The Clinical Evaluation of the Dose of Erythropoietins Trial (CEDOSE)

• Cardiovascular mortality [ Time Frame: after randomization at month 1, 2, 3, 6, 12 ] [ Designated as safety issue: No ]
• sudden death [ Time Frame: after randomization at month 1, 2, 3, 6, 12 ] [ Designated as safety issue: No ]
• Stroke [ Time Frame: after randomization at month 1, 2, 3, 6, 12 ] [ Designated as safety issue: No ]
• myocardial infarction [ Time Frame: after randomization at month 1, 2, 3, 6, 12 ] [ Designated as safety issue: No ]
• hospitalizations due to acute coronary syndrome, transitory ischemic attacks, not planned coronary revascularization, peripheric revascularization. [ Time Frame: after randomization at month 1, 2, 3, 6, 12 ] [ Designated as safety issue: No ]
• Thrombosis of the cardiovascular access [ Time Frame: after randomization at month 1, 2, 3, 6, 12 ] [ Designated as safety issue: Yes ]
• Seizures [ Time Frame: after randomization at month 1, 2, 3, 6, 12 ] [ Designated as safety issue: Yes ]
• Hypertensive events [ Time Frame: after randomization at month 1, 2, 3, 6, 12 ] [ Designated as safety issue: Yes ]
• Quality of life (QoL) [ Time Frame: at randomization and at 6 and 12 months ] [ Designated as safety issue: No ]
• 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. [ Time Frame: after randomization at month 1, 2, 3, 6, 12 ] [ Designated as safety issue: No ]

• Cardiovascular mortality [ Time Frame: after randomization at month 1, 2, 3, 6 and then every 6 months until the 48th month ] [ Designated as safety issue: No ]
• sudden death [ Time Frame: after randomization at month 1, 2, 3, 6 and then every 6 months until the 48th month ] [ Designated as safety issue: No ]
• Stroke [ Time Frame: after randomization at month 1, 2, 3, 6 and then every 6 months until the 48th month ] [ Designated as safety issue: No ]
• myocardial infarction [ Time Frame: after randomization at month 1, 2, 3, 6 and then every 6 months until the 48th month ] [ Designated as safety issue: No ]
• hospitalizations due to acute coronary syndrome, transitory ischemic attacks, not planned coronary revascularization, peripheric revascularization. [ Time Frame: after randomization at month 1, 2, 3, 6 and then every 6 months until the 48th month ] [ Designated as safety issue: No ]
• Thrombosis of the cardiovascular access [ Time Frame: after randomization at month 1, 2, 3, 6 and then every 6 months until the 48th month ] [ Designated as safety issue: Yes ]
• Seizures [ Time Frame: after randomization at month 1, 2, 3, 6 and then every 6 months until the 48th month ] [ Designated as safety issue: Yes ]
• Hypertensive events [ Time Frame: after randomization at month 1, 2, 3, 6 and then every 6 months until the 48th month ] [ Designated as safety issue: Yes ]
• Quality of life (QoL) [ Time Frame: at randomization and then every 6 months until the 48th month ] [ Designated as safety issue: No ]
• Costs [ Time Frame: At the end of the trial ] [ Designated as safety issue: No ]

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

1. the evaluation of biochemical markers to determine the efficacy of individual prediction of ESAs therapy
2. to determine the benefits and harms of different ESA doses therapeutic strategy for the management of anaemia of end stage kidney disease (ESKD).

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.

• Drug: Erythropoiesis Stimulating Agents (ESAs): epoetin alfa, beta or any other epoetin in equivalent dose.
  4000 IU/week I.V. Until the end of the trial
• Drug: Erythropoiesis Stimulating Agents (ESAs): epoetin alfa, beta or any other epoetin in equivalent dose.
  18000 IU/week I.V. Until the end of the trial

• Experimental: ESAs 1 low dose
  Intervention: Drug: Erythropoiesis Stimulating Agents (ESAs): epoetin alfa, beta or any other epoetin in equivalent dose.
• Active Comparator: ESAs 2 high dose
  Intervention: Drug: Erythropoiesis Stimulating Agents (ESAs): epoetin alfa, beta or any other epoetin in equivalent dose.

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