Clinical trial NCT06352957: Use of ETElcalcetidefor pReserving vitamiN K-dependent proteIn activiTY ITAlian Study
Official title: Use of ETElcalcetidefor pReserving vitamiN K-dependent proteIn activiTY ITAlian Study
Study type: OBSERVATIONAL
Overall status: NOT_YET_RECRUITING
Conditions: Hemodialysis
Keywords: Hemodialysis
Matrix Gla protein
Osteocalcin or Bone GLA Protein (BGP)
Vascular calcification
Vitamin K
Etecalcetide
Bone Fractures
Lead sponsor: Istituto di Fisiologia Clinica CNR
Sponsor class: OTHER
First posted: 2024-04-08
Enrollment: 160
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Hemodialysis patients

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Levels of VKDP
timeFrame: Baseline and after 3, 9, and 18 months of treatment
Secondary outcomes:
measure: Calcium
timeFrame: Baseline, 3, 9 and 18-months
measure: Phosphate
timeFrame: Baseline, 3, 9 and 18-months
measure: Magnesium
timeFrame: Baseline, 3, 9 and 18-months
measure: ALP
timeFrame: Baseline, 3, 9 and 18-months
measure: PTH
timeFrame: Baseline, 3, 9 and 18-months
measure: 25(OH)D
timeFrame: Baseline, 3, 9 and 18-months
measure: P1NP
timeFrame: Baseline, 3, 9 and 18-months
measure: CTX
timeFrame: Baseline, 3, 9 and 18-months
measure: TRAP 5b
timeFrame: Baseline, 3, 9 and 18-months
measure: BSAP
timeFrame: Baseline, 3, 9 and 18-months
measure: cFGF23
timeFrame: Baseline, 3, 9 and 18-months
measure: Klotho
timeFrame: Baseline, 3, 9 and 18-months
measure: Sclerostin
timeFrame: Baseline, 3, 9 and 18-months
measure: DKK1
timeFrame: Baseline, 3, 9 and 18-months
measure: Fetuin A
timeFrame: Baseline, 3, 9 and 18-months
measure: Zinc
timeFrame: Baseline, 3, 9 and 18-months
measure: Irisin
timeFrame: Baseline, 3, 9 and 18-months
measure: Serum Calcification Propensity T50 test
timeFrame: Baseline, 3, 9 and 18-months
measure: Hemoglobin (Hb)
timeFrame: Baseline, 3, 9 and 18-months
measure: Hematocrit (Ht)
timeFrame: Baseline, 3, 9 and 18-months
measure: Plates (PLTS)
timeFrame: Baseline, 3, 9 and 18-months
measure: Reticulocytes
timeFrame: Baseline, 3, 9 and 18-months
measure: Iron
timeFrame: Baseline, 3, 9 and 18-months
measure: Ferritin
timeFrame: Baseline, 3, 9 and 18-months
measure: Transferrin
timeFrame: Baseline, 3, 9 and 18-months
measure: Transferrin Saturation
timeFrame: Baseline, 3, 9 and 18-months
measure: Albumin
timeFrame: Baseline, 3, 9 and 18-months
measure: KT/V
timeFrame: Baseline, 3, 9 and 18-months
measure: Aluminium
timeFrame: Baseline, 3, 9 and 18-months
measure: C-reactive Protein (CRP)
timeFrame: Baseline, 3, 9 and 18-months
measure: Cholesterol
timeFrame: Baseline, 3, 9 and 18-months
measure: Triglycerides
timeFrame: Baseline, 3, 9 and 18-months
measure: Cholesterol HDL
timeFrame: Baseline, 3, 9 and 18-months
measure: Cholesterol LDL
timeFrame: Baseline, 3, 9 and 18-months
measure: Vascular Calcification
timeFrame: Baseline, 18-months
measure: Vertebral Fractures
timeFrame: Baseline, 18-months
measure: BMD: Bone Mineral Density
timeFrame: Baseline, 18-months
measure: Association between Verterbal Fractures and Vascular Calcificatiom
timeFrame: Baseline, 18-months
measure: Novel quantitative computer-assisted scoring method for vascular calcifications.
timeFrame: Baseline, 18-months
measure: Effect of Etelcalcetide on cardiovascular events and all-cause mortality.
timeFrame: Baseline, 18-months
measure: Etelcalcetide Safety: Number of participants with treatment-related adverse events.
timeFrame: Baseline, 18-months
Other outcomes:
Locations:
Study officials:
References: