Ignite Creation Date:
2024-05-05 @ 5:33 PM
Last Modification Date:
2024-10-26 @ 9:33 AM
Study NCT ID:
NCT00483587
Status:
COMPLETED
Last Update Posted:
2010-09-20
First Post:
2007-06-06
Brief Title:
Does Heme Oxygenase-1 Induction Ameliorate Cardiac Injury After Myocardial Infarction
Sponsor:
University Medical Center Groningen
Organization:
University Medical Center Groningen
Study Overview
Official Title:
A Safety and Efficacy Study to Evaluate Intravenous Heme Arginate Infusion in Patients With an Acute Coronary Syndrome Without ST-elevation NSTEMI
Status:
COMPLETED
Status Verified Date:
2010-09
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
HAEM
Brief Summary:
Rationale A safety and dose defining study in which the investigators hypothesize that in patients with acute coronary syndrome without ST-elevation NSTEMI treatment with heme arginate results in better clinical outcome by inducing the heme oxygenase-1 HO-1 pathway
Objective 1 Is induction of HO-1 and its degradation products especially bilirubin safe in patients with an acute coronary syndrome without ST-elevation 2 What is the optimal effective dose to administer in patients with NSTEMI 3 Are HO-1 and its degradation products endogenously activated in patients with acute coronary syndrome 4 Does treatment with heme arginate result in a less cardiac damage 5 Which other cardioprotecting pathways are activated by administration of heme arginate
Study population Male and female patients with confirmed acute coronary syndrome without ST-elevation between 18 - 80 yr old
Intervention 10 patients receive a single administration of heme arginate 3 mgkg administered intravenously in 15 minutes directly after admission 10 patients receive two administrations of heme arginate 3 mgkg on day 0 and 1 10 patients receive three administrations of heme arginate 3 mgkg on day 0 1 and 2 after admission administered intravenously in 15 minutes To determine endogenous levels of HO-1 and time course of HO-1 activation after NSTEMI blood is drawn and the same assays are performed in 15 patients with NSTEMI As controls for the blood tests blood is drawn and the same assays are performed in 15 patients with non-typical angina pectoris in whom no cardiac disease could be detected from the investigators out-patient clinic
Main study parametersendpoints The primary endpoint is the incidence rate of adverse events between the three treated groups This includes hemodynamic monitoring rhythm monitoring and biochemical and hematological difference between the three treated groups Secondary endpoints are the differences from baseline between heme arginate treated groups in activity of the HO-1 pathway including but not limited to HO-1 activity free heme bilirubin direct and indirect levels serum ferritin and carbon monoxide CO Furthermore differences between heme arginate treated groups on NTproBNP CK-MB and Troponin T and difference between heme arginate treated subjects in LVEF measured by echocardiography 3 and 7 days and 6 months after NSTEMI
Objective 1 Is induction of HO-1 and its degradation products especially bilirubin safe in patients with an acute coronary syndrome without ST-elevation 2 What is the optimal effective dose to administer in patients with NSTEMI 3 Are HO-1 and its degradation products endogenously activated in patients with acute coronary syndrome 4 Does treatment with heme arginate result in a less cardiac damage 5 Which other cardioprotecting pathways are activated by administration of heme arginate
Study population Male and female patients with confirmed acute coronary syndrome without ST-elevation between 18 - 80 yr old
Intervention 10 patients receive a single administration of heme arginate 3 mgkg administered intravenously in 15 minutes directly after admission 10 patients receive two administrations of heme arginate 3 mgkg on day 0 and 1 10 patients receive three administrations of heme arginate 3 mgkg on day 0 1 and 2 after admission administered intravenously in 15 minutes To determine endogenous levels of HO-1 and time course of HO-1 activation after NSTEMI blood is drawn and the same assays are performed in 15 patients with NSTEMI As controls for the blood tests blood is drawn and the same assays are performed in 15 patients with non-typical angina pectoris in whom no cardiac disease could be detected from the investigators out-patient clinic
Main study parametersendpoints The primary endpoint is the incidence rate of adverse events between the three treated groups This includes hemodynamic monitoring rhythm monitoring and biochemical and hematological difference between the three treated groups Secondary endpoints are the differences from baseline between heme arginate treated groups in activity of the HO-1 pathway including but not limited to HO-1 activity free heme bilirubin direct and indirect levels serum ferritin and carbon monoxide CO Furthermore differences between heme arginate treated groups on NTproBNP CK-MB and Troponin T and difference between heme arginate treated subjects in LVEF measured by echocardiography 3 and 7 days and 6 months after NSTEMI
Detailed Description:
The interventional part of this study is a single centre safety and dose defining pilot study in which patients are allocated to heme arginate infusion for 1 day hem-1d heme arginate infusion for 2 days or heme arginate infusion during 3 days hem-3d in consecutive order So the three patient groups consist of three intervention groups
Based upon the pharmacokinetic data in porphyria patients 3 mgkgday for 4-7 days the investigators rationalize that 3 fixed doses of heme arginate will be the optimal dose to counter attack the acute phase after NSTEMI Longer infusion of heme arginate seems at this moment not rational
The investigators will first administer in 10 patients 1 dose of heme arginate hem-1d day 0 to assess safety If safety is assured in the hem-1d group 10 patients will receive two days of heme arginate infusion day 0 and 1 After this group is completed and safety is assured the third group n 10 will receive heme arginate infusion in three consecutive days after NSTEMI day 0 1 and 2 after admission
Heme arginate is considered safe in NSTEMI patients if no adverse events occur in the consecutive groups To assess safety during the course of the study the following possible events are monitored
New onset of myocardial infarction with ST-elevation STEMI
Cardiac decompensation
Sustained ventricular arrhythmia requiring defibrillation
All cause death
Drop of mean arterial blood pressure MAP of more than 20 mmHg MAP is defined as 2 x diastolic blood pressure 1 x systolic blood pressure divided by 3 MAP 2 x Pdias Psys 3
Eosinophilia 05 x 109l in combination with fever andor rash andor shivering or anaphylactic shock
Renal insufficiency serum creatinine above 300 µmoll
ASAT or ALAT are elevated to at least 3 times the upper limit of normal
Severe hematological abnormalities defined as thrombocytopenia 40 x 109l leucocytopenia 20 x 109l or hemolytic anemia
Activated partial thromboplastin time aPTT elevated to at least 3 times the upper limit of normal
Severe bleeding defined as requiring blood transfusion
In the event one of the above mentioned effects occur the investigators will report this to the METC and deliberate before continuing the study If after deliberation with the METC heme arginate turns out not to be safe in NSTEMI patients the inclusion of patients will be terminated immediately and all patients who already received heme arginate will be followed thoroughly The investigator will take care that all subjects are kept informed
After completion of each group the METC will be informed about the progress of the study
Regardless of allocation all patients will receive care as usual according to nationalinternational guidelines 79 80
Patients with NSTEMI admitted to the University Medical Center Groningen UMCG are asked to participate in the study and will sign informed consent After signing consent blood is drawn via venipuncture for baseline data
On day 0 1 2 3 7 and 180 after NSTEMI blood is drawn for additional measurements Echocardiography is performed to determine left ventricular function including left ventricular ejection fraction LVEF after 3 days 7 days and 180 days To assess the possible anti-hypertensive component of heme arginate treatment 24 hour ambulatory blood pressure recordings will be conducted at day 7 and 6 months after NSTEMI
The following components of the heme pathway will be determined free heme hemoglobin ferritin carbon monoxide heme oxygenase HO-1 biliverdin and direct and non direct bilirubin To monitor safety the investigators will evaluate liver enzymes ALAT ASAT γ-GT AP LDH clotting times INR APTT PT electrolytes Na K Cl Mg and furthermore regular hematology Hb Ht thrombocytes and chemistry Blood Urea Nitrogen Creatinine CK CK-MB Troponin T Brain Natriuretic Peptide VEGF and Erythropoietin
All participants will also be asked for blood to assess DNA polymorphisms affecting HO-1 activity such as HO-1 polymorphisms and for assessment of quality of endothelial progenitor cells EPCs
Total number included patients into the interventional part of this study will be 30 patients Follow-up is completed 6 months after inclusion of the last patient The investigators estimate inclusion will take approximately 6 months The study duration therefore comes to a total of at least 12 months The maximal duration of the study will be 18 months including analysis of the results
In addition two groups of patients will be asked in the non-interventional part of this study
1 The investigators hypothesize that due to the acute coronary syndrome HO-1 is activated but at too low levels to have clinical benefit To determine the time course for HO-1 activity and its degradation products after NSTEMI the investigators will draw blood and perform all the same assays in 15 patients with NSTEMI as described above It is not possible to use the same assays executed in the interventional part of this study for heme arginate infusion will interfere with the outcomes
2 As healthy controls for the blood tests and to gain insight in normal levels of HO-1 activity the investigators will draw blood and do the same baseline assays in 15 patients with non-typical angina pectoris in whom no cardiac disease could be detected from our out-patient clinic
All these patients will be asked to participate in the non-intervention part of this study receive a separate information letter and will sign an informed consent form If consent is given blood is drawn via venipuncture
Based upon the pharmacokinetic data in porphyria patients 3 mgkgday for 4-7 days the investigators rationalize that 3 fixed doses of heme arginate will be the optimal dose to counter attack the acute phase after NSTEMI Longer infusion of heme arginate seems at this moment not rational
The investigators will first administer in 10 patients 1 dose of heme arginate hem-1d day 0 to assess safety If safety is assured in the hem-1d group 10 patients will receive two days of heme arginate infusion day 0 and 1 After this group is completed and safety is assured the third group n 10 will receive heme arginate infusion in three consecutive days after NSTEMI day 0 1 and 2 after admission
Heme arginate is considered safe in NSTEMI patients if no adverse events occur in the consecutive groups To assess safety during the course of the study the following possible events are monitored
New onset of myocardial infarction with ST-elevation STEMI
Cardiac decompensation
Sustained ventricular arrhythmia requiring defibrillation
All cause death
Drop of mean arterial blood pressure MAP of more than 20 mmHg MAP is defined as 2 x diastolic blood pressure 1 x systolic blood pressure divided by 3 MAP 2 x Pdias Psys 3
Eosinophilia 05 x 109l in combination with fever andor rash andor shivering or anaphylactic shock
Renal insufficiency serum creatinine above 300 µmoll
ASAT or ALAT are elevated to at least 3 times the upper limit of normal
Severe hematological abnormalities defined as thrombocytopenia 40 x 109l leucocytopenia 20 x 109l or hemolytic anemia
Activated partial thromboplastin time aPTT elevated to at least 3 times the upper limit of normal
Severe bleeding defined as requiring blood transfusion
In the event one of the above mentioned effects occur the investigators will report this to the METC and deliberate before continuing the study If after deliberation with the METC heme arginate turns out not to be safe in NSTEMI patients the inclusion of patients will be terminated immediately and all patients who already received heme arginate will be followed thoroughly The investigator will take care that all subjects are kept informed
After completion of each group the METC will be informed about the progress of the study
Regardless of allocation all patients will receive care as usual according to nationalinternational guidelines 79 80
Patients with NSTEMI admitted to the University Medical Center Groningen UMCG are asked to participate in the study and will sign informed consent After signing consent blood is drawn via venipuncture for baseline data
On day 0 1 2 3 7 and 180 after NSTEMI blood is drawn for additional measurements Echocardiography is performed to determine left ventricular function including left ventricular ejection fraction LVEF after 3 days 7 days and 180 days To assess the possible anti-hypertensive component of heme arginate treatment 24 hour ambulatory blood pressure recordings will be conducted at day 7 and 6 months after NSTEMI
The following components of the heme pathway will be determined free heme hemoglobin ferritin carbon monoxide heme oxygenase HO-1 biliverdin and direct and non direct bilirubin To monitor safety the investigators will evaluate liver enzymes ALAT ASAT γ-GT AP LDH clotting times INR APTT PT electrolytes Na K Cl Mg and furthermore regular hematology Hb Ht thrombocytes and chemistry Blood Urea Nitrogen Creatinine CK CK-MB Troponin T Brain Natriuretic Peptide VEGF and Erythropoietin
All participants will also be asked for blood to assess DNA polymorphisms affecting HO-1 activity such as HO-1 polymorphisms and for assessment of quality of endothelial progenitor cells EPCs
Total number included patients into the interventional part of this study will be 30 patients Follow-up is completed 6 months after inclusion of the last patient The investigators estimate inclusion will take approximately 6 months The study duration therefore comes to a total of at least 12 months The maximal duration of the study will be 18 months including analysis of the results
In addition two groups of patients will be asked in the non-interventional part of this study
1 The investigators hypothesize that due to the acute coronary syndrome HO-1 is activated but at too low levels to have clinical benefit To determine the time course for HO-1 activity and its degradation products after NSTEMI the investigators will draw blood and perform all the same assays in 15 patients with NSTEMI as described above It is not possible to use the same assays executed in the interventional part of this study for heme arginate infusion will interfere with the outcomes
2 As healthy controls for the blood tests and to gain insight in normal levels of HO-1 activity the investigators will draw blood and do the same baseline assays in 15 patients with non-typical angina pectoris in whom no cardiac disease could be detected from our out-patient clinic
All these patients will be asked to participate in the non-intervention part of this study receive a separate information letter and will sign an informed consent form If consent is given blood is drawn via venipuncture
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None
Secondary IDs
| Secondary ID | Type | Domain | Link |
|---|---|---|---|
| EudraCT 2006-006389-40 | None | None | None |