<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/NCT03018834</url>
  </required_header>
  <id_info>
    <org_study_id>P150921</org_study_id>
    <secondary_id>2016-003433-20</secondary_id>
    <nct_id>NCT03018834</nct_id>
  </id_info>
  <brief_title>Anakinra Versus Placebo for the Treatment of Acute MyocarditIS</brief_title>
  <acronym>ARAMIS</acronym>
  <official_title>Anakinra Versus Placebo Double Blind Randomized Controlled Trial for the Treatment of Acute MyocarditIS</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Assistance Publique - Hôpitaux de Paris</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Assistance Publique - Hôpitaux de Paris</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>
      There is no specific treatment of acute myocarditis, especially during the inflammatory&#xD;
      period. Interleukin (IL) is specifically involved during this period and play a role in&#xD;
      myocardial oedema. ANAKINRA, an IL-1β Blocker, is a new treatment that has never been&#xD;
      evaluated in myocarditis. The benefit for the patient could be important with a reduction of&#xD;
      heart failure and ventricular arrhythmias.&#xD;
&#xD;
      Hypothesis : ANAKINRA in addition to standard therapy for treatment of Acute Myocarditis is&#xD;
      superior to standard therapy based on an association of beta-blockers and&#xD;
      Angiotensin-Converting-Enzyme inhibitor (ACE).&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      It is a Double Blind Randomized clinical trial Phase IIb of superiority, enrolling two&#xD;
      groups: one group treated with the standard of care, defined as the maximum tolerated dosage&#xD;
      of any beta blockers and ACE, and placebo versus ANAKINRA in addition to the standard of care&#xD;
      in patients treated for an acute Myocarditis.&#xD;
&#xD;
      Patients will be randomized to receive ANAKINRA 100 mg/daily or placebo subcutaneously once a&#xD;
      day until hospital discharge, for a maximum of 14 days, in addition to standard care: ACE and&#xD;
      Beta-blocker for 6 months. Randomization 1:1 will be conducted centrally using the electronic&#xD;
      Case Report Form (eCRF).&#xD;
&#xD;
      As an exploratory analysis, a second randomization for ACE discontinuation in patients&#xD;
      without left ventricular dysfunction (LVEF &gt; 50%) at one month post discharge will be&#xD;
      performed.&#xD;
&#xD;
      One group will stopped the treatment at one month and the second group will continued the ACE&#xD;
      for 6 months. This second randomization is in open label.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">May 30, 2017</start_date>
  <completion_date type="Actual">May 30, 2022</completion_date>
  <primary_completion_date type="Actual">June 28, 2021</primary_completion_date>
  <phase>Phase 2/Phase 3</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>Triple (Participant, Care Provider, Investigator)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Number of days alive free of any myocarditis complications</measure>
    <time_frame>within 28 days post hospitalization</time_frame>
    <description>Number of days alive free of any myocarditis complications defined as ventricular arrhythmias, heart failure, chest pain, ventricular dysfunction defined as LVEF&lt;50%, within 28 days post hospitalization</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Total cost</measure>
    <time_frame>on average 14 days</time_frame>
    <description>Total cost</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Total Quality Adjusted Life Year (QALYs),</measure>
    <time_frame>on average 14 days</time_frame>
    <description>measure of the perceived utility by patients of a medication (Anakinra) that corresponds to a year of life gained</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Incremental cost effectiveness</measure>
    <time_frame>on average 14 days</time_frame>
    <description>cost-effectiveness of ANAKINRA in the setting of acute myocarditis</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cost utility ratios</measure>
    <time_frame>on average 14 days</time_frame>
    <description>Cost utility ratios</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Left Ventricul Ejection Fraction (LVEF) assessed by cardiac Magnetic Resonance Imaging (MRI)</measure>
    <time_frame>at 6 month</time_frame>
    <description>Left Ventricul Ejection Fraction (LVEF) assessed by cardiac Magnetic Resonance Imaging (MRI)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Left Ventricul Ejection Fraction (LVEF) assessed by Trans Thoracic Echocardiograhy (TTE)</measure>
    <time_frame>at 6 month</time_frame>
    <description>Left Ventricul Ejection Fraction (LVEF) assessed by Trans Thoracic Echocardiograhy (TTE)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>LVEF assessed by cardiac MRI</measure>
    <time_frame>at 1 year</time_frame>
    <description>LVEF assessed by cardiac MRI</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>LVEF assessed by cardiac TTE</measure>
    <time_frame>at 1 year</time_frame>
    <description>LVEF assessed by cardiac TTE</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>All cause of death rate</measure>
    <time_frame>during the 12 months follow-up</time_frame>
    <description>All cause of death rate</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cardiovascular death</measure>
    <time_frame>at 12 months</time_frame>
    <description>Cardiovascular death</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Heart Failure</measure>
    <time_frame>at 12 months</time_frame>
    <description>Heart Failure</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Ventricular tachycardia</measure>
    <time_frame>during the 12 months follow-up</time_frame>
    <description>Ventricular tachycardia</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>NT-proBNP above 450 pg/mL (in patients aged below 50); above 900 pg/mL (age 50-75 years) or BNP ≤ 400pg/mL 50% decrease of the troponin level at discharge compared to admission</measure>
    <time_frame>at Day0</time_frame>
    <description>NT-proBNP above 450 pg/mL (in patients aged below 50); above 900 pg/mL (age 50-75 years) or BNP ≤ 400pg/mL 50% decrease of the troponin level at discharge compared to admission</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>NT-proBNP above 450 pg/mL (in patients aged below 50); above 900 pg/mL (age 50-75 years) or BNP ≤ 400pg/mL 50% decrease of the troponin level at discharge compared to admission</measure>
    <time_frame>an average of 14 days</time_frame>
    <description>NT-proBNP above 450 pg/mL (in patients aged below 50); above 900 pg/mL (age 50-75 years) or BNP ≤ 400pg/mL</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">120</enrollment>
  <condition>Acute Myocarditis</condition>
  <arm_group>
    <arm_group_label>A: ANAKINRA</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>ANAKINRA 100 mg/daily subcutaneously once a day until hospital discharge, for a maximum of 14 days, in addition to standard care: ACE and Beta-blocker for 6 months.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>B: Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>PLACEBO 100 mg/daily subcutaneously once a day until hospital discharge, for a maximum of 14 days, in addition to standard care: ACE and Beta-blocker for 6 months.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>ANAKINRA 100 mg/daily subcutaneously</intervention_name>
    <description>ANAKINRA 100 mg/daily subcutaneously once a day until hospital discharge, for a maximum of 14 days, in addition to standard care: ACE and Beta-blocker for 6 months.</description>
    <arm_group_label>A: ANAKINRA</arm_group_label>
    <other_name>Kineret</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>PLACEBO 100 mg/daily subcutaneously once a day until hospital discharge, for a maximum of 14 days, in addition to standard care: ACE and Beta-blocker for 6 months.</description>
    <arm_group_label>B: Placebo</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Patients hospitalized for Acute myocarditis defined as:&#xD;
&#xD;
          -  Chest Pain (or modification of the ECG) AND Troponin Rise (*1.5 Normal range) AND&#xD;
             Myocarditis proven by MRI in the first 72h after admission&#xD;
&#xD;
          -  Age &gt; 18 and &lt;65 years old&#xD;
&#xD;
          -  Accepting effective contraception during treatment duration (men and women&#xD;
             childbearing potential)&#xD;
&#xD;
          -  Signed informed consent Normal Coronary angiography or coronary CT Scan (made during&#xD;
             the previous year is acceptable) (normal is defined as stenosis &lt; 50%) (In the case of&#xD;
             patients under 40 with typical MRI of myocarditis, coronary angiography is not&#xD;
             mandatory and left to the doctor's discretion)&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Active coronary disease&#xD;
&#xD;
          -  Clinical Suspicion or proven underlying disease: systemic lupus, antiphospholipid&#xD;
             antibodies, Lyme disease, trypanosomiase disease, myositis, signs of sarcoidosis,&#xD;
             giant cell myocarditis, treated chronic inflammatory disease, tuberculosis, HIV,&#xD;
             hepatitis B virus (HBV) or hepatitis C virus (HCV), Hepatitis B virus (HBV) infection,&#xD;
&#xD;
          -  Latex allergy&#xD;
&#xD;
          -  Pregnancy, breastfeeding&#xD;
&#xD;
          -  Contra-indication to ANAKINRA (known hypersensitivity to the active substance or to&#xD;
             any of the excipients, neutropenia &lt; 1,5.10^9/L)&#xD;
&#xD;
          -  Renal failure, Creatine Clearance (CrCl) &lt; 30 ml/min (MDRD)&#xD;
&#xD;
          -  Malignancy or any comorbidity limiting survival or conditions predicting inability to&#xD;
             complete the study&#xD;
&#xD;
          -  History of malignancy&#xD;
&#xD;
          -  Non Steroidian Anti Inflammatory drug within the past 14 days&#xD;
&#xD;
          -  Anti Tumor Necrosis Factor (TNF) within the past 14 days&#xD;
&#xD;
          -  No affiliation to the French Health Care System &quot;sécurité sociale&quot;&#xD;
&#xD;
          -  Hepatic impairment = Child-Pugh Class C&#xD;
&#xD;
          -  Mechanical ventilation&#xD;
&#xD;
          -  Circulatory assistance&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>64 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Mathieu KERNEIS, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>ACTION Study Group - Assistance Publique - Hôpitaux de Paris</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Fleur COHEN AUBART, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Assistance Publique - Hôpitaux de Paris</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Gilles MONTALESCOT, MD, PhD</last_name>
    <role>Study Director</role>
    <affiliation>ACTION Study Group - Assistance Publique - Hôpitaux de Paris</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>ACTION Study Group - Department of Cardiology - Pitié Salpétrière Hospital, 47 Bd de l'Hopital</name>
      <address>
        <city>Paris</city>
        <zip>75013</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Department of internal medicine - Pitié Salpétrière Hospital, 47 Bd de l'Hopital</name>
      <address>
        <city>Paris</city>
        <zip>75013</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>France</country>
  </location_countries>
  <verification_date>June 2022</verification_date>
  <study_first_submitted>December 12, 2016</study_first_submitted>
  <study_first_submitted_qc>January 10, 2017</study_first_submitted_qc>
  <study_first_posted type="Estimate">January 12, 2017</study_first_posted>
  <last_update_submitted>June 14, 2022</last_update_submitted>
  <last_update_submitted_qc>June 14, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">June 15, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Acute Myocarditis</keyword>
  <keyword>ANAKINRA</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Myocarditis</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Interleukin 1 Receptor Antagonist Protein</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Undecided</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/NCT03018834
org study id: P150921
secondary id: 2016-003433-20
nct id: NCT03018834
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
is us export: No
There is no specific treatment of acute myocarditis, especially during the inflammatory
      period. Interleukin (IL) is specifically involved during this period and play a role in
      myocardial oedema. ANAKINRA, an IL-1β Blocker, is a new treatment that has never been
      evaluated in myocarditis. The benefit for the patient could be important with a reduction of
      heart failure and ventricular arrhythmias.

      Hypothesis : ANAKINRA in addition to standard therapy for treatment of Acute Myocarditis is
      superior to standard therapy based on an association of beta-blockers and
      Angiotensin-Converting-Enzyme inhibitor (ACE).
It is a Double Blind Randomized clinical trial Phase IIb of superiority, enrolling two
      groups: one group treated with the standard of care, defined as the maximum tolerated dosage
      of any beta blockers and ACE, and placebo versus ANAKINRA in addition to the standard of care
      in patients treated for an acute Myocarditis.

      Patients will be randomized to receive ANAKINRA 100 mg/daily or placebo subcutaneously once a
      day until hospital discharge, for a maximum of 14 days, in addition to standard care: ACE and
      Beta-blocker for 6 months. Randomization 1:1 will be conducted centrally using the electronic
      Case Report Form (eCRF).

      As an exploratory analysis, a second randomization for ACE discontinuation in patients
      without left ventricular dysfunction (LVEF > 50%) at one month post discharge will be
      performed.

      One group will stopped the treatment at one month and the second group will continued the ACE
      for 6 months. This second randomization is in open label.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Triple (Participant, Care Provider, Investigator)
measure: Number of days alive free of any myocarditis complications
time frame: within 28 days post hospitalization
description: Number of days alive free of any myocarditis complications defined as ventricular arrhythmias, heart failure, chest pain, ventricular dysfunction defined as LVEF<50%, within 28 days post hospitalization
measure: Total cost
time frame: on average 14 days
description: Total cost
measure: Total Quality Adjusted Life Year (QALYs),
time frame: on average 14 days
description: measure of the perceived utility by patients of a medication (Anakinra) that corresponds to a year of life gained
measure: Incremental cost effectiveness
time frame: on average 14 days
description: cost-effectiveness of ANAKINRA in the setting of acute myocarditis
measure: Cost utility ratios
time frame: on average 14 days
description: Cost utility ratios
measure: Left Ventricul Ejection Fraction (LVEF) assessed by cardiac Magnetic Resonance Imaging (MRI)
time frame: at 6 month
description: Left Ventricul Ejection Fraction (LVEF) assessed by cardiac Magnetic Resonance Imaging (MRI)
measure: Left Ventricul Ejection Fraction (LVEF) assessed by Trans Thoracic Echocardiograhy (TTE)
time frame: at 6 month
description: Left Ventricul Ejection Fraction (LVEF) assessed by Trans Thoracic Echocardiograhy (TTE)
measure: LVEF assessed by cardiac MRI
time frame: at 1 year
description: LVEF assessed by cardiac MRI
measure: LVEF assessed by cardiac TTE
time frame: at 1 year
description: LVEF assessed by cardiac TTE
measure: All cause of death rate
time frame: during the 12 months follow-up
description: All cause of death rate
measure: Cardiovascular death
time frame: at 12 months
description: Cardiovascular death
measure: Heart Failure
time frame: at 12 months
description: Heart Failure
measure: Ventricular tachycardia
time frame: during the 12 months follow-up
description: Ventricular tachycardia
measure: NT-proBNP above 450 pg/mL (in patients aged below 50); above 900 pg/mL (age 50-75 years) or BNP ≤ 400pg/mL 50% decrease of the troponin level at discharge compared to admission
time frame: at Day0
description: NT-proBNP above 450 pg/mL (in patients aged below 50); above 900 pg/mL (age 50-75 years) or BNP ≤ 400pg/mL 50% decrease of the troponin level at discharge compared to admission
measure: NT-proBNP above 450 pg/mL (in patients aged below 50); above 900 pg/mL (age 50-75 years) or BNP ≤ 400pg/mL 50% decrease of the troponin level at discharge compared to admission
time frame: an average of 14 days
description: NT-proBNP above 450 pg/mL (in patients aged below 50); above 900 pg/mL (age 50-75 years) or BNP ≤ 400pg/mL
arm group label: A: ANAKINRA
arm group type: Experimental
description: ANAKINRA 100 mg/daily subcutaneously once a day until hospital discharge, for a maximum of 14 days, in addition to standard care: ACE and Beta-blocker for 6 months.
arm group label: B: Placebo
arm group type: Placebo Comparator
description: PLACEBO 100 mg/daily subcutaneously once a day until hospital discharge, for a maximum of 14 days, in addition to standard care: ACE and Beta-blocker for 6 months.
intervention type: Drug
intervention name: ANAKINRA 100 mg/daily subcutaneously
description: ANAKINRA 100 mg/daily subcutaneously once a day until hospital discharge, for a maximum of 14 days, in addition to standard care: ACE and Beta-blocker for 6 months.
arm group label: A: ANAKINRA
other name: Kineret
intervention type: Drug
intervention name: Placebo
description: PLACEBO 100 mg/daily subcutaneously once a day until hospital discharge, for a maximum of 14 days, in addition to standard care: ACE and Beta-blocker for 6 months.
arm group label: B: Placebo
criteria: 
gender: All
minimum age: 18 Years
maximum age: 64 Years
healthy volunteers: No
last name: Mathieu KERNEIS, MD
role: Principal Investigator
affiliation: ACTION Study Group - Assistance Publique - Hôpitaux de Paris
last name: Fleur COHEN AUBART, MD
role: Principal Investigator
affiliation: Assistance Publique - Hôpitaux de Paris
last name: Gilles MONTALESCOT, MD, PhD
role: Study Director
affiliation: ACTION Study Group - Assistance Publique - Hôpitaux de Paris
facility: 
facility: 
country: France
responsible party type: Sponsor
mesh term: Myocarditis
mesh term: Interleukin 1 Receptor Antagonist Protein
sharing ipd: Undecided