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One-Year Safety and Efficacy of Intravenous Etelcalcetide in Patients on Hemodialysis with Secondary Hyperparathyroidism

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One-Year Safety and Efficacy of Intravenous Etelcalcetide in Patients on Hemodialysis with Secondary Hyperparathyroidism hemodialysis: the EValuation Of Cinacalcet HCl Therapy to Lower 29. Shroff GR, Li S, Herzog CA. Trends in mortality following acute myocardial CardioVascular Events (EVOLVE) trial. J Am Heart Assoc 2014; 3: e001363 infarction among dialysis patients in the United States over 15 years. JAm 24. Roy-Chaudhury P, Tumlin JA, Koplan BA et al. Primary outcomes of the Heart Assoc 2015;4:e002460 monitoring in dialysis study indicate that clinically significant arrhythmias 30. Culleton BF, Hemmelgarn B. Inadequate treatment of cardiovascular dis- are common in hemodialysis patients and related to dialytic cycle. Kidney ease and cardiovascular disease risk factors in dialysis patients: a commen- Int 2018; 93: 941–951 tary. Semin Dial 2004; 17: 342–345 25. Green D, Roberts PR, New DI et al. Sudden cardiac death in hemodialysis 31. Winkelmayer WC, Charytan DM, Brookhart MA et al. Kidney function patients: an in-depth review. Am J Kidney Dis 2011; 57: 921–929 and use of recommended medications after myocardial infarction in elderly 26. Compton S, Grace H, Madgy A et al. Post-traumatic stress disorder sympto- patients. Clin J Am Soc Nephrol 2006; 1: 796–801 mology associated with witnessing unsuccessful out-of-hospital cardiopul- 32. Shroff GR, Frederick PD, Herzog CA. Renal failure and acute myocardial ORIGINAL ARTICLE monary resuscitation. Acad Emerg Med 2009; 16: 226–229 infarction: clinical characteristics in patients with advanced chronic kidney 27. Fox CS, Muntner P, Chen AY et al. Use of evidence-based therapies in disease, on dialysis, and without chronic kidney disease. A collaborative short-term outcomes of ST-segment elevation myocardial infarction and project of the United States Renal Data System/National Institutes of Health non-ST-segment elevation myocardial infarction in patients with chronic and the National Registry of Myocardial Infarction. Am Heart J 2012; 163: kidney disease: a report from the National Cardiovascular Data Acute 399–406 Coronary Treatment and Intervention Outcomes Network registry. 33. Maini R, Wong DB, Addison D et al. Persistent underrepresentation of kid- Circulation 2010; 121: 357–365 ney disease in randomized, controlled trials of cardiovascular disease in the 28. United States Renal Data System. USRDS Annual Data Report: contemporary era. J Am Soc Nephrol 2018; 29: 2782–2786 Epidemiology of Kidney Disease in the United States. Bethesda, MD: National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, 2018 Received: 22.10.2019; Editorial decision: 17.12.2019 Nephrol Dial Transplant (2020) 35: 1769–1778 doi: 10.1093/ndt/gfz039 Advance Access publication 11 March 2019 One-year safety and efficacy of intravenous etelcalcetide in patients on hemodialysis with secondary hyperparathyroidism David A. Bushinsky1, Glenn M. Chertow2, Sunfa Cheng3, Hongjie Deng4, Nelson Kopyt5, Kevin J. Martin6, Anjay Rastogi7, Pablo Urena-Torres~ 8, Marc Vervloet 9 and Geoffrey A. Block10 1Department of Medicine, Division of Nephrology, University of Rochester School of Medicine, Rochester, NY, USA, 2Department of Medicine, Division of Nephrology, Stanford University, Stanford, CA, USA, 3Clinical Development, Amgen Inc., Thousand Oaks, CA, USA, 4Biostatistics, Amgen Inc., Thousand Oaks, CA, USA, 5Department of Medicine, Division of Nephrology, Lehigh Valley Hospital, Allentown, PA, USA, 6Department of Internal Medicine, Division of Nephrology, Saint Louis University School of Medicine, St Louis, MO, USA, 7Department of Medicine, Division of Nephrology, University of California, Los Angeles, Los Angeles, CA, USA, 8Department of Nephrology and Dialysis, Ramsay-Ge´ne´rale de Sante´, Clinique du Landy, Saint Ouen, France and Necker Hospital, University of Paris Descartes, Paris, France, 9Department of Nephrology and Amsterdam Cardiovascular Sciences, VU University Medical Center, Amsterdam, The Netherlands and 10Denver Nephrology, Denver, CO, USA Correspondence and offprint requests to: David A. Bushinsky; E-mail: [email protected] ABSTRACT Methods. This 52-week, multicenter, single-arm OLE enrolled patients from three parent trials: two randomized, double-blind, Background. Secondary hyperparathyroidism (sHPT), a com- placebo-controlled trials and one open-label, single-arm, ‘switch’ mon complication of chronic kidney disease, is characterized by study from cinacalcet to etelcalcetide. The primary endpoint was elevated serum parathyroid hormone (PTH). Etelcalcetide is an to investigate the nature, frequency, severity and relation to treat- intravenous calcimimetic that increases sensitivity of the ment of all adverse events (AEs) reported throughout the trial. calcium-sensing receptor to calcium and decreases PTH Secondary endpoints included the proportion of patients with secretion. This open-label extension (OLE) trial evaluated the >30% reduction from baseline in PTH and the percentage long-term effects of etelcalcetide for sHPT treatment in patients change from baseline in PTH, albumin-corrected calcium (Ca), receiving hemodialysis. phosphate (P) and the calcium–phosphate product (Ca  P). VC The Author(s) 2019. Published by Oxford University Press on behalf of ERA-EDTA. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/ by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact [email protected] 1769 ClinicalTrials.gov identifier: NCT01785875; Amgen study: etelcalcetide conducted in 1023 patients (NCT01785849, 20120231. NCT01788046) [22], and the other was an open-label, single- Results. Overall, 89.8% of the patients experienced one or more arm, ‘switch’ study from cinacalcet to etelcalcetide in 158 treatment-emergent AE. The most common were decreased patients (NCT01932970) [23]. This OLE trial was conducted blood Ca (43.3%), diarrhea (10.8%), vomiting (10.4%) and nau- in 17 countries in North America, Europe and Australia in sea (9.6%); symptomatic hypocalcemia occurred in 3.7% of the accordance with the Declaration of Helsinki. All patients pro- patients. Approximately 68% of patients achieved >30% reduc- vided written informed consent via an institutional review tion in PTH, and 56% achieved PTH 300 pg/mL. Mean per- board-approved form. Patients were eligible if they com- cent changes from baseline ranged from À25.4% to À26.1% for pleted the treatment and follow-up period of (or had discon- PTH, À8.3% to À9.1% for Ca, À3.6% to À4.1% for P and tinued for rising PTH levels from) one of the etelcalcetide À12.0% to À12.6% for Ca  P. parent trials, had a prescribed dialysate Ca concentration Conclusions. Etelcalcetide effectively lowered PTH and its ef- 2.25 mEq/L and had not received cinacalcet between the fect was sustained, while no new safety concerns emerged over a last dose of investigational product in the parent trial and the 1-year treatment period. start of dosing in the OLE trial. A complete list of inclusion and exclusion criteria is available in Supplementary data, Keywords: chronic kidney disease, etelcalcetide, open-label Table S1. extension, safety, secondary hyperparathyroidism Trial drug administration INTRODUCTION After a 4-week washout period from the parent trial, Secondary hyperparathyroidism (sHPT) is a common and clin- patients initiated open-label treatment with etelcalcetide if ically significant complication of advanced chronic kidney dis- albumin-corrected Ca was 8.3 mg/dL within 2 weeks prior ease (CKD) [1–4]. sHPT is a component of CKD-mineral and to the visit. To maintain blinding from the parent trials, all bone disorder (MBD), which encompasses elevated serum patients underwent titration of their etelcalcetide dose from a parathyroid hormone (PTH) and fibroblast growth factor 23 starting dose of 5 mg per dialysis treatment, and investigators (FGF-23) concentrations, reduced 1,25(OH)2 vitamin D con- were blinded to central laboratory PTH results during the centrations and abnormal serum calcium (Ca) and phosphate first 10 weeks of open-label treatment. (P) concentrations [1, 3, 5–7]. These abnormalities of CKD- Patients were treated with etelcalcetide for 52 weeks. All MBD are associated with vascular calcification, cardiovascular patients initiated etelcalcetide at a starting dose of 5 mg IV morbidity and mortality, and bone fractures [3, 8, 9]. bolus TIW immediately after hemodialysis, before or during Multiple options for treating sHPT are available, including rinse back or after rinse back through the venous needle. At calcitriol and vitamin D analogs, calcimimetics, phosphate least 150 mL of rinse-back volume was administered after binders and subtotal parathyroidectomy [1–3, 10–13]. Although etelcalcetide injection to ensure etelcalcetide reached the sys- effective in lowering PTH concentrations, oral and intravenous temic circulation. If rinse back was completed without ad- (IV) vitamin D analogs can increase serum Ca, P and FGF-23 ministration of etelcalcetide, then etelcalcetide was concentrations [14, 15]. Utilization of oral cinacalcet (SensiparVR / VR administered IV followed by a saline flush of at least 10 mL. Mimpara ,AmgenInc.,ThousandOaks,CA,USA)hasbeen During the first 10 weeks of dosing, etelcalcetide was titrated limited by reduced adherence [16, 17]. Oral cinacalcet had been via an interactive voice/web response system by increments the only available calcimimetic until the recent
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