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| ID | Type | Description | Link |
|---|---|---|---|
| 2013-000887-27 | EudraCT Number |
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| Name | Class |
|---|---|
| National Bank of Austria | OTHER_GOV |
| Orphan Medical | INDUSTRY |
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Ischemia reperfusion injury may be attenuated by HO-1 induction. Our previous data confirmed strong HO-1 induction in peripheral blood cells following heme arginate infusion in healthy humans. Furthermore, we could demonstrate the amelioration of experimental ischemia reperfusion injury in the calf musculature by heme arginate in healthy subjects as measured by functional MRI.
Therefore, we propose that HO-1 induction in the human heart may be a suitable target to mitigate cardiac ischemia-reperfusion injury.
The HO-1 induction will be assessed in a clinical trial by myocardial biopsy prior to and after aortic cross-clamping in subjects with or without preceding heme arginate treatment in two different dosages. The HO-1 expression will also be measured in the clinical trials in peripheral blood mononuclear cells. As additional outcome, levels of myoglobin, creatine-kinase and troponin T and reactive oxygen species will be measured in plasma according to standard laboratory procedures.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Heme arginate (high dose) | Experimental | 24 hours prior to the planned surgical aortic valve replacement, heme arginate at a dose of 3 mg/kg diluted to 110ml with 0.9% sodium chloride was administered at a single intravenous infusion using an infusion pump. |
|
| Heme arginate (low dose) | Experimental | 24 hours prior to the planned surgical aortic valve replacement, heme arginate at a dose of 1 mg/kg diluted to 110ml with 0.9% sodium chloride was administered at a single intravenous infusion using an infusion pump. |
|
| Placebo | Placebo Comparator | 24 hours prior to the planned surgical aortic valve replacement, subjects received a single intravenous infusion of an equivalent volume of 0.9% sodium chloride solution. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Heme arginate 3mg/kg | Drug |
|
| |
| Heme arginate 1mg/kg |
| Measure | Description | Time Frame |
|---|---|---|
| Heme Oxygenase-1 (HO-1) Messenger Ribonucleic Acid (mRNA) Levels (Atrial Tissue) | The right atrial appendage was clamped and cut for cannulation before cardiopulmonary bypass. The tissue samples were snap-frozen in the operating theater after sampling. | intraoperative |
| Myocardial HO-1 mRNA Levels (Ventricular Tissue Before Aortic Cross-clamping) | A small biopsy was taken from the right ventricular free wall directly before aortic cross-clamping. The tissue samples were snap-frozen in the operating theater after sampling. | intraoperative |
| Myocardial HO-1 mRNA Levels (Ventricular Tissue After Aortic Cross-clamping) | A small biopsy was taken from the right ventricular free wall after aortic clamp release before weaning from cardiopulmonary bypass. The tissue samples were snap-frozen in the operating theater after sampling. | intraoperative |
| Myocardial HO-1 Protein Concentrations (Atrial Tissue) | The right atrial appendage was clamped and cut for cannulation before cardiopulmonary bypass.The tissue samples were snap-frozen. Western blot analysis was performed. The amount of HO-1 protein (quantified as pixels under the curve) was evaluated. | intraoperative |
| Myocardial HO-1 Protein Concentrations (Ventricular Tissue Before Aortic Cross-clamping) | A small biopsy was taken from the right ventricular free wall directly before aortic cross-clamping. The tissue samples were snap-frozen. Western blot analysis was performed. The amount of HO-1 protein (quantified as pixels under the curve) was evaluated. | intraoperative |
| Myocardial HO-1 Protein Concentrations (Ventricular Tissue After Aortic Cross-clamping) |
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Inclusion criteria:
Exclusion criteria (any of the following):
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| Name | Affiliation | Role |
|---|---|---|
| Alfred Kocher, M.D. | Medical University of Vienna | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Medical University of Vienna | Vienna | 1090 | Austria |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 30354231 | Derived | Andreas M, Oeser C, Kainz FM, Shabanian S, Aref T, Bilban M, Messner B, Heidtmann J, Laufer G, Kocher A, Wolzt M. Intravenous Heme Arginate Induces HO-1 (Heme Oxygenase-1) in the Human Heart. Arterioscler Thromb Vasc Biol. 2018 Nov;38(11):2755-2762. doi: 10.1161/ATVBAHA.118.311832. |
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A total of 31 patients signed the informed consent to participate in the study. Of them, 27 patients were assigned to a group and 4 patients (3 patients for organizational reasons and 1 patient for other reasons) were excluded from the study prior to assignment to a group.
Patients who were scheduled for elective surgical aortic valve replacement were assessed for eligibility after hospitalization at the Medical University of Vienna.
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| ID | Title | Description |
|---|---|---|
| FG000 | Heme Arginate (High Dose) | 24 hours prior to the planned surgical aortic valve replacement, heme arginate at a dose of 3 mg/kg diluted to 110ml with 0.9% sodium chloride was administered at a single intravenous infusion using an infusion pump. |
| FG001 | Heme Arginate (Low Dose) | 24 hours prior to the planned surgical aortic valve replacement, heme arginate at a dose of 1 mg/kg diluted to 110ml with 0.9% sodium chloride was administered at a single intravenous infusion using an infusion pump. |
| FG002 | Placebo | 24 hours prior to the planned surgical aortic valve replacement, subjects received a single intravenous infusion of an equivalent volume of 0.9% sodium chloride solution. |
| Title | Milestones | Reasons Not Completed | |||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Heme Arginate (High Dose) | 24 hours prior to the planned surgical aortic valve replacement, heme arginate at a dose of 3 mg/kg diluted to 110ml with 0.9% sodium chloride was administered at a single intravenous infusion using an infusion pump. |
| BG001 | Heme Arginate (Low Dose) |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Heme Oxygenase-1 (HO-1) Messenger Ribonucleic Acid (mRNA) Levels (Atrial Tissue) | The right atrial appendage was clamped and cut for cannulation before cardiopulmonary bypass. The tissue samples were snap-frozen in the operating theater after sampling. | Posted | Mean | Standard Deviation | arbitrary units | intraoperative |
|
Adverse events occuring within 96 hours after the administration of heme arginate/sodium chloride solution were reported.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Heme Arginate (High Dose) | 24 hours prior to the planned surgical aortic valve replacement, heme arginate at a dose of 3 mg/kg diluted to 110ml with 0.9% sodium chloride was administered at a single intravenous infusion using an infusion pump. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Post procedural haemorrhage | Injury, poisoning and procedural complications | MedDRA (22.0) | Systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Procedural pneumothorax | Injury, poisoning and procedural complications | MedDRA (22.0) | Systematic Assessment |
Biopsy samples were small and protein concentration could not be measured in every sample. The sample size calculation was based on previous results but is small for a 3-arm randomized controlled trial. Additional surgical procedures might impact the postoperative course of cardiac enzymes and obscure a potential effect in this small group. This study was powered to identify protein expression in the heart but not to evaluate potential therapeutic effects.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. Martin Andreas | Medical University of Vienna | + 43 1 40400 | 69660 | martin.andreas@meduniwien.ac.at |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | May 8, 2013 | Dec 22, 2020 | Prot_SAP_000.pdf |
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| ID | Term |
|---|---|
| D017202 | Myocardial Ischemia |
| D015427 | Reperfusion Injury |
| ID | Term |
|---|---|
| D006331 | Heart Diseases |
| D002318 | Cardiovascular Diseases |
| D014652 | Vascular Diseases |
| D011183 | Postoperative Complications |
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| ID | Term |
|---|---|
| C048849 | heme arginate |
| D012965 | Sodium Chloride |
| ID | Term |
|---|---|
| D002712 | Chlorides |
| D006851 | Hydrochloric Acid |
| D017606 | Chlorine Compounds |
| D007287 | Inorganic Chemicals |
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| Drug |
|
|
| Placebo | Drug |
|
|
A small biopsy was taken from the right ventricular free wall after aortic clamp release before weaning from cardiopulmonary bypass. The tissue samples were snap-frozen in the operating theater after sampling. Western blot analysis was performed. The amount of HO-1 protein (quantified as pixels under the curve) was evaluated. |
| intraoperative |
24 hours prior to the planned surgical aortic valve replacement, heme arginate at a dose of 1 mg/kg diluted to 110ml with 0.9% sodium chloride was administered at a single intravenous infusion using an infusion pump. |
| BG002 | Placebo | 24 hours prior to the planned surgical aortic valve replacement, subjects received a single intravenous infusion of an equivalent volume of 0.9% sodium chloride solution. |
| BG003 | Total | Total of all reporting groups |
| Participants |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race and Ethnicity Not Collected | Race and Ethnicity were not collected from any participant. | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| OG002 | Placebo | 24 hours prior to the planned surgical aortic valve replacement, subjects received a single intravenous infusion of an equivalent volume of 0.9% sodium chloride solution. |
|
|
|
| Primary | Myocardial HO-1 mRNA Levels (Ventricular Tissue Before Aortic Cross-clamping) | A small biopsy was taken from the right ventricular free wall directly before aortic cross-clamping. The tissue samples were snap-frozen in the operating theater after sampling. | Posted | Mean | Standard Deviation | arbitrary units | intraoperative |
|
|
|
|
| Primary | Myocardial HO-1 mRNA Levels (Ventricular Tissue After Aortic Cross-clamping) | A small biopsy was taken from the right ventricular free wall after aortic clamp release before weaning from cardiopulmonary bypass. The tissue samples were snap-frozen in the operating theater after sampling. | Posted | Mean | Standard Deviation | arbitrary units | intraoperative |
|
|
|
|
| Primary | Myocardial HO-1 Protein Concentrations (Atrial Tissue) | The right atrial appendage was clamped and cut for cannulation before cardiopulmonary bypass.The tissue samples were snap-frozen. Western blot analysis was performed. The amount of HO-1 protein (quantified as pixels under the curve) was evaluated. | Posted | Mean | Standard Deviation | pixels under the curve | intraoperative |
|
|
|
|
| Primary | Myocardial HO-1 Protein Concentrations (Ventricular Tissue Before Aortic Cross-clamping) | A small biopsy was taken from the right ventricular free wall directly before aortic cross-clamping. The tissue samples were snap-frozen. Western blot analysis was performed. The amount of HO-1 protein (quantified as pixels under the curve) was evaluated. | Posted | Mean | Standard Deviation | pixels under the curve | intraoperative |
|
|
|
|
| Primary | Myocardial HO-1 Protein Concentrations (Ventricular Tissue After Aortic Cross-clamping) | A small biopsy was taken from the right ventricular free wall after aortic clamp release before weaning from cardiopulmonary bypass. The tissue samples were snap-frozen in the operating theater after sampling. Western blot analysis was performed. The amount of HO-1 protein (quantified as pixels under the curve) was evaluated. | Posted | Mean | Standard Deviation | pixels under the curve | intraoperative |
|
|
|
|
| 0 |
| 9 |
| 2 |
| 9 |
| 1 |
| 9 |
| EG001 | Heme Arginate (Low Dose) | 24 hours prior to the planned surgical aortic valve replacement, heme arginate at a dose of 1 mg/kg diluted to 110ml with 0.9% sodium chloride was administered at a single intravenous infusion using an infusion pump. | 0 | 10 | 0 | 10 | 5 | 10 |
| EG002 | Placebo | 24 hours prior to the planned surgical aortic valve replacement, subjects received a single intravenous infusion of an equivalent volume of 0.9% sodium chloride solution. | 0 | 8 | 1 | 8 | 4 | 8 |
| Coronary artery compression | Injury, poisoning and procedural complications | MedDRA (22.0) | Systematic Assessment |
|
| Atrioventricular block complete | Cardiac disorders | MedDRA (22.0) | Systematic Assessment |
|
| Blood culture positive | Investigations | MedDRA (22.0) | Systematic Assessment |
|
| Atrial fibrillation | Cardiac disorders | MedDRA (22.0) | Systematic Assessment |
|
| Heparin-induced thrombocytopenia | Blood and lymphatic system disorders | MedDRA (22.0) | Systematic Assessment |
|
| Acute stress disorder | Psychiatric disorders | MedDRA (22.0) | Systematic Assessment |
|
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| D010335 |
| Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D017670 |
| Sodium Compounds |
| Between 18 and 65 years |
|
| >=65 years |
|
| Male |
|