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

Hiddo J L Heerspink, Dennis L Andress, George Bakris, John J Brennan, Ricardo Correa-Rotter, Jyotirmoy Dey, Fan Fan Hou, Dalane W Kitzman, Donald Kohan, Hirofumi Makino, John McMurray, Vlado Perkovic, Sheldon Tobe, Melissa Wigderson, Hans-Henrik Parving, Dick de Zeeuw

    Abstract

    AIMS: Individuals 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 with approximately 3500 participants who have stage 2-4 CKD and macroalbuminuria and are receiving a maximum tolerated dose of a renin-angiotensin system inhibitor.

    RESULTS: After 6 weeks of exposure to atrasentan 0.75 mg once daily (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 primary efficacy and safety analyses. Approximately 1000 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% reduction in relative risk (alpha level of .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.

    Original languageEnglish
    JournalDiabetes, Obesity and Metabolism
    Volume20
    Issue number6
    Pages (from-to)1369-1376
    Number of pages8
    ISSN1462-8902
    DOIs
    Publication statusPublished - Jun 2018

    Keywords

    • Adult
    • Angiotensin Receptor Antagonists/therapeutic use
    • Angiotensin-Converting Enzyme Inhibitors/therapeutic use
    • Atrasentan/adverse effects
    • Diabetes Mellitus, Type 2/complications
    • Diabetic Nephropathies/drug therapy
    • Disease Progression
    • Double-Blind Method
    • Drug Resistance
    • Drug Therapy, Combination/adverse effects
    • Endothelin A Receptor Antagonists/adverse effects
    • Female
    • Humans
    • Kidney/drug effects
    • Kidney Failure, Chronic/complications
    • Male
    • Precision Medicine
    • Randomized Controlled Trials as Topic
    • Renal Insufficiency, Chronic/complications
    • Research Design
    • Severity of Illness Index

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