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Ticagrelor and Intracoronary Morphine in Patients Undergoing Primary Percutaneous Coronary Intervention

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ClinicalTrials.gov Identifier: NCT01738100
Recruitment Status : Unknown
Verified October 2014 by Hyeon-Cheol Gwon, Samsung Medical Center.
Recruitment status was:  Recruiting
First Posted : November 30, 2012
Last Update Posted : July 6, 2016
Sponsor:
Information provided by (Responsible Party):
Hyeon-Cheol Gwon, Samsung Medical Center

Tracking Information
First Submitted Date  ICMJE November 23, 2012
First Posted Date  ICMJE November 30, 2012
Last Update Posted Date July 6, 2016
Study Start Date  ICMJE September 2012
Estimated Primary Completion Date December 2016   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: July 4, 2016)
Myocardial infarct size measured by magnetic resonance imaging (MRI) at 3-5 days after the index procedure [ Time Frame: Post-PCI 3-5 days ]
Original Primary Outcome Measures  ICMJE
 (submitted: November 29, 2012)
Myocardial salvage index measured by magnetic resonance imaging (MRI) at 3-5 days after the index procedure [ Time Frame: Post-PCI 3-5 days ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: July 4, 2016)
  • Rate of complete ST-segment resolution on ECG obtained 30 minutes after the procedure [ Time Frame: 30 min after completion of PCI ]
  • Enzymatic Infarct size by creatine kinase-MB (area under curve) [ Time Frame: 1 month later ]
  • Myocardial salvage index measured by MRI [ Time Frame: Post-PCI 3-5 days ]
  • Major adverse cardiac events (a composite of death, myocardial infarction, severe heart failure, or stent thrombosis) [ Time Frame: 1Month later ]
  • The extent of microvascular obstruction measured by MRI [ Time Frame: post-PCI 3-5days ]
  • The number of segments with >75% of infarct transmurality measured by MRI [ Time Frame: post-PCI 3-5 days ]
  • The presence of myocardial hemorrhage measured by MRI [ Time Frame: post-PCI 3-5 days ]
Original Secondary Outcome Measures  ICMJE
 (submitted: November 29, 2012)
  • Rate of complete ST-segment resolution on ECG obtained 30 minutes after the procedure [ Time Frame: 30 min after completion of PCI ]
  • Enzymatic Infarct size by creatine kinase-MB (area under curve) [ Time Frame: 1 month later ]
  • Myocardial infarct size measured by MRI [ Time Frame: Post-PCI 3-5 days ]
  • Major adverse cardiac events (a composite of death, myocardial infarction, severe heart failure, or stent thrombosis) [ Time Frame: 1Month later ]
  • The extent of microvascular obstruction measured by MRI [ Time Frame: post-PCI 3-5days ]
  • The number of segments with >75% of infarct transmurality measured by MRI [ Time Frame: post-PCI 3-5 days ]
  • The presence of myocardial hemorrhage measured by MRI [ Time Frame: post-PCI 3-5 days ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Ticagrelor and Intracoronary Morphine in Patients Undergoing Primary Percutaneous Coronary Intervention
Official Title  ICMJE Effects of Ticagrelor and Intracoronary Morphine on Myocardial Salvage in Patients With ST-Segment Elevation Myocardial Infarction Undergoing Primary Percutaneous Coronary Intervention
Brief Summary A 2 by 2 factorial, multicenter, prospective, randomized, open-label, blinded endpoint trial. Patients undergoing primary PCI for STEMI will be eligible. Enrolled patients will be randomly assigned to the ticagrelor group or the clopidogrel group in a 1:1 ratio. After emergent coronary angiography, patients who have thrombolysis in myocardial infarction (TIMI) flow grade <2 in coronary angiogram will be randomized again, to either bolus intracoronary injection of morphine sulfate or saline in a 1:1 ratio. Randomization will be stratified by infarct location (anterior vs. non-anterior), and morphine use for pain control before study enroll (for only intracoronary morphine).
Detailed Description

1.1. Ticagrelor versus Clopidogrel

  1. In spite of timely and successful reperfusion with primary percutaneous coronary intervention (PCI), the mortality rate still remains high1 and substantial numbers of patients suffer from subsequent left ventricular dysfunction or heart failure after ST-segment elevation myocardial infarction (STEMI).
  2. One of limitations of primary PCI is distal embolization and effective antiplatelet therapy is needed in patients with STEMI.
  3. Clopidogrel is a representative P2Y12 receptor antagonist and has shown consistent efficacy in patients with acute coronary syndromes. However, clopidogrel is a prodrug and has to be converted to an active metabolite to inhibit P2Y12 receptor. Therefore, onset of effect is relatively slow, antiplatelet effect is moderate, and response to clopidogrel shows wide individual variability.
  4. Ticagrelor is a new, direct, reversible P2Y12 receptor antagonist, which has rapid and potent antiplatelet effect. In patients who have an acute coronary syndrome with or without ST-segment elevation, treatment with ticagrelor as compared with clopidogrel significantly reduced the rate of death from vascular causes, myocardial infarction, or stroke without an increase in the rate of overall major bleeding.
  5. However, there has been no data whether ticagrelor can reduce infarct size compared with clopidogrel in patients undergoing primary PCI.

1.2. Intracoronary morphine administration

  1. Lethal reperfusion injury accounts for up to 50% of the final size of a myocardial infarct.5,6 Therefore, adjunctive therapy that is effective in preventing lethal reperfusion injury is needed to potentiate the benefits of primary PCI.
  2. During the past few decades, a large number of animal studies demonstrated that commonly used opioids could provide cardioprotection against ischemia-reperfusion injury. Opioid-induced preconditioning or postconditioning mimics ischemic preconditioning or ischemic postconditioning.
  3. Recent small clinical trial demonstrated the cardioprotective effect of remote ischemic preconditioning and morphine during primary PCI. But this study was small and did not demonstrate the separate effect of morphine-induced cardioprotection.

2. Study Objective

  1. To investigate the effects of ticagrelor on myocardial infarct size in patients with STEMI undergoing primary PCI compared with clopidogrel
  2. To investigate the effects of morphine-induced cardioprotection during primary PCI in patients with STEMI
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Factorial Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE ST-Segment Elevation Myocardial Infarction
Intervention  ICMJE
  • Drug: Ticagrelor
    Other Name: Brilinta
  • Drug: Clopidogrel
    Other Name: Plavix
  • Drug: Morphine Sulfate
    Other Name: Morphine
  • Drug: Saline
    Other Name: Normal Saline
Study Arms  ICMJE
  • Experimental: Ticagrelor + Intracoronary Morphine
    180 mg loading pre-PCI followed by 90 mg bid for 5 days. Intracoronary Morphine Sulfate 3 mg + Saline 3 ml mix.
    Interventions:
    • Drug: Ticagrelor
    • Drug: Morphine Sulfate
  • Experimental: Ticagrelor + Intracoronary Saline
    180 mg loading pre-PCI followed by 90 mg bid for 5 days. Saline 3 ml intracoronary injection.
    Interventions:
    • Drug: Ticagrelor
    • Drug: Saline
  • Experimental: Clopidogrel + Intracoronary Morphine
    600 mg loading pre-PCI followed by 75 mg qd for 5 days. Morphine Sulfate 3 mg + Saline 3 ml mix intracoronary injection.
    Interventions:
    • Drug: Clopidogrel
    • Drug: Morphine Sulfate
  • Active Comparator: Clopidogrel + Intracoronary Saline
    600 mg loading pre-PCI followed by 75 mg qd for 5 days. Saline 3 ml intracoronary injection.
    Interventions:
    • Drug: Clopidogrel
    • Drug: Saline
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Unknown status
Estimated Enrollment  ICMJE
 (submitted: November 29, 2012)
100
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE December 2016
Estimated Primary Completion Date December 2016   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE
  1. Inclusion criteria

    • Subject must be at least 20 years of age.
    • Patients undergoing primary PCI for STEMI

      • Diagnosis of STEMI: ST-segment elevation >0.1 millivolt in ≥2 contiguous leads or (presumably) new left bundle branch block
      • Presence of symptoms less than 12 hours
    • Additional inclusion criteria for intracoronary morphine

      • TIMI flow grade 0 or 1 of infarct related arteries
  2. Exclusion Criteria:

    • Known hypersensitivity or contraindication to study medications or contrast
    • Female of childbearing potential, unless a recent pregnancy test is negative, who possibly plan to become pregnant any time after enrollment into this study.
    • Rescue PCI after thrombolysis or facilitated PCI
    • Cardiogenic shock or cardiopulmonary resuscitation before randomization
    • Known chronic hepatic disease
    • Known renal dysfunction (creatinine level 3.0mg/dL or dependence on dialysis).
    • Decompensated chronic obstructive pulmonary disease or active asthma at inclusion
    • Mechanical ventilation at inclusion
    • Brain injury or intracranial hypertension
    • Acute alcohol intoxication
    • Known ulcerative colitis
    • Active epilepsy
    • Contraindications to undergo MRI imaging include any of the following

      • A cardiac pacemaker or implantable defibrillator; any implanted or magnetically activated device; or any history indicating contraindication to MRI including claustrophobia or allergy to gadolinium
    • Current use of oral anticoagulant
    • An increased risk of bradycardia

      • Sinus node dysfunction, atrioventricular dysfunction, or heart rate <40/min
    • Patients receiving clopidogrel 300 mg or more before randomization
    • One of followings

      • history of intracranial bleeding
      • intracranial tumor, arteriovenous malformation or aneurysm
      • stroke within past 3 months
    • Active bleeding of internal organ or bleeding diathesis
    • Acute aortic dissection
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 20 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Korea, Republic of
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01738100
Other Study ID Numbers  ICMJE 2012-08-010
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Hyeon-Cheol Gwon, Samsung Medical Center
Study Sponsor  ICMJE Hyeon-Cheol Gwon
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Hyeon-Cheol Gwon, MD/PhD Samsung Medical Center
PRS Account Samsung Medical Center
Verification Date October 2014

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP