<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/NCT01676285</url>
  </required_header>
  <id_info>
    <org_study_id>0010/11</org_study_id>
    <nct_id>NCT01676285</nct_id>
  </id_info>
  <brief_title>Metoprolol Succinate in Cardiac Remodeling Related to Cirrhosis</brief_title>
  <acronym>CARE Cirrhosis</acronym>
  <official_title>Effect of Metoprolol Succinate in Cardiac Remodeling Related to Nonalcoholic Cirrhosis. Randomized Study.</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Sao Paulo</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Fundação de Amparo à Pesquisa do Estado de São Paulo</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>University of Sao Paulo</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Cirrhotic cardiomyopathy is defined as a chronic cardiac dysfunction in patients with&#xD;
      cirrhosis. It is suspected that this specific cardiac dysfunction contributes to the onset of&#xD;
      complications in liver disease. The purpose of this prospective, randomized trial is to&#xD;
      determine whether metoprolol succinate can revert cardiac dysfunction secondary to cirrhosis&#xD;
      (cirrhotic cardiomyopathy), and prevent complications (renal dysfunction, mortality). A total&#xD;
      of 100 patients with cirrhotic cardiomyopathy will be randomized (Group R) to receive&#xD;
      metoprolol succinate or placebo; other 25 patients without cirrhotic cardiomyopathy (Group F)&#xD;
      will only be followed up without medication. All patients will be evaluated in the beginning&#xD;
      and again after six months. The assessment protocol includes clinical evaluation,&#xD;
      electrocardiogram, echocardiogram, laboratory analysis and life quality questionaire. The end&#xD;
      points will be cardiac remodeling, electrophysiologic changes, sympathetic activity,&#xD;
      laboratory issue changes, renal function, quality of life, and mortality.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Cirrhotic cardiomyopathy (CMC) is defined as a chronic cardiac dysfunction in patients with&#xD;
      cirrhosis. Moreover, it is characterized by an abnormal and blunted response to pathological&#xD;
      or pharmacological stress in the absence of any other associated cardiac disease. The&#xD;
      diagnostic criteria are: baseline increased cardiac output, attenuated myocardial contractile&#xD;
      response to stress, diastolic dysfunction, and electrophysiological repolarization&#xD;
      abnormalities. It is suspected that cardiac dysfunction in cirrhosis contribute to the onset&#xD;
      of complications in liver disease. We will investigate the effect of metoprolol succinate in&#xD;
      the reversal of cardiac dysfunction and prevention of complications of cirrhosis in patients&#xD;
      with cirrhotic cardiomyopathy. Furthermore, we want to study the influence of presence of CMC&#xD;
      in the evolution of cirrhotic patients. The study will be prospective, randomized,&#xD;
      double-blind, and placebo-controlled. The sample consists of 125 patients aged between 18 and&#xD;
      60 years old diagnosed with severe liver cirrhosis (Child B or C or MELD score above 10) with&#xD;
      cirrhotic cardiomyopathy or not. Of these, 100 patients with cirrhotic cardiomyopathy will be&#xD;
      randomized into two groups: group R1 (metoprolol succinate) and group R2 (placebo). Group F&#xD;
      will consist of cirrhotic patients without cardiomyopathy and will not receive medication.&#xD;
      Patients will be evaluated by clinical examination, resting electrocardiogram, 24-hour&#xD;
      Holter, stress echocardiography and laboratory (brain natriuretic peptide (BNP),&#xD;
      catecholamines, plasma renin activity, and troponin) at inclusion and after six months. The&#xD;
      end points are: 1) Reversal of cardiac dysfunction in patients with cirrhotic cardiomyopathy,&#xD;
      2) Development of hepatorenal syndrome, 3) Reversal of the electrophysiologic abnormalities,&#xD;
      4)Changes in laboratory tests, and 5) Mortality.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date>January 2012</start_date>
  <completion_date type="Actual">March 2014</completion_date>
  <primary_completion_date type="Actual">September 2013</primary_completion_date>
  <phase>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>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Improvement of systolic function</measure>
    <time_frame>six months</time_frame>
    <description>Systolic functional reserve is measured by aortic velocity time integral in echocardiographic at rest and stress with dobutamine.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Improvement in left ventricular diastolic function</measure>
    <time_frame>six months</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Renal function</measure>
    <time_frame>From randomization until six months</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Serum level of BNP, catecholamines, plasmatic renin activity</measure>
    <time_frame>Six months</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Mortality</measure>
    <time_frame>From randomization until six months of follow up</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Quality of life</measure>
    <time_frame>Six months</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Electrophysiologic modifications</measure>
    <time_frame>Six months</time_frame>
    <description>QT prolongation R-R variability</description>
  </secondary_outcome>
  <number_of_arms>3</number_of_arms>
  <enrollment type="Actual">125</enrollment>
  <condition>Cirrhosis</condition>
  <condition>Cirrhotic Cardiomyopathy</condition>
  <condition>Cardiac Remodeling</condition>
  <arm_group>
    <arm_group_label>Metoprolol succinate</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Metoprolol succinate</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Placebo</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Follow up</arm_group_label>
    <arm_group_type>No Intervention</arm_group_type>
    <description>Group without cirrhotic cardiomyopathy, only follow up without randomization.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Metoprolol succinate</intervention_name>
    <arm_group_label>Metoprolol succinate</arm_group_label>
    <other_name>Selozok</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>placebo</intervention_name>
    <arm_group_label>Placebo</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  more than 18 years old.&#xD;
&#xD;
          -  must have signed the written informed consent.&#xD;
&#xD;
          -  nonalcoholic cirrhosis.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Betablockers intolerance;&#xD;
&#xD;
          -  Diagnosis of other cardiomyopathy&#xD;
&#xD;
          -  Chronicle renal disease (Creatinine &gt; 2.5)&#xD;
&#xD;
          -  Heavy alcohol intake history&#xD;
&#xD;
          -  Presence of other disease with possible cardiac implication (infiltrative or storage&#xD;
             disease)&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>60 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Fernando Bacal, MD, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Sao Paulo School of Medicine</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>University of Sao Paulo School of Medicine</name>
      <address>
        <city>Sao Paulo</city>
        <zip>05403000</zip>
        <country>Brazil</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Brazil</country>
  </location_countries>
  <verification_date>September 2014</verification_date>
  <study_first_submitted>August 28, 2012</study_first_submitted>
  <study_first_submitted_qc>August 29, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">August 30, 2012</study_first_posted>
  <last_update_submitted>September 9, 2014</last_update_submitted>
  <last_update_submitted_qc>September 9, 2014</last_update_submitted_qc>
  <last_update_posted type="Estimate">September 11, 2014</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>University of Sao Paulo</investigator_affiliation>
    <investigator_full_name>Fernando Bacal</investigator_full_name>
    <investigator_title>MD; PhD</investigator_title>
  </responsible_party>
  <keyword>Cirrhosis</keyword>
  <keyword>cirrhotic cardiomyopathy</keyword>
  <keyword>cardiac remodeling</keyword>
  <keyword>cardiomyopathy</keyword>
  <keyword>metoprolol succinate</keyword>
  <keyword>betablockers</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Liver Cirrhosis</mesh_term>
    <mesh_term>Cardiomyopathies</mesh_term>
    <mesh_term>Fibrosis</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Metoprolol</mesh_term>
  </intervention_browse>
  <!-- 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/NCT01676285
org study id: 0010/11
nct id: NCT01676285
lead sponsor: 
collaborator: 
has dmc: Yes
Cirrhotic cardiomyopathy is defined as a chronic cardiac dysfunction in patients with
      cirrhosis. It is suspected that this specific cardiac dysfunction contributes to the onset of
      complications in liver disease. The purpose of this prospective, randomized trial is to
      determine whether metoprolol succinate can revert cardiac dysfunction secondary to cirrhosis
      (cirrhotic cardiomyopathy), and prevent complications (renal dysfunction, mortality). A total
      of 100 patients with cirrhotic cardiomyopathy will be randomized (Group R) to receive
      metoprolol succinate or placebo; other 25 patients without cirrhotic cardiomyopathy (Group F)
      will only be followed up without medication. All patients will be evaluated in the beginning
      and again after six months. The assessment protocol includes clinical evaluation,
      electrocardiogram, echocardiogram, laboratory analysis and life quality questionaire. The end
      points will be cardiac remodeling, electrophysiologic changes, sympathetic activity,
      laboratory issue changes, renal function, quality of life, and mortality.
Cirrhotic cardiomyopathy (CMC) is defined as a chronic cardiac dysfunction in patients with
      cirrhosis. Moreover, it is characterized by an abnormal and blunted response to pathological
      or pharmacological stress in the absence of any other associated cardiac disease. The
      diagnostic criteria are: baseline increased cardiac output, attenuated myocardial contractile
      response to stress, diastolic dysfunction, and electrophysiological repolarization
      abnormalities. It is suspected that cardiac dysfunction in cirrhosis contribute to the onset
      of complications in liver disease. We will investigate the effect of metoprolol succinate in
      the reversal of cardiac dysfunction and prevention of complications of cirrhosis in patients
      with cirrhotic cardiomyopathy. Furthermore, we want to study the influence of presence of CMC
      in the evolution of cirrhotic patients. The study will be prospective, randomized,
      double-blind, and placebo-controlled. The sample consists of 125 patients aged between 18 and
      60 years old diagnosed with severe liver cirrhosis (Child B or C or MELD score above 10) with
      cirrhotic cardiomyopathy or not. Of these, 100 patients with cirrhotic cardiomyopathy will be
      randomized into two groups: group R1 (metoprolol succinate) and group R2 (placebo). Group F
      will consist of cirrhotic patients without cardiomyopathy and will not receive medication.
      Patients will be evaluated by clinical examination, resting electrocardiogram, 24-hour
      Holter, stress echocardiography and laboratory (brain natriuretic peptide (BNP),
      catecholamines, plasma renin activity, and troponin) at inclusion and after six months. The
      end points are: 1) Reversal of cardiac dysfunction in patients with cirrhotic cardiomyopathy,
      2) Development of hepatorenal syndrome, 3) Reversal of the electrophysiologic abnormalities,
      4)Changes in laboratory tests, and 5) Mortality.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
measure: Improvement of systolic function
time frame: six months
description: Systolic functional reserve is measured by aortic velocity time integral in echocardiographic at rest and stress with dobutamine.
measure: Improvement in left ventricular diastolic function
time frame: six months
measure: Renal function
time frame: From randomization until six months
measure: Serum level of BNP, catecholamines, plasmatic renin activity
time frame: Six months
measure: Mortality
time frame: From randomization until six months of follow up
measure: Quality of life
time frame: Six months
measure: Electrophysiologic modifications
time frame: Six months
description: QT prolongation R-R variability
arm group label: Metoprolol succinate
arm group type: Active Comparator
description: Metoprolol succinate
arm group label: Placebo
arm group type: Placebo Comparator
description: Placebo
arm group label: Follow up
arm group type: No Intervention
description: Group without cirrhotic cardiomyopathy, only follow up without randomization.
intervention type: Drug
intervention name: Metoprolol succinate
arm group label: Metoprolol succinate
other name: Selozok
intervention type: Drug
intervention name: placebo
arm group label: Placebo
criteria: 
gender: All
minimum age: 18 Years
maximum age: 60 Years
healthy volunteers: No
last name: Fernando Bacal, MD, PhD
role: Principal Investigator
affiliation: University of Sao Paulo School of Medicine
facility: 
country: Brazil
responsible party type: Principal Investigator
investigator affiliation: University of Sao Paulo
investigator full name: Fernando Bacal
investigator title: MD; PhD
mesh term: Liver Cirrhosis
mesh term: Cardiomyopathies
mesh term: Fibrosis
mesh term: Metoprolol