<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/NCT02236247</url>
  </required_header>
  <id_info>
    <org_study_id>CAAE:09145612.8.0000.0068</org_study_id>
    <secondary_id>2012/06163-6</secondary_id>
    <nct_id>NCT02236247</nct_id>
  </id_info>
  <brief_title>Control of Sinus Node Tachycardia as an Additional Therapy in Patients With Decompensated Heart Failure</brief_title>
  <acronym>CONSTATHE</acronym>
  <official_title>Heart Rate Control as an Additional Therapeutic Strategy in Patients With Decompensated Heart Failure: a Prospective, Randomized, Double-blinded, Placebo-controlled 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>
      Study aims to compare the I(f) inhibitor ivabradine with placebo as strategy of heart rate&#xD;
      control in patients with decompensated heart failure (DHF).&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Sympathetic hyperactivity and consequent increase in heart rate (HR) are physiological&#xD;
      responses to low cardiac output in patients with decompensated heart failure (DHF). However,&#xD;
      elevated HR may become inappropriate in these patients, increasing myocardial oxygen demand&#xD;
      and decreasing diastolic filling time and might lead to hemodynamic deterioration,&#xD;
      ventricular dysfunction (tachycardiomyopathy) and clinical deterioration.&#xD;
&#xD;
      Studies show the elevated HR is a predictor of poor prognosis in DHF. Subanalyses of large&#xD;
      clinical trials using beta blockers (BBs) demonstrate the adequate control of HR correlates&#xD;
      with a better outcome in patients with stable chronic heart failure (HF). However, use of BBs&#xD;
      in patients with DHF is limited due to negative inotropic and hypotensive effects of these&#xD;
      drugs.&#xD;
&#xD;
      As alternative to BBs, ivabradine has shown to increase survival of patients with chronic&#xD;
      stable systolic HF. Compared to BBs, ivabradine has the advantage of &quot;pure&quot; negative&#xD;
      chronotropic effect, no effect on myocardial contractility or peripheral vascular resistance.&#xD;
      Despite the inhibition of I (f) has been validated as a therapeutic option in patients with&#xD;
      stable HF, there are no studies available on this strategy in patients with DHF.&#xD;
&#xD;
      We hypothesized that HR control by ivabradine might improve clinical, hemodynamic and&#xD;
      neurohormonal parameters in patients with DHF. The aim of this study was to evaluate the&#xD;
      efficacy of HR control with ivabradine in patients with DHF.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Recruiting</last_known_status>
  <start_date>May 2013</start_date>
  <completion_date type="Anticipated">August 2017</completion_date>
  <primary_completion_date type="Anticipated">January 2017</primary_completion_date>
  <phase>Phase 1/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>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Change from baseline heart rate</measure>
    <time_frame>Baseline, day 5 after intervention</time_frame>
    <description>Heart rate will be assessed at morning, after 30 minutes of rest, recorded by electrocardiogram.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Change from baseline blood pressure</measure>
    <time_frame>Baseline, day 5 after intervention</time_frame>
    <description>Blood pressure will be measured at morning by electronic cuff</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change from baseline ejection fraction</measure>
    <time_frame>Baseline, day 5 after intervention</time_frame>
    <description>Ejection fraction will be measured by echocardiography using Simpson´s rule</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change from baseline stroke volume</measure>
    <time_frame>Baseline, day 5 after intervention</time_frame>
    <description>Stroke volume will be measured by echocardiography using Doppler velocity-time integral technique.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change from baseline creatinine</measure>
    <time_frame>Baseline, day 5 after intervention</time_frame>
    <description>Serum creatinine will be measured</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change from baseline brain natriuretic peptide</measure>
    <time_frame>Baseline, day 5 after intervention</time_frame>
    <description>Serum brain natriuretic peptide will be measured</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Clinical</measure>
    <time_frame>Up to 6 months</time_frame>
    <description>Time of survival and free of readmission</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Safety/Adverse Event Outcome Measure</measure>
    <time_frame>Up to day 15 days after intervention</time_frame>
    <description>Number of Participants with Serious and Non-Serious Adverse Events</description>
  </other_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">50</enrollment>
  <condition>Decompensated Heart Failure</condition>
  <arm_group>
    <arm_group_label>ivabradine</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>I(f) inhibitor, heart rate controller</description>
  </arm_group>
  <arm_group>
    <arm_group_label>placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>placebo pill will be administered orally twice daily</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>ivabradine</intervention_name>
    <description>5 mg oral twice daily</description>
    <arm_group_label>ivabradine</arm_group_label>
    <other_name>procoralan</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>A placebo pill (identical to ivabradine) will be administered twice daily</description>
    <arm_group_label>placebo</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Sinus node rhythm&#xD;
&#xD;
          -  HR&gt; 80 bpm&#xD;
&#xD;
          -  Hospitalization for DHF&#xD;
&#xD;
          -  Ejection fraction ≤ 40%&#xD;
&#xD;
          -  Sign informed consent&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Systolic blood pressure &lt;85 mmHg&#xD;
&#xD;
          -  Signs of hypoperfusion&#xD;
&#xD;
          -  Dobutamine&gt;15 mcg/Kg/min&#xD;
&#xD;
          -  Acute myocarditis&#xD;
&#xD;
          -  Primary valvular disease requiring surgery&#xD;
&#xD;
          -  Stroke in the last three months&#xD;
&#xD;
          -  Hypertrophic or restrictive cardiomyopathy&#xD;
&#xD;
          -  Sinus node disease&#xD;
&#xD;
          -  Atrial fibrillation or flutter&#xD;
&#xD;
          -  Second or third degree atrio-ventricular blockade&#xD;
&#xD;
          -  Long QT syndrome&#xD;
&#xD;
          -  Severe pulmonary disease&#xD;
&#xD;
          -  Pulmonary embolism in the last three months&#xD;
&#xD;
          -  Need for invasive ventilatory support&#xD;
&#xD;
          -  Septicemia or septic shock&#xD;
&#xD;
          -  Hepatic failure&#xD;
&#xD;
          -  Creatinine &gt; 2.5 mg/dL&#xD;
&#xD;
          -  Hemodialysis&#xD;
&#xD;
          -  Advanced malignancy&#xD;
&#xD;
          -  Pregnancy or lactation&#xD;
&#xD;
          -  Immunosuppressive therapy&#xD;
&#xD;
          -  Use of cytochrome P450 inhibitors&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>75 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Edimar A Bocchi, MD-PHD</last_name>
    <role>Study Chair</role>
    <affiliation>Heart Failure Unit, Heart Institute, University of Sao Paulo Medical School</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Marco S. Alves, MD</last_name>
    <phone>+55 11 981431512</phone>
    <email>marco.alves@incor.usp.br</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Edimar A. Bocchi, MD-PHD</last_name>
    <phone>+55 11 2661-5419</phone>
    <email>edimar.bocchi@incor.usp.br</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>Heart Failure Unit, Heart Institute, University of Sao Paulo Medical School</name>
      <address>
        <city>Sao Paulo</city>
        <zip>05403-900</zip>
        <country>Brazil</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Marco S Alves, MD</last_name>
      <phone>+55 11 981431512</phone>
      <email>marco.alves@incor.usp.br</email>
    </contact>
    <contact_backup>
      <last_name>Edimar A Bocchi, MD-PHD</last_name>
      <phone>+55 11 2661-5419</phone>
      <email>edimar.bocchi@incor.usp.br</email>
    </contact_backup>
    <investigator>
      <last_name>Marco S Alves, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location_countries>
    <country>Brazil</country>
  </location_countries>
  <results_reference>
    <citation>Lofrano-Alves MS, Issa VS, Biselli B, Chizzola P, Ayub-Ferreira SM, Bocchi EA. Control of sinus tachycardia as an additional therapy in patients with decompensated heart failure (CONSTATHE-DHF): A randomized, double-blind, placebo-controlled trial. J Heart Lung Transplant. 2016 Oct;35(10):1260-1264. doi: 10.1016/j.healun.2016.06.005. Epub 2016 Jun 7. No abstract available.</citation>
    <PMID>27469019</PMID>
  </results_reference>
  <verification_date>December 2016</verification_date>
  <study_first_submitted>September 2, 2014</study_first_submitted>
  <study_first_submitted_qc>September 9, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">September 10, 2014</study_first_posted>
  <last_update_submitted>December 30, 2016</last_update_submitted>
  <last_update_submitted_qc>December 30, 2016</last_update_submitted_qc>
  <last_update_posted type="Estimate">January 2, 2017</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>University of Sao Paulo</investigator_affiliation>
    <investigator_full_name>Marco Stephan Lofrano Alves</investigator_full_name>
    <investigator_title>MD</investigator_title>
  </responsible_party>
  <keyword>ivabradine</keyword>
  <keyword>heart rate</keyword>
  <keyword>heart failure</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Heart Failure</mesh_term>
  </condition_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/NCT02236247
org study id: CAAE:09145612.8.0000.0068
secondary id: 2012/06163-6
nct id: NCT02236247
lead sponsor: 
collaborator: 
has dmc: Yes
Study aims to compare the I(f) inhibitor ivabradine with placebo as strategy of heart rate
      control in patients with decompensated heart failure (DHF).
Sympathetic hyperactivity and consequent increase in heart rate (HR) are physiological
      responses to low cardiac output in patients with decompensated heart failure (DHF). However,
      elevated HR may become inappropriate in these patients, increasing myocardial oxygen demand
      and decreasing diastolic filling time and might lead to hemodynamic deterioration,
      ventricular dysfunction (tachycardiomyopathy) and clinical deterioration.

      Studies show the elevated HR is a predictor of poor prognosis in DHF. Subanalyses of large
      clinical trials using beta blockers (BBs) demonstrate the adequate control of HR correlates
      with a better outcome in patients with stable chronic heart failure (HF). However, use of BBs
      in patients with DHF is limited due to negative inotropic and hypotensive effects of these
      drugs.

      As alternative to BBs, ivabradine has shown to increase survival of patients with chronic
      stable systolic HF. Compared to BBs, ivabradine has the advantage of "pure" negative
      chronotropic effect, no effect on myocardial contractility or peripheral vascular resistance.
      Despite the inhibition of I (f) has been validated as a therapeutic option in patients with
      stable HF, there are no studies available on this strategy in patients with DHF.

      We hypothesized that HR control by ivabradine might improve clinical, hemodynamic and
      neurohormonal parameters in patients with DHF. The aim of this study was to evaluate the
      efficacy of HR control with ivabradine in patients with DHF.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
measure: Change from baseline heart rate
time frame: Baseline, day 5 after intervention
description: Heart rate will be assessed at morning, after 30 minutes of rest, recorded by electrocardiogram.
measure: Change from baseline blood pressure
time frame: Baseline, day 5 after intervention
description: Blood pressure will be measured at morning by electronic cuff
measure: Change from baseline ejection fraction
time frame: Baseline, day 5 after intervention
description: Ejection fraction will be measured by echocardiography using Simpson´s rule
measure: Change from baseline stroke volume
time frame: Baseline, day 5 after intervention
description: Stroke volume will be measured by echocardiography using Doppler velocity-time integral technique.
measure: Change from baseline creatinine
time frame: Baseline, day 5 after intervention
description: Serum creatinine will be measured
measure: Change from baseline brain natriuretic peptide
time frame: Baseline, day 5 after intervention
description: Serum brain natriuretic peptide will be measured
measure: Clinical
time frame: Up to 6 months
description: Time of survival and free of readmission
measure: Safety/Adverse Event Outcome Measure
time frame: Up to day 15 days after intervention
description: Number of Participants with Serious and Non-Serious Adverse Events
arm group label: ivabradine
arm group type: Experimental
description: I(f) inhibitor, heart rate controller
arm group label: placebo
arm group type: Placebo Comparator
description: placebo pill will be administered orally twice daily
intervention type: Drug
intervention name: ivabradine
description: 5 mg oral twice daily
arm group label: ivabradine
other name: procoralan
intervention type: Drug
intervention name: Placebo
description: A placebo pill (identical to ivabradine) will be administered twice daily
arm group label: placebo
criteria: 
gender: All
minimum age: 18 Years
maximum age: 75 Years
healthy volunteers: No
last name: Edimar A Bocchi, MD-PHD
role: Study Chair
affiliation: Heart Failure Unit, Heart Institute, University of Sao Paulo Medical School
last name: Marco S. Alves, MD
phone: +55 11 981431512
email: marco.alves@incor.usp.br
last name: Edimar A. Bocchi, MD-PHD
phone: +55 11 2661-5419
email: edimar.bocchi@incor.usp.br
facility: 
status: Recruiting
contact: 
contact backup: 
investigator: 
country: Brazil
citation: Lofrano-Alves MS, Issa VS, Biselli B, Chizzola P, Ayub-Ferreira SM, Bocchi EA. Control of sinus tachycardia as an additional therapy in patients with decompensated heart failure (CONSTATHE-DHF): A randomized, double-blind, placebo-controlled trial. J Heart Lung Transplant. 2016 Oct;35(10):1260-1264. doi: 10.1016/j.healun.2016.06.005. Epub 2016 Jun 7. No abstract available.
PMID: 27469019
responsible party type: Principal Investigator
investigator affiliation: University of Sao Paulo
investigator full name: Marco Stephan Lofrano Alves
investigator title: MD
mesh term: Heart Failure
sharing ipd: No