<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/NCT04442919</url>
  </required_header>
  <id_info>
    <org_study_id>METHANE</org_study_id>
    <nct_id>NCT04442919</nct_id>
  </id_info>
  <brief_title>Influence of METHoxyflurane on ANtiplatelet Effect of Ticagrelor in Patients With Unstable Angina Pectoris</brief_title>
  <acronym>METHANE</acronym>
  <official_title>Influence of METHoxyflurane on ANtiplatelet Effect of Ticagrelor in Patients With Unstable Angina Pectoris - METHANE Study</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Collegium Medicum w Bydgoszczy</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Collegium Medicum w Bydgoszczy</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>
  </oversight_info>
  <brief_summary>
    <textblock>
      The purpose of this study is to evaluate differences in the pharmacokinetics and&#xD;
      pharmacodynamics of ticagrelor and its active metabolite in patients who received ticagrelor&#xD;
      followed with methoxyflurane versus ticagrelor followed with morphine or ticagrelor alone due&#xD;
      to unstable angina pectoris&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Results of the IMPRESSION trial published in 2015 proved that morphine use in patients with&#xD;
      acute coronary syndromes (ACS) is associated with undesirable impact on pharmacokinetics (PK)&#xD;
      and pharmacodynamics (PD) of ticagrelor. Despite that, morphine is still a standard analgesic&#xD;
      treatment in ACS patients and it should not be routinely withdrawn. Based on contemporary&#xD;
      knowledge, morphine, acting via mi-opioid receptors, was found to inhibit gastrointestinal&#xD;
      motility or induce adverse effects such as nausea or vomiting.&#xD;
&#xD;
      We decided to design a clinical study aiming to evaluate the impact of methoxyflurane on PD&#xD;
      of ticagrelor in patients diagnosed with unstable angina pectoris (UA). Methoxyflurane is an&#xD;
      inhaled anesthetic, registered in Poland in emergency medicine for pain alleviation in trauma&#xD;
      patients. The drug was widely used in 1960s to induce general anesthesia, however its&#xD;
      clinical utility was reduced with the development of novel anesthetic agents. Taking into&#xD;
      account its different mechanism of action, it can be presumed that, contrary to morphine, no&#xD;
      respiratory depression should be observed as well as no attenuation or delay of&#xD;
      antiaggregatory effect of ticagrelor should occur, as no interaction with mi-receptor in&#xD;
      gastrointestinal tract is related to activity of methoxyflurane.&#xD;
&#xD;
      Patients will be randomized in a 1:1:1 ratio into the study arms as follows: 1) 180 mg&#xD;
      ticagrelor (2 integral tablets of 90 mg ticagrelor) followed by 3 mg inhaled methoxyflurane,&#xD;
      2) 180 mg ticagrelor followed by 5 mg intravenous morphine, 3) 180 mg ticagrelor alone&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">June 1, 2020</start_date>
  <completion_date type="Anticipated">December 31, 2023</completion_date>
  <primary_completion_date type="Anticipated">October 30, 2023</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>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Mean platelet reactivity between the study arms</measure>
    <time_frame>6 hours</time_frame>
    <description>Mean platelet reactivity between the study arms, assessed using the Multiplate Analyzer</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>The percentage of high platelet reactivity patients (HPR) throughout the study period</measure>
    <time_frame>6 hours</time_frame>
    <description>the percentage of patients with high platelet reactivity throughout the study period</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Mean time to achieve platelet reactivity below the threshold for HPR</measure>
    <time_frame>6 hours</time_frame>
    <description>Mean time required for patients to receive low platelet reactivity in each study arm</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>area under the plasma concentration-time curve for ticagrelor and its active metabolite between the study arms</measure>
    <time_frame>6 hours</time_frame>
    <description>area under the plasma concentration-time curve for ticagrelor and its active metabolite between the study arms</description>
  </secondary_outcome>
  <number_of_arms>3</number_of_arms>
  <enrollment type="Anticipated">75</enrollment>
  <condition>Unstable Angina</condition>
  <arm_group>
    <arm_group_label>Ticagrelor followed with methoxyflurane</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>patients who received ticagrelor followed with inhaled methoxyflurane due to unstable angina</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Ticagrelor followed with morphine</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>patients who received ticagrelor followed with intravenous morphine due to unstable angina</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Ticagrelor</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>patients who received ticagrelor without any analgesia due to unstable angina</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Ticagrelor followed with Methoxyflurane</intervention_name>
    <description>patients who received ticagrelor followed with inhaled methoxyflurane due to unstable angina</description>
    <arm_group_label>Ticagrelor followed with methoxyflurane</arm_group_label>
    <other_name>Brilique + Penthrox</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Ticagrelor followed with Morphine</intervention_name>
    <description>patients who received ticagrelor followed with intravenous morphine due to unstable angina</description>
    <arm_group_label>Ticagrelor followed with morphine</arm_group_label>
    <other_name>Brilique + Morphine</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Ticagrelor alone</intervention_name>
    <description>patients who received ticagrelor without any analgesia due to unstable angina</description>
    <arm_group_label>Ticagrelor</arm_group_label>
    <other_name>Brilique</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Provision of informed consent prior to any study specific procedures&#xD;
&#xD;
          -  Diagnosis of unstable angina&#xD;
&#xD;
          -  Male or non-pregnant female, aged 18-80 years&#xD;
&#xD;
          -  Provision of informed consent for angiography and PCI&#xD;
&#xD;
          -  GRACE score &lt;140 pts&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Treatment with ticlopidine, clopidogrel, prasugrel or ticagrelor within 14 days before&#xD;
             the study enrollment&#xD;
&#xD;
          -  Current treatment with morphine or any opioid &quot;mi&quot; receptor agonist&#xD;
&#xD;
          -  Hypersensitivity to ticagrelor&#xD;
&#xD;
          -  Current treatment with oral anticoagulant or chronic therapy with low-molecular-weight&#xD;
             heparin&#xD;
&#xD;
          -  Active bleeding&#xD;
&#xD;
          -  History of intracranial hemorrhage&#xD;
&#xD;
          -  Recent gastrointestinal bleeding (within 30 days)&#xD;
&#xD;
          -  History of coagulation disorders&#xD;
&#xD;
          -  Platelet count less than &lt;100 x10^3/mcl&#xD;
&#xD;
          -  Hemoglobin concentration less than 10.0 g/dl&#xD;
&#xD;
          -  History of moderate or severe hepatic impairment&#xD;
&#xD;
          -  History of major surgery or severe trauma (within 3 months)&#xD;
&#xD;
          -  Risk of bradycardic events as judged by the investigator&#xD;
&#xD;
          -  Second- or third-degree atrioventricular block during screening for eligibility&#xD;
&#xD;
          -  History of asthma or severe chronic obstructive pulmonary disease&#xD;
&#xD;
          -  Kidney disease requiring dialysis&#xD;
&#xD;
          -  Manifest infection or inflammatory state&#xD;
&#xD;
          -  Killip class III or IV during screening for eligibility&#xD;
&#xD;
          -  Respiratory failure&#xD;
&#xD;
          -  History of severe chronic heart failure (NYHA class III or IV)&#xD;
&#xD;
          -  Concomitant therapy with strong CYP3A inhibitors (ketoconazole, itraconazole,&#xD;
             voriconazole, telithromycin, clarithromycin, nefazadone, ritonavir, saquinavir,&#xD;
             nelfinavir, indinavir, atazanavir) or strong CYP3A inducers (rifampicin, phenytoin,&#xD;
             carbamazepine, dexamethasone, phenobarbital) within 14 days and during study treatment&#xD;
&#xD;
          -  Body weight below 50 kg&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>80 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Jacek Kubica, Professor</last_name>
    <role>Principal Investigator</role>
    <affiliation>Collegium Medicum w Bydgoszczy</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Piotr Niezgoda, MD</last_name>
    <phone>+48 52 585 4023</phone>
    <email>piotr.niezgoda1986@gmail.com</email>
  </overall_contact>
  <location>
    <facility>
      <name>Cardiology Department, Dr. A. Jurasz University Hospital</name>
      <address>
        <city>Bydgoszcz</city>
        <state>Kujawsko-Pomorskie</state>
        <zip>85-094</zip>
        <country>Poland</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Piotr Niezgoda, M.D.</last_name>
      <phone>+48525854023</phone>
      <email>piotr.niezg@gmail.com</email>
    </contact>
  </location>
  <location_countries>
    <country>Poland</country>
  </location_countries>
  <verification_date>September 2023</verification_date>
  <study_first_submitted>June 19, 2020</study_first_submitted>
  <study_first_submitted_qc>June 19, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">June 23, 2020</study_first_posted>
  <last_update_submitted>September 8, 2023</last_update_submitted>
  <last_update_submitted_qc>September 8, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">September 11, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Collegium Medicum w Bydgoszczy</investigator_affiliation>
    <investigator_full_name>Jacek Kubica</investigator_full_name>
    <investigator_title>Professor</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Angina Pectoris</mesh_term>
    <mesh_term>Angina, Unstable</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Morphine</mesh_term>
    <mesh_term>Methoxyflurane</mesh_term>
    <mesh_term>Ticagrelor</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/NCT04442919
org study id: METHANE
nct id: NCT04442919
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
The purpose of this study is to evaluate differences in the pharmacokinetics and
      pharmacodynamics of ticagrelor and its active metabolite in patients who received ticagrelor
      followed with methoxyflurane versus ticagrelor followed with morphine or ticagrelor alone due
      to unstable angina pectoris
Results of the IMPRESSION trial published in 2015 proved that morphine use in patients with
      acute coronary syndromes (ACS) is associated with undesirable impact on pharmacokinetics (PK)
      and pharmacodynamics (PD) of ticagrelor. Despite that, morphine is still a standard analgesic
      treatment in ACS patients and it should not be routinely withdrawn. Based on contemporary
      knowledge, morphine, acting via mi-opioid receptors, was found to inhibit gastrointestinal
      motility or induce adverse effects such as nausea or vomiting.

      We decided to design a clinical study aiming to evaluate the impact of methoxyflurane on PD
      of ticagrelor in patients diagnosed with unstable angina pectoris (UA). Methoxyflurane is an
      inhaled anesthetic, registered in Poland in emergency medicine for pain alleviation in trauma
      patients. The drug was widely used in 1960s to induce general anesthesia, however its
      clinical utility was reduced with the development of novel anesthetic agents. Taking into
      account its different mechanism of action, it can be presumed that, contrary to morphine, no
      respiratory depression should be observed as well as no attenuation or delay of
      antiaggregatory effect of ticagrelor should occur, as no interaction with mi-receptor in
      gastrointestinal tract is related to activity of methoxyflurane.

      Patients will be randomized in a 1:1:1 ratio into the study arms as follows: 1) 180 mg
      ticagrelor (2 integral tablets of 90 mg ticagrelor) followed by 3 mg inhaled methoxyflurane,
      2) 180 mg ticagrelor followed by 5 mg intravenous morphine, 3) 180 mg ticagrelor alone
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Mean platelet reactivity between the study arms
time frame: 6 hours
description: Mean platelet reactivity between the study arms, assessed using the Multiplate Analyzer
measure: The percentage of high platelet reactivity patients (HPR) throughout the study period
time frame: 6 hours
description: the percentage of patients with high platelet reactivity throughout the study period
measure: Mean time to achieve platelet reactivity below the threshold for HPR
time frame: 6 hours
description: Mean time required for patients to receive low platelet reactivity in each study arm
measure: area under the plasma concentration-time curve for ticagrelor and its active metabolite between the study arms
time frame: 6 hours
description: area under the plasma concentration-time curve for ticagrelor and its active metabolite between the study arms
arm group label: Ticagrelor followed with methoxyflurane
arm group type: Experimental
description: patients who received ticagrelor followed with inhaled methoxyflurane due to unstable angina
arm group label: Ticagrelor followed with morphine
arm group type: Active Comparator
description: patients who received ticagrelor followed with intravenous morphine due to unstable angina
arm group label: Ticagrelor
arm group type: Active Comparator
description: patients who received ticagrelor without any analgesia due to unstable angina
intervention type: Drug
intervention name: Ticagrelor followed with Methoxyflurane
description: patients who received ticagrelor followed with inhaled methoxyflurane due to unstable angina
arm group label: Ticagrelor followed with methoxyflurane
other name: Brilique + Penthrox
intervention type: Drug
intervention name: Ticagrelor followed with Morphine
description: patients who received ticagrelor followed with intravenous morphine due to unstable angina
arm group label: Ticagrelor followed with morphine
other name: Brilique + Morphine
intervention type: Drug
intervention name: Ticagrelor alone
description: patients who received ticagrelor without any analgesia due to unstable angina
arm group label: Ticagrelor
other name: Brilique
criteria: 
gender: All
minimum age: 18 Years
maximum age: 80 Years
healthy volunteers: No
last name: Jacek Kubica, Professor
role: Principal Investigator
affiliation: Collegium Medicum w Bydgoszczy
last name: Piotr Niezgoda, MD
phone: +48 52 585 4023
email: piotr.niezgoda1986@gmail.com
facility: 
status: Recruiting
contact: 
country: Poland
responsible party type: Principal Investigator
investigator affiliation: Collegium Medicum w Bydgoszczy
investigator full name: Jacek Kubica
investigator title: Professor
mesh term: Angina Pectoris
mesh term: Angina, Unstable
mesh term: Morphine
mesh term: Methoxyflurane
mesh term: Ticagrelor
sharing ipd: No