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Trials / Completed

CompletedNCT03182699

Effect of Etelcalcetide on Cardiac Hypertrophy in Hemodialysis Patients

Effect of Etelcalcetide on Cardiac Hypertrophy in Hemodialysis Patients: A Randomized Controlled Trial

Status
Completed
Phase
Phase 4
Study type
Interventional
Enrollment
62 (actual)
Sponsor
Rainer Oberbauer · Academic / Other
Sex
All
Age
18 Years
Healthy volunteers
Not accepted

Summary

Background: Calcimimetic therapy has been shown to reduce systemic FGF23 levels, which themselves are associated with left ventricular hypertrophy (LVH) in chronic kidney disease (CKD). Methods/design: This is a randomized multicenter trial in which the effect of etelcalcetide in comparison to alfacalcidol on LVH and cardiac fibrosis in hemodialysis patients with secondary hyperparathyroidism (sHPT) will be investigated. The investigators will perform a comparative trial testing etelcalcetide vs. alfacalcidol treatment on top of conventional HPT therapy for 12 months. A total of 62 hemodialysis patients with sHPT and LVH will be enrolled in the study. After a washout of all calcimimetic and vitamin D treatment, subjects will be randomized at 1:1 ratio to either etelcalcetide or alfacalcidol. The participants will undergo cardiac imaging consisting of cardiac resonance imaging (cMRI) and strain echocardiography before and at baseline and one year. Etelcalcetide or alfacalcidol will be administered intravenously three times per week following chronic hemodialysis treatment. The primary end point will be a change in left ventricular mass index (LVMI) measured in g/m2. As secondary end points the changes in left atrial diameter (LAD), cardiac fibrosis, wall motion abnormalities and left ventricular function, changes in serum FGF 23 and soluble Klotho levels as well as changes in proBNP as well as pre- and postdialysis troponin T (TnT) levels will be determined. Additionally a quantitative analysis of the treatment influence on the individual metabolites of the renin-angiotensin-aldosterone system (RAAS) will be performed using mass spectrometry ("RAAS fingerprint").

Detailed description

Hypothesis and specific aims In this randomized multicenter trial the investigators will study the effect of etelcalcetide in comparison to alfacalcidol on left ventricular hypertrophy and fibrosis in hemodialysis patients with secondary hyperparathyroidism (sHPT). Etelcalcetide is a calcimimetic drug that has been approved for the treatment of secondary HPT in hemodialysis patients. Fibroblast growth factor 23 (FGF23) levels rise early in the development of chronic kidney disease (CKD) and recent studies have shown that FGF23 increases the development of left ventricular hypertrophy in these patients. Elevated FGF 23 levels are further associated with progression to end-stage renal disease, cardiac events and all-cause mortality. In animal models a blockade of FGF23 ameliorates the pathologic effect on left ventricular mass and function. Calcimimetic therapy has been shown to reduce systemic FGF23 levels, while vitamin D therapy is known to elevate FGF23. However, there is limited data on the clinical relevance of therapeutic modification of FGF23 levels in humans. The investigators specifically hypothesize that treatment with etelcalcetide ameliorates pathological changes in cardiac structure in dialysis patients with sHPT by suppression of systemic FGF23 levels. Specific aim 1 In this trial the investigators will determine the influence of calcimimetic therapy on left ventricular hypertrophy (LVH) in hemodialysis patients with sHPT: They will perform a head-2-head trial testing etelcalcetide vs. alfacalcidol treatment on top of conventional HPT therapy (phosphate binders, calcium supplementation and if necessary vitamin D substitution or cinacalcet) for 12 months. Etelcalcetide or alfacalcidol will be administered intravenously three times per week following chronic hemodialysis treatment. The primary end point will be a change in left ventricular mass index (LVMI) that will be assessed using cardiac magnetic resonance imaging (cMRI) at baseline and after 12 months of treatment. As secondary end points we will measure changes in left atrial diameter (LAD), cardiac fibrosis (using T1 mapping and cardiac strain), wall motion abnormalities and left ventricular function (measured in cMRI and echocardiography), changes in serum FGF 23 and soluble Klotho levels as well as changes in proBNP as well as pre- and postdialysis troponin T (TnT) levels. Specific aim 2 The pathophysiology by which elevated FGF 23 levels can cause cardiac remodeling is still unresolved. The two major hypothesis propose either a direct effect of FGF 23 on the myocardium or a predominantly volume dependent effect caused by FGF 23 and Klotho mediated renal sodium retention: * Sodium and volume balance in dialysis patients without residual renal function is regulated by ultrafiltration and not by renal sodium handling. In this trial the investigators will perform a stratified randomization procedure to ensure an equal distribution of dialysis patients with residual renal function and those without in both treatment groups. * Additionally, FGF 23 directly inhibits Angiotensin converting enzyme 2 (ACE 2) as the central enzyme of the antifibrotic alternative renin-angiotensin-aldosterone system (RAAS) and shifting the RAAS toward the pro fibrotic Angiotensin II. To assess suppression of ACE 2 we will measure Ang 1-5 and Ang 1-7 levels by quantitative analysis of the individual metabolites of the RAAS using mass spectrometry ("RAAS fingerprint"). The specific design of this trial will therefore contribute to the fundamental understanding of FGF 23 mediated myocardial remodeling. After completion of the trial two T-50-test will be performed in each patient from existing frozen serum samples (one at baseline and one at the end of 12 months of treatment). The measurement of the T50-time can evaluate an individual's risk for the development of vascular calcification

Conditions

Interventions

TypeNameDescription
DIAGNOSTIC_TESTcardiac MRInon contrast heart MRI at baseline and after 1 year of therapy
DIAGNOSTIC_TESTechocardiography with strainechocardiography at baseline and after 1 year of therapy
DIAGNOSTIC_TESTLaboratory testsdrawing blood from dialysis machine
DIAGNOSTIC_TESTBody composition monitoringMeasurement with BCM (Fresenius) machine
DIAGNOSTIC_TESTlung ultrasoundultrasound

Timeline

Start date
2017-10-01
Primary completion
2019-12-20
Completion
2019-12-20
First posted
2017-06-09
Last updated
2020-06-09

Locations

2 sites across 1 country: Austria

Source: ClinicalTrials.gov record NCT03182699. Inclusion in this directory is not an endorsement.