Use of ETElcalcetidefor pReserving vitamiN K-dependent proteIn activiTY ITAlian Study (ETERNITY-ITA)

The goal of this Prospective Observational Study of comparative effectiveness is to provide real world evidence of the effect of Etelcalcetide in increasing actives form VKDPs levels such as BGP and MGP at 3, 9 and 18 months from baseline, with resulting correct bone mineralization and inhibition vascular calcification in hemodialysis patients.

The study will enroll 160 hemodialysis patients: 80 patients treated with Etelcalcetide and 80 age and sex matched patients treated with Calcitriol or vitamin D analogs. The treating nephrologist will base the target dose of Etelcalcetide on individual-level in order to achieve the KDIGO PTH target. In the Etelcalcetide-treated group, the addition of calcitriol will be allowed when required by clinical practice (for correction of hypocalcemia). The main endpoint is the comparison of the levels of active forms of VKDP (MGP and BGP) between patients treated with Etelcalcetide and those treated with vitamin D or vitamin D analogues. The measurements of the biomarkers are scheduled at baseline and after 3, 9, and 18 months.

Study Overview

• Status: Not yet recruiting
• Conditions: Hemodialysis

Detailed Description

Vascular calcifications (VCs) are frequent complications of chronic kidney disease (CKD), and mineral disorders are associated with aortic calcifications and increased risk of bone fractures. The complex pathogenesis of VCs involves various factors such as calcium overload, phosphate imbalance, and secondary hyperparathyroidism. Key inhibitors, such as vitamin K-dependent proteins (VKDPs) like matrix Gla protein (MGP) play pivotal roles in VCs development. Traditional treatments to reduce VC focus on lowering PTH, calcium and phosphorus levels and etelcalcetide revealed as a promising therapy to this scope. Accordingly, the VItamin K Italian study (VIKI) reported that calcimimetics treated hemodialysis patients had higher levels of total BGP and MGP versus those untreated, suggesting a protective effect of this drugs class. These findings point out the multifactorial nature of VC in CKD and suggest new treatment strategies and targeted pathways for improving outcomes. The ETERNITY-ITA study will investigate the real world effect of Etelcalcetide in increasing actives form VKDPs levels such as BGP and MGP thus contributing to bone and vascular health in hemodialysis patients. ETERNITY-ITA is a multi-center comparative effectiveness, observational, longitudinal study. The study will enroll 160 hemodialysis patients: 80 patients treated with Etelcalcetide and 80 age and sex matched patients treated with Calcitriol or vitamin D analogs. The treating nephrologist will base the target dose of Etelcalcetide on individual-level in order to achieve the KDIGO PTH target. In the Etelcalcetide-treated group, the addition of calcitriol will be allowed when required by clinical practice (for correction of hypocalcemia). The main endpoint is the comparison of the levels of active forms of VKDP (MGP and BGP) between patients treated with Etelcalcetide and those treated with vitamin D or vitamin D analogues. The measurements of the biomarkers are scheduled at baseline and after 3, 9, and 18 months.

• Study Type: Observational
• Enrollment (Estimated): 160

Contacts and Locations

• Study Contact: Name: Maria Fusaro, MD; Phone Number: 0965393253; Email: dante.lucia11@gmail.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

Hemodialysis patients

Description

Inclusion Criteria:

1. Patient has provided informed consent;
2. Patient is 18 years of age or older of both gender;
3. Patients receiving maintenance HD three times per week (Kt/V >1.2);
4. Parathyroid hormone concentrations >500 ng/l at screening, or if parathyroidectomy is planned or expected, Ca >8.3 mg/dl;

5. Will be considered patients in the exposed group:

   1. Patients who have started Etelcalcetide within 1-month before the study enrolment;
   2. Patients naïve to intravenous calcimimetics use;
   3. Patients who have suspended oral calcimimetics from at least 1-month;
   4. Patients who are not responder or not compliant to the treatment with calcitriol;
6. In the unexposed group, patients on treatment with calcitriol or vitamin D analogs and who are age (± 2 years) and sex comparable (matching) to those in the exposed group will be considered;
7. Native vitamin D can be used in both groups and should be administered to target a 25(OH)D level > 30 ng/ml;
8. Dialysate calcium concentration must be stable for at least 4 weeks prior to screening laboratory assessments;
9. Patient must have severe HPT as defined by two laboratory screening pre-dialysis serum PTH values > 500 pg/ml, measured on two consecutive lab checks prior to entering the study. PTH levels should be standardized according to the following table (Souberbielle et al. Kidney Int 2010);
10. Total alkaline phosphatase greater than the normal range, or even within the normal range but if greater than the tertile of the reference range for the assay;
11. Patients will be eligible only if they will show at least a moderate Aorta VCs and/or Iliac arteries VCs and at least a mild VF.

Exclusion Criteria:

1. Previous treatment with oral calcimimetics (cinacalcet) must have been suspended for at least 30 days. Recent start of calcimimetics (Etelcalcetide) is acceptable, but patients are excluded if treatment lasts for more than 1 month;
2. Patients has received a bisphosphonate, denosumab or teriparatide during the 12 months prior to screening;
3. The patient underwent parathyroidectomy in the 6 months before the start of the study or if scheduled soon;
4. Scheduled kidney transplant during the study period or anticipated living donor evaluation within three months of recruitment;
5. Patient has an unstable medical condition based on medical history, physical examination, and routine laboratory tests, or is otherwise unstable in the judgment of the Investigator;
6. Metabolic bone diseases not related to the kidney (i.e., Pagets, Osteogenesis Imprefecta);
7. Severe untreated hyperthyroidism;
8. Malignancy within the last 3 years (except non-melanoma skin cancers or cervical carcinoma in situ);
9. Patient is pregnant or nursing;
10. Patients with Long QT Syndrome;
11. Patient likely to not be available to complete all protocol-required study visits or procedures, and/or to comply with all required study procedures to the best of the patient and Investigator's knowledge.

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort
Etecalcetide Group; Drug: Etelcalcetide Administered intravenously at the end of each dialysis session. Dosing ranges from 2.5 mg to 15 mg set by the patient's physician. Other Name: Parsabiv
Standard of Care; Drug: Vitamin D or Vitamin D analogs

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Levels of VKDP	The primary endpoint is the comparison of the levels of active forms of VKDP between patients treated with Etelcalcetide and those treated with vitamin D or vitamin D analogues (MGP and BGP).	Baseline and after 3, 9, and 18 months of treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Calcium	Concentration of calcium (mg/dL)	Baseline, 3, 9 and 18-months
Phosphate	Concentration of phosphate (mg/dL)	Baseline, 3, 9 and 18-months
Magnesium	Concentration of magnesium (mg/dL)	Baseline, 3, 9 and 18-months
ALP	Concentration of ALP (U/L)	Baseline, 3, 9 and 18-months
PTH	Concentration of PTH (pg/ml)	Baseline, 3, 9 and 18-months
25(OH)D	Concentration of 25(OH)D (ng/mL)	Baseline, 3, 9 and 18-months
P1NP	Concentration of Procollagen I Intact N-Terminal or P1NP (ug/L )	Baseline, 3, 9 and 18-months
CTX	Concentration of C-terminal telopeptide or CTX (pg/mL)	Baseline, 3, 9 and 18-months
TRAP 5b	Concentration of Tartrate-resistant acid phosphatase 5b or TRAP 5bC-Terminal to Intact (U/L)	Baseline, 3, 9 and 18-months
BSAP	Concentration of Bone-specific alkaline phosphatase or BSAP (mcg/L)	Baseline, 3, 9 and 18-months
cFGF23	Concentration of Fibroblast Growth Factor 23 or cFGF23 (pmol/L) and iFGF23 (pg/mL)	Baseline, 3, 9 and 18-months
Klotho	Concentration of Klotho (pg/mL) and soluble α-Klotho (pg/mL)	Baseline, 3, 9 and 18-months
Sclerostin	Concentration of Sclerostin and Bioactive Sclerostin (pmol/L)	Baseline, 3, 9 and 18-months
DKK1	Concentration of DKK1 (pmol/L)	Baseline, 3, 9 and 18-months
Fetuin A	Concentration of Fetuin A (ng/mL)	Baseline, 3, 9 and 18-months
Zinc	Concentration of Zinc (μmol/L)	Baseline, 3, 9 and 18-months
Irisin	Concentration of Irisin	Baseline, 3, 9 and 18-months
Serum Calcification Propensity T50 test	Serum Calcification Propensity T50 test (minutes)	Baseline, 3, 9 and 18-months
Hemoglobin (Hb)	Concentration of Hemoglobin (g/dl)	Baseline, 3, 9 and 18-months
Hematocrit (Ht)	Concentration of Hematocrit (%)	Baseline, 3, 9 and 18-months
Plates (PLTS)	Concentration of plates (g/L)	Baseline, 3, 9 and 18-months
Reticulocytes	Concentration of reticulocytes (%)	Baseline, 3, 9 and 18-months
Iron	Concentration of iron (µg/dL)	Baseline, 3, 9 and 18-months
Ferritin	Concentration of ferritin (ng/ml )	Baseline, 3, 9 and 18-months
Transferrin	Concentration of transferrin (mg/dL)	Baseline, 3, 9 and 18-months
Transferrin Saturation	Transferrin saturation (%)	Baseline, 3, 9 and 18-months
Albumin	Concentration of Albumin (g/dl)	Baseline, 3, 9 and 18-months
KT/V	Level of KT/V	Baseline, 3, 9 and 18-months
Aluminium	Concentration of aluminium (mcg/L)	Baseline, 3, 9 and 18-months
C-reactive Protein (CRP)	Concentration of C-reactive Protein (mg/L)	Baseline, 3, 9 and 18-months
Cholesterol	Concentration of cholesterol (mg/dl)	Baseline, 3, 9 and 18-months
Triglycerides	Concentration of triglycerides (mg/dl)	Baseline, 3, 9 and 18-months
Cholesterol HDL	Concentration of Cholesterol HDL (mg/dl)	Baseline, 3, 9 and 18-months
Cholesterol LDL	Concentration of Cholesterol LDL (mg/dl)	Baseline, 3, 9 and 18-months
Vascular Calcification	Number of participants with vascular calcification (Aorta and Iliac arteries) by lateral Dorsal Lumbar spine x-Ray.	Baseline, 18-months
Vertebral Fractures	Changes from baseline prevalence Vertebral Fractures (VFs, quantitative vertebral morphometry using dedicated software) by lateral Dorsal Lumbar spine x-Ray	Baseline, 18-months
BMD: Bone Mineral Density	Changes from baseline Total Hip, Femoral neck Bone Mass Density (BMD) by Dual-energy X-ray absorptiometry (DEXA) including Trabecular Bone Score where it will be available (TBS).	Baseline, 18-months
Association between Verterbal Fractures and Vascular Calcificatiom	To evaluate the relationship of bone vascular biomarkers on clinical outcomes: VFs and VCs	Baseline, 18-months
Novel quantitative computer-assisted scoring method for vascular calcifications.	To compare a novel quantitative computer-assisted scoring method for vascular calcifications with a three-dimensional assessment from CT data	Baseline, 18-months
Effect of Etelcalcetide on cardiovascular events and all-cause mortality.	Effect of Etelcalcetide on the number of cardiovascular events and on the number of all-cause deaths.	Baseline, 18-months
Etelcalcetide Safety: Number of participants with treatment-related adverse events.	The outcome can identify potential adverse events, such as: Blood calcium decrease, Muscle spasms, Diarrhea, Nausea, Vomiting, Headache, Hypocalcaemia, Hypertension, Hypotension, Arteriovenous fistula site complication, Pain in extremity, Paresthesia, Back pain, Upper respiratory tract infection.	Baseline, 18-months

Collaborators and Investigators

• Sponsor: Istituto di Fisiologia Clinica CNR

Study record dates

Study Major Dates

• Study Start (Estimated): May 1, 2024
• Primary Completion (Estimated): December 31, 2026
• Study Completion (Estimated): December 31, 2027

Study Registration Dates

• First Submitted: March 21, 2024
• First Submitted That Met QC Criteria: April 3, 2024
• First Posted (Actual): April 8, 2024

Study Record Updates

• Last Update Posted (Actual): April 8, 2024
• Last Update Submitted That Met QC Criteria: April 3, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: Hemodialysis; Vascular calcification; Vitamin K; Matrix Gla protein; Bone Fractures; Osteocalcin or Bone GLA Protein (BGP); Etecalcetide
• Other Study ID Numbers: 23022022CERC

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No