<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03273075</url>
  </required_header>
  <id_info>
    <org_study_id>Cang 2016-003265-26</org_study_id>
    <nct_id>NCT03273075</nct_id>
  </id_info>
  <brief_title>Add-on Cangrelor in STEMI-triggered Cardiac Arrest</brief_title>
  <official_title>Pharmacokinetic/Pharmacodynamic Effects of add-on Antiplatelet Therapy With Parenteral Cangrelor as Compared to Standard Dual Antiplatelet Treatment in Patients With ST-elevation Myocardial Infarction Complicated by Out-of-hospital Cardiac Arrest and Treated With Targeted Temperature Management</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Medical University of Vienna</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Medical University of Vienna</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      In patients with ST-elevation myocardial infarction (STEMI) undergoing percutaneous coronary&#xD;
      angioplasty (PCI) P2Y12 receptor (P2Y12r) inhibition should be achieved as soon as possible.&#xD;
      Resuscitated STEMI-patients receiving targeted temperature management (TTM, therapeutic&#xD;
      hypothermia) after cardiac arrest, however, show deteriorated and delayed early response to&#xD;
      available oral P2Y12r inhibitors. Therapeutic hypothermia attenuates the drugs' effectiveness&#xD;
      by reducing its gastrointestinal absorption and metabolic activation. Acute stent thrombosis&#xD;
      is 5-fold increased after angioplasty following resuscitated cardiac arrest because of&#xD;
      insufficient early platelet suppression. Thus, aggressive antiplatelet strategies are needed&#xD;
      to achieve optimal platelet suppression during PCI in those patients. The first intravenous&#xD;
      P2Y12r inhibitor, cangrelor, has recently received marketing authorization for the acute&#xD;
      treatment of STEMI. We hypothesize that add-on antiplatelet therapy with intravenous&#xD;
      Cangrelor on-top of standard dual anti platelet therapy (DAPT) with Prasugrel or Ticagrelor&#xD;
      is superior to standard antiplatelet therapy alone in terms of suppressing ADP-dependent&#xD;
      platelet activation in resuscitated STEMI-patients receiving TTM.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Neurologic damage after cardiac arrest is frequent and therapeutic options to improve&#xD;
      neurological outcome are limited. Treatment by therapeutic hypothermia (TH, 32-34◦C) for&#xD;
      12-24 h showed improved neurological outcome in several trials. Therefore, international&#xD;
      guidelines recommend targeted temperature management (TTM) to 32-34◦C (or at least 36°C) for&#xD;
      12-24 h, especially when the initial rhythm was ventricular fibrillation.&#xD;
&#xD;
      However, patients treated with TTM after cardiac arrest show deteriorated and delayed&#xD;
      response to P2Y12 receptor (P2Y12r) inhibitors as determined by platelet reactivity index&#xD;
      vasodilator-stimulated phosphoprotein phosphorylation (PRI VASP) after administration of the&#xD;
      loading dose of clopidogrel, prasugrel and ticagrelor. Especially the response to clopidogrel&#xD;
      is poor with up to &gt;80% non-responder after 24 hours. Impaired P2Y12r blockade may lead to&#xD;
      acute stent-thrombosis and trigger overall adverse outcome.&#xD;
&#xD;
      There are several explanations for the impaired efficacy of P2Y12r inhibitors in cardiac&#xD;
      arrest patients. First, marketed oral P2Y12r inhibitors have to be applied in crushed form&#xD;
      via nasogastric tube in comatose post cardiac arrest patients. Placement of nasogastric tube&#xD;
      and crushing may delay onset of therapy. Second, drug uptake and bioavailability of oral&#xD;
      P2Y12r inhibitors are dependent on gastric motility and sufficient splanchnic blood supply,&#xD;
      which is affected by TTM, acute critical illness (shock) and concomitant therapy.&#xD;
      Particularly, sedation and analgesic agents, especially concomitant morphine therapy, can&#xD;
      hamper gastric emptying. Various recent trials demonstrated that morphine administration&#xD;
      delays and attenuates clopidogrel, prasugrel and ticagrelor exposure and action in healthy&#xD;
      subjects and patients with myocardial infarction.&#xD;
&#xD;
      The recently authorized parenteral cangrelor is an adenosine triphosphate (ATP) analogue that&#xD;
      binds reversibly and with high affinity to the platelet P2Y12r. It induces a highly effective&#xD;
      inhibition of ADP-induced platelet aggregation immediately after intravenous (iv) bolus&#xD;
      administration and allows for restoration of platelet function within 1-2 h of infusion&#xD;
      discontinuation. The pharmacokinetic properties known so far suggest cangrelor being the&#xD;
      &quot;ideal&quot; P2Y12r inhibitor for patients with cardiac-ischemia triggered OHCA treated with TH&#xD;
      and may overcome the impaired and delayed P2Y12r blockade seen with the oral P2Y12r&#xD;
      inhibitors.&#xD;
&#xD;
      Cardiac arrest is a leading cause of death among adults over the age of 40 in the European&#xD;
      Union (EU) and other western countries. In the EU alone, more than 400.000 people of all ages&#xD;
      experience EMS-assessed out-of-hospital non-traumatic cardiac arrest each year and most of&#xD;
      them die. In a large proportion of these patients (about 50%) an acute coronary syndrome&#xD;
      (ACS), mainly acute ST-elevation myocardial infarction, leading to ventricular fibrillation&#xD;
      and cardiac standstill is the cause of the cardiac arrest. Various trials demonstrated that&#xD;
      early cardiac intervention including stent placement to the culprit lesion improves outcome&#xD;
      in this patient group. The P2Y12r plays a central role in platelet activation and P2Y12r&#xD;
      inhibitors are part of standard care in patients with ACS. Delayed and insufficient P2Y12r&#xD;
      inhibition may predispose to acute stent thrombosis with potential devastating effects&#xD;
      including cardiogenic shock, re-arrest and death. Given the deteriorated and delayed response&#xD;
      to oral P2Y12r inhibitors in cardiac arrest patients treated with TH, clinical evaluation of&#xD;
      the recently marketed parenteral P2Y12r inhibitor cangrelor is mandatory in this patient&#xD;
      group.&#xD;
&#xD;
      To determine the effect of add-on cangrelor in STEMI-associated out-of-hospital cardiac&#xD;
      arrest (OHCA) who receive TTM and are scheduled for PCI, a phase 4 trial will be&#xD;
      conducted.The trial consists of 2 parts. Part A (n=12, 8months duration): An open-fashioned&#xD;
      pilot safety-study to ensure sufficient platelet suppression (&lt;466AU*min, impedance&#xD;
      aggregometry) over 24 hours after concurrent cangrelor-prasugrel/ticagrelor administration.&#xD;
      The aim is to determine pharmacokinetics and -dynamics of oral P2Y12r-inhibitors with and&#xD;
      without concomitant administration of cangrelor. Part B (n=48, 32months duration): A&#xD;
      factorial randomized, placebo-controlled, double-blind study with 4 study cohorts enrolling&#xD;
      48 patients who will first be randomised to receive prasugrel (n=24) or ticagrelor (n=24) and&#xD;
      secondly to additionally receive cangrelor or placebo (sterile saline). Primary endpoint:&#xD;
      ADP-dependent platelet reactivity at time of stent placement (AU*min). Student's t-test to&#xD;
      test H0 (no difference in AU*min, cangrelor vs placebo).&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Recruiting</last_known_status>
  <start_date type="Anticipated">September 2017</start_date>
  <completion_date type="Anticipated">December 2021</completion_date>
  <primary_completion_date type="Anticipated">May 2021</primary_completion_date>
  <phase>Phase 4</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Factorial Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Platelet reactivity at stent placement</measure>
    <time_frame>up to 4 hours; time from study drug administration (Cangrelor/Placebo) to stent placement</time_frame>
    <description>Platelet reactivity (ADP-dependent platelet inhibition) at the time of cardiac intervention (i.e. at the time of stent placement) measured by impedance aggregometry (Multiplate Analyzer; aggregation units/min, AU*min)</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Platelet reactivity</measure>
    <time_frame>15 minutes, 30 minutes, 60 minutes, 120 minutes, 240 minutes, 12hours from administration of study drug.</time_frame>
    <description>Platelet reactivity at baseline, 15 minutes, 30 minutes, 60minutes, 120 minutes, 240 minutes and 12 hours after study drug administration (Multiplate Analyzer, AU*min; VASP assay, platelet reactivity units PRU; PFA-100, closure time, CT).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Platelet inhibition</measure>
    <time_frame>15 minutes, 30 minutes, 60 minutes, 120 minutes, 240 minutes, 12hours from administration of study drug.</time_frame>
    <description>Onset of ADP-dependent platelet inhibition (Multiplate Analyzer, VASP assay, PFA-100).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Maximum Plasma Concentration [Cmax]</measure>
    <time_frame>15 minutes, 30 minutes, 60 minutes, 120 minutes, 240 minutes, 12hours from administration of study drug.</time_frame>
    <description>Prasugrel/Ticagrelor/Cangrelor metabolites will be measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS) at the time of stent placement, 15minutes, 30 minutes, 60 minutes, 120 minutes, 240 minutes and 12 hours after study drug administration</description>
  </secondary_outcome>
  <number_of_arms>4</number_of_arms>
  <enrollment type="Anticipated">60</enrollment>
  <condition>Cardiopulmonary Arrest With Successful Resuscitation</condition>
  <condition>ACS - Acute Coronary Syndrome</condition>
  <condition>Hypothermia, Induced</condition>
  <arm_group>
    <arm_group_label>Prasugrel + Cangrelor</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>If eligible, assigned to this arm and without contraindications to prasugrel administration, patients will receive a loading dose of prasugrel (60 mg) via nasogastric tube as soon as possible after arrival at the emergency department. Afterwards a 30 micrograms (mcg)/kg iv bolus of cangrelor followed immediately by a 4 mcg/kg/min iv infusion (lasting for at least 2 hours or for the duration of the revascularization procedure, whichever is longer) will be administered.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Ticagrelor + Cangrelor</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>If eligible and assigned to this arm (i.e. patients who have contraindications against prasugrel (age &gt;75years, weight &lt;60kg, history of transient ischemic attack, ischemic stroke, intracranial bleeding, known allergy against prasugrel/Efient), patients will receive a loading dose of ticagrelor (180 mg) via nasogastric tube as soon as possible after arrival at the emergency department. Afterwards a 30 micrograms (mcg)/kg iv bolus of cangrelor followed immediately by a 4 mcg/kg/min iv infusion (lasting for at least 2 hours or for the duration of the revascularization procedure, whichever is longer) will be administered.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Prasugrel + Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>If eligible, assigned to this arm and no contraindications to prasugrel, patients will receive a loading dose of prasugrel (60 mg) via nasogastric tube as soon as possible after arrival at the emergency department.&#xD;
Afterwards a 30 micrograms (mcg)/kg iv bolus of placebo (0.9% NaCl) followed immediately by a 4 mcg/kg/min iv infusion of placebo (0.9% NaCl) (lasting for at least 2 hours or for the duration of the revascularization procedure, whichever is longer) will be administered.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Ticagrelor + Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>If eligible and assigned to this arm (i.e. patients who have contraindications against prasugrel (age &gt;75years, weight &lt;60kg, history of transient ischemic attack, ischemic stroke, intracranial bleeding, known allergy against prasugrel/Efient), patients will receive a loading dose of ticagrelor (180 mg) via nasogastric tube as soon as possible after arrival at the emergency department.&#xD;
Afterwards a 30 micrograms (mcg)/kg iv bolus of placebo (0.9% NaCl) followed immediately by a 4 mcg/kg/min iv infusion placebo (0.9% NaCl) (lasting for at least 2 hours or for the duration of the revascularization procedure, whichever is longer) will be administered.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Cangrelor</intervention_name>
    <description>The intervention comprises add-on Cangrelor infusion (administration in compliance with manufacturer instructions) in addition to and after administration of standard P2Y12-blocker (prasugrel or ticagrelor) therapy.</description>
    <arm_group_label>Prasugrel + Cangrelor</arm_group_label>
    <arm_group_label>Ticagrelor + Cangrelor</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>The intervention comprises add-on placebo infusion (0.9% NaCl) in addition to and after administration of standard P2Y12-blocker (prasugrel or ticagrelor) therapy as placebo comparator</description>
    <arm_group_label>Prasugrel + Placebo</arm_group_label>
    <arm_group_label>Ticagrelor + Placebo</arm_group_label>
    <other_name>0.9% NaCl</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Prasugrel</intervention_name>
    <description>The intervention comprises the standard P2Y12-blocker prasugrel therapy if not contraindicated.</description>
    <arm_group_label>Prasugrel + Cangrelor</arm_group_label>
    <arm_group_label>Prasugrel + Placebo</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Ticagrelor</intervention_name>
    <description>The intervention comprises the standard P2Y12-blocker ticagrelor therapy if prasugrel is contraindicated and no contraindication to ticagrelor is present.</description>
    <arm_group_label>Ticagrelor + Cangrelor</arm_group_label>
    <arm_group_label>Ticagrelor + Placebo</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Age 18-74 years&#xD;
&#xD;
          -  comatose survivors of OHCA&#xD;
&#xD;
          -  initial shockable rhythm (i.e. ventricular fibrillation or pulseless ventricular&#xD;
             tachycardia)&#xD;
&#xD;
          -  STEMI (post-ROSC electrocardiography)&#xD;
&#xD;
          -  application of TTM;&#xD;
&#xD;
          -  scheduled for PCI&#xD;
&#xD;
          -  interval of &lt;10 min from cardiac arrest to initiation of cardiopulmonary&#xD;
&#xD;
          -  resuscitation (no-flow interval); interval of &lt;60 min from initiation of&#xD;
             cardiopulmonary resuscitation&#xD;
&#xD;
          -  to ROSC (low-flow interval)&#xD;
&#xD;
          -  eligible for treatment with standard loading doses of DAPT including&#xD;
&#xD;
          -  aspirin and either prasugrel or ticagrelor.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Pregnant or breast-feeding patients&#xD;
&#xD;
          -  Body weight &lt;60kg&#xD;
&#xD;
          -  Response to verbal commands after ROSC&#xD;
&#xD;
          -  (thus not eligible for TTM)&#xD;
&#xD;
          -  Cardiac arrest due to: trauma, exsanguination, strangulation, smoke&#xD;
&#xD;
          -  inhalation, drug overdose, electrocution, hanging or drowning, or intracranial&#xD;
             hemorrhage&#xD;
&#xD;
          -  Patients not&#xD;
&#xD;
          -  achieving ROSC or subjected to an extracorporeal circulatory assist device&#xD;
&#xD;
          -  Acute treatment with P2Y12r inhibitor other than prasugrel or ticagrelor&#xD;
&#xD;
          -  Active bleeding or increased risk of bleeding because of irreversible coagulation&#xD;
             disorders or due to recent major surgery/trauma or uncontrolled&#xD;
&#xD;
          -  severe hypertension&#xD;
&#xD;
          -  Known history of ischemic or hemorrhagic stroke or transient ischemic attack&#xD;
&#xD;
          -  (TIA)&#xD;
&#xD;
          -  Known history of severe hepatic impairment (Child Pugh C)&#xD;
&#xD;
          -  Known history of severe renal impairment (creatinine clearance &lt;30mL/min)&#xD;
&#xD;
          -  Hypersensitivity to the active substance or to any of the excipients&#xD;
&#xD;
          -  Terminal illness present before cardiac arrest&#xD;
&#xD;
          -  Thrombolysis therapy&#xD;
&#xD;
          -  Scheduled for coronary bypass surgery (CABG)&#xD;
&#xD;
          -  Prior P2Y12r inhibitor use in the past 7 days&#xD;
&#xD;
          -  Prior vitamin K antagonists/NOACs use in past 7 days&#xD;
&#xD;
          -  Patients with known allergic reaction to P2Y12r inhibitors.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>74 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Alexander o: Spiel, Prof., MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Medical University of Vienna</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Alexander O. Spiel, Prof., MD</last_name>
    <phone>+4314040039530</phone>
    <email>alexander.spiel@meduinwien.ac.at</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Michael Schwameis, MD</last_name>
    <phone>+4314040019640</phone>
    <email>michael.schwameis@meduinwien.ac.at</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>Medical University of Vienna</name>
      <address>
        <city>Vienna</city>
        <country>Austria</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Alexander O Spiel, MD</last_name>
    </contact>
  </location>
  <location_countries>
    <country>Austria</country>
  </location_countries>
  <verification_date>September 2017</verification_date>
  <study_first_submitted>August 23, 2017</study_first_submitted>
  <study_first_submitted_qc>September 3, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">September 6, 2017</study_first_posted>
  <last_update_submitted>September 11, 2017</last_update_submitted>
  <last_update_submitted_qc>September 11, 2017</last_update_submitted_qc>
  <last_update_posted type="Actual">September 13, 2017</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Medical University of Vienna</investigator_affiliation>
    <investigator_full_name>Alexander Spiel</investigator_full_name>
    <investigator_title>Assoc.Prof. Priv.Doz. Dr.med.univ. Alexander Spiel</investigator_title>
  </responsible_party>
  <keyword>P2Y12r inhibitor</keyword>
  <keyword>Cardiac Arrest</keyword>
  <keyword>STEMI</keyword>
  <keyword>HTPR</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Acute Coronary Syndrome</mesh_term>
    <mesh_term>Heart Arrest</mesh_term>
    <mesh_term>Hypothermia</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Ticagrelor</mesh_term>
    <mesh_term>Prasugrel Hydrochloride</mesh_term>
    <mesh_term>Cangrelor</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03273075
org study id: Cang 2016-003265-26
nct id: NCT03273075
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
is us export: No
In patients with ST-elevation myocardial infarction (STEMI) undergoing percutaneous coronary
      angioplasty (PCI) P2Y12 receptor (P2Y12r) inhibition should be achieved as soon as possible.
      Resuscitated STEMI-patients receiving targeted temperature management (TTM, therapeutic
      hypothermia) after cardiac arrest, however, show deteriorated and delayed early response to
      available oral P2Y12r inhibitors. Therapeutic hypothermia attenuates the drugs' effectiveness
      by reducing its gastrointestinal absorption and metabolic activation. Acute stent thrombosis
      is 5-fold increased after angioplasty following resuscitated cardiac arrest because of
      insufficient early platelet suppression. Thus, aggressive antiplatelet strategies are needed
      to achieve optimal platelet suppression during PCI in those patients. The first intravenous
      P2Y12r inhibitor, cangrelor, has recently received marketing authorization for the acute
      treatment of STEMI. We hypothesize that add-on antiplatelet therapy with intravenous
      Cangrelor on-top of standard dual anti platelet therapy (DAPT) with Prasugrel or Ticagrelor
      is superior to standard antiplatelet therapy alone in terms of suppressing ADP-dependent
      platelet activation in resuscitated STEMI-patients receiving TTM.
Neurologic damage after cardiac arrest is frequent and therapeutic options to improve
      neurological outcome are limited. Treatment by therapeutic hypothermia (TH, 32-34◦C) for
      12-24 h showed improved neurological outcome in several trials. Therefore, international
      guidelines recommend targeted temperature management (TTM) to 32-34◦C (or at least 36°C) for
      12-24 h, especially when the initial rhythm was ventricular fibrillation.

      However, patients treated with TTM after cardiac arrest show deteriorated and delayed
      response to P2Y12 receptor (P2Y12r) inhibitors as determined by platelet reactivity index
      vasodilator-stimulated phosphoprotein phosphorylation (PRI VASP) after administration of the
      loading dose of clopidogrel, prasugrel and ticagrelor. Especially the response to clopidogrel
      is poor with up to >80% non-responder after 24 hours. Impaired P2Y12r blockade may lead to
      acute stent-thrombosis and trigger overall adverse outcome.

      There are several explanations for the impaired efficacy of P2Y12r inhibitors in cardiac
      arrest patients. First, marketed oral P2Y12r inhibitors have to be applied in crushed form
      via nasogastric tube in comatose post cardiac arrest patients. Placement of nasogastric tube
      and crushing may delay onset of therapy. Second, drug uptake and bioavailability of oral
      P2Y12r inhibitors are dependent on gastric motility and sufficient splanchnic blood supply,
      which is affected by TTM, acute critical illness (shock) and concomitant therapy.
      Particularly, sedation and analgesic agents, especially concomitant morphine therapy, can
      hamper gastric emptying. Various recent trials demonstrated that morphine administration
      delays and attenuates clopidogrel, prasugrel and ticagrelor exposure and action in healthy
      subjects and patients with myocardial infarction.

      The recently authorized parenteral cangrelor is an adenosine triphosphate (ATP) analogue that
      binds reversibly and with high affinity to the platelet P2Y12r. It induces a highly effective
      inhibition of ADP-induced platelet aggregation immediately after intravenous (iv) bolus
      administration and allows for restoration of platelet function within 1-2 h of infusion
      discontinuation. The pharmacokinetic properties known so far suggest cangrelor being the
      "ideal" P2Y12r inhibitor for patients with cardiac-ischemia triggered OHCA treated with TH
      and may overcome the impaired and delayed P2Y12r blockade seen with the oral P2Y12r
      inhibitors.

      Cardiac arrest is a leading cause of death among adults over the age of 40 in the European
      Union (EU) and other western countries. In the EU alone, more than 400.000 people of all ages
      experience EMS-assessed out-of-hospital non-traumatic cardiac arrest each year and most of
      them die. In a large proportion of these patients (about 50%) an acute coronary syndrome
      (ACS), mainly acute ST-elevation myocardial infarction, leading to ventricular fibrillation
      and cardiac standstill is the cause of the cardiac arrest. Various trials demonstrated that
      early cardiac intervention including stent placement to the culprit lesion improves outcome
      in this patient group. The P2Y12r plays a central role in platelet activation and P2Y12r
      inhibitors are part of standard care in patients with ACS. Delayed and insufficient P2Y12r
      inhibition may predispose to acute stent thrombosis with potential devastating effects
      including cardiogenic shock, re-arrest and death. Given the deteriorated and delayed response
      to oral P2Y12r inhibitors in cardiac arrest patients treated with TH, clinical evaluation of
      the recently marketed parenteral P2Y12r inhibitor cangrelor is mandatory in this patient
      group.

      To determine the effect of add-on cangrelor in STEMI-associated out-of-hospital cardiac
      arrest (OHCA) who receive TTM and are scheduled for PCI, a phase 4 trial will be
      conducted.The trial consists of 2 parts. Part A (n=12, 8months duration): An open-fashioned
      pilot safety-study to ensure sufficient platelet suppression (<466AU*min, impedance
      aggregometry) over 24 hours after concurrent cangrelor-prasugrel/ticagrelor administration.
      The aim is to determine pharmacokinetics and -dynamics of oral P2Y12r-inhibitors with and
      without concomitant administration of cangrelor. Part B (n=48, 32months duration): A
      factorial randomized, placebo-controlled, double-blind study with 4 study cohorts enrolling
      48 patients who will first be randomised to receive prasugrel (n=24) or ticagrelor (n=24) and
      secondly to additionally receive cangrelor or placebo (sterile saline). Primary endpoint:
      ADP-dependent platelet reactivity at time of stent placement (AU*min). Student's t-test to
      test H0 (no difference in AU*min, cangrelor vs placebo).
allocation: Randomized
intervention model: Factorial Assignment
primary purpose: Treatment
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
measure: Platelet reactivity at stent placement
time frame: up to 4 hours; time from study drug administration (Cangrelor/Placebo) to stent placement
description: Platelet reactivity (ADP-dependent platelet inhibition) at the time of cardiac intervention (i.e. at the time of stent placement) measured by impedance aggregometry (Multiplate Analyzer; aggregation units/min, AU*min)
measure: Platelet reactivity
time frame: 15 minutes, 30 minutes, 60 minutes, 120 minutes, 240 minutes, 12hours from administration of study drug.
description: Platelet reactivity at baseline, 15 minutes, 30 minutes, 60minutes, 120 minutes, 240 minutes and 12 hours after study drug administration (Multiplate Analyzer, AU*min; VASP assay, platelet reactivity units PRU; PFA-100, closure time, CT).
measure: Platelet inhibition
time frame: 15 minutes, 30 minutes, 60 minutes, 120 minutes, 240 minutes, 12hours from administration of study drug.
description: Onset of ADP-dependent platelet inhibition (Multiplate Analyzer, VASP assay, PFA-100).
measure: Maximum Plasma Concentration [Cmax]
time frame: 15 minutes, 30 minutes, 60 minutes, 120 minutes, 240 minutes, 12hours from administration of study drug.
description: Prasugrel/Ticagrelor/Cangrelor metabolites will be measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS) at the time of stent placement, 15minutes, 30 minutes, 60 minutes, 120 minutes, 240 minutes and 12 hours after study drug administration
arm group label: Prasugrel + Cangrelor
arm group type: Active Comparator
description: If eligible, assigned to this arm and without contraindications to prasugrel administration, patients will receive a loading dose of prasugrel (60 mg) via nasogastric tube as soon as possible after arrival at the emergency department. Afterwards a 30 micrograms (mcg)/kg iv bolus of cangrelor followed immediately by a 4 mcg/kg/min iv infusion (lasting for at least 2 hours or for the duration of the revascularization procedure, whichever is longer) will be administered.
arm group label: Ticagrelor + Cangrelor
arm group type: Active Comparator
description: If eligible and assigned to this arm (i.e. patients who have contraindications against prasugrel (age >75years, weight <60kg, history of transient ischemic attack, ischemic stroke, intracranial bleeding, known allergy against prasugrel/Efient), patients will receive a loading dose of ticagrelor (180 mg) via nasogastric tube as soon as possible after arrival at the emergency department. Afterwards a 30 micrograms (mcg)/kg iv bolus of cangrelor followed immediately by a 4 mcg/kg/min iv infusion (lasting for at least 2 hours or for the duration of the revascularization procedure, whichever is longer) will be administered.
arm group label: Prasugrel + Placebo
arm group type: Placebo Comparator
description: If eligible, assigned to this arm and no contraindications to prasugrel, patients will receive a loading dose of prasugrel (60 mg) via nasogastric tube as soon as possible after arrival at the emergency department.
Afterwards a 30 micrograms (mcg)/kg iv bolus of placebo (0.9% NaCl) followed immediately by a 4 mcg/kg/min iv infusion of placebo (0.9% NaCl) (lasting for at least 2 hours or for the duration of the revascularization procedure, whichever is longer) will be administered.
arm group label: Ticagrelor + Placebo
arm group type: Placebo Comparator
description: If eligible and assigned to this arm (i.e. patients who have contraindications against prasugrel (age >75years, weight <60kg, history of transient ischemic attack, ischemic stroke, intracranial bleeding, known allergy against prasugrel/Efient), patients will receive a loading dose of ticagrelor (180 mg) via nasogastric tube as soon as possible after arrival at the emergency department.
Afterwards a 30 micrograms (mcg)/kg iv bolus of placebo (0.9% NaCl) followed immediately by a 4 mcg/kg/min iv infusion placebo (0.9% NaCl) (lasting for at least 2 hours or for the duration of the revascularization procedure, whichever is longer) will be administered.
intervention type: Drug
intervention name: Cangrelor
description: The intervention comprises add-on Cangrelor infusion (administration in compliance with manufacturer instructions) in addition to and after administration of standard P2Y12-blocker (prasugrel or ticagrelor) therapy.
arm group label: Prasugrel + Cangrelor
arm group label: Ticagrelor + Cangrelor
intervention type: Drug
intervention name: Placebo
description: The intervention comprises add-on placebo infusion (0.9% NaCl) in addition to and after administration of standard P2Y12-blocker (prasugrel or ticagrelor) therapy as placebo comparator
arm group label: Prasugrel + Placebo
arm group label: Ticagrelor + Placebo
other name: 0.9% NaCl
intervention type: Drug
intervention name: Prasugrel
description: The intervention comprises the standard P2Y12-blocker prasugrel therapy if not contraindicated.
arm group label: Prasugrel + Cangrelor
arm group label: Prasugrel + Placebo
intervention type: Drug
intervention name: Ticagrelor
description: The intervention comprises the standard P2Y12-blocker ticagrelor therapy if prasugrel is contraindicated and no contraindication to ticagrelor is present.
arm group label: Ticagrelor + Cangrelor
arm group label: Ticagrelor + Placebo
criteria: 
gender: All
minimum age: 18 Years
maximum age: 74 Years
healthy volunteers: No
last name: Alexander o: Spiel, Prof., MD
role: Principal Investigator
affiliation: Medical University of Vienna
last name: Alexander O. Spiel, Prof., MD
phone: +4314040039530
email: alexander.spiel@meduinwien.ac.at
last name: Michael Schwameis, MD
phone: +4314040019640
email: michael.schwameis@meduinwien.ac.at
facility: 
status: Recruiting
contact: 
country: Austria
responsible party type: Principal Investigator
investigator affiliation: Medical University of Vienna
investigator full name: Alexander Spiel
investigator title: Assoc.Prof. Priv.Doz. Dr.med.univ. Alexander Spiel
mesh term: Acute Coronary Syndrome
mesh term: Heart Arrest
mesh term: Hypothermia
mesh term: Ticagrelor
mesh term: Prasugrel Hydrochloride
mesh term: Cangrelor
sharing ipd: No