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Rationale and protocol of the Study Of diabetic Nephropathy with AtRasentan
(SONAR) trial: A clinical trial design novel to diabetic nephropathy
#MMPMID29405626
Heerspink HJL
; Andress DL
; Bakris G
; Brennan JJ
; Correa-Rotter R
; Dey J
; Hou FF
; Kitzman DW
; Kohan D
; Makino H
; McMurray J
; Perkovic V
; Tobe S
; Wigderson M
; Parving HH
; de Zeeuw D
Diabetes Obes Metab
2018[Jun]; 20
(6
): 1369-1376
PMID29405626
show ga
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.
|*Precision Medicine
[MESH]
|Adult
[MESH]
|Angiotensin Receptor Antagonists/therapeutic use
[MESH]
|Angiotensin-Converting Enzyme Inhibitors/therapeutic use
[MESH]
|Atrasentan/adverse effects/*therapeutic use
[MESH]
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