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Atrasentan

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Donald E Kohan – 1st expert on this subject based on the ideXlab platform

  • 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, 2018
    Co-Authors: Hiddo J L Heerspink, Donald E Kohan, Dennis L Andress, John J. Brennan, Dalane W. Kitzman, Ricardo Correarotter, Hirofumi Makino, George L Bakris, John J V Mcmurray, Vlado Perkovic

    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.

  • Baseline characteristics and enrichment results from the SONAR trial
    Diabetes Obesity and Metabolism, 2018
    Co-Authors: Hiddo J L Heerspink, Donald E Kohan, Dennis L Andress, John J. Brennan, Dalane W. Kitzman, Hirofumi Makino, Ricardo Correa-rotter, George L Bakris, John J V Mcmurray

    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 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.

  • 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, 2018
    Co-Authors: Hiddo J L Heerspink, Donald E Kohan, Dennis L Andress, John J. Brennan, Dalane W. Kitzman, Ricardo Correa-rotter, George L Bakris, Hirofumi Makino

    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

Hirofumi Makino – 2nd expert on this subject based on the ideXlab platform

  • 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, 2018
    Co-Authors: Hiddo J L Heerspink, Donald E Kohan, Dennis L Andress, John J. Brennan, Dalane W. Kitzman, Ricardo Correarotter, Hirofumi Makino, George L Bakris, John J V Mcmurray, Vlado Perkovic

    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.

  • Baseline characteristics and enrichment results from the SONAR trial
    Diabetes Obesity and Metabolism, 2018
    Co-Authors: Hiddo J L Heerspink, Donald E Kohan, Dennis L Andress, John J. Brennan, Dalane W. Kitzman, Hirofumi Makino, Ricardo Correa-rotter, George L Bakris, John J V Mcmurray

    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 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.

  • 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, 2018
    Co-Authors: Hiddo J L Heerspink, Donald E Kohan, Dennis L Andress, John J. Brennan, Dalane W. Kitzman, Ricardo Correa-rotter, George L Bakris, Hirofumi Makino

    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

Dennis L Andress – 3rd expert on this subject based on the ideXlab platform

  • 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, 2018
    Co-Authors: Hiddo J L Heerspink, Donald E Kohan, Dennis L Andress, John J. Brennan, Dalane W. Kitzman, Ricardo Correarotter, Hirofumi Makino, George L Bakris, John J V Mcmurray, Vlado Perkovic

    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.

  • Baseline characteristics and enrichment results from the SONAR trial
    Diabetes Obesity and Metabolism, 2018
    Co-Authors: Hiddo J L Heerspink, Donald E Kohan, Dennis L Andress, John J. Brennan, Dalane W. Kitzman, Hirofumi Makino, Ricardo Correa-rotter, George L Bakris, John J V Mcmurray

    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 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.

  • 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, 2018
    Co-Authors: Hiddo J L Heerspink, Donald E Kohan, Dennis L Andress, John J. Brennan, Dalane W. Kitzman, Ricardo Correa-rotter, George L Bakris, Hirofumi Makino

    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