Does Heme Oxygenase-1 Induction Ameliorate Cardiac Injury After Myocardial Infarction?

NCT00483587 | Completed Phase 1

• 2 other identifiers: WTR-ECG-1EudraCT 2006-006389-40
• Study Type: interventional
• Target: 15
• Locations: 1 country
• Sites: 1

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 mg/kg), administered intravenously in 15 minutes directly after admission; 10 patients receive two administrations of heme arginate (3 mg/kg) on day 0 and 1; 10 patients receive three administrations of heme arginate (3 mg/kg) 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 parameters/endpoints: 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.

Conditions

Acute Myocardial Infarction

Keywords

NSTEMI; Acute coronary syndrome; Heme arginate; HO-1; Heme oxygenase-1

Outcome Measures

Primary Outcomes (2)

• Subject's incidence rates of adverse events between the three treated groups with heme arginate

  6 months

• Difference between the three intervention groups in liver enzymes levels (ASAT, ALAT, γ-GT, AP, LDH), blood clotting factor parameters ((INR, APTT, PT) and electrolytes (Na, K, Cl, Mg)) as safety monitoring of heme arginate administration.

  6 months

Secondary Outcomes (7)

• Difference 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 CO.

  6 months

• Difference between heme arginate treated groups on NTproBNP, CK-MB and Troponin T.

  6 months

• Difference between heme arginate treated groups in LVEF measured by echocardiography, 3 and 7 days and 6 months after NSTEMI.

  6 months

• The time course of HO-1 activation after NSTEMI, including, but not limited to, HO-1 activity, free heme, bilirubin (direct and indirect) levels, serum ferritin, and CO.

  6 months

• Basal levels of HO-1 activity, including, but not limited to, free heme, bilirubin (direct and indirect) levels, serum ferritin, and CO.

  6 months

Interventions

Heme arginate DRUG

1-3 x heme arginate infusion, in 30 minutes iv. Heme arginate is dissolved in 250 ml NACl.

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Before any study-specific procedures, the appropriate written informed consent must be obtained.
• Male and female between 18 to 80 years of age.
• Having NSTEMI confirmed by elevated CK (CK-total (\>200 U/l), CK-MB act, CK-mass (\>5.00 µg/l) and/or Troponin T (\>0.01µg/l) levels.
• Before any study-specific procedures, the appropriate written informed consent must be obtained.
• Male en female between 18 and 80 years of age.
• patients having NSTEMI confirmed by elevated CK (CK-total (\>200 U/l), CK-MB act, CK-mass (\>5.00 µg/l) and/or Troponin T (\>0.01µg/l)levels.
• patients with non-typical angina pectoris in whom no cardiac disease could be detected.

You may not qualify if:

• ST-elevation on the electrocardiogram.
• An unstable medical condition, defined as having been hospitalized for a noncardiac condition within 4 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).
• Younger than 18 and older than 80 years of age.
• Normal levels of CK en Troponin T.
• Clinical history of chronic kidney disease (at any point prior to registration).
• Any known hepatic disease.
• Recent (within 3 months) history of alcohol or illicit drug abuse disorder, based on self report.
• Clinically significant abnormality in chemistry, hematology, or urinalysis parameters performed within the screening period.
• Participation in any investigational device or drug trial(s) or receiving investigational agent(s) within 30 days.
• Any condition (e.g. 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.
• Legally incompetent adults, for which reason what so ever.
• Any known hypersensitivity/allergic reaction to one of the constituents of heme arginate (hemin, L-arginin, propylene glycol, ethanol).
• Any known hypersensitivity/allergic reaction to any known drugs or constituents of medication.
• ST-elevation on the electrocardiogram.
• An unstable medical condition, defined as having been hospitalized for a noncardiac condition within 4 weeks of screening, or otherwise unstable in the judgment of the investigator.

Sponsors & Collaborators

• University Medical Center Groningen: lead

Study Sites (1)

University Medical Centre Groningen

Groningen, Provincie Groningen, 9700 RB, Netherlands

Location

MeSH Terms

Conditions

Non-ST Elevated Myocardial Infarction; Acute Coronary Syndrome

Interventions

heme arginate

Condition Hierarchy (Ancestors)

Myocardial Infarction; Myocardial Ischemia; Heart Diseases; Cardiovascular Diseases; Vascular Diseases; Infarction; Ischemia; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Necrosis

Study Officials

• Prof. F. Zijlstra, MD, PhD

  University Medical Centre Groningen, Dept. of Cardiology

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER

Study Record Dates

• First Submitted: June 6, 2007
• First Posted: June 7, 2007
• Study Start: July 1, 2007
• Primary Completion: February 1, 2010
• Study Completion: February 1, 2010
• Last Updated: September 20, 2010

Record last verified: 2010-09

Locations

NL (1)