<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/NCT03274752</url>
  </required_header>
  <id_info>
    <org_study_id>2016-00349</org_study_id>
    <nct_id>NCT03274752</nct_id>
  </id_info>
  <brief_title>Paroxetine-mediated GRK2 Inhibition to Reduce Cardiac Remodeling After Acute Myocardial Infarction</brief_title>
  <acronym>CARE-AMI</acronym>
  <official_title>Paroxetine-mediated GRK2 Inhibition to Reduce Cardiac Remodeling After Acute Myocardial Infarction (CARE-AMI): a Randomized Controlled Pilot Study</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Insel Gruppe AG, University Hospital Bern</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Insel Gruppe AG, University Hospital Bern</source>
  <oversight_info>
    <has_dmc>Yes</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>
      This study evaluates the off-target effect of paroxetine to reverse cardiac remodeling and&#xD;
      improve left ventricular ejection fraction in patients after acute myocardial infarction.&#xD;
      Half of the participants will receive paroxetine, while the other half will receive placebo&#xD;
      treatment.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Cardiac remodeling is characterized by a composite of structural, geometric, molecular, and&#xD;
      functional changes of the myocardium, and is an important determinant of heart failure and&#xD;
      cardiovascular outcome in survivors of acute myocardial infarction. Progression of heart&#xD;
      failure secondary to the remodeling process results from dysregulation of the G&#xD;
      protein-coupled receptor (GPCR). Excessive adrenergic drive in patients with heart failure&#xD;
      results in an enhanced activation of GPCR kinases (GRKs) that is considered to have a central&#xD;
      role in adverse cardiac remodeling after ischemic injury. The selective Serotonin reuptake&#xD;
      inhibitor paroxetine specifically binds to the catalytic domain of GRK2 as an off-target&#xD;
      effect, and has been shown to reverse cardiac remodeling and increase left ventricular&#xD;
      ejection fraction in a mouse model. The effect was observed at serum levels achieved with&#xD;
      standard dosages of paroxetine, and was robust in mice with and without concomitant heart&#xD;
      failure treatment, respectively.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">October 26, 2017</start_date>
  <completion_date type="Actual">March 1, 2022</completion_date>
  <primary_completion_date type="Actual">January 1, 2021</primary_completion_date>
  <phase>Phase 2</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>Double (Participant, Investigator)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Difference in the change of left ventricular ejection fraction (LVEF)</measure>
    <time_frame>12 weeks after randomization</time_frame>
    <description>Assessment by cardiac magnetic resonance imaging</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Difference in change in left left-ventricular end-diastolic volume (LVEDV)</measure>
    <time_frame>12 weeks after randomization</time_frame>
    <description>Assessment by cardiac magnetic resonance imaging</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Difference in change in left left-ventricular end-systolic volume (LVESV)</measure>
    <time_frame>12 weeks after randomization</time_frame>
    <description>Assessment by cardiac magnetic resonance imaging</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Difference in late-enhancement</measure>
    <time_frame>12 weeks after randomization</time_frame>
    <description>Assessment by cardiac magnetic resonance imaging</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Difference in LVEF between baseline and 12 weeks, and 12 months, respectively</measure>
    <time_frame>12 months after randomization</time_frame>
    <description>Assessment by transthoracic echocardiography</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Major adverse cardiac events</measure>
    <time_frame>12 weeks and 12 months after randomization</time_frame>
    <description>Cardiac death, myocardial infarction, repeat hospitalization for heart failure</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Clinical symptoms of heart failure</measure>
    <time_frame>12 weeks and 12 months after randomization</time_frame>
    <description>Assessed by New York Heart Association (NYHA) categorization</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">50</enrollment>
  <condition>Cardiac Remodeling</condition>
  <condition>Myocardial Infarction</condition>
  <arm_group>
    <arm_group_label>Paroxetine</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Paroxetine 20mg QD per os for 12 weeks followed by 10mg for one additional week</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Placebo oral capsule QD per os for 13 weeks</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Paroxetine</intervention_name>
    <description>Paroxetine (Deroxat) will be administered in a dosage of 20mg q.d. per os continuously for 12 weeks after primary PCI. In week 13, Paroxetine (Deroxat) will be administered in a dosage of 10mg q.d. per os.</description>
    <arm_group_label>Paroxetine</arm_group_label>
    <other_name>Deroxat</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo oral capsule</intervention_name>
    <description>Placebo will be given q.d. per os continuously for 12 weeks after primary PCI. In addition, a placebo will be given q.d. per os in week 13 as well.</description>
    <arm_group_label>Placebo</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Anterior wall ST-segment elevation myocardial infarction&#xD;
&#xD;
          -  Primary percutaneous coronary intervention (PCI) within 24 hours of symptom onset&#xD;
&#xD;
          -  Left ventricular ejection fraction ≤ 45% within 48-96 hours after primary PCI&#xD;
             (transthoracic echocardiography)&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Female patients at reproductive age (&lt;50 years)&#xD;
&#xD;
          -  Known intolerance to paroxetine&#xD;
&#xD;
          -  Inability to provide informed consent&#xD;
&#xD;
          -  Currently participating in another trial before reaching first endpoint&#xD;
&#xD;
          -  Current medical therapy with MAO-blocker (during, 14 days before, and 14 days after&#xD;
             treatment with MAO-blocker), lithium, thioridazide, or pimozide&#xD;
&#xD;
          -  Concomitant tamoxifen intake&#xD;
&#xD;
          -  Previous myocardial infarction&#xD;
&#xD;
          -  Previous revascularization procedure (percutaneous coronary intervention or coronary&#xD;
             artery bypass grafting).&#xD;
&#xD;
          -  Contraindication to cardiac magnetic resonance imaging&#xD;
&#xD;
          -  Obvious or questionable inability to appropriately cooperate (alcohol, drugs etc.)&#xD;
&#xD;
          -  Relevant nephropathy or hepatopathy&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Thomas Pilgrim, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Bern University Hospital, Department of Cardiology, Freiburgstrasse 10, CH-3010 Bern, Switzerland</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Bern University Hospital, Department of Cardiology</name>
      <address>
        <city>Bern</city>
        <zip>3010</zip>
        <country>Switzerland</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Switzerland</country>
  </location_countries>
  <reference>
    <citation>Schumacher SM, Gao E, Zhu W, Chen X, Chuprun JK, Feldman AM, Tesmer JJ, Koch WJ. Paroxetine-mediated GRK2 inhibition reverses cardiac dysfunction and remodeling after myocardial infarction. Sci Transl Med. 2015 Mar 4;7(277):277ra31. doi: 10.1126/scitranslmed.aaa0154.</citation>
    <PMID>25739765</PMID>
  </reference>
  <reference>
    <citation>Sutton MG, Sharpe N. Left ventricular remodeling after myocardial infarction: pathophysiology and therapy. Circulation. 2000 Jun 27;101(25):2981-8. doi: 10.1161/01.cir.101.25.2981. No abstract available.</citation>
    <PMID>10869273</PMID>
  </reference>
  <verification_date>May 2022</verification_date>
  <study_first_submitted>August 29, 2017</study_first_submitted>
  <study_first_submitted_qc>September 4, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">September 7, 2017</study_first_posted>
  <last_update_submitted>May 29, 2022</last_update_submitted>
  <last_update_submitted_qc>May 29, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">June 1, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Paroxetine</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Myocardial Infarction</mesh_term>
    <mesh_term>Infarction</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Paroxetine</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/NCT03274752
org study id: 2016-00349
nct id: NCT03274752
lead sponsor: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
This study evaluates the off-target effect of paroxetine to reverse cardiac remodeling and
      improve left ventricular ejection fraction in patients after acute myocardial infarction.
      Half of the participants will receive paroxetine, while the other half will receive placebo
      treatment.
Cardiac remodeling is characterized by a composite of structural, geometric, molecular, and
      functional changes of the myocardium, and is an important determinant of heart failure and
      cardiovascular outcome in survivors of acute myocardial infarction. Progression of heart
      failure secondary to the remodeling process results from dysregulation of the G
      protein-coupled receptor (GPCR). Excessive adrenergic drive in patients with heart failure
      results in an enhanced activation of GPCR kinases (GRKs) that is considered to have a central
      role in adverse cardiac remodeling after ischemic injury. The selective Serotonin reuptake
      inhibitor paroxetine specifically binds to the catalytic domain of GRK2 as an off-target
      effect, and has been shown to reverse cardiac remodeling and increase left ventricular
      ejection fraction in a mouse model. The effect was observed at serum levels achieved with
      standard dosages of paroxetine, and was robust in mice with and without concomitant heart
      failure treatment, respectively.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Double (Participant, Investigator)
measure: Difference in the change of left ventricular ejection fraction (LVEF)
time frame: 12 weeks after randomization
description: Assessment by cardiac magnetic resonance imaging
measure: Difference in change in left left-ventricular end-diastolic volume (LVEDV)
time frame: 12 weeks after randomization
description: Assessment by cardiac magnetic resonance imaging
measure: Difference in change in left left-ventricular end-systolic volume (LVESV)
time frame: 12 weeks after randomization
description: Assessment by cardiac magnetic resonance imaging
measure: Difference in late-enhancement
time frame: 12 weeks after randomization
description: Assessment by cardiac magnetic resonance imaging
measure: Difference in LVEF between baseline and 12 weeks, and 12 months, respectively
time frame: 12 months after randomization
description: Assessment by transthoracic echocardiography
measure: Major adverse cardiac events
time frame: 12 weeks and 12 months after randomization
description: Cardiac death, myocardial infarction, repeat hospitalization for heart failure
measure: Clinical symptoms of heart failure
time frame: 12 weeks and 12 months after randomization
description: Assessed by New York Heart Association (NYHA) categorization
arm group label: Paroxetine
arm group type: Experimental
description: Paroxetine 20mg QD per os for 12 weeks followed by 10mg for one additional week
arm group label: Placebo
arm group type: Placebo Comparator
description: Placebo oral capsule QD per os for 13 weeks
intervention type: Drug
intervention name: Paroxetine
description: Paroxetine (Deroxat) will be administered in a dosage of 20mg q.d. per os continuously for 12 weeks after primary PCI. In week 13, Paroxetine (Deroxat) will be administered in a dosage of 10mg q.d. per os.
arm group label: Paroxetine
other name: Deroxat
intervention type: Drug
intervention name: Placebo oral capsule
description: Placebo will be given q.d. per os continuously for 12 weeks after primary PCI. In addition, a placebo will be given q.d. per os in week 13 as well.
arm group label: Placebo
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Thomas Pilgrim, MD
role: Principal Investigator
affiliation: Bern University Hospital, Department of Cardiology, Freiburgstrasse 10, CH-3010 Bern, Switzerland
facility: 
country: Switzerland
citation: Schumacher SM, Gao E, Zhu W, Chen X, Chuprun JK, Feldman AM, Tesmer JJ, Koch WJ. Paroxetine-mediated GRK2 inhibition reverses cardiac dysfunction and remodeling after myocardial infarction. Sci Transl Med. 2015 Mar 4;7(277):277ra31. doi: 10.1126/scitranslmed.aaa0154.
PMID: 25739765
citation: Sutton MG, Sharpe N. Left ventricular remodeling after myocardial infarction: pathophysiology and therapy. Circulation. 2000 Jun 27;101(25):2981-8. doi: 10.1161/01.cir.101.25.2981. No abstract available.
PMID: 10869273
responsible party type: Sponsor
mesh term: Myocardial Infarction
mesh term: Infarction
mesh term: Paroxetine
sharing ipd: No