Baseline characteristics and enrichment results from the SONAR trial

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

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

Aim: The SONAR trial uses an enrichment design based on the individual response to the selective endothelin receptor antagonist atrasentan on efficacy (the degree of the individual response in the urinary albumin-to-creatinine ratio [UACR]) and safety/tolerability (signs of sodium retention and acute increases in serum creatinine) to assess the effects of this agent on major renal outcomes. The patient population and enrichment results are described here. Methods: Patients with type 2 diabetes with an estimated glomerular filtration rate (eGFR) within 25 to 75 mL/min/1.73 m2 and UACR between 300 and 5000 mg/g were enrolled. After a run-in period, eligible patients received 0.75 mg/d of atrasentan for 6 weeks. A total of 2648 responder patients in whom UACR decreased by ≥30% compared to baseline were enrolled, as were 1020 non-responders with a UACR decrease of <30%. Patients who experienced a weight gain of >3 kg and in whom brain natriuretic peptide exceeded ≥300 pg/mL, or who experienced an increase in serum creatinine >20% (0.5 mg/dL), were not randomized. Results: Baseline characteristics were similar for atrasentan responders and non-responders. Upon entry to the study, median UACR was 802 mg/g in responders and 920 mg/g in non-responders. After 6 weeks of treatment with atrasentan, the UACR change in responders was −48.8% (95% CI, −49.8% to −47.9%) and in non-responders was −1.2% (95% CI, −6.4% to 3.9%). Changes in other renal risk markers were similar between responders and non-responders except for a marginally greater reduction in systolic blood pressure and eGFR in responders. Conclusions: The enrichment period has successfully identified a population with a profound UACR reduction without clinical signs of sodium retention in whom a large atrasentan effect on clinically important renal outcomes is possible. The SONAR trial aims to establish whether atrasentan confers renal protection.

Original languageEnglish
Pages (from-to)1829-1835
Number of pages7
JournalDiabetes, Obesity and Metabolism
Volume20
Issue number8
DOIs
Publication statusPublished - Aug 1 2018

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Creatinine
Albumins
Kidney
Glomerular Filtration Rate
Sodium
Blood Pressure
Brain Natriuretic Peptide
Serum
Type 2 Diabetes Mellitus
Population
atrasentan
Safety

Keywords

  • atrasentan
  • diabetic kidney disease
  • endothelin receptor antagonist
  • precision medicine
  • randomized controlled clinical trial

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism
  • Endocrinology

Cite this

Heerspink, H. J. L., Andress, D. L., Bakris, G., Brennan, J. J., Correa-Rotter, R., Hou, F. F., ... de Zeeuw, D. (2018). Baseline characteristics and enrichment results from the SONAR trial. Diabetes, Obesity and Metabolism, 20(8), 1829-1835. https://doi.org/10.1111/dom.13315

Baseline characteristics and enrichment results from the SONAR trial. / Heerspink, Hiddo J.L.; Andress, Dennis L.; Bakris, George; Brennan, John J.; Correa-Rotter, Ricardo; Hou, Fan Fan; Kitzman, Dalane W.; Kohan, Donald; Makino, Hirofumi; McMurray, John; Perkovic, Vlado; Tobe, Sheldon; Wigderson, Melissa; Yi, Tingting; Parving, Hans Henrik; de Zeeuw, Dick.

In: Diabetes, Obesity and Metabolism, Vol. 20, No. 8, 01.08.2018, p. 1829-1835.

Research output: Contribution to journalArticle

Heerspink, HJL, Andress, DL, Bakris, G, Brennan, JJ, Correa-Rotter, R, Hou, FF, Kitzman, DW, Kohan, D, Makino, H, McMurray, J, Perkovic, V, Tobe, S, Wigderson, M, Yi, T, Parving, HH & de Zeeuw, D 2018, 'Baseline characteristics and enrichment results from the SONAR trial', Diabetes, Obesity and Metabolism, vol. 20, no. 8, pp. 1829-1835. https://doi.org/10.1111/dom.13315
Heerspink HJL, Andress DL, Bakris G, Brennan JJ, Correa-Rotter R, Hou FF et al. Baseline characteristics and enrichment results from the SONAR trial. Diabetes, Obesity and Metabolism. 2018 Aug 1;20(8):1829-1835. https://doi.org/10.1111/dom.13315
Heerspink, Hiddo J.L. ; Andress, Dennis L. ; Bakris, George ; Brennan, John J. ; Correa-Rotter, Ricardo ; Hou, Fan Fan ; Kitzman, Dalane W. ; Kohan, Donald ; Makino, Hirofumi ; McMurray, John ; Perkovic, Vlado ; Tobe, Sheldon ; Wigderson, Melissa ; Yi, Tingting ; Parving, Hans Henrik ; de Zeeuw, Dick. / Baseline characteristics and enrichment results from the SONAR trial. In: Diabetes, Obesity and Metabolism. 2018 ; Vol. 20, No. 8. pp. 1829-1835.
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AU - Heerspink, Hiddo J.L.

AU - Andress, Dennis L.

AU - Bakris, George

AU - Brennan, John J.

AU - Correa-Rotter, Ricardo

AU - Hou, Fan Fan

AU - Kitzman, Dalane W.

AU - Kohan, Donald

AU - Makino, Hirofumi

AU - McMurray, John

AU - Perkovic, Vlado

AU - Tobe, Sheldon

AU - Wigderson, Melissa

AU - Yi, Tingting

AU - Parving, Hans Henrik

AU - de Zeeuw, Dick

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N2 - Aim: The SONAR trial uses an enrichment design based on the individual response to the selective endothelin receptor antagonist atrasentan on efficacy (the degree of the individual response in the urinary albumin-to-creatinine ratio [UACR]) and safety/tolerability (signs of sodium retention and acute increases in serum creatinine) to assess the effects of this agent on major renal outcomes. The patient population and enrichment results are described here. Methods: Patients with type 2 diabetes with an estimated glomerular filtration rate (eGFR) within 25 to 75 mL/min/1.73 m2 and UACR between 300 and 5000 mg/g were enrolled. After a run-in period, eligible patients received 0.75 mg/d of atrasentan for 6 weeks. A total of 2648 responder patients in whom UACR decreased by ≥30% compared to baseline were enrolled, as were 1020 non-responders with a UACR decrease of <30%. Patients who experienced a weight gain of >3 kg and in whom brain natriuretic peptide exceeded ≥300 pg/mL, or who experienced an increase in serum creatinine >20% (0.5 mg/dL), were not randomized. Results: Baseline characteristics were similar for atrasentan responders and non-responders. Upon entry to the study, median UACR was 802 mg/g in responders and 920 mg/g in non-responders. After 6 weeks of treatment with atrasentan, the UACR change in responders was −48.8% (95% CI, −49.8% to −47.9%) and in non-responders was −1.2% (95% CI, −6.4% to 3.9%). Changes in other renal risk markers were similar between responders and non-responders except for a marginally greater reduction in systolic blood pressure and eGFR in responders. Conclusions: The enrichment period has successfully identified a population with a profound UACR reduction without clinical signs of sodium retention in whom a large atrasentan effect on clinically important renal outcomes is possible. The SONAR trial aims to establish whether atrasentan confers renal protection.

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