The Experts below are selected from a list of 978 Experts worldwide ranked by ideXlab platform
Donald E Kohan - One of the best experts on this subject based on the ideXlab platform.
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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
Diabetes Obesity and Metabolism, 2018Co-Authors: Hiddo J L Heerspink, Donald E Kohan, Dennis L Andress, Ricardo Correarotter, Hirofumi Makino, John J. Brennan, Dalane W. Kitzman, George L Bakris, John J V Mcmurray, Vlado PerkovicAbstract: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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Baseline characteristics and enrichment results from the SONAR trial
Diabetes Obesity and Metabolism, 2018Co-Authors: Hiddo J L Heerspink, Donald E Kohan, Dennis L Andress, Hirofumi Makino, John J. Brennan, Dalane W. Kitzman, Ricardo Correa-rotter, George L Bakris, John J V McmurrayAbstract: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.
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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.
Diabetes Obesity and Metabolism, 2018Co-Authors: Hiddo J L Heerspink, Donald E Kohan, Dennis L Andress, John J. Brennan, Dalane W. Kitzman, Ricardo Correa-rotter, George L Bakris, Hirofumi MakinoAbstract: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
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longitudinal assessment of the effect of Atrasentan on thoracic bioimpedance in diabetic nephropathy a randomized double blind placebo controlled trial
Drugs in R & D, 2017Co-Authors: David J Webb, Donald E Kohan, Blai Coll, Ricardo Correarotter, Hiddo J L Heerspink, John J. Brennan, Mark Houser, Yili Pritchett, Dennis Andress, Hirofumi MakinoAbstract:Background Fluid retention is a common adverse event in patients who receive endothelin (ET) receptor antagonist therapy, including the highly selective ETA receptor antagonist, Atrasentan.
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the effects of Atrasentan on urinary metabolites in patients with type 2 diabetes and nephropathy
Diabetes Obesity and Metabolism, 2017Co-Authors: Michelle J Pena, Donald E Kohan, Blai Coll, Dennis L Andress, Ricardo Correarotter, Vlado Perkovic, Hirofumi Makino, John J. Brennan, Dick De Zeeuw, Giuseppe RemuzziAbstract:We assessed the effect of Atrasentan therapy on a pre-specified panel of 13 urinary metabolites known to reflect mitochondrial function in patients with diabetic kidney disease. This post-hoc analysis was performed using urine samples collected during the RADAR study which was a randomized, double-blind, placebo-controlled trial that tested the effects of Atrasentan on albuminuria reduction in patients with type 2 diabetes and nephropathy. At baseline, four of the 13 metabolites, quantified by gas-chromatography mass spectrometry, were below detectable levels, and six were reduced in patients with eGFR <60 ml/min/1.73 m(2) . After 12-weeks of Atrasentan treatment in patients with eGFR <60 ml/min/1.73 m(2) , a single-value index of the metabolites changed by -0.31 (95%CI -0.60 to -0.02; p = 0.035), -0.08 (-12 to 0.29; p = 0.43) and 0.01 (-0.21 to 0.19; p = 0.913) in placebo, Atrasentan 0.75 mg/d and 1.25 mg/d, respectively. The metabolite index difference compared to placebo was 0.13 (-0.17 to 0.43; p = 0.40) and 0.35 (0.05 to 0.65; p = 0.02) for Atrasentan 0.75 mg/d and 1.25 mg/d, respectively. These data corroborate previous findings of mitochondrial dysfunction in patients with type 2 diabetes, nephropathy, and eGFR <60 ml/min/1.73 m(2) , suggesting that Atrasentan may prevent the progression of mitochondrial dysfunction common to this specific patient population. Future studies of longer treatment duration with Atrasentan are indicated.
Hirofumi Makino - One of the best experts on this subject based on the ideXlab platform.
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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
Diabetes Obesity and Metabolism, 2018Co-Authors: Hiddo J L Heerspink, Donald E Kohan, Dennis L Andress, Ricardo Correarotter, Hirofumi Makino, John J. Brennan, Dalane W. Kitzman, George L Bakris, John J V Mcmurray, Vlado PerkovicAbstract: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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Baseline characteristics and enrichment results from the SONAR trial
Diabetes Obesity and Metabolism, 2018Co-Authors: Hiddo J L Heerspink, Donald E Kohan, Dennis L Andress, Hirofumi Makino, John J. Brennan, Dalane W. Kitzman, Ricardo Correa-rotter, George L Bakris, John J V McmurrayAbstract: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.
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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.
Diabetes Obesity and Metabolism, 2018Co-Authors: Hiddo J L Heerspink, Donald E Kohan, Dennis L Andress, John J. Brennan, Dalane W. Kitzman, Ricardo Correa-rotter, George L Bakris, Hirofumi MakinoAbstract: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
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longitudinal assessment of the effect of Atrasentan on thoracic bioimpedance in diabetic nephropathy a randomized double blind placebo controlled trial
Drugs in R & D, 2017Co-Authors: David J Webb, Donald E Kohan, Blai Coll, Ricardo Correarotter, Hiddo J L Heerspink, John J. Brennan, Mark Houser, Yili Pritchett, Dennis Andress, Hirofumi MakinoAbstract:Background Fluid retention is a common adverse event in patients who receive endothelin (ET) receptor antagonist therapy, including the highly selective ETA receptor antagonist, Atrasentan.
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the effects of Atrasentan on urinary metabolites in patients with type 2 diabetes and nephropathy
Diabetes Obesity and Metabolism, 2017Co-Authors: Michelle J Pena, Donald E Kohan, Blai Coll, Dennis L Andress, Ricardo Correarotter, Vlado Perkovic, Hirofumi Makino, John J. Brennan, Dick De Zeeuw, Giuseppe RemuzziAbstract:We assessed the effect of Atrasentan therapy on a pre-specified panel of 13 urinary metabolites known to reflect mitochondrial function in patients with diabetic kidney disease. This post-hoc analysis was performed using urine samples collected during the RADAR study which was a randomized, double-blind, placebo-controlled trial that tested the effects of Atrasentan on albuminuria reduction in patients with type 2 diabetes and nephropathy. At baseline, four of the 13 metabolites, quantified by gas-chromatography mass spectrometry, were below detectable levels, and six were reduced in patients with eGFR <60 ml/min/1.73 m(2) . After 12-weeks of Atrasentan treatment in patients with eGFR <60 ml/min/1.73 m(2) , a single-value index of the metabolites changed by -0.31 (95%CI -0.60 to -0.02; p = 0.035), -0.08 (-12 to 0.29; p = 0.43) and 0.01 (-0.21 to 0.19; p = 0.913) in placebo, Atrasentan 0.75 mg/d and 1.25 mg/d, respectively. The metabolite index difference compared to placebo was 0.13 (-0.17 to 0.43; p = 0.40) and 0.35 (0.05 to 0.65; p = 0.02) for Atrasentan 0.75 mg/d and 1.25 mg/d, respectively. These data corroborate previous findings of mitochondrial dysfunction in patients with type 2 diabetes, nephropathy, and eGFR <60 ml/min/1.73 m(2) , suggesting that Atrasentan may prevent the progression of mitochondrial dysfunction common to this specific patient population. Future studies of longer treatment duration with Atrasentan are indicated.
Dennis L Andress - One of the best experts on this subject based on the ideXlab platform.
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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
Diabetes Obesity and Metabolism, 2018Co-Authors: Hiddo J L Heerspink, Donald E Kohan, Dennis L Andress, Ricardo Correarotter, Hirofumi Makino, John J. Brennan, Dalane W. Kitzman, George L Bakris, John J V Mcmurray, Vlado PerkovicAbstract: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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Baseline characteristics and enrichment results from the SONAR trial
Diabetes Obesity and Metabolism, 2018Co-Authors: Hiddo J L Heerspink, Donald E Kohan, Dennis L Andress, Hirofumi Makino, John J. Brennan, Dalane W. Kitzman, Ricardo Correa-rotter, George L Bakris, John J V McmurrayAbstract: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.
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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.
Diabetes Obesity and Metabolism, 2018Co-Authors: Hiddo J L Heerspink, Donald E Kohan, Dennis L Andress, John J. Brennan, Dalane W. Kitzman, Ricardo Correa-rotter, George L Bakris, Hirofumi MakinoAbstract: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
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the effects of Atrasentan on urinary metabolites in patients with type 2 diabetes and nephropathy
Diabetes Obesity and Metabolism, 2017Co-Authors: Michelle J Pena, Donald E Kohan, Blai Coll, Dennis L Andress, Ricardo Correarotter, Vlado Perkovic, Hirofumi Makino, John J. Brennan, Dick De Zeeuw, Giuseppe RemuzziAbstract:We assessed the effect of Atrasentan therapy on a pre-specified panel of 13 urinary metabolites known to reflect mitochondrial function in patients with diabetic kidney disease. This post-hoc analysis was performed using urine samples collected during the RADAR study which was a randomized, double-blind, placebo-controlled trial that tested the effects of Atrasentan on albuminuria reduction in patients with type 2 diabetes and nephropathy. At baseline, four of the 13 metabolites, quantified by gas-chromatography mass spectrometry, were below detectable levels, and six were reduced in patients with eGFR <60 ml/min/1.73 m(2) . After 12-weeks of Atrasentan treatment in patients with eGFR <60 ml/min/1.73 m(2) , a single-value index of the metabolites changed by -0.31 (95%CI -0.60 to -0.02; p = 0.035), -0.08 (-12 to 0.29; p = 0.43) and 0.01 (-0.21 to 0.19; p = 0.913) in placebo, Atrasentan 0.75 mg/d and 1.25 mg/d, respectively. The metabolite index difference compared to placebo was 0.13 (-0.17 to 0.43; p = 0.40) and 0.35 (0.05 to 0.65; p = 0.02) for Atrasentan 0.75 mg/d and 1.25 mg/d, respectively. These data corroborate previous findings of mitochondrial dysfunction in patients with type 2 diabetes, nephropathy, and eGFR <60 ml/min/1.73 m(2) , suggesting that Atrasentan may prevent the progression of mitochondrial dysfunction common to this specific patient population. Future studies of longer treatment duration with Atrasentan are indicated.
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comparison of exposure response relationship of Atrasentan between north american and asian populations
Diabetes Obesity and Metabolism, 2017Co-Authors: Hiddo J L Heerspink, Donald E Kohan, Blai Coll, Dennis L Andress, Ricardo Correarotter, Hirofumi Makino, John J. Brennan, Justin W Davis, Ken Idler, Vlado PerkovicAbstract:AIMS: The selective endothelin (ET) A receptor antagonist Atrasentan has been shown to lower albuminuria in North American and Asian patients with type 2 diabetes and nephropathy. As drug responses to many drugs may differ between North American and Asian populations, we assessed the influence of geographical region on the albuminuria and fluid retention response to Atrasentan. MATERIALS AND METHODS: Two 12-week double-blind randomised controlled trials were performed with Atrasentan 0.75 or 1.25 mg/d vs placebo in patients with type 2 diabetes and nephropathy. The efficacy endpoint was the percentage change in albuminuria. Bodyweight change, a proxy of fluid retention, was used as a safety endpoint. Pharmacodynamics were determined in Asians (N = 77) and North Americans (N = 134). Atrasentan plasma concentration was measured in 161 Atrasentan-treated patients. RESULTS: Mean albuminuria reduction in Asian, compared to North American, patients was, respectively, -34.4% vs -26.3% for 0.75 mg/d ( P = .44) and -48.0% vs -28.9% for 1.25 mg/d ( P = .035). Bodyweight gain did not differ between North American and Asian populations. Atrasentan plasma concentrations were higher in Asians compared to North Americans and correlated with albuminuria response (7.2% albuminuria reduction per doubling Atrasentan concentration; P = .024). Body surface area (β = -1.09 per m2 ; P < .001) and bilirubin, as a marker of hepatic organic anion transporter activity, (β = 0.69 per mg/dL increment; P = .010) were independent determinants of Atrasentan plasma concentration; correction by body surface area and bilirubin left no significant difference in plasma concentration between Asian and North American populations. CONCLUSION: The higher exposure and albuminuria reduction of Atrasentan in Asian patients is not associated with more fluid retention, suggesting that Asian patients are less sensitive to Atrasentan-induced sodium retention.
John J. Brennan - One of the best experts on this subject based on the ideXlab platform.
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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
Diabetes Obesity and Metabolism, 2018Co-Authors: Hiddo J L Heerspink, Donald E Kohan, Dennis L Andress, Ricardo Correarotter, Hirofumi Makino, John J. Brennan, Dalane W. Kitzman, George L Bakris, John J V Mcmurray, Vlado PerkovicAbstract: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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Baseline characteristics and enrichment results from the SONAR trial
Diabetes Obesity and Metabolism, 2018Co-Authors: Hiddo J L Heerspink, Donald E Kohan, Dennis L Andress, Hirofumi Makino, John J. Brennan, Dalane W. Kitzman, Ricardo Correa-rotter, George L Bakris, John J V McmurrayAbstract: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.
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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.
Diabetes Obesity and Metabolism, 2018Co-Authors: Hiddo J L Heerspink, Donald E Kohan, Dennis L Andress, John J. Brennan, Dalane W. Kitzman, Ricardo Correa-rotter, George L Bakris, Hirofumi MakinoAbstract: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
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longitudinal assessment of the effect of Atrasentan on thoracic bioimpedance in diabetic nephropathy a randomized double blind placebo controlled trial
Drugs in R & D, 2017Co-Authors: David J Webb, Donald E Kohan, Blai Coll, Ricardo Correarotter, Hiddo J L Heerspink, John J. Brennan, Mark Houser, Yili Pritchett, Dennis Andress, Hirofumi MakinoAbstract:Background Fluid retention is a common adverse event in patients who receive endothelin (ET) receptor antagonist therapy, including the highly selective ETA receptor antagonist, Atrasentan.
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relationship between Atrasentan concentrations and urinary albumin to creatinine ratio in western and japanese patients with diabetic nephropathy
Clinical Therapeutics, 2017Co-Authors: Nael M Mostafa, John J. Brennan, Dennis Andress, Cheri E Klein, Walid M AwniAbstract:Abstract Purpose The objective of the current analyses was to characterize the pharmacokinetic properties of Atrasentan and the exposure-response relationships for the efficacy end point, urinary albumin to creatinine ratio (UACR), and the treatment-emergent adverse event, peripheral edema, during 8 or 12 weeks of treatment. Methods Results from 3 Phase II, randomized, double-blind, placebo-controlled studies (N = 257) were used for the population pharmacokinetic and exposure-response models. Concentration-time and response data for efficacy and tolerability were analyzed using a nonlinear mixed-effects population analysis and logistic regression approaches. Findings The pharmacokinetic data were adequately described by a 2-compartment model with first-order absorption and elimination. After weight was accounted for, no clinically meaningful differences were found in CL/F or Vd/F of the central compartment between Western and Japanese patients. Exposure-response analyses confirmed the efficacy of Atrasentan in reducing UACR, with an estimated decrease in UACR of ≥37% when the Atrasentan dose was 0.75 mg or higher. No significant association between Atrasentan exposure and the rate of edema was identified at Atrasentan doses of 0.5, 0.75, and 1.25 mg. The rates of peripheral edema were comparable in patients receiving active treatment and placebo. Implications The exposure-response relationships for efficacy and tolerability were consistent between Western and Japanese patients. On the basis of these analyses, a dose of 0.75 mg/d was selected for the Phase III trial. ClinicalTrials.gov identifiers: NCT01356849, NCT01399580, and NCT01424319.
Michael A Carducci - One of the best experts on this subject based on the ideXlab platform.
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Effect o f E ndothelin-A R eceptor B lockade W ith A trasentan o n Tumor P rogression i n M en W ith H ormone-Refracto ry P rostate Cancer: A R andomized, P hase I I, P lacebo-Controll ed T rial
2020Co-Authors: Michael A Carducci, Jurgen Breul, Danai D. Daliani, Azmi A. Nabulsi, Bernard A Zonnenberg, Nicholas J Vogelzang, Rod A Humerickhouse, Robert J. Padley, Claude Schulman, Mark A. WeinbergAbstract:Purpose: To evaluate the efficacy and safety of Atrasentan (ABT-627), an endothelin-A receptor antagonist, in the treatment of asymptomatic, hormone-refractory prostatic adenocarcinoma. Patients and Methods: A double-blind, randomized, placebo-controlled clinical trial of hormone-refractory prostate cancer (HRPCa) patients was conducted in the United States and Europe. Two hundred eighty-eight asymptomatic patients with HRPCa and evidence of metastatic disease were randomly assigned to one of three study groups receiving a once-daily oral dose of placebo, 2.5 mg Atrasentan, or 10 mg Atrasentan, respectively. Primary end point was time to progression; secondary end points included time to prostate-specific antigen (PSA) progression, bone scan changes, and changes in bone and tumor markers. Results: The three treatment groups were similar in all baseline characteristics. Median time to progression in intent-to-treat (ITT) patients (n 288) was longer in the 10-mg Atrasentan group compared with the placebo group: 183 v 137 days, respectively; (P .13). Median time to progression in evaluable patients (n 244) was significantly prolonged, from 129 days (placebo group) to 196 days (10-mg Atrasentan group; P .021). For both ITT and evaluable populations in the 10-mg Atrasentan group, median time to PSA progression was twice that of the placebo group (155 v 71 days; P .002). Patients who received placebo continued to have significant increases from baseline in serum (lactate dehydrogenase [LDH]), a marker of disease burden; elevations in LDH were uniformly attenuated by Atrasentan in the ITT population. Headache, peripheral edema, and rhinitis were primary side effects, typically of mild to moderate severity. Quality of life was not adversely affected by Atrasentan. Conclusion: Atrasentan is an oral, targeted therapy with favorable tolerability and the potential to delay progression of HRPCa. J Clin Oncol 21:679-689. © 2003 by American Society of Clinical Oncology.
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Atrasentan in patients with advanced renal cell carcinoma a phase 2 trial of the ecog acrin cancer research group e6800
Clinical Genitourinary Cancer, 2015Co-Authors: Michael A Carducci, Judith Manola, Suresh G Nair, Steven R Rousey, Janice P Dutcher, G WildingAbstract:Abstract Background Atrasentan, an oral endothelin receptor A antagonist, demonstrated phase 1 activity in patients with renal cell carcinoma (RCC). A phase 2 study was undertaken in patients with measurable or bone-only metastatic RCC in the pre-VEGF/TKI era. Methods and Materials Patients were stratified by disease status and prior immunotherapy. Eligible patients had no prior chemotherapy, 0 to 1 prior immunotherapies, and an Eastern Cooperative Oncology Group performance status of 0 to 2. Patients received Atrasentan 10 mg per day until progression. The primary end point was progression-free (PF) rate at 6 months. Rates of 25% among patients treated with prior immunotherapy and 45% among patients with no prior immunotherapy were considered promising. A 2-stage design was used for cohorts without prior immunotherapy. Results From 2003 to 2005, 98 patients were registered. Median treatment duration was 9.9 weeks (range, 0.3-107 weeks). Toxicities were mild; 71% of patients reported no grade 3 or higher treatment-related events. Grade 4 events included neutropenia (n = 3), dyspnea (n = 2), thrombosis (n = 1), and arrhythmia (n = 1). Two grade 5 events (dyspnea and constitutional) were possibly treatment related. Six-month PF rates (90% confidence interval) were 14% (6-25), 0% (0-39), 8% (1-23), and 22% (8-44), respectively, for patients with prior immunotherapy/measurable disease (n = 44), prior immunotherapy/bone metastases (n = 6), no prior immunotherapy/measurable disease (n = 25), and no prior immunotherapy/bone metastases (n = 18). Median PF survival was 2.3 months (95% confidence interval, 2.0-3.5 months). Conclusion Although well tolerated, Atrasentan did not yield 6-month PF rates supporting its use as first-line monotherapy in patients with advanced RCC.
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docetaxel and Atrasentan versus docetaxel and placebo for men with advanced castration resistant prostate cancer swog s0421 a randomised phase 3 trial
Lancet Oncology, 2013Co-Authors: David I Quinn, Michael A Carducci, Catherine M Tangen, Maha Hussain, Primo N Lara, Amir Goldkorn, Carol M Moinpour, Mark Garzotto, Philip C Mack, Paul J MonkAbstract:Summary Background The endothelin pathway has a role in bone metastases, which are characteristic of advanced prostate cancer. Atrasentan, an endothelin receptor antagonist, has shown activity in prostate cancer. We therefore assessed its effect on survival in patients with castration-resistant prostate cancer with bone metastases. Methods In a double-blind phase 3 trial, men with metastatic castration-resistant prostate cancer, stratified for progression type (prostate-specific antigen or radiological), baseline pain, extraskeletal metastases, and bisphosphonate use, were randomly assigned in a 1:1 ratio to docetaxel (75 mg/m 2 every 21 days, intravenously) with Atrasentan (10 mg/day, orally) or placebo for up to 12 cycles and treated until disease progression or unacceptable toxicity. Patients who did not progress on treatment were permitted to continue Atrasentan or placebo for up to 52 weeks. Coprimary endpoints were progression-free survival (PFS) and overall survival. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00134056. Findings 498 patients were randomly assigned to the Atrasentan group and 496 to the placebo group. The trial was halted early for futility in April, 2011, after a planned interim analysis. Median PFS was 9·2 months (95% CI 8·5–9·9) in the Atrasentan group and 9·1 months (8·4–10·2) in the placebo group (hazard ratio 1·02, 0·89–1·16; p=0·81). Median overall survival was 17·8 months (16·4–19·8) in the Atrasentan group versus 17·6 months (16·4–20·1) in the placebo group (1·04, 0·90–1·19; p=0·64). 278 (57%) of 492 patients in the Atrasentan group had grade 3 and greater toxicity compared with 294 (60%) of 486 in the placebo group (p=0·22). Three deaths in the Atrasentan group and seven in the placebo group were judged to be possibly or probably due to protocol treatment. Interpretation Atrasentan, when added to docetaxel, does not improve overall survival or PFS in men with castration-resistant prostate cancer and bone metastases; therefore, single-agent docetaxel should remain as one of the standard treatments. Funded National Cancer Institute, Sanofi-Aventis, and Abbott Laboratories.
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phase 3 randomized controlled trial of Atrasentan in patients with nonmetastatic hormone refractory prostate cancer
Cancer, 2008Co-Authors: Joel B Nelson, Claude Schulman, Fred Saad, D J Sleep, Joseph L Chin, W Love, Jiang Qian, Joyce Steinberg, Michael A CarducciAbstract:Background Atrasentan is a potent, oral, selective endothelin-A (ETA) receptor antagonist with clinical activity in patients with hormone-refractory prostate cancer (HRPC). This reports the results of a Phase 3, randomized, double-blind, placebo-controlled trial of Atrasentan in patients with nonmetastatic HRPC.
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a phase 3 randomized controlled trial of the efficacy and safety of Atrasentan in men with metastatic hormone refractory prostate cancer
Cancer, 2007Co-Authors: Michael A Carducci, Claude Schulman, Fred Saad, Per Anders Abrahamsson, D P Dearnaley, Scott North, D J Sleep, Jeffrey D Isaacson, Joel B NelsonAbstract:BACKGROUND. The objective of this study was to evaluate the efficacy and safety of Atrasentan (Xinlay), a selective endothelin-A receptor antagonist, in patients with metastatic hormone- refractory prostate cancer (HRPC). METHODS. This multinational, double-blind, placebo-controlled trial enrolled 809 men with metastatic HRPC. Patients were randomized 1:1 to receive either Atrasentan 10 mg per day or placebo. The primary endpoint was time to disease progression (TTP), which was determined according to radiographic and clinical measures. Analyses of overall survival and changes in biomarkers also were performed. RESULTS. Atrasentan did not reduce the risk of disease progression relative to placebo (hazards ratio, 0.89; 95% confidence interval, 0.76-1.04; P =.136). Most patients progressed radiographically at the first 12-week bone scan without concomitant clinical progression. In exploratory analyses, increases from baseline to final bone alkaline phosphatase (BAP) and prostate-specific antigen (PSA) levels were significantly lower with Atrasentan treatment (P 50% increase from nadir) was twice as long with Atrasentan treatment (505 days vs 254 days; P <.01). The delay in time to PSA progression did not reach statistical significance. Atrasentan generally was tolerated well, and the most common adverse events associated with treatment were headache, rhinitis, and peripheral edema, reflecting the vasodilatory and fluid-retention properties of endothelin-A receptor antagonism. CONCLUSIONS. Atrasentan did not delay disease progression in men with metastatic HRPC despite evidence of biologic effects on PSA and BAP as markers of disease burden.
