The Clinical Evaluation of the Dose of Erythropoietins Trial

Study Overview
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Brief Summary
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Anaemia is a risk factor for death, cardiac-cerebrovascular events and poor quality of life in patients with chronic kidney disease (CKD). Erythropoietin Stimulating Agents (ESAs) are the most used treatment option. The purpose of this study is the evaluation of biochemical markers to determine the efficacy of individual prediction of ESAs therapy to determine the benefits and harms of different ESA doses therapeutic strategy for the management of anaemia of end stage kidney disease (ESKD).

Detailed Description
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Phase III pragmatic, randomized-controlled trial comparing different doses of ESAs in patients with renal anaemia. Study Sample: Total of 900 participants from Italy Background and Rationale: Anaemia is a risk factor for death, cardiac-cerebrovascular events and poor quality of life in patients with chronic kidney disease (CKD). Erythropoietin Stimulating Agents (ESA) are the most used treatment option. In observational studies higher haemoglobin (Hb) levels (around 10-13 g/dL) are associated with improved survival and quality of life compared to lower Hb levels (around 9 g/dL). Randomized studies have found that higher Hb targets, achieved and maintained with ESA, cause an increased risk of death, mainly due to adverse cardiac-cerebrovascular outcomes. It is possible that such effect is mediated by ESA dose. This hypothesis has not been formally tested and is the aim of the Clinical Evaluation of the DOSe of Erythropoietins (CEDOSE) trial. CEDOSE is the first independent multicentre trial exploring the benefits and harms of different ESA doses therapeutic strategy for the management of anaemia of end stage kidney disease (ESKD). Hypothesis: ESA resistance is associated with adverse vascular outcomes and poor quality of life in ESKD. The CEDOSE trial will evaluate the biochemical markers to determine the efficacy of individual prediction of ESAs therapy; moreover it will evaluate the benefits and harms of two fixed ESA doses and explore the role of two treatment strategies, one based on a low and one based on a high ESA dose. Interventions and Comparison: Patients will be randomized 1:1 to 4000 IU/week iv. versus 18000 IU/week iv. of epoetin alfa, beta or any other epoetin in equivalent doses.

Official Title
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Effects of the Dose of Erythropoiesis Stimulating Agents on Cardiac-cerebrovascular Outcomes Quality of Life and Costs in Hemodialysis Patients. The Clinical Evaluation of the DOSe of Erythropoietins (C.E. DOSE) Trial

Conditions
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Kidney Failure, Chronic

Intervention / Treatment
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* Drug: Erythropoiesis Stimulating Agents (ESAs): epoetin alfa, beta or any other epoetin in equivalent dose.
* Drug: Erythropoiesis Stimulating Agents (ESAs): epoetin alfa, beta or any other epoetin in equivalent dose.


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age > = 18, End stage kidney disease and anemia Treatment with hemodialysis for renal replacement therapy no contraindications to erythropoietin stimulating agents (ESAs) or already treated with ESAs Exclusion Criteria: Patients with Hb levels > 10 g/dl without ESAs

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ESAs 1 low dose<br> | Drug: Erythropoiesis Stimulating Agents (ESAs): epoetin alfa, beta or any other epoetin in equivalent dose.<br>* 4000 IU/week I.V. Until the end of the trial<br>|
| Active Comparator: ESAs 2 high dose<br> | Drug: Erythropoiesis Stimulating Agents (ESAs): epoetin alfa, beta or any other epoetin in equivalent dose.<br>* 18000 IU/week I.V. Until the end of the trial<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| TSAT (transferrin saturation), serum albumin, serum ferritin, serum transferrin, serum C reactive protein |  | after randomization at month 1, 2, 3, 6, 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cardiovascular mortality |  | after randomization at month 1, 2, 3, 6, 12 | 
| sudden death |  | after randomization at month 1, 2, 3, 6, 12 | 
| Stroke |  | after randomization at month 1, 2, 3, 6, 12 | 
| myocardial infarction |  | after randomization at month 1, 2, 3, 6, 12 | 
| hospitalizations due to acute coronary syndrome, transitory ischemic attacks, not planned coronary revascularization, peripheric revascularization. |  | after randomization at month 1, 2, 3, 6, 12 | 
| Thrombosis of the cardiovascular access |  | after randomization at month 1, 2, 3, 6, 12 | 
| Seizures |  | after randomization at month 1, 2, 3, 6, 12 | 
| Hypertensive events |  | after randomization at month 1, 2, 3, 6, 12 | 
| Quality of life (QoL) |  | at randomization and at 6 and 12 months | 
| composite of all-cause mortality, non fatal myocardial infarction and stroke, hospitalizations due to acute coronary syndrome, transitory ischaemic attacks, not planned coronary revascularization procedures, peripheric revascularization procedures. |  | after randomization at month 1, 2, 3, 6, 12 |