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

This study has been completed.
Sponsor:
Information provided by:
University Medical Centre Groningen
ClinicalTrials.gov Identifier:
NCT00483587
First received: June 6, 2007
Last updated: September 17, 2010
Last verified: September 2010
  Purpose

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.


Condition Intervention Phase
Acute Myocardial Infarction
Drug: Heme arginate
Phase 1
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Safety and Efficacy Study to Evaluate Intravenous Heme Arginate Infusion in Patients With an Acute Coronary Syndrome Without ST-elevation (NSTEMI)

Resource links provided by NLM:


Further study details as provided by University Medical Centre Groningen:

Primary Outcome Measures:
  • Subject's incidence rates of adverse events between the three treated groups with heme arginate [ Time Frame: 6 months ] [ Designated as safety issue: Yes ]
  • 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. [ Time Frame: 6 months ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • 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. [ Time Frame: 6 months ] [ Designated as safety issue: No ]
  • Difference between heme arginate treated groups on NTproBNP, CK-MB and Troponin T. [ Time Frame: 6 months ] [ Designated as safety issue: No ]
  • Difference between heme arginate treated groups in LVEF measured by echocardiography, 3 and 7 days and 6 months after NSTEMI. [ Time Frame: 6 months ] [ Designated as safety issue: Yes ]
  • 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. [ Time Frame: 6 months ] [ Designated as safety issue: No ]
  • Basal levels of HO-1 activity, including, but not limited to, free heme, bilirubin (direct and indirect) levels, serum ferritin, and CO. [ Time Frame: 6 months ] [ Designated as safety issue: No ]
  • DNA polymorphisms affecting HO-1 activity. [ Time Frame: 6 months ] [ Designated as safety issue: No ]
  • Which other cardioprotecting pathways are activated by administration of heme arginate (e.g. serum levels of erythropoietin, VEGF and number of circulating EPCs)? [ Time Frame: 6 months ] [ Designated as safety issue: No ]

Enrollment: 15
Study Start Date: July 2007
Study Completion Date: February 2010
Primary Completion Date: February 2010 (Final data collection date for primary outcome measure)
Intervention Details:
    Drug: Heme arginate
    1-3 x heme arginate infusion, in 30 minutes iv. Heme arginate is dissolved in 250 ml NACl.
  Show Detailed Description

  Eligibility

Ages Eligible for Study:   18 Years to 80 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Inclusion criteria for the interventional part of this study

    • 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.
  2. Inclusion criteria for the non-interventional part of this study

    • Before any study-specific procedures, the appropriate written informed consent must be obtained.
    • Male en female between 18 and 80 years of age.

      • 15 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.
      • 15 patients with non-typical angina pectoris in whom no cardiac disease could be detected.

Exclusion Criteria:

  1. Exclusion criteria for the interventional part of this study

    • 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.
  2. Exclusion criteria for the non-interventional part of this study

    • 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.
    • Younger than 18 and older than 80 years of age.
    • Clinical history of metabolic diseases, e.g. chronic kidney disease, hepatic disease or otherwise in the investigator's opinion.
    • 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.
    • Legally incompetent adults, for which reason what so ever.
    • For the 15 patients which act as controls for the NSTEMI patients: no history for cardiac disease.
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT00483587

Locations
Netherlands
University Medical Centre Groningen
Groningen, Netherlands, 9700 RB
Sponsors and Collaborators
University Medical Centre Groningen
Investigators
Principal Investigator: Prof. F. Zijlstra, MD, PhD University Medical Centre Groningen, Dept. of Cardiology
  More Information

Additional Information:
No publications provided

Responsible Party: W.T. Ruifrok, University Medical Centre Groningen
ClinicalTrials.gov Identifier: NCT00483587     History of Changes
Other Study ID Numbers: WTR-ECG-1, EudraCT 2006-006389-40
Study First Received: June 6, 2007
Last Updated: September 17, 2010
Health Authority: Netherlands: Medical Ethics Review Committee (METC)
Netherlands: The Central Committee on Research Involving Human Subjects (CCMO)

Keywords provided by University Medical Centre Groningen:
NSTEMI
Acute coronary syndrome
Heme arginate
HO-1
Heme oxygenase-1

Additional relevant MeSH terms:
Infarction
Myocardial Infarction
Acute Coronary Syndrome
Ischemia
Pathologic Processes
Necrosis
Myocardial Ischemia
Heart Diseases
Cardiovascular Diseases
Vascular Diseases
Angina Pectoris
Chest Pain
Pain
Signs and Symptoms

ClinicalTrials.gov processed this record on April 17, 2014