Heart Failure, CongestivePhase 3NCT00356733
Mechanisms of Erythropoietin Action in the Cardiorenal Syndrome
A Phase 3 study testing Erythropoietin administration in people with Heart Failure, Congestive and Renal Insufficiency, Chronic, run by UMC Utrecht at 2 sites in Netherlands.
Trial summary
Erythropoietin (EPO) treatment in patients with the severe cardiorenal syndrome increases cardiac performance and decreases progression of renal failure by dampening the main driving forces of the cardiorenal syndrome in part via non-erythropoietic pathways. I. Read more about this study
- Who is it for?
- Ages 18 to 80 years
- Conditions the study is for
- Heart Failure, Congestive, Renal Insufficiency, Chronic
- What is being tested?
- Erythropoietin administration
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 62 participants
- Where
- 2 sitesNetherlands
- Study dates
- Jan 2007to Jul 2011
- Phase
- Phase 3
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 80 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Patients with moderate renal failure (glomerular filtration rate [GFR] by Cockroft formula of 20-70 ml/min)
- Patients with heart failure NYHA class II-III-IV
- Hemoglobin (Hb) between 6.4 - 7.8 mmol/L in men and between 6.0 - 7.4 mmol/L in women
- Age > 18 years, < 80 years
- Written informed consent must be obtained from the subject or legally accepted representative before study-specific procedures, including screening procedures, are performed.
Who cannot join
- Therapy within 1 year before randomisation or any planned erythropoietic therapy between randomisation and study day 1
- Known intolerance to EPO administration
- Previously suspected of or confirmed to have neutralizing antibodies to recombinant human erythropoietin (rHuEPO)
- Uncontrolled hypertension (RR > 160 systolic, >100 diastolic)
- Forms of secondary hypertension other than renal hypertension
- Uncontrolled diabetes (HbA1c > 8.0 %)
Show all 21Show fewer
- Primary dyslipidemia
- Kidney transplantation
- Proteinuria > 3.5 g/L
- Acute renal failure or rapidly progressive glomerulonephritis
- Hyperparathyroidism (parathyroid hormone [PTH] > 40)
- Bleeding or haemolysis as a cause of anaemia
- Deficiency of iron, folate, and/or vitamin B12
- Presence of chronic inflammatory disease or clinically significant infection
- Haematologic malignancy or solid tumour < 5 years ago
- Chronic liver disease
- Haemoglobinopathies
- Alcohol and/or drug abuse
- Enrolment in another study
- Child bearing potential (pre-menopausal woman who is not using adequate contraceptive precautions)
- Any kind of disorder that compromises the ability of the subject to give written informed consent and/or to comply with study procedures
Trial locations and contacts
2 sites in 1 country.
Netherlands2 sites
Meander Medical Center Amersfoort
Amersfoort, Utrecht, 3800 BM
Univ. Medical Center Utrecht
Utrecht, Utrecht, 3508 GA
About this study
Erythropoietin (EPO) treatment in patients with the severe cardiorenal syndrome increases cardiac performance and decreases progression of renal failure by dampening the main driving forces of the cardiorenal syndrome in part via non-erythropoietic pathways.
- Does EPO administration to patients with the severe cardiorenal syndrome increase cardiac performance and decrease progression of renal disease?
Read more
II. Does EPO treatment affect the main driving forces of the cardiorenal connection, that is, dampen the activated renin-angiotensin system (RAS), attenuate increased reactive oxygen species (ROS), normalize increased sympathetic activity, and decrease inflammation?
III. Does EPO treatment positively affect the cell function of patients with the cardiorenal syndrome:
- are gene expression signatures of leukocytes positively influenced by EPO treatment,
- does EPO shift the Jak/STAT pathway to a less pro-inflammatory profile in monocytes, and
- are function and number of endothelial progenitor cells (EPCs) affected by treatment with EPO in the cardiorenal syndrome?
IV. Can the direct actions of EPO be differentiated from the effects on hemoglobin levels?
Read the detailed description
The combination of renal and cardiac failure is associated with an extraordinary cardiovascular morbidity and mortality. We propose that the severe cardiorenal syndrome (SCRS), the pathophysiological condition in which there is combined cardiac and renal dysfunction, amplifies the progression of the failure of the individual organ. Central in the pathogenesis of the cardiorenal syndrome is enhanced oxidative stress, inflammation and enhanced activation of the renin-angiotensin and sympathetic nervous system. Chronic renal failure is further accompanied by anemia due to a gradual decline in erythropoietin (EPO) formation by the diseased kidneys and/or by EPO resistance. Recently, the interest in EPO is increasing since it serves not only as a hematopoietic factor, but also has been shown to increase the number of endothelial progenitor cells (EPCs) in end-stage renal disease (ESRD) patients. Moreover, EPO is involved in signaling via Akt to support NO release and may act as an anti-apoptotic. Some evidence supports the idea that EPO improves cardiac and renal function in the syndrome; however, no information is available about the mechanisms. The hypothesis of the present proposal is that EPO treatment in patients with the severe cardiorenal syndrome increases cardiac performance and decreases progression of renal failure in part via non-erythropoietic pathways. The questions are whether EPO administration to patients with the severe cardiorenal syndrome:
- increases cardiac performance and decreases progression of renal disease,
- dampens the activated RAS and sympathetic nervous system, attenuates increased ROS and decreases signs of inflammation and
- positively influences cell function of leukocytes (assessed by gene expression signatures), of monocytes (shifts to a less pro-inflammatory Jak/Stat signaling) and of EPC (number and function).
This will be addressed in a two-part clinical study in patients with combined moderate chronic renal failure and heart failure (New York Heart Association [NYHA] II-III). First, patients will be treated with EPO for 12 months, and hemoglobin levels will be kept constant at initial levels or will be allowed to increase; another group will be left untreated. Besides cardiac and renal function, the RAS, the SNS, and ROS/NOS balance and inflammatory parameters will be assessed. Furthermore, cell function of leukocytes (gene expression signatures), monocytes (Jak/STAT activation) and EPCs (number and function) will be studied. Taken together, central in the proposal is that combined heart-kidney failure is accompanied by relative or absolute EPO dysfunction, disproportional to the degree of renal failure and that treatment with EPO improves cardiac performance and renal function.
- Being tested
- Erythropoietin administration
- Keywords
- cardiorenal syndrome, erythropoietin, Heart Failure, Congestive, Renal Insufficiency, Chronic
- Medical subject headings
- Heart Failure, Renal Insufficiency, Chronic, Cardio-Renal Syndrome
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Erythropoietin administrationDrug
50 IU/kg/week EPO to a target haemoglobin level of 13.7 g/dL for men and 13.4 g/dL for women (group A) or to a target comparable to starting hemoglobin level (group B)
| Study group | Role | What they receive |
|---|---|---|
| EPO rise | Experimental | EPO administration Receives: Drug: Erythropoietin administration |
| EPO stable | Experimental | EPO and stable Hemoglobin Receives: Drug: Erythropoietin administration |
| control | No intervention | standard treatment |
What is being measured
The primary outcome is the main question the study is designed to answer.
changes in gene-arrays, EPC and biomarkers panels
Measured: 14 days, 6 and 12 months
Secondary outcomes (2)
cardiac performance and renal function
Measured: 6 and 12 months
QoL
Measured: 6 and 12 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted26 Jul 2006 (estimated)
- Study startJan 2007
- Primary completionJul 2011
- Study completionJul 2011
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (4)Papers the sponsor has linked to this study.
- Other trials for Heart Failure, CongestiveStudies of the same condition, open and under way.
- More trials run by UMC UtrechtThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Factorial
- Masking
- None (open label)
- Enrolment
- 62 participants (actual)
Sponsor and investigators
- Lead sponsor
- UMC Utrecht
- Sponsor type
- University, hospital or other
- Collaborators
- Dutch Heart Foundation
- Responsible party
- Principal investigator, G.B. Braam, University of Alberta
- Investigators
- Branko Braam, MD, PhD, Principal investigator, UMC Utrecht, The NetherlandsCarlo AJ Gaillard, MD, PhD, Principal investigator, Meander Medical Center Amersfoort, The NetherlandsPieter AF Doevendans, MD, PhD, Study director, UMC Utrecht, The Netherlands
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00356733
- Sponsor's protocol ID
- NHS-2005B192
- Status last verified
- Nov 2011
- First submitted
- 25 Jul 2006
- Last updated
- 2 Dec 2011
- Results posted
- No
Publications
Chung EY, Palmer SC, Saglimbene VM, Craig JC, Tonelli M, Strippoli GF. Erythropoiesis-stimulating agents for anaemia in adults with chronic kidney disease: a network meta-analysis. Cochrane Database Syst Rev. 2023 Feb 13;2(2):CD010590. doi: 10.1002/14651858.CD010590.pub3.
PubMed 36791280Eisenga MF, Emans ME, van der Putten K, Cramer MJ, Diepenbroek A, Velthuis BK, Doevendans PA, Verhaar MC, Joles JA, Bakker SJL, Nolte IM, Braam B, Gaillard CAJM. Epoetin Beta and C-Terminal Fibroblast Growth Factor 23 in Patients With Chronic Heart Failure and Chronic Kidney Disease. J Am Heart Assoc. 2019 Aug 20;8(16):e011130. doi: 10.1161/JAHA.118.011130. Epub 2019 Aug 17.
PubMed 31423921Emans ME, van der Putten K, Velthuis BK, de Vries JJ, Cramer MJ, America YG, Hillege HL, Meiss L, Doevendans PA, Braam B, Gaillard CA. Atherosclerotic renal artery stenosis is prevalent in cardiorenal patients but not associated with left ventricular function and myocardial fibrosis as assessed by cardiac magnetic resonance imaging. BMC Cardiovasc Disord. 2012 Sep 18;12:76. doi: 10.1186/1471-2261-12-76.
PubMed 22989293van der Putten K, Jie KE, Emans ME, Verhaar MC, Joles JA, Cramer MJ, Velthuis BK, Meiss L, Kraaijenhagen RJ, Doevendans PA, Braam B, Gaillard CA. Erythropoietin treatment in patients with combined heart and renal failure: objectives and design of the EPOCARES study. J Nephrol. 2010 Jul-Aug;23(4):363-8.
PubMed 20383871
Study at a glance
From the registry record, last updated by the sponsor on 2 Dec 2011. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Mechanisms of Erythropoietin Action in the Cardiorenal Syndrome
- ClinicalTrials.gov ID
- NCT00356733
- Acronym / sponsor ID
- NHS-2005B192
- Keywords
- cardiorenal syndrome, erythropoietin, Heart Failure, Congestive, Renal Insufficiency, Chronic
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 62 participants (actual)
- Lead sponsor
- UMC UtrechtUniversity, hospital or other
- Collaborators
- Dutch Heart Foundation
- Study start
- Jan 2007
- Primary completion
- Jul 2011 (actual)
- Study completion
- Jul 2011 (actual)
- First posted
- 26 Jul 2006 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Erythropoietin (EPO) treatment in patients with the severe cardiorenal syndrome increases cardiac performance and decreases progression of renal failure by dampening the main driving forces of the cardiorenal syndrome in part via non-erythropoietic pathways.
- Does EPO administration to patients with the severe cardiorenal syndrome increase cardiac performance and decrease progression of renal disease?
II. Does EPO treatment affect the main driving forces of the cardiorenal connection, that is, dampen the activated renin-angiotensin system (RAS), attenuate increased reactive oxygen species (ROS), normalize increased sympathetic activity, and decrease inflammation?
III. Does EPO treatment positively affect the cell function of patients with the cardiorenal syndrome:
- are gene expression signatures of leukocytes positively influenced by EPO treatment,
- does EPO shift the Jak/STAT pathway to a less pro-inflammatory profile in monocytes, and
- are function and number of endothelial progenitor cells (EPCs) affected by treatment with EPO in the cardiorenal syndrome?
IV. Can the direct actions of EPO be differentiated from the effects on hemoglobin levels?
Detailed description
The combination of renal and cardiac failure is associated with an extraordinary cardiovascular morbidity and mortality. We propose that the severe cardiorenal syndrome (SCRS), the pathophysiological condition in which there is combined cardiac and renal dysfunction, amplifies the progression of the failure of the individual organ. Central in the pathogenesis of the cardiorenal syndrome is enhanced oxidative stress, inflammation and enhanced activation of the renin-angiotensin and sympathetic nervous system. Chronic renal failure is further accompanied by anemia due to a gradual decline in erythropoietin (EPO) formation by the diseased kidneys and/or by EPO resistance. Recently, the interest in EPO is increasing since it serves not only as a hematopoietic factor, but also has been shown to increase the number of endothelial progenitor cells (EPCs) in end-stage renal disease (ESRD) patients. Moreover, EPO is involved in signaling via Akt to support NO release and may act as an anti-apoptotic. Some evidence supports the idea that EPO improves cardiac and renal function in the syndrome; however, no information is available about the mechanisms. The hypothesis of the present proposal is that EPO treatment in patients with the severe cardiorenal syndrome increases cardiac performance and decreases progression of renal failure in part via non-erythropoietic pathways. The questions are whether EPO administration to patients with the severe cardiorenal syndrome:
- increases cardiac performance and decreases progression of renal disease,
- dampens the activated RAS and sympathetic nervous system, attenuates increased ROS and decreases signs of inflammation and
- positively influences cell function of leukocytes (assessed by gene expression signatures), of monocytes (shifts to a less pro-inflammatory Jak/Stat signaling) and of EPC (number and function).
This will be addressed in a two-part clinical study in patients with combined moderate chronic renal failure and heart failure (New York Heart Association [NYHA] II-III). First, patients will be treated with EPO for 12 months, and hemoglobin levels will be kept constant at initial levels or will be allowed to increase; another group will be left untreated. Besides cardiac and renal function, the RAS, the SNS, and ROS/NOS balance and inflammatory parameters will be assessed. Furthermore, cell function of leukocytes (gene expression signatures), monocytes (Jak/STAT activation) and EPCs (number and function) will be studied. Taken together, central in the proposal is that combined heart-kidney failure is accompanied by relative or absolute EPO dysfunction, disproportional to the degree of renal failure and that treatment with EPO improves cardiac performance and renal function.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Factorial
- Masking
- None (open label)
- Number of arms
- 3
| Arm | Type | Receives |
|---|---|---|
| EPO rise | Experimental | Drug: Erythropoietin administrationEPO administration |
| EPO stable | Experimental | Drug: Erythropoietin administrationEPO and stable Hemoglobin |
| control | No intervention | –standard treatment |
Who may qualify
- Ages
- 18 to 80 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (5 listed)
- Patients with moderate renal failure (glomerular filtration rate [GFR] by Cockroft formula of 20-70 ml/min)
- Patients with heart failure NYHA class II-III-IV
- Hemoglobin (Hb) between 6.4 - 7.8 mmol/L in men and between 6.0 - 7.4 mmol/L in women
- Age > 18 years, < 80 years
- Written informed consent must be obtained from the subject or legally accepted representative before study-specific procedures, including screening procedures, are performed.
Key exclusion criteria (21 listed)
- Therapy within 1 year before randomisation or any planned erythropoietic therapy between randomisation and study day 1
- Known intolerance to EPO administration
- Previously suspected of or confirmed to have neutralizing antibodies to recombinant human erythropoietin (rHuEPO)
- Uncontrolled hypertension (RR > 160 systolic, >100 diastolic)
- Forms of secondary hypertension other than renal hypertension
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Erythropoietin administration50 IU/kg/week EPO to a target haemoglobin level of 13.7 g/dL for men and 13.4 g/dL for women (group A) or to a target comparable to starting hemoglobin level (group B) | Drug | EPO rise, EPO stable |
Primary outcome
changes in gene-arrays, EPC and biomarkers panels
Time frame: 14 days, 6 and 12 months
2 secondary outcomes
cardiac performance and renal function
Time frame: 6 and 12 months
QoL
Time frame: 6 and 12 months
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 2 Dec 2011.
- Derived from this study: PubMed 36791280Chung EY, Palmer SC, Saglimbene VM, Craig JC, Tonelli M, Strippoli GF. Erythropoiesis-stimulating agents for anaemia in adults with chronic kidney disease: a network meta-analysis. Cochrane Database Syst Rev. 2023 Feb 13;2(2):CD010590. doi: 10.1002/14651858.CD010590.pub3.
- Derived from this study: PubMed 31423921Eisenga MF, Emans ME, van der Putten K, Cramer MJ, Diepenbroek A, Velthuis BK, Doevendans PA, Verhaar MC, Joles JA, Bakker SJL, Nolte IM, Braam B, Gaillard CAJM. Epoetin Beta and C-Terminal Fibroblast Growth Factor 23 in Patients With Chronic Heart Failure and Chronic Kidney Disease. J Am Heart Assoc. 2019 Aug 20;8(16):e011130. doi: 10.1161/JAHA.118.011130. Epub 2019 Aug 17.
- Derived from this study: PubMed 22989293Emans ME, van der Putten K, Velthuis BK, de Vries JJ, Cramer MJ, America YG, Hillege HL, Meiss L, Doevendans PA, Braam B, Gaillard CA. Atherosclerotic renal artery stenosis is prevalent in cardiorenal patients but not associated with left ventricular function and myocardial fibrosis as assessed by cardiac magnetic resonance imaging. BMC Cardiovasc Disord. 2012 Sep 18;12:76. doi: 10.1186/1471-2261-12-76.
- Derived from this study: PubMed 20383871van der Putten K, Jie KE, Emans ME, Verhaar MC, Joles JA, Cramer MJ, Velthuis BK, Meiss L, Kraaijenhagen RJ, Doevendans PA, Braam B, Gaillard CA. Erythropoietin treatment in patients with combined heart and renal failure: objectives and design of the EPOCARES study. J Nephrol. 2010 Jul-Aug;23(4):363-8.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Branko Braam, MD, PhD principal investigator
UMC Utrecht, The Netherlands
Carlo AJ Gaillard, MD, PhD principal investigator
Meander Medical Center Amersfoort, The Netherlands
Pieter AF Doevendans, MD, PhD study director
UMC Utrecht, The Netherlands
2 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing Erythropoietin administration in people with Heart Failure, Congestive and Renal Insufficiency, Chronic, run by UMC Utrecht at 2 sites in Netherlands.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 5 inclusion and 21 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 2 Dec 2011. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 2 sites in Netherlands. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
changes in gene-arrays, EPC and biomarkers panels (time frame: 14 days, 6 and 12 months). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT00356733, which also lists 4 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 2 Dec 2011.