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Study of the Use of a Single Dose of Erythropoietin to Treat Acute Myocardial Ischemia (DREAM)

Primary Purpose

CABG, Coronary Artery Disease

Status

Completed

Phase

Phase 2

Locations

Netherlands

Study Type

Interventional

Intervention

Epoetin alpha

NaCl 0.9%

About this trial

This is an interventional treatment trial for CABG focused on measuring Apoptosis, CABG, Coronary Artery Disease, Three Vessel Disease, Erythropoietin, EPO-receptor signaling

Eligibility Criteria

18 Years - 80 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Before any study-specific procedure, including assessments for screening, the appropriate written informed consent must be obtained.
Man or woman 18 to 80 years of age .
Undergoing a planned, elective cardiopulmonary bypass operation for the first time for 3-vessel coronary artery disease with an anticipated aortic cross clamp time of approximately 40 minutes and a total bypass time of approximately 90 minutes.
Hemoglobin (Hb) concentration ≥7.4 mmol/l and ≤9.9 mmol/l within 7 days prior to CABG surgery and no major acute blood loss since this Hb determination.

Exclusion Criteria:

An unstable medical condition, defined as having been hospitalized for a non-cardiac condition within 4 weeks of screening, major surgery within 24 weeks of screening, or otherwise unstable in the judgment of the investigator (e.g., at risk of complications or adverse events unrelated to study participation).
Left ventricular ejection fraction (LVEF) < 40%.
Clinical history of chronic kidney disease (CKD) (at any point prior to registration) defined as serum creatinine >105 μmol/l for all females, >130 μmol/l for black males, and >115 μmol/l for non-black males.
Atrial fibrillation, paroxysmal atrial fibrillation or atrial flutter.
Clinically significant abnormality in chemistry, hematology, or urinalysis parameters performed within the screening period.
Current symptoms of polyurea, polydipsia, or increased thirst.
Grand mal seizure within 1 year of enrollment.
Poorly controlled hypertension, defined as systolic blood pressure (SBP) > 180 mmHg or diastolic blood pressure (DBP) > 105 mmHg on day of CABG surgery.
Use of any erythropoietic protein (e.g., rHuEPO; Procrit®, Eprex®, Neorecormon®, Epogen®, Aranesp®) within 12 weeks of enrolment.
Positive pregnancy test or known to be pregnant at the time of screening.
Recent (within 3 months) history of alcohol or illicit drug abuse disorder, based on self-report.
Severe uncorrected valvular disease (including pulmonary and tricuspid) or left ventricular outflow obstruction which, in the opinion of the investigator, requires surgery.
Pulmonary hypertension, defined as a pulmonary artery pressure > 30 mmHg at rest.
Participation in any investigational device or drug trial(s) or receiving other investigational agent(s) within 30 days.
Known positive for HIV antibodies, hepatitis B surface antigen, or hepatitis C antibodies.
Any condition (e.g., unsuitable anatomy of the atrium; psychiatric illness; etc.) or situation that, in the investigator's opinion, could put the subject at significant risk, confound the study results, or interfere significantly with the subject's participation in the study.

Sites / Locations

University Medical Center Groningen, Dept. of Cardiology

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Arm Description

25 patients undergoing CABG for three vessel disease, receiving a single dose of erythropoietin periprocedural.

25 patients undergoing CABG for three vessel disease, receiving placebo (NaCl 0.9%) periprocedural.

Outcomes

Primary Outcome Measures

The increase from baseline between EPO and saline treated subjects in activity of EPOR-STC including but not limited to, phospho Erk1/2, phospho Akt, activated caspase-3, and activated STAT5 in the second atrial biopsy.

Secondary Outcome Measures

Difference in apoptosis between atrial and ventricular specimens at the end of CPB, defined as the number of TUNEL and activated caspase-3 positive cells per high power field.

Difference between EPO- and saline treated subjects in TUNEL and active caspase-3 positive cells in ventricular and atrial biopsies.

Difference in AUC for CK-MB, Troponin T, NT-proBNP, and cystatin C between EPO- and saline treated patients.

Subject incidence rates of adverse events.

Full Information

NCT ID

NCT00524901

First Posted

September 4, 2007

Last Updated

February 13, 2013

Sponsor

University Medical Center Groningen

1. Study Identification

Unique Protocol Identification Number

NCT00524901

Brief Title

Study of the Use of a Single Dose of Erythropoietin to Treat Acute Myocardial Ischemia

Acronym

DREAM

Official Title

An Open Label Study to Evaluate the Effect of Intravenous Erythropoietin on Erythropoietin Receptor Signaling and Markers for Apoptosis, Myocardial Damage and Renal Dysfunction in Patients Undergoing Coronary Artery Bypass Graft (CABG) Surgery

Study Type

Interventional

2. Study Status

Record Verification Date

February 2013

Overall Recruitment Status

Completed

Study Start Date

September 2007 (undefined)

Primary Completion Date

January 2011 (Actual)

Study Completion Date

April 2011 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

University Medical Center Groningen

4. Oversight

Data Monitoring Committee

5. Study Description

Brief Summary

This is a phase 2 study that evaluates the effect of intravenous administration of a bolus EPO on the activation of EPOR-signal transduction cascades and myocardial apoptosis during cardiopulmonary bypass surgery. Human atrial and ventricular tissue will be collected during CABG surgery for 3-vessel disease for the assay of EPOR signaling and apoptosis. Two atrial specimens will be collected before and at the end of cardiopulmonary bypass (CPB). Concomitantly, two transmural ventricular biopsies will be obtained, at the start and at the end of CPB. Immediately after obtaining the first atrial biopsy, one bolus of EPO will be administered intravenously. The atrial tissue will be split and appropriate sections will be frozen for determination of baseline expression or activity of a number of molecules including Erk1/2, STAT5, Akt and caspase-3 or embedded in paraffin for immunohistochemistry. Ventricular tissue will only be processed for immunohistochemistry. Additionally, plasma will be collected before the procedure and for up to 30 days post-procedure to examine release of markers of both myocardial ischemia and stress (CK-MB, Troponin T and NT-proBNP) and renal dysfunction (cystatin C, creatinine for eGFR). Before initializing the randomised study, a pilot study will be performed with 5 subjects that will not be treated to evaluate the feasibility of myocardial sample collection. Initiation of the randomised study will only commence if baseline activity of EPOR-STC can be determined in the atrial tissue and caspase-3 positive cells can be identified in the second ventricular biopsy.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

CABG, Coronary Artery Disease

Keywords

Apoptosis, CABG, Coronary Artery Disease, Three Vessel Disease, Erythropoietin, EPO-receptor signaling

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Parallel Assignment

Masking

None (Open Label)

Allocation

Randomized

Enrollment

10 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Arm Type

Experimental

Arm Description

25 patients undergoing CABG for three vessel disease, receiving a single dose of erythropoietin periprocedural.

Arm Title

Arm Type

Placebo Comparator

Arm Description

25 patients undergoing CABG for three vessel disease, receiving placebo (NaCl 0.9%) periprocedural.

Intervention Type

Drug

Intervention Name(s)

Epoetin alpha

Other Intervention Name(s)

Eprex

Intervention Description

A single dose of epoetin alpha during CABG for three vessel disease, 60.000 IU intravenously.

Intervention Type

Drug

Intervention Name(s)

NaCl 0.9%

Other Intervention Name(s)

Saline

Intervention Description

A single dose of NaCl 0.9% during CABG for three vessel disease, 1 ml intravenously.

Primary Outcome Measure Information:

Title

Time Frame

2 hours

Secondary Outcome Measure Information:

Title

Difference in apoptosis between atrial and ventricular specimens at the end of CPB, defined as the number of TUNEL and activated caspase-3 positive cells per high power field.

Time Frame

2 hours

Title

Difference between EPO- and saline treated subjects in TUNEL and active caspase-3 positive cells in ventricular and atrial biopsies.

Time Frame

2 hours

Title

Difference in AUC for CK-MB, Troponin T, NT-proBNP, and cystatin C between EPO- and saline treated patients.

Time Frame

30 days

Title

Subject incidence rates of adverse events.

Time Frame

30 days

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

80 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Before any study-specific procedure, including assessments for screening, the appropriate written informed consent must be obtained. Man or woman 18 to 80 years of age . Undergoing a planned, elective cardiopulmonary bypass operation for the first time for 3-vessel coronary artery disease with an anticipated aortic cross clamp time of approximately 40 minutes and a total bypass time of approximately 90 minutes. Hemoglobin (Hb) concentration ≥7.4 mmol/l and ≤9.9 mmol/l within 7 days prior to CABG surgery and no major acute blood loss since this Hb determination. Exclusion Criteria: An unstable medical condition, defined as having been hospitalized for a non-cardiac condition within 4 weeks of screening, major surgery within 24 weeks of screening, or otherwise unstable in the judgment of the investigator (e.g., at risk of complications or adverse events unrelated to study participation). Left ventricular ejection fraction (LVEF) < 40%. Clinical history of chronic kidney disease (CKD) (at any point prior to registration) defined as serum creatinine >105 μmol/l for all females, >130 μmol/l for black males, and >115 μmol/l for non-black males. Atrial fibrillation, paroxysmal atrial fibrillation or atrial flutter. Clinically significant abnormality in chemistry, hematology, or urinalysis parameters performed within the screening period. Current symptoms of polyurea, polydipsia, or increased thirst. Grand mal seizure within 1 year of enrollment. Poorly controlled hypertension, defined as systolic blood pressure (SBP) > 180 mmHg or diastolic blood pressure (DBP) > 105 mmHg on day of CABG surgery. Use of any erythropoietic protein (e.g., rHuEPO; Procrit®, Eprex®, Neorecormon®, Epogen®, Aranesp®) within 12 weeks of enrolment. Positive pregnancy test or known to be pregnant at the time of screening. Recent (within 3 months) history of alcohol or illicit drug abuse disorder, based on self-report. Severe uncorrected valvular disease (including pulmonary and tricuspid) or left ventricular outflow obstruction which, in the opinion of the investigator, requires surgery. Pulmonary hypertension, defined as a pulmonary artery pressure > 30 mmHg at rest. Participation in any investigational device or drug trial(s) or receiving other investigational agent(s) within 30 days. Known positive for HIV antibodies, hepatitis B surface antigen, or hepatitis C antibodies. Any condition (e.g., unsuitable anatomy of the atrium; psychiatric illness; etc.) or situation that, in the investigator's opinion, could put the subject at significant risk, confound the study results, or interfere significantly with the subject's participation in the study.

Overall Study Officials: