chicago, Chicago, Illinois, United States

Arlene B. Chapman,

• Horie, Shigeo, Department of Urology, Juntendo University Graduate School of Medicine, Tokyo, Japan

Shigeo Horie,

• Knebelmann, Bertrand, Université Paris-Descartes, Faculté de Médecine, AP-HP, Service de Néphrologie, Hôpital Necker-Enfants Malades, Paris, France

Bertrand Knebelmann,

• Mrug, Michal, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, United States

Michal Mrug,

• Ong, Albert C., Department of Infection Immunity & Cardiovascular Disease, University of Sheffield, Sheffield, United Kingdom

Albert C. Ong,

• Pei, York P., Division of Nephrology, University of Toronto, Toronto, Ontario, Canada

York P. Pei,

• Torres, Vicente E., Mayo Translational Polycystic Kidney Disease Center, Mayo Clinic, Rochester, Minnesota, United States

Vicente E. Torres,

• Modur, Vijay, Sanofi Genzyme, Cambridge, Massachusetts, United States

Vijay Modur,

• Gansevoort, Ron T., Department of Nephrology, University Medical Center Groningen, Groningen, Netherlands

Ron T. Gansevoort,

Background

Total kidney volume (TKV) and eGFR slope are key endpoints in autosomal dominant polycystic kidney disease (ADPKD) trials, indicative of cyst growth and kidney function decline. To date, unequivocal demonstration of drug effect on these endpoints required two trials. STAGED-PKD assesses the effect of glucosylceramide synthase inhibition with venglustat on both endpoints in one efficient, short-duration trial.

Methods

Retrospective analysis of TKV and eGFR slope data from CRISP (3-yr) and HALT-A combined identified rapidly progressing patients for enrichment. A statistical relationship between TKV growth vs eGFR slope was derived by modeling. Meta-analysis was conducted of randomized clinical trials assessing treatment impact on both TKV and eGFR. These analyses enabled study powering for both endpoints. Comparison of design efficiency was performed vs prior trials.

Results

Retrospective analysis of CRISP and HALT-A confirmed a significant correlation between TKV growth and eGFR slope (correlation 0.346, p<0.0001; Figure). Different statistical approaches showed that in rapidly progressing ADPKD patients, 50% reduction in TKV growth is associated with a ~30% reduction in eGFR slope. Thus, STAGED-PKD is powered to detect 50% reduction in TKV growth and 30% reduction in eGFR slope. STAGED-PKD is highly efficient vs HALT-A and -B, TEMPO 3:4, and REPRISE.

Conclusion

Modeling allowed the design and powering of a two-stage study to assess venglustat impact on TKV growth and eGFR slope. STAGED-PKD improves study efficiency via modeling and patient enrichment to reduce patient number and trial duration.

Modeling of the Relationship Between TKV Growth Rate and eGFR Decline

Funding

• Commercial Support