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Background: Fibroblast growth factor 23 (FGF23) is associated with left ventricular hypertrophy (LVH) in patients with chronic kidney disease, and calcimimetic therapy reduces plasma concentrations of FGF23. It remains unknown whether treatment with the calcimimetic etelcalcetide (ETL) reduces LVH in patients on hemodialysis., Methods/design: This single-blinded randomized trial of 12 months duration will test the effects of ETL compared with alfacalcidol on LVH and cardiac fibrosis in maintenance hemodialysis patients with secondary hyperparathyroidism. Both treatment regimens will be titrated to equally suppress secondary hyperparathyroidism while alfacalcidol treatment causes an increase and ETL a decrease in FGF23, respectively. Patients treated thrice weekly with hemodialysis for ≥ 3 months and ≤ 3 years with parathyroid hormone levels ≥ 300 pg/ml and LVH will be enrolled in the study. The primary study endpoint is change from baseline to 12 months in left ventricular mass index (LVMI; g/m 2 ) measured by cardiac magnetic resonance imaging. Sample size calculations showed that 62 randomized patients will be necessary to detect a difference in LVMI of at least 20 g/m 2 between the two groups at 12 months. Due to the strong association of volume overload and LVH, randomization will be stratified by residual kidney function, and regular body composition monitoring will be performed to control the volume status of patients. Study medication will be administered intravenously by the dialysis nurses after every hemodialysis session, thus omitting adherence issues. Secondary study endpoints are cardiac parameters measured by echocardiography, biomarker concentrations of bone metabolism (FGF23, vitamin D, parathyroid hormone, calcium, phosphate, s-Klotho), cardiac markers (pro-brain natriuretic peptide, pre- and postdialysis troponin T) and metabolites of the renin-angiotensin-aldosterone cascade (angiotensin I (Ang I), Ang II, Ang-(1-7), Ang-(1-5), Ang-(1-9), and aldosterone)., Discussion: The causal inference and pathophysiology of LVH regression by FGF23 reduction using calcimimetic treatment has not yet been shown. This intervention study has the potential to discover a new strategy for the treatment of cardiac hypertrophy and fibrosis in patients on maintenance hemodialysis. It might be speculated that successful treatment of cardiac morphology will also reduce the risk of cardiac death in this population., Trial Registration: European Clinical Trials Database, EudraCT number 2017-000222-35; ClinicalTrials.gov, NCT03182699 . Registered on.