Effects of Bardoxolone Methyl on QT Interval in Healthy Volunteers
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, “t...
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| Published in | Cardiorenal medicine Vol. 9; no. 5; pp. 326 - 333 |
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| Main Authors | , , , , |
| Format | Journal Article |
| Language | English |
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Basel, Switzerland
S. Karger AG
01.01.2019
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| 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. |
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| AbstractList | 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. 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. 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. 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. In healthy subjects, treatment with 20 or 80 mg bardoxolone methyl did not affect the QTcF interval. 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.BACKGROUNDBardoxolone 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.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.METHODSSubjects 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.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.RESULTSThe 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.In healthy subjects, treatment with 20 or 80 mg bardoxolone methyl did not affect the QTcF interval.CONCLUSIONSIn healthy subjects, treatment with 20 or 80 mg bardoxolone methyl did not affect the QTcF interval. |
| Author | Goldsberry, Angie Meyer, Colin J. Chin, Melanie P. Rich, Shannon O'Grady, Megan |
| AuthorAffiliation | Product Development, Reata Pharmaceuticals, Irving, Texas, USA |
| AuthorAffiliation_xml | – name: Product Development, Reata Pharmaceuticals, Irving, Texas, USA |
| Author_xml | – sequence: 1 givenname: Melanie P. surname: Chin fullname: Chin, Melanie P. – sequence: 2 givenname: Shannon surname: Rich fullname: Rich, Shannon – sequence: 3 givenname: Angie surname: Goldsberry fullname: Goldsberry, Angie – sequence: 4 givenname: Megan surname: O'Grady fullname: O'Grady, Megan – sequence: 5 givenname: Colin J. surname: Meyer fullname: Meyer, Colin J. email: colin.meyer@reatapharma.com |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/31158840$$D View this record in MEDLINE/PubMed |
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| CitedBy_id | crossref_primary_10_1159_000502105 crossref_primary_10_3390_antiox9080716 crossref_primary_10_1016_j_phytochem_2022_113397 crossref_primary_10_3390_antiox9030193 crossref_primary_10_1016_j_pupt_2021_102094 crossref_primary_10_1007_s12272_024_01510_4 |
| Cites_doi | 10.1074/jbc.M607160200 10.1056/NEJMoa1105351 10.1046/j.1523-1755.2001.00939.x 10.1016/j.cardfail.2014.10.001 10.1073/pnas.0500815102 10.1158/1535-7163.MCT-06-0516 10.3109/00498254.2013.852705 10.1159/000327599 10.1056/NEJMoa1306033 10.1038/nri2294 10.1378/chest.2345856 10.1152/physiolgenomics.00209.2003 10.1152/ajprenal.00353.2010 10.1038/ki.2012.393 10.1159/000486398 10.1073/pnas.97.9.4844 10.1159/000362906 10.2353/ajpath.2006.051113 10.1042/bj20031049 10.1021/np100826q |
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| Keywords | QT interval Bardoxolone methyl Chronic kidney diseases |
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J Nat Prod. 2011Mar;74(3):537–45. 10.1021/np100826q213095920163-3864 Ma R, Bumeister R, Stidham R, Kambuj P, Sprouse M, Ferguson D, et al.Bardoxolone Methyl (BARD). Germany: Inhibits Inflammatory Signaling in Cultured Mesangial Cells. Poster ERA-EDTA Meeting Munich; 2010. Serhan CN, Chiang N, Van Dyke TE. Resolving inflammation: dual anti-inflammatory and pro-resolution lipid mediators. Nat Rev Immunol. 2008May;8(5):349–61. 10.1038/nri2294184371551474-1733 Block GA, Pergola PE, Inker LA, McCullough PA, Chin MP, Meyer CJ, et al.. Initial Data Report from “CARDINAL”: A Phase 2/3 Study of Bardoxolone Methyl in Patients with Alport Syndrome. J Am Soc Nephrol. 2017;28:B3.1046-6673 Straus DS, Pascual G, Li M, Welch JS, Ricote M, Hsiang CH, et al.. 15-deoxy-delta 12,14-prostaglandin J2 inhibits multiple steps in the NF-kappa B signaling pathway. Proc Natl Acad Sci USA. 2000Apr;97(9):4844–9. 10.1073/pnas.97.9.4844107810900027-8424 Aminzadeh MA, Reisman SA, Vaziri ND, Khazaeli M, Yuan J, Meyer CJ. The synthetic triterpenoid RTA dh404 (CDDO-dhTFEA) restores Nrf2 activity and attenuates oxidative stress, inflammation, and fibrosis in rats with chronic kidney disease. Xenobiotica. 2014Jun;44(6):570–8. 10.3109/00498254.2013.852705241955890049-8254 Wu QQ, Wang Y, Senitko M, Meyer C, Wigley WC, Ferguson DA, et al.. Bardoxolone methyl (BARD) ameliorates ischemic AKI and increases expression of protective genes Nrf2, PPARγ, and HO-1. Am J Physiol Renal Physiol. 2011May;300(5):F1180–92. 10.1152/ajprenal.00353.2010212890521931-857X Miller G, Bumeister R, Laidlaw J, Kambuj P, Probst B, Ferguson DA, et al.. Bardoxolone Methyl Transcriptionally Regulates Transaminase Levels and Increases Glutathione Levels. J Am Soc Nephrol. 2011;22:770A.1046-6673 Ma Q, Battelli L, Hubbs AF. Multiorgan autoimmune inflammation, enhanced lymphoproliferation, and impaired homeostasis of reactive oxygen species in mice lacking the antioxidant-activated transcription factor Nrf2. Am J Pathol. 2006Jun;168(6):1960–74. 10.2353/ajpath.2006.051113167237110002-9440 ICH E14 Clinical Evaluation of QT/QTc Interval Prolingation and Proarrhythmic Potential for Non-Antiarrhythmic Drugs. US Department of Heath and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) Center for Biologics Evaluation and Research. CBER; 2005. Chin MP, Wrolstad D, Bakris GL, Chertow GM, de Zeeuw D, Goldsberry A, et al.. Risk factors for heart failure in patients with type 2 diabetes mellitus and stage 4 chronic kidney disease treated with bardoxolone methyl. J Card Fail. 2014Dec;20(12):953–8. 10.1016/j.cardfail.2014.10.001253072951071-9164 Li J, Stein TD, Johnson JA. Genetic dissection of systemic autoimmune disease in Nrf2-deficient mice. 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Mechanisms contributing to adverse cardiovascular events in patients with type 2 diabetes mellitus and stage 4 chronic kidney disease treated with bardoxolone methyl. Am J Nephrol. 2014;39(6):499–508. 10.1159/000362906249034670250-8095 Dinkova-Kostova AT, Liby KT, Stephenson KK, Holtzclaw WD, Gao X, Suh N, et al.. Extremely potent triterpenoid inducers of the phase 2 response: correlations of protection against oxidant and inflammatory stress. Proc Natl Acad Sci USA. 2005Mar;102(12):4584–9. 10.1073/pnas.0500815102157675730027-8424 Yoh K, Itoh K, Enomoto A, Hirayama A, Yamaguchi N, Kobayashi M, et al.. Nrf2-deficient female mice develop lupus-like autoimmune nephritis. Kidney Int. 2001Oct;60(4):1343–53. 10.1046/j.1523-1755.2001.00939.x115763480085-2538 Ahmad R, Raina D, Meyer C, Kharbanda S, Kufe D. Triterpenoid CDDO-Me blocks the NF-kappaB pathway by direct inhibition of IKKbeta on Cys-179. J Biol Chem. 2006Nov;281(47):35764–9. 10.1074/jbc.M607160200169982370021-9258 de Zeeuw D, Akizawa T, Audhya P, Bakris GL, Chin M, Christ-Schmidt H, et al.; BEACON Trial Investigators. Bardoxolone methyl in type 2 diabetes and stage 4 chronic kidney disease. N Engl J Med. 2013Dec;369(26):2492–503. 10.1056/NEJMoa1306033242064590028-4793 Chin MP, Bakris GL, Block GA, Chertow GM, Goldsberry A, Inker LA, et al.. 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. Am J Nephrol. 2018;47(1):40–7. 10.1159/000486398294027670250-8095 Ding Y, Stidham RD, Bumeister R, Trevino I, Winters A, Sprouse M, et al.. The synthetic triterpenoid, RTA 405, increases the glomerular filtration rate and reduces angiotensin II-induced contraction of glomerular mesangial cells. Kidney Int. 2013May;83(5):845–54. 10.1038/ki.2012.393232355690085-2538 Pergola PE, Raskin P, Toto RD, Meyer CJ, Huff JW, Grossman EB, et al.; BEAM Study Investigators. Bardoxolone methyl and kidney function in CKD with type 2 diabetes. N Engl J Med. 2011Jul;365(4):327–36. 10.1056/NEJMoa1105351216994840028-4793 ref13 ref12 ref15 ref14 ref20 ref11 ref10 ref2 ref1 ref17 ref16 ref19 ref18 ref8 ref7 ref9 ref4 ref3 ref6 ref5 31357201 - Cardiorenal Med. 2019;9(5):334-336 |
| References_xml | – reference: de Zeeuw D, Akizawa T, Audhya P, Bakris GL, Chin M, Christ-Schmidt H, et al.; BEACON Trial Investigators. Bardoxolone methyl in type 2 diabetes and stage 4 chronic kidney disease. N Engl J Med. 2013Dec;369(26):2492–503. 10.1056/NEJMoa1306033242064590028-4793 – reference: Serhan CN, Chiang N, Van Dyke TE. Resolving inflammation: dual anti-inflammatory and pro-resolution lipid mediators. Nat Rev Immunol. 2008May;8(5):349–61. 10.1038/nri2294184371551474-1733 – reference: Chin MP, Reisman SA, Bakris GL, O’Grady M, Linde PG, McCullough PA, et al.. Mechanisms contributing to adverse cardiovascular events in patients with type 2 diabetes mellitus and stage 4 chronic kidney disease treated with bardoxolone methyl. Am J Nephrol. 2014;39(6):499–508. 10.1159/000362906249034670250-8095 – reference: Oudiz RJ, Meyer C, Chin M, Feldman J, Goldsberry A, McConnell J, et al.. Bardoxolone Methyl Evaluation in Patients with Pulmonary Arterial Hypertension (PAH). Initial Data Report from LARIAT: A Phase 2 Study of Barodoxolone Methyl in PAH Patients on Stable Background Therapy. Chest. 2015;148:639A. 10.1378/chest.23458560012-3692 – reference: Pergola PE, Krauth M, Huff JW, Ferguson DA, Ruiz S, Meyer CJ, et al.. Effect of bardoxolone methyl on kidney function in patients with T2D and Stage 3b-4 CKD. Am J Nephrol. 2011;33(5):469–76. 10.1159/000327599215086350250-8095 – reference: Nangaku M, Shimazaki R, Akizawa T. Bardoxolone Methyl Improved GFR Measured by Standard Inulin Clearance: the TSUBAKI Study. J Am Soc Nephrol. 2017;28:B1.1046-6673 – reference: Ma R, Bumeister R, Stidham R, Kambuj P, Sprouse M, Ferguson D, et al.Bardoxolone Methyl (BARD). Germany: Inhibits Inflammatory Signaling in Cultured Mesangial Cells. Poster ERA-EDTA Meeting Munich; 2010. – reference: Miller G, Bumeister R, Laidlaw J, Kambuj P, Probst B, Ferguson DA, et al.. Bardoxolone Methyl Transcriptionally Regulates Transaminase Levels and Increases Glutathione Levels. 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| Snippet | 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... 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... |
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| SubjectTerms | Adolescent Adult Blood Pressure - drug effects Dose-Response Relationship, Drug Double-Blind Method Drug Administration Schedule Electrocardiography - drug effects Female Healthy Volunteers Humans Male Middle Aged Moxifloxacin - adverse effects Moxifloxacin - pharmacology Oleanolic Acid - administration & dosage Oleanolic Acid - adverse effects Oleanolic Acid - analogs & derivatives Oleanolic Acid - pharmacology Research Article Young Adult |
| Title | Effects of Bardoxolone Methyl on QT Interval in Healthy Volunteers |
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