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

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

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).

Study Overview

• Status: Completed
• Conditions: Kidney Failure, Chronic
• Intervention / Treatment: 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.

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 656
• Phase: Phase 3

Contacts and Locations

Study Locations

• Italy
  • Acri, Italy
    • Ospedale Beato Angelo
  • Agrigento, Italy
    • Ospedale S. Giovanni di Dio
  • Alghero, Italy
    • Ospedale Civile di Alghero ASL n°1
  • Anzio, Italy
    • Ospedali Riuniti di Anzio e Nettuno
  • Bellaria, Italy
    • Ospedale Bellaria
  • Bologna, Italy
    • Policlinico S. Orsola - Malpighi
  • Brindisi, Italy
    • "A. Perrino" Hospital
  • Chieri, Italy
    • Ospedale Maggiore di Chieri ASL TO 5
  • Como, Italy
    • Ospedale Sant'Anna, San Fermo Battaglia
  • Ferrara, Italy
    • Ospedale Nuovo Sant'Anna
  • Foggia, Italy
    • Azienda Ospedaliera Universitaria OO.RR Foggia
  • Formia, Italy
    • P.O. SUD - Formia ASL Latina
  • Gorizia, Italy
    • Ospedale S. Giovanni di Dio di Gorizia
  • Jesi, Italy
    • Jesi (Carlo Urbani)
  • Ladispoli, Italy
    • Centro Dialitico Diaverum, Ladispoli
  • Lanciano, Italy
    • Ospedale Renzetti ASL Lanciano Vasto
  • Legnano, Italy
    • Azienda Ospedaliera Ospedale Civile di Legnano
  • Magenta, Italy
    • Ospedale Fornaroli
  • Manduria, Italy
    • Ospedale di Manduria
  • Marsala, Italy
    • Centro Dialitico Diaverum Marsala
  • Martina Franca, Italy
    • Ospedale Valle D'Itria ASL TA
  • Nicosia, Italy
    • Ospedale di Nicosia
  • Novi Ligure, Italy
    • Ospedale San Giacomo
  • Ortona, Italy
    • Ospedale G. Bernabeo
  • Palermo, Italy
    • Arnas Civico Di Cristina
  • Parma, Italy
    • Azienda Ospedaliera Universitaria di Parma
  • Parma, Italy
    • Centro di Emodialisi ausl Parma
  • Pordenone, Italy
    • Ospedale S. Maria degli Angeli
  • Priverno, Italy
    • P.P.I. Priverno
  • Reggio Emilia, Italy
    • Arcispedale S. Maria Nuova, Reggio Emilia
  • Riesi, Italy
    • Centro Dialitico Diaverum, Riesi
  • Rogliano, Italy
    • Ospedale S. Barbara
  • Roma, Italy
    • Ospedale S. Eugenio ASL RMC
  • Rozzano, Italy
    • Istituto Clinico Humanitas, Rozzano
  • San Donato Milanese, Italy
    • Policlínico San Donato
  • Sassari, Italy
    • Ospedale SS Annunziata
  • Solofra, Italy
    • Ospedale A.Landolfi
  • Terracina, Italy
    • Ospedale Alfredo Fiorini di Terracina
  • Torino, Italy
    • Ospedale San Giovanni Bosco
  • Torino, Italy
    • Azienda Ospedaliera C.T.O./C.R.F./ M. Adelaide
  • Vasto, Italy
    • S. Pio da Pietrelcina

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: ESAs 1 low dose	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
ACTIVE_COMPARATOR: ESAs 2 high dose	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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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	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

Collaborators and Investigators

• Sponsor: Giovanni FM Strippoli, MD
• Investigators: Study Chair: Giovanni FM Strippoli, MD, Fondazione Mario Negri Sud

Publications and helpful links

General Publications

• Strippoli GF; Clinical Evaluation of the DOse of Erythropoietins Study Group (C.E. DOSE). Effects of the dose of erythropoiesis stimulating agents on cardiovascular events, quality of life, and health-related costs in hemodialysis patients: the clinical evaluation of the dose of erythropoietins (C.E. DOSE) trial protocol. Trials. 2010 Jun 9;11:70. doi: 10.1186/1745-6215-11-70.
• Saglimbene V, D'Alonzo D, Ruospo M, Vecchio M, Natale P, Gargano L, Nicolucci A, Pellegrini F, Craig JC, Triolo G, Procaccini DA, Santoro A, Di Giulio S, La Rosa S, Murgo A, Di Toro Mammarella R, Sambati M, D'Ambrosio N, Greco V, Giannoccaro G, Flammini A, Boccia E, Montalto G, Pagano S, Amaru S, Fici M, Lumaga GB, Mancini E, Veronesi M, Patregnani L, Querques M, Schiavone P, Chimienti S, Palumbo R, Di Franco D, Della Volpe M, Gori E, Salomone M, Iacono A, Moscoloni M, Treglia A, Casu D, Piras AM, Di Silva A, Mandreoli M, Lopez A, Quarello F, Catizone L, Russo G, Forcellini S, Maccarone M, Catucci G, Di Paolo B, Stingone A, D'Angelo B, Guastoni C, Pasquali S, Minoretti C, Bellasi A, Boscutti G, Martone M, David S, Schito F, Urban L, Di Iorio B, Caruso F, Mazzoni A, Musacchio R, Andreoli D, Cossu M, Li Cavoli G, Cornacchiari M, Granata A, Clementi A, Giordano R, Guastoni C, Barzaghi W, Valentini M, Hegbrant J, Tognoni G, Strippoli GF. [Effects of dose of erythropoiesis stimulating agents on cardiovascular outcomes, quality of life and costs of haemodialysis. the clinical evaluation of the DOSe of erythropoietins (C.E. DOSE) Trial]. G Ital Nefrol. 2013 Mar-Apr;30(2):gin/30.2.21. Italian.

Study record dates

Study Major Dates

• Study Start: July 1, 2009
• Primary Completion (ACTUAL): July 1, 2014
• Study Completion (ACTUAL): July 1, 2014

Study Registration Dates

• First Submitted: January 21, 2009
• First Submitted That Met QC Criteria: January 21, 2009
• First Posted (ESTIMATE): January 22, 2009

Study Record Updates

• Last Update Posted (ESTIMATE): July 19, 2016
• Last Update Submitted That Met QC Criteria: July 15, 2016
• Last Verified: July 1, 2016

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Kidney Diseases; Urologic Diseases; Renal Insufficiency, Chronic; Kidney Failure, Chronic; Renal Insufficiency; Epoetin Alfa; Hematinics
• Other Study ID Numbers: FARM6X822T; 2008-006014-20