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Melanie P Chin - One of the best experts on this subject based on the ideXlab platform.

  • study design and baseline characteristics of the cardinal trial a phase 3 study of Bardoxolone methyl in patients with alport syndrome
    American Journal of Nephrology, 2021
    Co-Authors: Glenn M Chertow, Melanie P Chin, Angie Goldsberry, Geoffrey A Block, Gerald B Appel, Sharon P Andreoli, Sripal Bangalore, Arlene B Chapman, Keisha L Gibson, Kazumoto Iijima
    Abstract:

    INTRODUCTION Alport syndrome is a rare genetic disorder that affects as many as 60,000 persons in the USA and a total of 103,000 persons ( 200 pg/mL at baseline or with significant cardiovascular histories were excluded. Patients were randomized 1:1 to Bardoxolone methyl or placebo, with stratification by baseline UACR. RESULTS A total of 371 patients were screened, and 157 patients were randomly assigned to receive Bardoxolone methyl (n = 77) or placebo (n = 80). The average age at screening was 39.2 years, and 23 (15%) were <18 years of age. Of the randomized population, 146 (93%) had confirmed genetic diagnosis of Alport syndrome, and 62% of patients had X-linked mode of inheritance. Mean baseline eGFR was 62.7 mL/min/1.73 m2, and the geometric mean UACR was 141.0 mg/g. The average annual rate of eGFR decline prior to enrollment in the study was -4.9 mL/min/1.73 m2 despite 78% of the patient population receiving ACE inhibitor (ACEi) or ARB therapy. DISCUSSION/CONCLUSION CARDINAL is one of the largest interventional, randomized controlled trials in Alport syndrome conducted to date. Despite the use of ACEi or ARB, patients were experiencing significant loss of kidney function prior to study entry.

  • study design and baseline characteristics of the cardinal trial a phase 3 study of Bardoxolone methyl in patients with alport syndrome
    American Journal of Nephrology, 2021
    Co-Authors: Glenn M Chertow, Melanie P Chin, Angie Goldsberry, Geoffrey A Block, Gerald B Appel, Sripal Bangalore, Arlene B Chapman, Keisha L Gibson, Sharon Andreoli, Kazumoto Iijima
    Abstract:

    Introduction: Alport syndrome is a rare genetic disorder that affects as many as 60,000 persons in the USA and a total of 103,000 persons (<5 per 10,000) in the European Union [1, 2]. It is the second most common inherited cause of kidney failure and is characterized by progressive loss of kidney function that often leads to end-stage kidney disease. Currently, there are no approved disease-specific agents for therapeutic use. We designed a phase 3 study (CARDINAL; NCT03019185) to evaluate the safety, tolerability, and efficacy of Bardoxolone methyl in patients with Alport syndrome. Methods: The CARDINAL phase 3 study is an international, multicenter, double-blind, placebo-controlled, randomized registrational trial. Eligible patients were of ages 12–70 years with confirmed genetic or histologic diagnosis of Alport syndrome, eGFR 30–90 mL/min/1.73 m2, and urinary albumin to creatinine ratio (UACR) ≤3,500 mg/g. Patients with B-type natriuretic peptide values >200 pg/mL at baseline or with significant cardiovascular histories were excluded. Patients were randomized 1:1 to Bardoxolone methyl or placebo, with stratification by baseline UACR. Results: A total of 371 patients were screened, and 157 patients were randomly assigned to receive Bardoxolone methyl ( n = 77) or placebo ( n = 80). The average age at screening was 39.2 years, and 23 (15%) were <18 years of age. Of the randomized population, 146 (93%) had confirmed genetic diagnosis of Alport syndrome, and 62% of patients had X-linked mode of inheritance. Mean baseline eGFR was 62.7 mL/min/1.73 m2, and the geometric mean UACR was 141.0 mg/g. The average annual rate of eGFR decline prior to enrollment in the study was −4.9 mL/min/1.73 m2 despite 78% of the patient population receiving ACE inhibitor (ACEi) or ARB therapy. Discussion/Conclusion: CARDINAL is one of the largest interventional, randomized controlled trials in Alport syndrome conducted to date. Despite the use of ACEi or ARB, patients were experiencing significant loss of kidney function prior to study entry.

  • effect of Bardoxolone methyl on the urine albumin to creatinine ratio in patients with type 2 diabetes and stage 4 chronic kidney disease
    Kidney International, 2019
    Co-Authors: Peter Rossing, Melanie P Chin, Angie Goldsberry, Colin J Meyer, Pablo E Pergola, Hiddo J L Heerspink, Geoffrey A Block, Peter Mccullough, David K Packham, Bruce Spinowitz
    Abstract:

    Bardoxolone methyl attenuates inflammation by inducing nuclear factor erythroid-derived 2-related factor 2 and suppressing nuclear factor κB. The Bardoxolone Methyl Evaluation in Patients With Chronic Kidney Disease and Type 2 Diabetes (BEACON) trial was a phase 3 placebo-controlled, randomized, double-blind, parallel-group, international, multicenter trial in 2185 patients with type 2 diabetes mellitus and stage 4 chronic kidney disease. BEACON was terminated because of safety concerns, largely related to a significant increase in early heart failure events in patients randomized to Bardoxolone methyl. Bardoxolone methyl resulted in increased estimated glomerular filtration rate (eGFR) and urine albumin-to-creatinine ratio. Herein, we present post hoc analyses characterizing the relation between the urine albumin-to-creatinine ratio and eGFR. The urine albumin-to-creatinine ratio and eGFR were assessed every four weeks through Week 12, followed by assessments every eight weeks thereafter, and 4 weeks after the last dose of Bardoxolone methyl was administered. The initial increases in urine albumin-to-creatinine ratio observed in patients randomized to Bardoxolone methyl were attenuated after six months. Multivariable regression analysis identified baseline eGFR and eGFR over time as the dominant factors associated with change in the urine albumin-to-creatinine ratio. Relative to placebo, Bardoxolone methyl resulted in a significant decrease in albuminuria when indexed to eGFR (least-squared means: −0.035 [95% confidence interval −0.031 to −0.039]). Thus, among patients with type 2 diabetes mellitus and stage 4 chronic kidney disease treated with Bardoxolone methyl, changes in albuminuria are directly related to changes in eGFR, challenging the conventional construct that increases in albuminuria universally reflect kidney injury and denote harm.

  • effects of Bardoxolone methyl on qt interval in healthy volunteers
    CardioRenal Medicine, 2019
    Co-Authors: Melanie P Chin, Shannon Rich, Angie Goldsberry, Megan Ogrady, Colin J Meyer
    Abstract:

    Background Bardoxolone methyl has been shown to increase eGFR in several clinical trials, including a phase 3 trial in patients with type 2 diabetes and stage 4 CKD (BEACON), which was terminated early due to an increase in heart failure events in Bardoxolone methyl-treated patients. A separate, "thorough QT" study was conducted in parallel with BEACON to evaluate the cardiovascular safety of Bardoxolone methyl in healthy subjects. Methods Subjects in the "thorough QT" study were randomized to receive Bardoxolone methyl 20 mg (therapeutic dose) or 80 mg (supratherapeutic dose), placebo, or moxifloxacin (400 mg; an active comparator). ECG results and supine blood pressure measurements were analyzed. The effects of Bardoxolone methyl on QT interval changes from baseline were quantified compared to the effect of placebo by calculating mean, time-matched, placebo-corrected, baseline-adjusted QTcF values (ΔΔQTcF) after 6 days of daily administration of Bardoxolone methyl. Results The study was halted early due to emerging safety information from the BEACON trial; however, 142/179 patients received all doses of the study drug and completed the study. For both Bardoxolone methyl-treated groups (20 and 80 mg), the upper limits of the 2-sided 90% confidence interval for ΔΔQTcF were less than the significance limit (10 ms) at all time points. Changes in blood pressure were similar in all treatment groups, and no serious adverse events were reported. Conclusions In healthy subjects, treatment with 20 or 80 mg Bardoxolone methyl did not affect the QTcF interval.

  • effects of Bardoxolone methyl on magnesium in patients with type 2 diabetes mellitus and chronic kidney disease
    CardioRenal Medicine, 2019
    Co-Authors: Dana V Rizk, Melanie P Chin, Angie Goldsberry, Megan Ogrady, Colin J Meyer, Pablo E Pergola, Robert D Toto, David G Warnock, Arnold L Silva, Peter A Mccullough
    Abstract:

    Background: Treatment with Bardoxolone methyl (Bard) in a multinational phase 3 trial, Bardoxolone Methyl Evaluation in Patients with Chronic Kidney Disease and Type 2 Diabetes (BEACON), resulted in increases in estimated glomerular filtration rate with concurrent reductions in serum magnesium. We analyzed data from several trials to characterize reductions in magnesium with Bard. Methods: BEACON randomized patients (n = 2,185) with type 2 diabetes (T2DM) and stage 4 chronic kidney disease (CKD) 1:1 to receive Bard (20 mg) or placebo once daily. In a separate open-label study, magnesium levels from 24-hour urine and sublingual epithelial cell samples were analyzed in patients with stage 3b-4 CKD and T2DM administered 20 mg Bard for 56 consecutive days. Results: BEACON patients randomized to Bard experienced significant reductions in serum magnesium from baseline relative to patients randomized to placebo (–0.17 mEq/L, 95% CI –0.18 to –0.60 mEq/L; p < 0.001). A separate study showed intracellular and urinary magnesium levels were unchanged with Bard treatment. Conclusions: Bard treatment results in significant decreases in serum magnesium that are not associated with changes in intracellular and urinary magnesium levels, indicating that magnesium decreases are not due to renal magnesium wasting or total body magnesium depletion. Importantly, the decreases in serum magnesium with Bard are not associated with adverse effects on QT interval.

Colin J Meyer - One of the best experts on this subject based on the ideXlab platform.

  • effect of Bardoxolone methyl on the urine albumin to creatinine ratio in patients with type 2 diabetes and stage 4 chronic kidney disease
    Kidney International, 2019
    Co-Authors: Peter Rossing, Melanie P Chin, Angie Goldsberry, Colin J Meyer, Pablo E Pergola, Hiddo J L Heerspink, Geoffrey A Block, Peter Mccullough, David K Packham, Bruce Spinowitz
    Abstract:

    Bardoxolone methyl attenuates inflammation by inducing nuclear factor erythroid-derived 2-related factor 2 and suppressing nuclear factor κB. The Bardoxolone Methyl Evaluation in Patients With Chronic Kidney Disease and Type 2 Diabetes (BEACON) trial was a phase 3 placebo-controlled, randomized, double-blind, parallel-group, international, multicenter trial in 2185 patients with type 2 diabetes mellitus and stage 4 chronic kidney disease. BEACON was terminated because of safety concerns, largely related to a significant increase in early heart failure events in patients randomized to Bardoxolone methyl. Bardoxolone methyl resulted in increased estimated glomerular filtration rate (eGFR) and urine albumin-to-creatinine ratio. Herein, we present post hoc analyses characterizing the relation between the urine albumin-to-creatinine ratio and eGFR. The urine albumin-to-creatinine ratio and eGFR were assessed every four weeks through Week 12, followed by assessments every eight weeks thereafter, and 4 weeks after the last dose of Bardoxolone methyl was administered. The initial increases in urine albumin-to-creatinine ratio observed in patients randomized to Bardoxolone methyl were attenuated after six months. Multivariable regression analysis identified baseline eGFR and eGFR over time as the dominant factors associated with change in the urine albumin-to-creatinine ratio. Relative to placebo, Bardoxolone methyl resulted in a significant decrease in albuminuria when indexed to eGFR (least-squared means: −0.035 [95% confidence interval −0.031 to −0.039]). Thus, among patients with type 2 diabetes mellitus and stage 4 chronic kidney disease treated with Bardoxolone methyl, changes in albuminuria are directly related to changes in eGFR, challenging the conventional construct that increases in albuminuria universally reflect kidney injury and denote harm.

  • effects of Bardoxolone methyl on qt interval in healthy volunteers
    CardioRenal Medicine, 2019
    Co-Authors: Melanie P Chin, Shannon Rich, Angie Goldsberry, Megan Ogrady, Colin J Meyer
    Abstract:

    Background Bardoxolone methyl has been shown to increase eGFR in several clinical trials, including a phase 3 trial in patients with type 2 diabetes and stage 4 CKD (BEACON), which was terminated early due to an increase in heart failure events in Bardoxolone methyl-treated patients. A separate, "thorough QT" study was conducted in parallel with BEACON to evaluate the cardiovascular safety of Bardoxolone methyl in healthy subjects. Methods Subjects in the "thorough QT" study were randomized to receive Bardoxolone methyl 20 mg (therapeutic dose) or 80 mg (supratherapeutic dose), placebo, or moxifloxacin (400 mg; an active comparator). ECG results and supine blood pressure measurements were analyzed. The effects of Bardoxolone methyl on QT interval changes from baseline were quantified compared to the effect of placebo by calculating mean, time-matched, placebo-corrected, baseline-adjusted QTcF values (ΔΔQTcF) after 6 days of daily administration of Bardoxolone methyl. Results The study was halted early due to emerging safety information from the BEACON trial; however, 142/179 patients received all doses of the study drug and completed the study. For both Bardoxolone methyl-treated groups (20 and 80 mg), the upper limits of the 2-sided 90% confidence interval for ΔΔQTcF were less than the significance limit (10 ms) at all time points. Changes in blood pressure were similar in all treatment groups, and no serious adverse events were reported. Conclusions In healthy subjects, treatment with 20 or 80 mg Bardoxolone methyl did not affect the QTcF interval.

  • effects of Bardoxolone methyl on magnesium in patients with type 2 diabetes mellitus and chronic kidney disease
    CardioRenal Medicine, 2019
    Co-Authors: Dana V Rizk, Melanie P Chin, Angie Goldsberry, Megan Ogrady, Colin J Meyer, Pablo E Pergola, Robert D Toto, David G Warnock, Arnold L Silva, Peter A Mccullough
    Abstract:

    Background: Treatment with Bardoxolone methyl (Bard) in a multinational phase 3 trial, Bardoxolone Methyl Evaluation in Patients with Chronic Kidney Disease and Type 2 Diabetes (BEACON), resulted in increases in estimated glomerular filtration rate with concurrent reductions in serum magnesium. We analyzed data from several trials to characterize reductions in magnesium with Bard. Methods: BEACON randomized patients (n = 2,185) with type 2 diabetes (T2DM) and stage 4 chronic kidney disease (CKD) 1:1 to receive Bard (20 mg) or placebo once daily. In a separate open-label study, magnesium levels from 24-hour urine and sublingual epithelial cell samples were analyzed in patients with stage 3b-4 CKD and T2DM administered 20 mg Bard for 56 consecutive days. Results: BEACON patients randomized to Bard experienced significant reductions in serum magnesium from baseline relative to patients randomized to placebo (–0.17 mEq/L, 95% CI –0.18 to –0.60 mEq/L; p < 0.001). A separate study showed intracellular and urinary magnesium levels were unchanged with Bard treatment. Conclusions: Bard treatment results in significant decreases in serum magnesium that are not associated with changes in intracellular and urinary magnesium levels, indicating that magnesium decreases are not due to renal magnesium wasting or total body magnesium depletion. Importantly, the decreases in serum magnesium with Bard are not associated with adverse effects on QT interval.

  • effects of Bardoxolone methyl on body weight waist circumference and glycemic control in obese patients with type 2 diabetes mellitus and stage 4 chronic kidney disease
    Journal of Diabetes and Its Complications, 2018
    Co-Authors: Glenn M Chertow, Melanie P Chin, Angie Goldsberry, Colin J Meyer, Geoffrey A Block, Gerald B Appel, Daniel W Coyne, Kamyar Kalantarzadeh, Mark E Molitch, Pablo E Pergola
    Abstract:

    Abstract Aims Obesity is associated with progression of chronic kidney disease (CKD). Treatment with Bardoxolone methyl in a multinational phase 3 trial, Bardoxolone Methyl Evaluation in Patients with Chronic Kidney Disease and Type 2 Diabetes (BEACON), resulted in increases in estimated glomerular filtration rate (eGFR) with concurrent reductions in body weight. We performed post-hoc analyses to further characterize reductions in body weight with Bardoxolone methyl. Methods Eligible patients with type 2 diabetes (T2DM) and CKD stage 4 (eGFR 15 to Results BEACON enrolled 2185 patients. Patients randomized to Bardoxolone methyl experienced significant reductions in body weight from baseline relative to patients randomized to placebo (−5.7 kg; 95% CI: −6.0 to −5.3 kg; p  Conclusions Bardoxolone methyl resulted in significant weight loss in a generally obese patient population with T2DM and stage 4 CKD, with the magnitude and rate dependent on baseline BMI.

  • a food effect study and dose proportionality study to assess the pharmacokinetics and safety of Bardoxolone methyl in healthy volunteers
    Clinical pharmacology in drug development, 2014
    Co-Authors: Nathan S Teuscher, Richard J Kelley, Emily O Dumas, Cheri E Klein, Walid M Awni, Colin J Meyer
    Abstract:

    This study investigated the effect of food on the plasma pharmacokinetics of Bardoxolone methyl, an antioxidant inflammation modulator, at a 20mg dose, and the dose proportionality of Bardoxolone methyl pharmacokinetics from 20 to 80mg. It was a single‐dose study conducted at a single center in 32 healthy volunteers aged 18–45 years using an amorphous spray‐dried dispersion formulation of Bardoxolone methyl. In Part A, 16 subjects received single 20mg doses of Bardoxolone methyl under fasting and non‐fasting conditions. In Part B, 16 subjects received a single 60 or 80mg dose of Bardoxolone methyl and a matching placebo dose under fasting conditions.Blood samples for pharmacokinetic analysis were taken over 120hours following dose administration. Single dose administration of 20, 60, and 80mg Bardoxolone methyl was safe and well‐tolerated in healthy volunteers. Total Bardoxolone methyl exposure was unchanged in the presence of food. However, doses of Bardoxolone methyl above 20mg appear to have a saturated dissolution or absorption process and are associated with less than proportional increases in drug exposure.

Xu-feng Huang - One of the best experts on this subject based on the ideXlab platform.

  • Bardoxolone methyl prevents obesity and hypothalamic dysfunction
    Chemico-Biological Interactions, 2016
    Co-Authors: Danielle Camer, Chi H. L Dinh, Alexander M Szabo, Hongqin Wang, Xu-feng Huang
    Abstract:

    High-fat (HF) diet-induced obesity is associated with hypothalamic leptin resistance and low grade chronic inflammation, which largely impairs the neuroregulation of negative energy balance. Neuroregulation of negative energy balance is largely controlled by the mediobasal and paraventricular nuclei regions of the hypothalamus via leptin signal transduction. Recently, a derivative of oleanolic acid, Bardoxolone methyl (BM), has been shown to have anti-inflammatory effects. We tested the hypothesis that BM would prevent HF diet-induced obesity, hypothalamic leptin resistance, and inflammation in mice fed a HF diet. Oral administration of BM via drinking water (10 mg/kg daily) for 21 weeks significantly prevented an increase in body weight, energy intake, hyperleptinemia, and peripheral fat accumulation in mice fed a HF diet. Furthermore, BM treatment prevented HF diet-induced decreases in the anorexigenic effects of peripheral leptin administration. In the mediobasal and paraventricular nuclei regions of the hypothalamus, BM administration prevented HF diet-induced impairments of the downstream protein kinase b (Akt) pathway of hypothalamic leptin signalling. BM treatment also prevented an increase in inflammatory cytokines, tumour necrosis factor alpha (TNFα) and interleukin 6 (IL-6) in these two hypothalamic regions. These results identify a potential novel neuropharmacological application for BM in preventing HF diet-induced obesity, hypothalamic leptin resistance, and inflammation.

  • Bardoxolone methyl prevents high fat diet induced colon inflammation in mice
    Journal of Histochemistry and Cytochemistry, 2016
    Co-Authors: Chi H. L Dinh, Alexander M Szabo, Qingsheng Zhang, Peng Zhang, Xu-feng Huang
    Abstract:

    Obesity induces chronic, low-grade inflammation, which increases the risk of colon cancer. We investigated the preventive effects of Bardoxolone methyl (BARD) on high-fat diet (HFD)-induced inflammation in a mouse colon. Male C57BL/6J mice (n=7) were fed a HFD (HFD group), HFD plus BARD (10 mg/kg) in drinking water (HFD/BARD group), or normal laboratory chow diet (LFD group) for 21 weeks. In HFD mice, BARD reduced colon thickness and decreased colon weight per length. This was associated with an increase in colon crypt depth and the number of goblet cells per crypt. BARD reduced the expression of F4/80 and CD11c but increased CD206 and IL-10, indicating an anti-inflammatory effect. BARD prevented an increase of the intracellular pro-inflammatory biomarkers (NF-қB, p NF-қB, IL-6, TNF-α) and cell proliferation markers (Cox2 and Ki67). BARD prevented fat deposition in the colon wall and prevented microbial population changes. Overall, we report the preventive effects of BARD on colon inflammation in HFD-fed mice through its regulation of macrophages, NF-қB, cytokines, Cox2 and Ki67, fat deposition and microflora.

  • Bardoxolone Methyl Prevents Mesenteric Fat Deposition and Inflammation in High-Fat Diet Mice
    TheScientificWorldJournal, 2015
    Co-Authors: Chi H. L Dinh, Alexander M Szabo, Danielle Camer, Hongqin Wang, Xu-feng Huang
    Abstract:

    Mesenteric fat belongs to visceral fat. An increased deposition of mesenteric fat contributes to obesity associated complications such as type 2 diabetes and cardiovascular diseases. We have investigated the therapeutic effects of Bardoxolone methyl (BARD) on mesenteric adipose tissue of mice fed a high-fat diet (HFD). Male C57BL/6J mice were administered oral BARD during HFD feeding (HFD/BARD), only fed a high-fat diet (HFD), or fed low-fat diet (LFD) for 21 weeks. Histology and immunohistochemistry were used to analyse mesenteric morphology and macrophages, while Western blot was used to assess the expression of inflammatory, oxidative stress, and energy expenditure proteins. Supplementation of drinking water with BARD prevented mesenteric fat deposition, as determined by a reduction in large adipocytes. BARD prevented inflammation as there were fewer inflammatory macrophages and reduced proinflammatory cytokines (interleukin-1 beta and tumour necrosis factor alpha). BARD reduced the activation of extracellular signal-regulated kinase (ERK) and Akt, suggesting an antioxidative stress effect. BARD upregulates energy expenditure proteins, judged by the increased activity of tyrosine hydroxylase (TH) and AMP-activated protein kinase (AMPK) and increased peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), and uncoupling protein 2 (UCP2) proteins. Overall, BARD induces preventive effect in HFD mice through regulation of mesenteric adipose tissue.

  • is b type natriuretic peptide a risk factor for heart failure in patients treated with Bardoxolone methyl
    Journal of Cardiac Failure, 2015
    Co-Authors: Danielle Camer, Xu-feng Huang
    Abstract:

    Letter to the Editor, comment on article entitled "Risk Factors for Heart Failure in Patients With Type 2 Diabetes Mellitus and Stage 4 Chronic Kidney Disease Treated With Bardoxolone Methyl" by Chin et al in the Journal of Cardiac Failure. Disciplines Medicine and Health Sciences Publication Details Camer, D. & Huang, X. (2015). Is B-type natriuretic peptide a risk factor for heart failure in patients treated with Bardoxolone methyl?. Journal of Cardiac Failure, 21 (3), 258-259. This journal article is available at Research Online: http://ro.uow.edu.au/ihmri/513 Comment on: Risk Factors for Heart Failure in Patients with Type 2 Diabetes Mellitus and Stage 4 Chronic Kidney Disease Treated with Bardoxolone Methyl Authors: Danielle Camer and Xu-Feng Huang Affiliation: School of Medicine and Illawarra Health and Medical Research Institute, University of Wollongong, NSW, 2522, Australia. *Corresponding author: Professor Xu-Feng Huang, MD, PhD, DSc Illawarra Health and Medical Research Institute, School of Medicine, University of Wollongong, Northfields Avenue, NSW, 2522, Australia Tel.: 61-02-42214300 Fax: 61-02-42214096 E-mail address: xhuang@uow.edu.au

  • Bardoxolone methyl a potential therapeutic for the prevention of anti psychotic drug induced obesity
    2015
    Co-Authors: Danielle Camer, Alexander M Szabo, Christopher Bell, Francesca Fernandezenright, Hoang Lan Chi Dinh, Xu-feng Huang
    Abstract:

    Abstract of a presentation. Disciplines Medicine and Health Sciences Publication Details Camer, D., Bell, C. J., Yu, Y., Szabo, A., Fernandez, F., Dinh, H. C. & Huang, X. F. (2015). Bardoxolone methyl: a potential therapeutic for the prevention of anti-psychotic drug-induced obesity?. Proceedings of 22nd Multidisciplinary ISBS International Neuroscience and Biological Psychiatry "Stress and Behavior" Conference (pp. 22-22). Authors Danielle Camer, Christopher Bell, Yinghua Yu, Alexander M. Szabo, Francesca Fernandez-Enright, Hoang Lan Chi Dinh, and Xu-Feng Huang This conference paper is available at Research Online: http://ro.uow.edu.au/ihmri/536

Angie Goldsberry - One of the best experts on this subject based on the ideXlab platform.

  • study design and baseline characteristics of the cardinal trial a phase 3 study of Bardoxolone methyl in patients with alport syndrome
    American Journal of Nephrology, 2021
    Co-Authors: Glenn M Chertow, Melanie P Chin, Angie Goldsberry, Geoffrey A Block, Gerald B Appel, Sripal Bangalore, Arlene B Chapman, Keisha L Gibson, Sharon Andreoli, Kazumoto Iijima
    Abstract:

    Introduction: Alport syndrome is a rare genetic disorder that affects as many as 60,000 persons in the USA and a total of 103,000 persons (<5 per 10,000) in the European Union [1, 2]. It is the second most common inherited cause of kidney failure and is characterized by progressive loss of kidney function that often leads to end-stage kidney disease. Currently, there are no approved disease-specific agents for therapeutic use. We designed a phase 3 study (CARDINAL; NCT03019185) to evaluate the safety, tolerability, and efficacy of Bardoxolone methyl in patients with Alport syndrome. Methods: The CARDINAL phase 3 study is an international, multicenter, double-blind, placebo-controlled, randomized registrational trial. Eligible patients were of ages 12–70 years with confirmed genetic or histologic diagnosis of Alport syndrome, eGFR 30–90 mL/min/1.73 m2, and urinary albumin to creatinine ratio (UACR) ≤3,500 mg/g. Patients with B-type natriuretic peptide values >200 pg/mL at baseline or with significant cardiovascular histories were excluded. Patients were randomized 1:1 to Bardoxolone methyl or placebo, with stratification by baseline UACR. Results: A total of 371 patients were screened, and 157 patients were randomly assigned to receive Bardoxolone methyl ( n = 77) or placebo ( n = 80). The average age at screening was 39.2 years, and 23 (15%) were <18 years of age. Of the randomized population, 146 (93%) had confirmed genetic diagnosis of Alport syndrome, and 62% of patients had X-linked mode of inheritance. Mean baseline eGFR was 62.7 mL/min/1.73 m2, and the geometric mean UACR was 141.0 mg/g. The average annual rate of eGFR decline prior to enrollment in the study was −4.9 mL/min/1.73 m2 despite 78% of the patient population receiving ACE inhibitor (ACEi) or ARB therapy. Discussion/Conclusion: CARDINAL is one of the largest interventional, randomized controlled trials in Alport syndrome conducted to date. Despite the use of ACEi or ARB, patients were experiencing significant loss of kidney function prior to study entry.

  • study design and baseline characteristics of the cardinal trial a phase 3 study of Bardoxolone methyl in patients with alport syndrome
    American Journal of Nephrology, 2021
    Co-Authors: Glenn M Chertow, Melanie P Chin, Angie Goldsberry, Geoffrey A Block, Gerald B Appel, Sharon P Andreoli, Sripal Bangalore, Arlene B Chapman, Keisha L Gibson, Kazumoto Iijima
    Abstract:

    INTRODUCTION Alport syndrome is a rare genetic disorder that affects as many as 60,000 persons in the USA and a total of 103,000 persons ( 200 pg/mL at baseline or with significant cardiovascular histories were excluded. Patients were randomized 1:1 to Bardoxolone methyl or placebo, with stratification by baseline UACR. RESULTS A total of 371 patients were screened, and 157 patients were randomly assigned to receive Bardoxolone methyl (n = 77) or placebo (n = 80). The average age at screening was 39.2 years, and 23 (15%) were <18 years of age. Of the randomized population, 146 (93%) had confirmed genetic diagnosis of Alport syndrome, and 62% of patients had X-linked mode of inheritance. Mean baseline eGFR was 62.7 mL/min/1.73 m2, and the geometric mean UACR was 141.0 mg/g. The average annual rate of eGFR decline prior to enrollment in the study was -4.9 mL/min/1.73 m2 despite 78% of the patient population receiving ACE inhibitor (ACEi) or ARB therapy. DISCUSSION/CONCLUSION CARDINAL is one of the largest interventional, randomized controlled trials in Alport syndrome conducted to date. Despite the use of ACEi or ARB, patients were experiencing significant loss of kidney function prior to study entry.

  • effect of Bardoxolone methyl on the urine albumin to creatinine ratio in patients with type 2 diabetes and stage 4 chronic kidney disease
    Kidney International, 2019
    Co-Authors: Peter Rossing, Melanie P Chin, Angie Goldsberry, Colin J Meyer, Pablo E Pergola, Hiddo J L Heerspink, Geoffrey A Block, Peter Mccullough, David K Packham, Bruce Spinowitz
    Abstract:

    Bardoxolone methyl attenuates inflammation by inducing nuclear factor erythroid-derived 2-related factor 2 and suppressing nuclear factor κB. The Bardoxolone Methyl Evaluation in Patients With Chronic Kidney Disease and Type 2 Diabetes (BEACON) trial was a phase 3 placebo-controlled, randomized, double-blind, parallel-group, international, multicenter trial in 2185 patients with type 2 diabetes mellitus and stage 4 chronic kidney disease. BEACON was terminated because of safety concerns, largely related to a significant increase in early heart failure events in patients randomized to Bardoxolone methyl. Bardoxolone methyl resulted in increased estimated glomerular filtration rate (eGFR) and urine albumin-to-creatinine ratio. Herein, we present post hoc analyses characterizing the relation between the urine albumin-to-creatinine ratio and eGFR. The urine albumin-to-creatinine ratio and eGFR were assessed every four weeks through Week 12, followed by assessments every eight weeks thereafter, and 4 weeks after the last dose of Bardoxolone methyl was administered. The initial increases in urine albumin-to-creatinine ratio observed in patients randomized to Bardoxolone methyl were attenuated after six months. Multivariable regression analysis identified baseline eGFR and eGFR over time as the dominant factors associated with change in the urine albumin-to-creatinine ratio. Relative to placebo, Bardoxolone methyl resulted in a significant decrease in albuminuria when indexed to eGFR (least-squared means: −0.035 [95% confidence interval −0.031 to −0.039]). Thus, among patients with type 2 diabetes mellitus and stage 4 chronic kidney disease treated with Bardoxolone methyl, changes in albuminuria are directly related to changes in eGFR, challenging the conventional construct that increases in albuminuria universally reflect kidney injury and denote harm.

  • effects of Bardoxolone methyl on qt interval in healthy volunteers
    CardioRenal Medicine, 2019
    Co-Authors: Melanie P Chin, Shannon Rich, Angie Goldsberry, Megan Ogrady, Colin J Meyer
    Abstract:

    Background Bardoxolone methyl has been shown to increase eGFR in several clinical trials, including a phase 3 trial in patients with type 2 diabetes and stage 4 CKD (BEACON), which was terminated early due to an increase in heart failure events in Bardoxolone methyl-treated patients. A separate, "thorough QT" study was conducted in parallel with BEACON to evaluate the cardiovascular safety of Bardoxolone methyl in healthy subjects. Methods Subjects in the "thorough QT" study were randomized to receive Bardoxolone methyl 20 mg (therapeutic dose) or 80 mg (supratherapeutic dose), placebo, or moxifloxacin (400 mg; an active comparator). ECG results and supine blood pressure measurements were analyzed. The effects of Bardoxolone methyl on QT interval changes from baseline were quantified compared to the effect of placebo by calculating mean, time-matched, placebo-corrected, baseline-adjusted QTcF values (ΔΔQTcF) after 6 days of daily administration of Bardoxolone methyl. Results The study was halted early due to emerging safety information from the BEACON trial; however, 142/179 patients received all doses of the study drug and completed the study. For both Bardoxolone methyl-treated groups (20 and 80 mg), the upper limits of the 2-sided 90% confidence interval for ΔΔQTcF were less than the significance limit (10 ms) at all time points. Changes in blood pressure were similar in all treatment groups, and no serious adverse events were reported. Conclusions In healthy subjects, treatment with 20 or 80 mg Bardoxolone methyl did not affect the QTcF interval.

  • effects of Bardoxolone methyl on magnesium in patients with type 2 diabetes mellitus and chronic kidney disease
    CardioRenal Medicine, 2019
    Co-Authors: Dana V Rizk, Melanie P Chin, Angie Goldsberry, Megan Ogrady, Colin J Meyer, Pablo E Pergola, Robert D Toto, David G Warnock, Arnold L Silva, Peter A Mccullough
    Abstract:

    Background: Treatment with Bardoxolone methyl (Bard) in a multinational phase 3 trial, Bardoxolone Methyl Evaluation in Patients with Chronic Kidney Disease and Type 2 Diabetes (BEACON), resulted in increases in estimated glomerular filtration rate with concurrent reductions in serum magnesium. We analyzed data from several trials to characterize reductions in magnesium with Bard. Methods: BEACON randomized patients (n = 2,185) with type 2 diabetes (T2DM) and stage 4 chronic kidney disease (CKD) 1:1 to receive Bard (20 mg) or placebo once daily. In a separate open-label study, magnesium levels from 24-hour urine and sublingual epithelial cell samples were analyzed in patients with stage 3b-4 CKD and T2DM administered 20 mg Bard for 56 consecutive days. Results: BEACON patients randomized to Bard experienced significant reductions in serum magnesium from baseline relative to patients randomized to placebo (–0.17 mEq/L, 95% CI –0.18 to –0.60 mEq/L; p < 0.001). A separate study showed intracellular and urinary magnesium levels were unchanged with Bard treatment. Conclusions: Bard treatment results in significant decreases in serum magnesium that are not associated with changes in intracellular and urinary magnesium levels, indicating that magnesium decreases are not due to renal magnesium wasting or total body magnesium depletion. Importantly, the decreases in serum magnesium with Bard are not associated with adverse effects on QT interval.

George L Bakris - One of the best experts on this subject based on the ideXlab platform.

  • Bardoxolone methyl improves kidney function in patients with chronic kidney disease stage 4 and type 2 diabetes post hoc analyses from Bardoxolone methyl evaluation in patients with chronic kidney disease and type 2 diabetes study
    American Journal of Nephrology, 2018
    Co-Authors: Melanie P Chin, Angie Goldsberry, Megan Ogrady, Glenn M Chertow, Pablo E Pergola, George L Bakris, Hiddo J L Heerspink, Geoffrey A Block, Lesley A Inker, Christoph Wanner
    Abstract:

    Background: Increases in measured inulin clearance, measured creatinine clearance, and estimated glomerular filtration rate (eGFR) have been observed with Bardoxolone methyl in 7 studies enrolling approximately 2,600 patients with type 2 diabetes (T2D) and chronic kidney disease (CKD). The largest of these studies was Bardoxolone Methyl Evaluation in Patients with Chronic Kidney Disease and Type 2 Diabetes (BEACON), a multinational, randomized, double-blind, placebo-controlled phase 3 trial which enrolled patients with T2D and CKD stage 4. The BEACON trial was terminated after preliminary analyses showed that patients randomized to Bardoxolone methyl experienced significantly higher rates of heart failure events. We performed post-hoc analyses to characterize changes in kidney func-tion induced by Bardoxolone methyl. Methods: Patients in -BEACON (n = 2,185) were randomized 1: 1 to receive oncedaily Bardoxolone methyl (20 mg) or placebo. We compared the effects of Bardoxolone methyl and placebo on a post-hoc composite renal endpoint consisting of = 30% decline from baseline in eGFR, eGFR <15 mL/min/1.73 m2, and end-stage renal disease (ESRD) events (provision of dialysis or kidney transplantation). Results: Consistent with prior studies, patients randomized to Bardoxolone methyl experienced mean increases in eGFR that were sustained through study week 48. Moreover, increases in eGFR from baseline were sustained 4 weeks after cessation of treatment. Patients randomized to Bardoxolone methyl were significantly less likely to experience the composite renal endpoint (hazards ratio 0.48 [95% CI 0.36-0.64]; p <0.0001). Conclusions: Bardoxolone methyl preserves kidney function and may delay the onset of ESRD in patients with T2D and stage 4 CKD. (C) 2018 The Author(s) Published by S. Karger AG, Basel

  • risk factors for heart failure in patients with type 2 diabetes mellitus and stage 4 chronic kidney disease treated with Bardoxolone methyl
    Journal of Cardiac Failure, 2014
    Co-Authors: Melanie P Chin, Angie Goldsberry, Glenn M Chertow, Dick De Zeeuw, George L Bakris, Peter G Linde, Peter A Mccullough, Danielle Wrolstad, John J V Mcmurray
    Abstract:

    Abstract Background A phase 3 randomized clinical trial was designed to test whether Bardoxolone methyl, a nuclear factor erythroid-2–related factor 2 (Nrf2) activator, slows progression to end-stage renal disease in patients with stage 4 chronic kidney disease and type 2 diabetes mellitus. The trial was terminated because of an increase in heart failure in the Bardoxolone methyl group; many of the events were clinically associated with fluid retention. Methods and Results We randomized 2,185 patients with type 2 diabetes mellitus (T2DM) and stage 4 chronic kidney disease (CKD) (estimated glomerular filtration rate 15 to −1 1.73 m −2 ) to once-daily Bardoxolone methyl (20 mg) or placebo. We used classification and regression tree analysis to identify baseline factors predictive of heart failure or fluid overload events. Elevated baseline B-type natriuretic peptide and previous hospitalization for heart failure were identified as predictors of heart failure events; Bardoxolone methyl increased the risk of heart failure by 60% in patients with these risk factors. For patients without these baseline characteristics, the risk for heart failure events among Bardoxolone methyl– and placebo-treated patients was similar (2%). The same risk factors were also identified as predictors of fluid overload and appeared to be related to other serious adverse events. Conclusions Bardoxolone methyl contributed to events related to heart failure and/or fluid overload in a subpopulation of susceptible patients with an increased risk for heart failure at baseline. Careful selection of participants and vigilant monitoring of the study drug will be required in any future trials of Bardoxolone methyl to mitigate the risk of heart failure and other serious adverse events.

  • mechanisms contributing to adverse cardiovascular events in patients with type 2 diabetes mellitus and stage 4 chronic kidney disease treated with Bardoxolone methyl
    American Journal of Nephrology, 2014
    Co-Authors: Melanie P Chin, Scott A Reisman, Keith W Ward, Megan Ogrady, Nosratola D Vaziri, George L Bakris, David K Packham, Peter G Linde, Peter A Mccullough, David G Warnock
    Abstract:

    Background: Bardoxolone methyl, an Nrf2-activating and nuclear factor-κB-inhibiting semisynthetic oleanane triterpenoid compound, was evaluated in a phase 3 trial (BEACON) in patients with type 2 diabetes mellitus (T2DM) and stage 4 chronic kidney disease (CKD). The trial was terminated because of an increase in heart failure events in the Bardoxolone methyl group, many of which appeared related to fluid retention. Thus, additional analyses were conducted to explain these serious adverse events. Methods: Patients (n = 2,185) were randomized to receive once-daily Bardoxolone methyl (20 mg) or placebo. Twenty-four-hour urine collections were analyzed in a subset of the BEACON population and from a separate, open-label pharmacology study in patients with stage 3b/4 CKD and T2DM administered 20 mg Bardoxolone methyl once daily for 56 consecutive days. Results: Bardoxolone-methyl-treated patients in the BEACON substudy had a clinically meaningful reduction in urine volume and sodium excretion at week 4 relative to baseline (p Conclusions: The totality of the evidence suggests that through modulation of the endothelin pathway, Bardoxolone methyl may pharmacologically promote acute sodium and volume retention and increase blood pressure in patients with more advanced CKD.

  • mechanisms contributing to adverse cardiovascular events in patients with type 2 diabetes mellitus and stage 4 chronic kidney disease treated with Bardoxolone methyl
    American Journal of Nephrology, 2014
    Co-Authors: Melanie P Chin, Scott A Reisman, Keith W Ward, Megan Ogrady, Nosratola D Vaziri, George L Bakris, David K Packham, Peter G Linde, Peter A Mccullough, David G Warnock
    Abstract:

    BACKGROUND: Bardoxolone methyl, an Nrf2-activating and nuclear factor-κB-inhibiting semisynthetic oleanane triterpenoid compound, was evaluated in a phase 3 trial (BEACON) in patients with type 2 diabetes mellitus (T2DM) and stage 4 chronic kidney disease (CKD). The trial was terminated because of an increase in heart failure events in the Bardoxolone methyl group, many of which appeared related to fluid retention. Thus, additional analyses were conducted to explain these serious adverse events. METHODS: Patients (n = 2,185) were randomized to receive once-daily Bardoxolone methyl (20 mg) or placebo. Twenty-four-hour urine collections were analyzed in a subset of the BEACON population and from a separate, open-label pharmacology study in patients with stage 3b/4 CKD and T2DM administered 20 mg Bardoxolone methyl once daily for 56 consecutive days. RESULTS: Bardoxolone-methyl-treated patients in the BEACON substudy had a clinically meaningful reduction in urine volume and sodium excretion at week 4 relative to baseline (p < 0.05), and a separate study revealed that decreased sodium excretion and urine output occurred in some patients with stage 4 CKD but not those with stage 3b CKD. The clinical phenotype of fluid overload and heart failure in BEACON was similar to that observed with endothelin receptor antagonists in advanced CKD patients, and preclinical data demonstrate that Bardoxolone methyl modifies endothelin signaling. CONCLUSIONS: The totality of the evidence suggests that through modulation of the endothelin pathway, Bardoxolone methyl may pharmacologically promote acute sodium and volume retention and increase blood pressure in patients with more advanced CKD.

  • Bardoxolone methyl in type 2 diabetes and stage 4 chronic kidney disease
    The New England Journal of Medicine, 2013
    Co-Authors: Dick De Zeeuw, Angie Goldsberry, Melissa Krauth, Paul Audhya, Heidi Christschmidt, Tadao Akizawa, George L Bakris, Melanie Chin, Mark Houser, Hiddo J L Heerspink
    Abstract:

    BACKGROUND: Although inhibitors of the renin-angiotensin-aldosterone system can slow the progression of diabetic kidney disease, the residual risk is high. Whether nuclear 1 factor (erythroid-derived 2)-related factor 2 activators further reduce this risk is unknown. METHODS: We randomly assigned 2185 patients with type 2 diabetes mellitus and stage 4 chronic kidney disease (estimated glomerular filtration rate [GFR], 15 to <30 ml per minute per 1.73 m(2) of body-surface area) to Bardoxolone methyl, at a daily dose of 20 mg, or placebo. The primary composite outcome was end-stage renal disease (ESRD) or death from cardiovascular causes. RESULTS: The sponsor and the steering committee terminated the trial on the recommendation of the independent data and safety monitoring committee; the median follow-up was 9 months. A total of 69 of 1088 patients (6%) randomly assigned to Bardoxolone methyl and 69 of 1097 (6%) randomly assigned to placebo had a primary composite outcome (hazard ratio in the Bardoxolone methyl group vs. the placebo group, 0.98; 95% confidence interval [CI], 0.70 to 1.37; P=0.92). In the Bardoxolone methyl group, ESRD developed in 43 patients, and 27 patients died from cardiovascular causes; in the placebo group, ESRD developed in 51 patients, and 19 patients died from cardiovascular causes. A total of 96 patients in the Bardoxolone methyl group were hospitalized for heart failure or died from heart failure, as compared with 55 in the placebo group (hazard ratio, 1.83; 95% CI, 1.32 to 2.55; P<0.001). Estimated GFR, blood pressure, and the urinary albumin-to-creatinine ratio increased significantly and body weight decreased significantly in the Bardoxolone methyl group, as compared with the placebo group. CONCLUSIONS: Among patients with type 2 diabetes mellitus and stage 4 chronic kidney disease, Bardoxolone methyl did not reduce the risk of ESRD or death from cardiovascular causes. A higher rate of cardiovascular events with Bardoxolone methyl than with placebo prompted termination of the trial. (Funded by Reata Pharmaceuticals; BEACON ClinicalTrials.gov number, NCT01351675.).