Effect of Etelcalcetide on Cardiac Hypertrophy in Hemodialysis Patients

Study Overview
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Brief Summary
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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
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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

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

Conditions
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Secondary Hyperparathyroidism, Chronic Kidney Disease Requiring Chronic Dialysis, Left Ventricular Hypertrophy

Intervention / Treatment
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* Diagnostic Test: cardiac MRI
* Diagnostic Test: echocardiography with strain
* Diagnostic Test: Laboratory tests
* Diagnostic Test: Body composition monitoring
* Diagnostic Test: lung ultrasound


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: ≥ 18 years of age Treatment with maintenance hemodialysis 3 times a week for ≥ 3 months and ≤3 years sHPT defined by PTH levels obtained from the central laboratory of ≥300 pg/mL and no prior treatment with a calcimimetic drug, or PTH levels obtained from the central laboratory of ≥300 pg/mL in patients under vitamin D treatment following a washout phase of 4 weeks patients under treatment with cinacalcet who will be eligible following a washout phase of 4 weeks serum calcium (corrected for serum albumin) levels obtained from the central laboratory of ≥ 2.08 mmol/L Signs of LVH (increased myocardial thickness in the left ventricle, increased interventricular septum thickness i.e. ≥12mm) irrespective of signs of cardiac fibrosis in cardiac imaging (Echocardiography) State of optimal fluid composition i.e. reaching the individual dry weight as measured with the help of a Body Composition Monitor (BCM) (more see below under section 4.9.2). Pulmonary edema will be excluded with the help of lung ultrasound (lung comet tails). No substantial dose change of calcium supplements, phosphate binders, dialysate calcium, or active vitamin D for 4 weeks before screening Exclusion Criteria: Unstable medical condition based on medical history, physical examination, and routine laboratory tests, or judged unstable in the investigator's opinion Significantly impaired left ventricular systolic function or significant, hemodynamically effective heart valve defects History of any illness, which in the investigator's opinion, might confound the results of the study or pose additional risk Anticipated parathyreoidectomy within 12 months after randomization Scheduled date for kidney transplant from a living donor Uncontrolled hyperphosphatemia Subject is currently enrolled in or has not yet completed at least 30 days since ending other investigational device or drug trial(s), or subject is receiving other investigational agent(s) Subject has known sensitivity or intolerance to any of the products to be administered for the purpose of this study Subject has any kind of disorder that compromises the ability of the subject to give written informed consent and/or to comply with the study procedures Subject is pregnant, or is of child-bearing potential and not using adequate contraceptive precautions although this is highly unlikely in patients on maintenance hemodialysis. Contraindications for MRI (implanted MR-Unsafe - objects that are significantly ferromagnetic and pose a clear and direct threat to persons and equipment within the magnet room) Overhydration as measured in BCM or visualized in lung ultrasound

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Etelcalcetide<br>Patients will receive Etelcalcetide i.v. 3 times per week after dialysis Dose titration will take plac every 4 weeks in the first 16 weeks Dose adaptation is based on PTH, SerumCa++, SerumPhosphate, T-50-time | Diagnostic Test: cardiac MRI<br>* non contrast heart MRI at baseline and after 1 year of therapy<br>Diagnostic Test: echocardiography with strain<br>* echocardiography at baseline and after 1 year of therapy<br>Diagnostic Test: Laboratory tests<br>* drawing blood from dialysis machine<br>Diagnostic Test: Body composition monitoring<br>* Measurement with BCM (Fresenius) machine<br>Diagnostic Test: lung ultrasound<br>* ultrasound<br>|
| Active Comparator: Alfacalcidol<br>Patients will receive Alfacalcidol i.v. 3 times per week after dialysis Dose titration will take plac every 4 weeks in the first 16 weeks Dose adaptation is based on PTH, SerumCa++, SerumPhosphate, T-50-time | Diagnostic Test: cardiac MRI<br>* non contrast heart MRI at baseline and after 1 year of therapy<br>Diagnostic Test: echocardiography with strain<br>* echocardiography at baseline and after 1 year of therapy<br>Diagnostic Test: Laboratory tests<br>* drawing blood from dialysis machine<br>Diagnostic Test: Body composition monitoring<br>* Measurement with BCM (Fresenius) machine<br>Diagnostic Test: lung ultrasound<br>* ultrasound<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Left ventricular mass index | Change of LVMI from baseline after a year-long treatment with either etelcalcetide or alfacalcidol. Measurement of LVMI (g/m2) with the help of cMRI | one year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cardiac structure | Difference in left atrial diameter measured by cMRI (mm) | one year | 
| Cardiac structure | Change in LVMI progression in either treatment group (%) measured in cMRI | one year | 
| Cardiac structure | Change in LAD progression in either treatment group (%) measured in cMRI | one year | 
| Cardiac structure | Difference in cardiac fibrosis (%) measured by cMRI and cardiac strain | one year | 
| Cardiac structure | Difference in the progression of cardiac fibrosis (%) measured by cMRI and cardiac strain | one year | 
| Cardiac structure | Differences in cardiac function (ejection fraction - %) measured in cMRI | one year | 
| Cardiac structure | Differences in wall motion abnormalities measured in cMRI (%) | one year | 
| Laboratory parameters | Changes in metabolites of the RAAS (pg/ml) using mass spectrometry (RAAS fingerprint) under either treatment | one year | 
| Laboratory parameters | Change from baseline serum levels of FGF23 (RU/mL) under either drug | one year | 
| Laboratory parameters | Change from baseline serum levels of s-klotho (pg/mL) under either drug | one year | 
| Laboratory parameters | Change from baseline in PTH (ng/l) under either treatment | one year | 
| Laboratory parameters | Change from baseline in 25-OH-Vit-D (nmol/L) under either treatment | one year | 
| Laboratory parameters | Change from baseline in 1,25-(OH)2-Vit-D (pg/mL) under either treatment | one year | 
| Laboratory parameters | Change from baseline in serum phosphate (mmol/l) under either treatment | one year | 
| Laboratory parameters | Change from baseline in serum calcium (mmol/l) corrected for serum albumin under either treatment | one year | 
| Laboratory parameters | Changes from baseline in proBNP (pg/ml) in either medication group | one year | 
| Laboratory parameters | Changes from baseline in pre- and postdialysis TnT (ng/ml) in either medication group | one year | 
| T-50-time measurement | 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 | one year | 
| Laboratory parameters | Longitudinal change in serum levels of FGF23 in pg/mL from baseline. | One year | 
| Laboratory parameters | Longitudinal change in serum levels of PTH in ng/L from baseline. | One year | 
| Laboratory parameters | Longitudinal change in serum levels of calcium corrected for albumin in mg/dL from baseline. | One year | 
| Laboratory parameters | Longitudinal change in serum levels of s-klotho in pg/mL from baseline. | One year | 
| Laboratory parameters | Longitudinal change in serum levels of phosphate in mg/dL from baseline. | One year | 
| Laboratory parameters | Longitudinal change in serum levels of 25-OH-Vitamin-D in nmol/L from baseline | One year | 
| Laboratory parameters | Longitudinal change in serum levels of 1,25-(OH)2-Vitamin-D in pg/mL from baseline. | One year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Secondary Hyperparathyroidism, Hemodialysis, Left Ventricular Hypertrophy, FGF 23, Etelcalcetide, Alfacalcidol