Use of ETElcalcetidefor pReserving vitamiN K-dependent proteIn activiTY ITAlian Study

Not yet recruiting

• Conditions: Hemodialysis

• Registration Number: NCT06352957
• Lead Sponsor: Istituto di Fisiologia Clinica CNR

Brief Summary

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.

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 Timeline

• Status Verified: 2024-03
• Study First Submitted: 2024-03-21
• Study First Submitted QC: 2024-04-03
• Last Update Submitted: 2024-04-03
• Study First Posted: 2024-04-08
• Last Update Posted: 2024-04-08
• Study Start: 2024-05-01
• Primary Completion: 2026-12-31
• Study Completion: 2027-12-31

Recruitment & Eligibility

• Status: NOT_YET_RECRUITING
• Sex: All
• Target Recruitment: 160

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 & Design

• Study Type: OBSERVATIONAL
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Levels of VKDP	Baseline and after 3, 9, and 18 months of treatment	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).

Secondary Outcome Measures

Name	Time	Method
Hematocrit (Ht)	Baseline, 3, 9 and 18-months	Concentration of Hematocrit (%)
Plates (PLTS)	Baseline, 3, 9 and 18-months	Concentration of plates (g/L)
Reticulocytes	Baseline, 3, 9 and 18-months	Concentration of reticulocytes (%)
Calcium	Baseline, 3, 9 and 18-months	Concentration of calcium (mg/dL)
Phosphate	Baseline, 3, 9 and 18-months	Concentration of phosphate (mg/dL)
PTH	Baseline, 3, 9 and 18-months	Concentration of PTH (pg/ml)
25(OH)D	Baseline, 3, 9 and 18-months	Concentration of 25(OH)D (ng/mL)
P1NP	Baseline, 3, 9 and 18-months	Concentration of Procollagen I Intact N-Terminal or P1NP (ug/L )
CTX	Baseline, 3, 9 and 18-months	Concentration of C-terminal telopeptide or CTX (pg/mL)
TRAP 5b	Baseline, 3, 9 and 18-months	Concentration of Tartrate-resistant acid phosphatase 5b or TRAP 5bC-Terminal to Intact (U/L)
BSAP	Baseline, 3, 9 and 18-months	Concentration of Bone-specific alkaline phosphatase or BSAP (mcg/L)
DKK1	Baseline, 3, 9 and 18-months	Concentration of DKK1 (pmol/L)
Irisin	Baseline, 3, 9 and 18-months	Concentration of Irisin
Ferritin	Baseline, 3, 9 and 18-months	Concentration of ferritin (ng/ml )
KT/V	Baseline, 3, 9 and 18-months	Level of KT/V
Aluminium	Baseline, 3, 9 and 18-months	Concentration of aluminium (mcg/L)
Cholesterol	Baseline, 3, 9 and 18-months	Concentration of cholesterol (mg/dl)
Triglycerides	Baseline, 3, 9 and 18-months	Concentration of triglycerides (mg/dl)
Magnesium	Baseline, 3, 9 and 18-months	Concentration of magnesium (mg/dL)
Klotho	Baseline, 3, 9 and 18-months	Concentration of Klotho (pg/mL) and soluble α-Klotho (pg/mL)
ALP	Baseline, 3, 9 and 18-months	Concentration of ALP (U/L)
cFGF23	Baseline, 3, 9 and 18-months	Concentration of Fibroblast Growth Factor 23 or cFGF23 (pmol/L) and iFGF23 (pg/mL)
Sclerostin	Baseline, 3, 9 and 18-months	Concentration of Sclerostin and Bioactive Sclerostin (pmol/L)
Fetuin A	Baseline, 3, 9 and 18-months	Concentration of Fetuin A (ng/mL)
Zinc	Baseline, 3, 9 and 18-months	Concentration of Zinc (μmol/L)
Serum Calcification Propensity T50 test	Baseline, 3, 9 and 18-months	Serum Calcification Propensity T50 test (minutes)
Hemoglobin (Hb)	Baseline, 3, 9 and 18-months	Concentration of Hemoglobin (g/dl)
Iron	Baseline, 3, 9 and 18-months	Concentration of iron (µg/dL)
Transferrin Saturation	Baseline, 3, 9 and 18-months	Transferrin saturation (%)
Albumin	Baseline, 3, 9 and 18-months	Concentration of Albumin (g/dl)
Transferrin	Baseline, 3, 9 and 18-months	Concentration of transferrin (mg/dL)
C-reactive Protein (CRP)	Baseline, 3, 9 and 18-months	Concentration of C-reactive Protein (mg/L)
Association between Verterbal Fractures and Vascular Calcificatiom	Baseline, 18-months	To evaluate the relationship of bone vascular biomarkers on clinical outcomes: VFs and VCs
Novel quantitative computer-assisted scoring method for vascular calcifications.	Baseline, 18-months	To compare a novel quantitative computer-assisted scoring method for vascular calcifications with a three-dimensional assessment from CT data
Cholesterol LDL	Baseline, 3, 9 and 18-months	Concentration of Cholesterol LDL (mg/dl)
Vertebral Fractures	Baseline, 18-months	Changes from baseline prevalence Vertebral Fractures (VFs, quantitative vertebral morphometry using dedicated software) by lateral Dorsal Lumbar spine x-Ray
BMD: Bone Mineral Density	Baseline, 18-months	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).
Cholesterol HDL	Baseline, 3, 9 and 18-months	Concentration of Cholesterol HDL (mg/dl)
Vascular Calcification	Baseline, 18-months	Number of participants with vascular calcification (Aorta and Iliac arteries) by lateral Dorsal Lumbar spine x-Ray.
Effect of Etelcalcetide on cardiovascular events and all-cause mortality.	Baseline, 18-months	Effect of Etelcalcetide on the number of cardiovascular events and on the number of all-cause deaths.
Etelcalcetide Safety: Number of participants with treatment-related adverse events.	Baseline, 18-months	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.