Optimal Anemia Treatment in End Stage Renal Disease (ERSD)

Study Overview
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Brief Summary
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Clinical study aimed at improving anemia management in End Stage Renal Disease Patient (ESRD) on maintenance Hemodialysis with evidence of Chronic Kidney disease Mineral Bone Disorder (CKD-MBD)

Detailed Description
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Anemia is one of the most worrisome complications of Chronic Kidney Disease (CKD). Numerous prospective studies have repeatedly documented an increase risk of morbidity and mortality associated with lower levels of hemoglobin (Hb). Hence the international guidelines on patient care suggest the use of Erythropoietin Stimulating Agents (ESA), iron, folates supplementation for anemia correction. However, recent randomized controlled trials (RCT) have demonstrated that hemoglobin correction to normal levels increases the risk of major cardiovascular (CV) events. Though, the reasons are still unclear, the cumulative ESA dose may at least partly explain these findings suggesting limiting ESA to the minimal dose allowed to achieve the suggested Hb targets in ESRD patients. Among other factors, CKD-MBD has been repeatedly associated with poor more severe anemia and higher dose of ESA. However, the latest Kidney Disease: Improving Global Outcomes (KDIGO) guidelines on CKD-MBD management suggest a higher reference target for intact parathyroid hormone (iPTH) (2-9 fold the upper level of the normal range) when compared to the National Kidney Foundation (NKF) guidelines published in 2003 (150-300 pg/ml). A few observational studies suggest a linear inverse association between intact iPTH and ESA dose even for iPTH value within the iPTH target level proposed by the KDIGO working group. Similarly, a large body of evidence supports the notion that the higher the iPTH the faster the CV system deterioration in ESRD. Aim of the study is to test whether a tighter iPTH control to achieve a iPTH level lower than 300 pg/ml vs iPTH levels between 300-540 pg/ml is associated with a ESA dose reduction and a slower CV system deterioration in ESRD patients receiving dialysis. STUDY DESIGN Pilot, single center, open label with blinded end point (PROBE-Prospective Randomized Open Blinded End-Point) aimed at improving patient care. Eligible patients will be randomized (1:1) to either: (A) Control group: standard care. The iPTH target in this group is 300-540 pg/ml (B) Optimal CKD-MBD control: in this group the iPTH target is150-300 pg/ml to be achieved with a therapeutic algorithm. TREATMENTS All patients will be randomized (1:1) to either: (A) Control group: standard care. The iPTH target in this group is 300-540 pg/ml. (B) Optimal CKD-MBD control:: in this group the iPTH target is 150-300 pg/ml to be achieved with a therapeutic algorithm: I. iPTH control: in order to achieve the iPTH target (150-300 pg/ml), all patients will receive 400 IU/day of vitamin-25-OH-D (25OHD) and a flexible dose of any active vitamin D available in Italy (calcitriol and paricalcitol-Zemplar®) at the maximum dose of 6 mcg/week of paricalcitol(Zemplar®)of equivalent (see existing conversion table). Patients will also receive a flexible dose of cinacalcet(Mimpara®) to a maximum dose of 90 mg/day. II. Phosphorous control: all patients need to achieve a serum phosphorous level lower than 5.5 mg/dl. All available phosphate binders are allowed [sevelamer(Renvela®), calcium carbonate, calcium acetate(Phoslo®), calcium acetate/magnesium carbonate (Osvaren®), lanthanum carbonate Foznol®). A rescue therapy with aluminum(Maalox®) is allowed for no more than 30 days. III. Serum calcium control: the suggested target is less than 9.5 mg/dl. In case of serum calcium greater than 9.5 mg/dl the calcium and vitamin D dose should be lowered in order to lower the risk of vascular calcification deposition and progression

Official Title
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Single-center, Open-label, Randomized Study of Anemia Management Improvement in End Stage Renal Disease (ESRD) Patients With Secondary Hyperparathyroidism

Conditions
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Hyperparathyroidism, Secondary

Intervention / Treatment
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* Drug: standard care
* Drug: Optimal (I. iPTH control: Zemplar®,Mimpara®; phosphorous control: Renvela®, Phoslo®, Osvaren®, Foznol®,Maalox®; calcium control: calcium and vitamin D


Participation Criteria
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Eligibility Criteria
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INCLUSION CRITERIA. Men and women Age >18 years Maintenance dialysis via Artero-Venous fistula ESA use iPTH between 300-600 pg/ml Hb between 10.0-11.5 Kt/V greater/equal than 1.2 Signed informed consent prior to the initiation of the study EXCLUSION CRITERIA: None.

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: Supportive Care
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: control<br>Control group: standard care. The iPTH target in this group is 300-540 pg/ml | Drug: standard care<br>* Standard care. Patients allocated to this study arm will be treated with all drugs available for PTH control (at the investigator discretion) to obtain a iPTH of 300-540 pg/ml.<br>* Other names: Drugs available on the market control iPTH;|
| Experimental: Optimal CKD-MBD control<br>Optimal CKD-MBD control: in this group the PTH target is150-300 pg/ml to be achieved with a therapeutic algorithm | Drug: Optimal (I. iPTH control: Zemplar®,Mimpara®; phosphorous control: Renvela®, Phoslo®, Osvaren®, Foznol®,Maalox®; calcium control: calcium and vitamin D<br>* Optimal care. Patients allocated to this study arm will be treated with all drugs available for PTH control (at the investigator discretion - see therapeutic algorithm) to obtain a iPTH of less than 300 pg/ml.<br>* Other names: Drugs available on the market control iPTH;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| percent reduction in weekly ESA consumption to maintain Hb levels within the recommended range 10.0-11.5 g/dl | Primary objective: to test whether a tighter PTH control to achieve a PTH level lower than 300 pg/ml vs PTH levels between 300-540 pg/ml is associated with a lower ESA dose use to achieve the target Hb of 10.0-11.5 g/dl | baseline and after 12 months of followup | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in iron status and storage. | Secondary objective: to test whether a tighter PTH control to achieve a PTH level lower than 300 pg/ml vs PTH levels between 300-540 pg/ml is associated with a better iron storage and mobilization. | baseline and after 12 months of followup | 
| Difference in prevalence of cardiac valvular calcification progression detected by echocardiography between groups. | Secondary objective: to test whether a tighter PTH control to achieve a PTH level lower than 300 pg/ml vs PTH levels between 300-540 pg/ml is associated with cardiac valves deposition and progression attenuation. | baseline and after 12 months of followup | 
| Difference in pulse wave velocity assessed by applanation tonometry between groups. | Secondary objective: to test whether a tighter PTH control to achieve a PTH level lower than 300 pg/ml vs PTH levels between 300-540 pg/ml is associated with arterial stiffness increase attenuation | baseline and after 12 months of followup | 
| CKD-MBD control | Secondary objective: to test whether a tighter PTH control to achieve a PTH level lower than 300 pg/ml vs PTH levels between 300-540 pg/ml is associated with a better CKD-MBD control | baseline and after 12 months of followup | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Anemia, Hyperparathyroidism, Secondary, Vascular Stiffness, Vascular Calcification