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Rationale and protocol of the Study Of diabetic Nephropathy with AtRasentan (SONAR) trial: A clinical trial design
Hiddo J L Heerspink1, Dennis L Andress2, George Bakris3
1Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
Insights
Atrasentan may reduce kidney events in diabetic kidney disease patients. The SONAR trial used an enrichment design to identify patients most likely to benefit from this endothelin A receptor antagonist.
Area of Science:
- Nephrology
- Endocrinology
- Clinical Pharmacology
Background:
- Diabetic kidney disease (DKD) and chronic kidney disease (CKD) patients face high renal event risks.
- Previous trials with novel treatments showed negative results, potentially due to variable patient responses.
- Atrasentan, an endothelin A receptor antagonist, reduces albuminuria but shows significant inter-patient variability.
Purpose of the Study:
- To evaluate if atrasentan reduces CKD progression and delays end-stage renal disease in type 2 diabetes patients with nephropathy.
- To determine if an enrichment design, selecting patients based on initial response, improves trial efficacy for personalized DKD treatment.
Main Methods:
- The Study Of diabetic Nephropathy with AtRasentan (SONAR) is a randomized, double-blind, placebo-controlled trial.
- It involves ~3500 participants with stage 2-4 CKD, macroalbuminuria, on maximal renin-angiotensin system inhibitors.
- An enrichment period identified responders (≥30% UACR decrease) for primary analysis, with non-responders also randomized.
Main Results:
- The primary endpoint is a composite of sustained doubling of serum creatinine or end-stage renal disease.
- The responder group was powered to detect a 27% relative risk reduction with 90% power.
- Data on the primary endpoint from the responder group are pending analysis.
Conclusions:
- SONAR investigates atrasentan's efficacy and safety in DKD patients.
- The study assesses the utility of an enrichment design for personalized DKD therapy.
- Results will inform the role of atrasentan and personalized approaches in managing diabetic kidney disease.
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.
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