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

Hemodialysis Clinical Trial

— ETERNITY-ITA  

Official title:

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

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT06352957
• Other study ID #: 23022022CERC
• Status: Not yet recruiting
• Start date: May 1, 2024
• Est. completion date: December 31, 2027

Study information

• Verified date: March 2024
• Source: Istituto di Fisiologia Clinica CNR
• Contact: Maria Fusaro, MD
• Phone: 0965393253
• Email: dante.lucia11[@]gmail.com
• Is FDA regulated: No
• Study type: Observational

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 160
• Est. completion date: December 31, 2027
• Est. primary completion date: December 31, 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Hemodialysis

Locations

Country	Name	City	State
n/a

Sponsors (1)

Lead Sponsor	Collaborator
Istituto di Fisiologia Clinica CNR

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	Calcium	Concentration of calcium (mg/dL)	Baseline, 3, 9 and 18-months
Secondary	Phosphate	Concentration of phosphate (mg/dL)	Baseline, 3, 9 and 18-months
Secondary	Magnesium	Concentration of magnesium (mg/dL)	Baseline, 3, 9 and 18-months
Secondary	ALP	Concentration of ALP (U/L)	Baseline, 3, 9 and 18-months
Secondary	PTH	Concentration of PTH (pg/ml)	Baseline, 3, 9 and 18-months
Secondary	25(OH)D	Concentration of 25(OH)D (ng/mL)	Baseline, 3, 9 and 18-months
Secondary	P1NP	Concentration of Procollagen I Intact N-Terminal or P1NP (ug/L )	Baseline, 3, 9 and 18-months
Secondary	CTX	Concentration of C-terminal telopeptide or CTX (pg/mL)	Baseline, 3, 9 and 18-months
Secondary	TRAP 5b	Concentration of Tartrate-resistant acid phosphatase 5b or TRAP 5bC-Terminal to Intact (U/L)	Baseline, 3, 9 and 18-months
Secondary	BSAP	Concentration of Bone-specific alkaline phosphatase or BSAP (mcg/L)	Baseline, 3, 9 and 18-months
Secondary	cFGF23	Concentration of Fibroblast Growth Factor 23 or cFGF23 (pmol/L) and iFGF23 (pg/mL)	Baseline, 3, 9 and 18-months
Secondary	Klotho	Concentration of Klotho (pg/mL) and soluble a-Klotho (pg/mL)	Baseline, 3, 9 and 18-months
Secondary	Sclerostin	Concentration of Sclerostin and Bioactive Sclerostin (pmol/L)	Baseline, 3, 9 and 18-months
Secondary	DKK1	Concentration of DKK1 (pmol/L)	Baseline, 3, 9 and 18-months
Secondary	Fetuin A	Concentration of Fetuin A (ng/mL)	Baseline, 3, 9 and 18-months
Secondary	Zinc	Concentration of Zinc (µmol/L)	Baseline, 3, 9 and 18-months
Secondary	Irisin	Concentration of Irisin	Baseline, 3, 9 and 18-months
Secondary	Serum Calcification Propensity T50 test	Serum Calcification Propensity T50 test (minutes)	Baseline, 3, 9 and 18-months
Secondary	Hemoglobin (Hb)	Concentration of Hemoglobin (g/dl)	Baseline, 3, 9 and 18-months
Secondary	Hematocrit (Ht)	Concentration of Hematocrit (%)	Baseline, 3, 9 and 18-months
Secondary	Plates (PLTS)	Concentration of plates (g/L)	Baseline, 3, 9 and 18-months
Secondary	Reticulocytes	Concentration of reticulocytes (%)	Baseline, 3, 9 and 18-months
Secondary	Iron	Concentration of iron (µg/dL)	Baseline, 3, 9 and 18-months
Secondary	Ferritin	Concentration of ferritin (ng/ml )	Baseline, 3, 9 and 18-months
Secondary	Transferrin	Concentration of transferrin (mg/dL)	Baseline, 3, 9 and 18-months
Secondary	Transferrin Saturation	Transferrin saturation (%)	Baseline, 3, 9 and 18-months
Secondary	Albumin	Concentration of Albumin (g/dl)	Baseline, 3, 9 and 18-months
Secondary	KT/V	Level of KT/V	Baseline, 3, 9 and 18-months
Secondary	Aluminium	Concentration of aluminium (mcg/L)	Baseline, 3, 9 and 18-months
Secondary	C-reactive Protein (CRP)	Concentration of C-reactive Protein (mg/L)	Baseline, 3, 9 and 18-months
Secondary	Cholesterol	Concentration of cholesterol (mg/dl)	Baseline, 3, 9 and 18-months
Secondary	Triglycerides	Concentration of triglycerides (mg/dl)	Baseline, 3, 9 and 18-months
Secondary	Cholesterol HDL	Concentration of Cholesterol HDL (mg/dl)	Baseline, 3, 9 and 18-months
Secondary	Cholesterol LDL	Concentration of Cholesterol LDL (mg/dl)	Baseline, 3, 9 and 18-months
Secondary	Vascular Calcification	Number of participants with vascular calcification (Aorta and Iliac arteries) by lateral Dorsal Lumbar spine x-Ray.	Baseline, 18-months
Secondary	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
Secondary	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
Secondary	Association between Verterbal Fractures and Vascular Calcificatiom	To evaluate the relationship of bone vascular biomarkers on clinical outcomes: VFs and VCs	Baseline, 18-months
Secondary	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
Secondary	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
Secondary	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