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The Effects of Intravenous Heme Arginate on Heme Oxygenase-1 Expression (HO-1) and Oxidative Stress in the Human Heart

Primary Purpose

Myocardial Ischemia

Status
Completed
Phase
Phase 2
Locations
Austria
Study Type
Interventional
Intervention
Heme arginate 3mg/kg
Heme arginate 1mg/kg
Placebo
Sponsored by
Martin Andreas, M.D.
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Myocardial Ischemia focused on measuring carboxyhemoglobin, neutrophil, reactive oxygen species, reperfusion injury

Eligibility Criteria

40 Years - 85 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion criteria:

  • Signed informed consent
  • Men and women aged between 40 and 85 years (inclusive)
  • Body mass index < 35 kg/m2
  • Ability to communicate well with the investigator in the local language and to understand and comply with the requirements of the study

Exclusion criteria (any of the following):

  • Known hypersensitivity to the study drug or any excipients of the drug formulation
  • Treatment with another investigational drug within 3 weeks prior to screening
  • History or clinical evidence of any disease and/or existence of any surgical or medical condition, which might interfere with the absorption, distribution, metabolism or excretion of the study drug
  • Severe renal failure (glomerula filtration rate < 30 ml/min)
  • Moderately or severe impaired left ventricular function (ejection fraction < 40%)
  • Moderately or severe impaired right ventricular function
  • Systolic pulmonary pressure > 45 mmHg
  • Acute or recent (<7 days) myocardial infarction
  • Child bearing potential

Sites / Locations

  • Medical University of Vienna

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Experimental

Placebo Comparator

Arm Label

Heme arginate (high dose)

Heme arginate (low dose)

Placebo

Arm Description

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.

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.

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.

Outcomes

Primary Outcome Measures

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.
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.
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.
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.
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.
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.

Secondary Outcome Measures

Full Information

First Posted
December 8, 2014
Last Updated
January 26, 2021
Sponsor
Martin Andreas, M.D.
Collaborators
National Bank of Austria, Orphan Medical
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1. Study Identification

Unique Protocol Identification Number
NCT02314780
Brief Title
The Effects of Intravenous Heme Arginate on Heme Oxygenase-1 Expression (HO-1) and Oxidative Stress in the Human Heart
Official Title
Pilot Trial: The Effects of Intravenous Heme Arginate on HO-1 Expression and Oxidative Stress in the Human Heart
Study Type
Interventional

2. Study Status

Record Verification Date
January 2021
Overall Recruitment Status
Completed
Study Start Date
March 29, 2015 (Actual)
Primary Completion Date
June 13, 2017 (Actual)
Study Completion Date
June 13, 2017 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor-Investigator
Name of the Sponsor
Martin Andreas, M.D.
Collaborators
National Bank of Austria, Orphan Medical

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Myocardial Ischemia
Keywords
carboxyhemoglobin, neutrophil, reactive oxygen species, reperfusion injury

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigator
Allocation
Randomized
Enrollment
31 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Heme arginate (high dose)
Arm Type
Experimental
Arm Description
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.
Arm Title
Heme arginate (low dose)
Arm Type
Experimental
Arm Description
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.
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Heme arginate 3mg/kg
Other Intervention Name(s)
Normosang
Intervention Type
Drug
Intervention Name(s)
Heme arginate 1mg/kg
Other Intervention Name(s)
Normosang
Intervention Type
Drug
Intervention Name(s)
Placebo
Other Intervention Name(s)
0.9% sodium chloride solution
Primary Outcome Measure Information:
Title
Heme Oxygenase-1 (HO-1) Messenger Ribonucleic Acid (mRNA) Levels (Atrial Tissue)
Description
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.
Time Frame
intraoperative
Title
Myocardial HO-1 mRNA Levels (Ventricular Tissue Before Aortic Cross-clamping)
Description
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.
Time Frame
intraoperative
Title
Myocardial HO-1 mRNA Levels (Ventricular Tissue After Aortic Cross-clamping)
Description
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.
Time Frame
intraoperative
Title
Myocardial HO-1 Protein Concentrations (Atrial Tissue)
Description
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.
Time Frame
intraoperative
Title
Myocardial HO-1 Protein Concentrations (Ventricular Tissue Before Aortic Cross-clamping)
Description
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.
Time Frame
intraoperative
Title
Myocardial HO-1 Protein Concentrations (Ventricular Tissue After Aortic Cross-clamping)
Description
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.
Time Frame
intraoperative

10. Eligibility

Sex
All
Minimum Age & Unit of Time
40 Years
Maximum Age & Unit of Time
85 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion criteria: Signed informed consent Men and women aged between 40 and 85 years (inclusive) Body mass index < 35 kg/m2 Ability to communicate well with the investigator in the local language and to understand and comply with the requirements of the study Exclusion criteria (any of the following): Known hypersensitivity to the study drug or any excipients of the drug formulation Treatment with another investigational drug within 3 weeks prior to screening History or clinical evidence of any disease and/or existence of any surgical or medical condition, which might interfere with the absorption, distribution, metabolism or excretion of the study drug Severe renal failure (glomerula filtration rate < 30 ml/min) Moderately or severe impaired left ventricular function (ejection fraction < 40%) Moderately or severe impaired right ventricular function Systolic pulmonary pressure > 45 mmHg Acute or recent (<7 days) myocardial infarction Child bearing potential
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Alfred Kocher, M.D.
Organizational Affiliation
Medical University of Vienna
Official's Role
Principal Investigator
Facility Information:
Facility Name
Medical University of Vienna
City
Vienna
ZIP/Postal Code
1090
Country
Austria

12. IPD Sharing Statement

Citations:
PubMed Identifier
30354231
Citation
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.
Results Reference
derived

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The Effects of Intravenous Heme Arginate on Heme Oxygenase-1 Expression (HO-1) and Oxidative Stress in the Human Heart

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