Rationale and protocol of the Study of Diabetic Nephropathy with Atrasentan (SONAR) trial: A clinical trial design novel to diabetic nephropathy

Heerspink, H. J.L. et al. (2018) Rationale and protocol of the Study of Diabetic Nephropathy with Atrasentan (SONAR) trial: A clinical trial design novel to diabetic nephropathy. Diabetes, Obesity and Metabolism, 20(6), pp. 1369-1376. (doi: 10.1111/dom.13245) (PMID:29405626)

Abstract

Aims: People with diabetes and chronic kidney disease (CKD) are at high risk for renal events. Recent trials of novel treatments have been negative, possibly because of variability in response to treatment of the target risk factor. Atrasentan is a selective endothelin A receptor antagonist that reduces urinary albumin-to-creatinine ratio (UACR) with a large variability between patients. We are assessing its effect on renal outcomes in the Study of Diabetic Nephropathy with atrasentan (SONAR; NCT01858532) with an enrichment design (>30% lowering of albuminuria) to select patients most likely to benefit. Materials and Methods: SONAR is a randomized, double-blind, placebo-controlled trial in approximately 3,500 participants, with CKD stage 2–4 and macroalbuminuria receiving a maximum tolerated dose of a renin angiotensin system inhibitor. Results: After 6 weeks’ exposure to 0.75 mg once daily atrasentan (enrichment period), participants with ≥30% UACR decrease and no tolerability issues (responders) were randomly assigned to placebo or atrasentan 0.75 mg/day. The responder group will be used for the primary efficacy and safety analyses. Approximately 1,000 participants with <30% UACR reduction (non-responders) were also randomized to placebo or atrasentan. The primary endpoint is a composite of a sustained doubling of serum creatinine or end-stage renal disease. The original power calculation indicated that a total of 425 primary renal events in the responder group provides 90% power to detect a 27% relative risk reduction (alpha level of 0.05). Conclusion: SONAR aims to determine whether atrasentan, added to guideline-recommended therapies, safely reduces the risk of CKD progression and delays the onset of end-stage renal disease in patients with type 2 diabetes and nephropathy. SONAR also aims to establish whether the enrichment of patients based on their initial “surrogate” response to atrasentan will deliver a trial design in accord with personalized treatment of diabetic kidney disease.

• Item Type: Articles
• Keywords: Internal medicine, endocrinology, diabetes and metabolism, endocrinology.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: McMurray, Professor John
• Authors: Heerspink, H. J.L., Andress, D. L., Bakris, G., Brennan, J. J., Correa-Rotter, R., Dey, J., Hou, F.-F., Kitzman, D. W., Kohan, D., Makino, H., McMurray, J., Perkovic, V., Tobe, S., Wigderson, M., Parving, H.-H., and de Zeeuw, D.
• College/School: College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health
• Journal Name: Diabetes, Obesity and Metabolism
• Publisher: Wiley
• ISSN: 1462-8902
• ISSN (Online): 1463-1326
• Published Online: 06 February 2018
• Copyright Holders: Copyright © 2018 The Authors
• First Published: First published in Diabetes, Obesity and Metabolism 20(6):1369-1376
• Publisher Policy: Reproduced under a Creative Commons License