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

NCT02314780 | Completed Phase 2 Results DMC

• 2 other identifiers: HO-1 in the Heart2013-000887-27
• Study Type: interventional
• Target: 31
• Locations: 1 country
• Sites: 1

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.

Conditions

Myocardial Ischemia

Keywords

carboxyhemoglobin; neutrophil; reactive oxygen species; reperfusion injury

Outcome Measures

Primary Outcomes (6)

• 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)

  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

Study Arms (3)

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.

Drug: Heme arginate 3mg/kg

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.

Drug: Heme arginate 1mg/kg

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.

Drug: Placebo

Interventions

Heme arginate 3mg/kg DRUG

Also known as: Normosang

Heme arginate (high dose)

Heme arginate 1mg/kg DRUG

Also known as: Normosang

Heme arginate (low dose)

Placebo DRUG

Also known as: 0.9% sodium chloride solution

Placebo

Eligibility Criteria

• Age: 40 Years - 85 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Martin Andreas, M.D.: lead
• National Bank of Austria: collaborator
• Orphan Medical: collaborator

Study Sites (1)

Medical University of Vienna

Vienna, 1090, Austria

Location

Related Publications (1)

• 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.

  PMID: 30354231 DERIVED

MeSH Terms

Conditions

Myocardial Ischemia; Reperfusion Injury

Interventions

heme arginate; Sodium Chloride

Condition Hierarchy (Ancestors)

Heart Diseases; Cardiovascular Diseases; Vascular Diseases; Postoperative Complications; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Chlorides; Hydrochloric Acid; Chlorine Compounds; Inorganic Chemicals; Sodium Compounds

Limitations and Caveats

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.

Results Point of Contact

• Title: Dr. Martin Andreas
• Organization: Medical University of Vienna

martin.andreas@meduniwien.ac.at

+ 43 1 40400

Study Officials

• Alfred Kocher, M.D.

  Medical University of Vienna

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: M.D., PhD

Study Record Dates

• First Submitted: December 8, 2014
• First Posted: December 11, 2014
• Study Start: March 29, 2015
• Primary Completion: June 13, 2017
• Study Completion: June 13, 2017
• Last Updated: February 15, 2021
• Results First Posted: February 15, 2021

Record last verified: 2021-01

Locations

AU (1)