<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/NCT04405804</url>
  </required_header>
  <id_info>
    <org_study_id>1986 / 2019</org_study_id>
    <secondary_id>2019-003902-29</secondary_id>
    <nct_id>NCT04405804</nct_id>
  </id_info>
  <brief_title>Early Administration of Ivabradine in Children With Heart Failure</brief_title>
  <acronym>EASI-Child</acronym>
  <official_title>A Monocentric, Open Label, Single Arm, Pilot Study on the Early Administration of Ivabradine in Children Aged &gt;6 Months and &lt;18 Years With Dilated Cardiomyopathy and Acute Heart Failure</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Bambino Gesù Hospital and Research Institute</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Ministero della Salute, Italy</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Bambino Gesù Hospital and Research Institute</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>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      This is a monocentric, prospective, single arm, not for profit study. It is designed to study&#xD;
      the early use of ivabradine in patients with dilated cardiomyopathy and Ejection Fraction&#xD;
      (EF) &lt; 45%.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The study is divided into a screening and enrollment visit (V1) where eligibility for&#xD;
      treatment will be confirmed. Ivabradine will be administered to eligible patients with&#xD;
      increasing dosage during the titration period (TP) which will last from a minimum of 3 days&#xD;
      to a maximum of 15 days. This will be followed by a maintenance period (MP) of the drug for a&#xD;
      further 14 days. The follow-up period (FU) will last 4 months.&#xD;
&#xD;
      The dose of ACE inhibitors will be introduced after 72 hours of clinical stability after the&#xD;
      introduction of titrated ivabradine at maximum dose according to protocol. The&#xD;
      anti-aldosterone will be introduced 24 hours after the introduction of ivabradine. The&#xD;
      diuretic will not be modified during the titration phase of the drug, unless there is&#xD;
      clinical necessity.&#xD;
&#xD;
      During the FU ivabradine will be continued at stable dosage, in order to maintain the target&#xD;
      heart rate (HR) reached during the maintenance phase (HR &gt; 80 bpm, in the group of patients&#xD;
      older than 6-12 months, or HR &gt; 70 bpm in patients aged 1-3 years or HR &gt; 50 bpm between 3-18&#xD;
      years). In all patients, the drug dose will be decreased or discontinued in case of&#xD;
      bradycardia (HR&lt; 80 bpm in patients 6-12 months, HR&lt; 70 bpm in patients 1-3 years of age or&#xD;
      HR&lt; 60 bpm in patients 3-18 years of age) and/or symptoms related to bradycardia or for other&#xD;
      safety reasons.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Enrolling by invitation</last_known_status>
  <start_date type="Actual">June 20, 2020</start_date>
  <completion_date type="Anticipated">May 2021</completion_date>
  <primary_completion_date type="Anticipated">January 2021</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <intervention_model_description>Simon's two-stage design</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Heart rate in b.p.m. (mean (±SD) difference from baseline) at the end of maintenance</measure>
    <time_frame>At the end of the two weeks maintenance period (17-29 days from enrollment)</time_frame>
    <description>To assess the response to ivabradine on heart rate after 14 days of stable therapy</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Heart rate in b.p.m. (mean (±SD) difference from baseline) at the end of follow-up</measure>
    <time_frame>At the end of the 16 weeks follow-up period (129-141 days from enrollment)</time_frame>
    <description>To assess the response to ivabradine on heart rate after 16 weeks of follow-up</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Serum NT-proBNP in pg/mL (mean (±SD) difference from baseline) at the end of maintenance</measure>
    <time_frame>At the end of the two weeks maintenance period (17-29 days from enrollment)</time_frame>
    <description>To assess the response to ivabradine on serum NT-proBNP levels after 14 days of stable therapy</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Serum NT-proBNP in pg/mL (mean (±SD) difference from baseline) at the end of follow-up</measure>
    <time_frame>At the end of the 16 weeks follow-up period (129-141 days from enrollment)</time_frame>
    <description>To assess the response to ivabradine on serum NT-proBNP levels after 16 weeks of follow-up</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Correlation between heart rate and NT-proBNP value (Pearson correlation) at the end of maintenance</measure>
    <time_frame>At the end of the two weeks maintenance period (17-29 days from enrollment)</time_frame>
    <description>To assess the correlation between heart rate and serum NT-proBNP levels after 14 days of stable therapy</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Correlation between heart rate and NT-proBNP value (Pearson correlation) at the end of follow-up</measure>
    <time_frame>At the end of the 16 weeks follow-up period (129-141 days from enrollment)</time_frame>
    <description>To assess the correlation between heart rate and serum NT-proBNP levels after 16 weeks of follow-up</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Left ventricular function, calculated by 2D echocardiographic technique (calculation of left ventricular volume and ejection fraction - mean (±SD) difference from baseline) at the end of maintenance</measure>
    <time_frame>At the end of the two weeks maintenance period (17-29 days from enrollment)</time_frame>
    <description>To assess EF, Left Ventricular End Diastolic Volume (LVEDV), Left Ventricular End Systolic Volume (LVESV) after 14 days of stable therapy</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Left ventricular function, calculated by 2D echocardiographic technique (calculation of left ventricular volume and ejection fraction - mean (±SD) difference from baseline) at the end of follow-up</measure>
    <time_frame>At the end of the 16 weeks follow-up period (129-141 days from enrollment)</time_frame>
    <description>To assess EF, LVSV, LVDV after 16 weeks of follow-up</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Systolic blood pressure in mmHg (mean (±SD) difference from baseline) at the end of maintenance</measure>
    <time_frame>At the end of the two weeks maintenance period (17-29 days from enrollment)</time_frame>
    <description>To assess the response to ivabradine on systolic blood pressure after 14 days of stable therapy</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Systolic blood pressure in mmHg (mean (±SD) difference from baseline) at the end of follow-up</measure>
    <time_frame>At the end of the 16 weeks follow-up period (129-141 days from enrollment)</time_frame>
    <description>To assess the response to ivabradine on systolic blood pressure after 16 weeks of follow-up</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Use of inotropic drugs (number and % of patients who had to use inotropes at the end of maintenance)</measure>
    <time_frame>At the end of the two weeks maintenance period (17-29 days from enrollment)</time_frame>
    <description>To assess the need to resort to inotropic drugs within 14 days of stable ivabradine therapy</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Use of inotropic drugs (number and % of patients who had to use inotropes at the end of follow-up)</measure>
    <time_frame>At the end of the 16 weeks follow-up period (129-141 days from enrollment)</time_frame>
    <description>To assess the need to resort to inotropic drugs within 16 weeks of follow-up</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number and % of dropouts at the end of maintenance</measure>
    <time_frame>At the end of the two weeks maintenance period (17-29 days from enrollment)</time_frame>
    <description>To assess the frequency of patients who exit from the study within 14 days of stable ivabradine therapy</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number and % of dropouts at the end of follow-up</measure>
    <time_frame>At the end of the 16 weeks follow-up period (129-141 days from enrollment)</time_frame>
    <description>To assess the frequency of patients who exit from the study within 16 weeks of follow-up</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Time (days) from start of ivabradine therapy and new episode of acute heart failure, and/or implantation of mechanical assist device at the end of follow up</measure>
    <time_frame>At the end of the 16 weeks follow-up period (129-141 days from enrollment)</time_frame>
    <description>To assess the period within main cardiological events would occur after the start of ivabradine therapy</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Anticipated">9</enrollment>
  <condition>Acute Heart Failure</condition>
  <condition>Dilated Cardiomyopathy</condition>
  <arm_group>
    <arm_group_label>Ivabradine</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Eligible patients will be given treatment with ivabradine during a titration period which will last from a minimum of 3 days to a maximum of 15 days. This will be followed by a maintenance period of another 14 days. At the end of maintenance period, primary endpoint will be assessed. After maintenance period, the patient will continue ivabradine at the same dosage during a follow-up period that will last 4 months.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Ivabradine 5Mg Tab</intervention_name>
    <description>Initial dose of ivabradine will be:&#xD;
0.02 mg/kg/dose twice daily in patients between 6-12 months 0.05 mg/kg/dose twice daily in patients between 1-3 years and 3-18 years with a weight &lt; 40 kg 2.5 mg/day in patients between 3-18 years with weight &gt; 40 kg During titration phase, the dose may be increased, maintained, reduced or discontinued in accordance with titration rules. The titration rules will be adjusted on the basis of age subset and of each patient's evaluation during the titration phase, whether or not the target heart rate is reached (HR ≥ 20% compared to baseline HR) and whether or not are present bradycardia (HR should be greater than predefined by a HR threshold per age subset) and/or bradycardia-related symptoms.&#xD;
Maximum dose to be reached will be:&#xD;
0.2 mg/kg/dose twice daily in patients between 6-12 months 0.3 mg/kg/dose twice daily in patients between 1-3 years and 3-18 years with a weight &lt; 40 kg 15 mg/day in patients between 3-18 years, weight &gt; 40 kg</description>
    <arm_group_label>Ivabradine</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Dilated cardiomyopathy defined according to the indications of the Cardiomyopathy Task&#xD;
             Force (dilation &gt; 2 Standard Deviations (SD) and hypokinesia);&#xD;
&#xD;
          -  Class NYHA/Ross ≥ II;&#xD;
&#xD;
          -  Ejection fraction &lt; 40%;&#xD;
&#xD;
          -  Patients with acute heart failure episodes (both new episode and relapse) in the last&#xD;
             three months;&#xD;
&#xD;
          -  Systolic blood pressure &gt; 50° age and height;&#xD;
&#xD;
          -  Heart rate: 6-12 months: ≥105 bpm, &gt;1 year &lt;3 years: ≥95 bpm, 3-5 years: ≥75 bpm, 5-18&#xD;
             years: &gt;70 bpm.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Cardiogenic shock in the three months;&#xD;
&#xD;
          -  Hypertrophic, restrictive or mixed cardiomyopathy;&#xD;
&#xD;
          -  Acute lymphocytic myocarditis diagnosed with endomyocardial biopsy;&#xD;
&#xD;
          -  Significant Valvular Pathology;&#xD;
&#xD;
          -  Sinus block and congenital long QT syndrome;&#xD;
&#xD;
          -  Atrial Fibrillation;&#xD;
&#xD;
          -  Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels &gt; 2.5 times&#xD;
             normal, bilirubin &gt; 3 and creatinine &gt; 2.5 mg/dL;&#xD;
&#xD;
          -  Pregnancy and/or positive pregnancy test patients;&#xD;
&#xD;
          -  Hypersensitivity to the active substance or any of the excipients;&#xD;
&#xD;
          -  Participation in a clinical trial in which an experimental drug was administered&#xD;
             within 30 days or 5 half-lives of the investigational drug;&#xD;
&#xD;
          -  Chronic lung disease or other clinical condition that the investigating physician&#xD;
             believes is incompatible with the study;&#xD;
&#xD;
          -  eGFR &lt;15 mL/min/1.73 m2.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>6 Months</minimum_age>
    <maximum_age>17 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Rachele Adorisio, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Bambino Gesù Hospital and Research Institute</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Bambino Gesù Hospital and Research Institute</name>
      <address>
        <city>Rome</city>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Italy</country>
  </location_countries>
  <verification_date>December 2020</verification_date>
  <study_first_submitted>May 26, 2020</study_first_submitted>
  <study_first_submitted_qc>May 26, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">May 28, 2020</study_first_posted>
  <last_update_submitted>December 4, 2020</last_update_submitted>
  <last_update_submitted_qc>December 4, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">December 8, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Bambino Gesù Hospital and Research Institute</investigator_affiliation>
    <investigator_full_name>Rachele Adorisio</investigator_full_name>
    <investigator_title>MD</investigator_title>
  </responsible_party>
  <keyword>Ivabradine</keyword>
  <keyword>Heart Failure</keyword>
  <keyword>Pediatric</keyword>
  <keyword>Cardiomyopathy</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Heart Failure</mesh_term>
    <mesh_term>Cardiomyopathies</mesh_term>
    <mesh_term>Cardiomyopathy, Dilated</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/NCT04405804
org study id: 1986 / 2019
secondary id: 2019-003902-29
nct id: NCT04405804
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
is us export: No
This is a monocentric, prospective, single arm, not for profit study. It is designed to study
      the early use of ivabradine in patients with dilated cardiomyopathy and Ejection Fraction
      (EF) < 45%.
The study is divided into a screening and enrollment visit (V1) where eligibility for
      treatment will be confirmed. Ivabradine will be administered to eligible patients with
      increasing dosage during the titration period (TP) which will last from a minimum of 3 days
      to a maximum of 15 days. This will be followed by a maintenance period (MP) of the drug for a
      further 14 days. The follow-up period (FU) will last 4 months.

      The dose of ACE inhibitors will be introduced after 72 hours of clinical stability after the
      introduction of titrated ivabradine at maximum dose according to protocol. The
      anti-aldosterone will be introduced 24 hours after the introduction of ivabradine. The
      diuretic will not be modified during the titration phase of the drug, unless there is
      clinical necessity.

      During the FU ivabradine will be continued at stable dosage, in order to maintain the target
      heart rate (HR) reached during the maintenance phase (HR > 80 bpm, in the group of patients
      older than 6-12 months, or HR > 70 bpm in patients aged 1-3 years or HR > 50 bpm between 3-18
      years). In all patients, the drug dose will be decreased or discontinued in case of
      bradycardia (HR< 80 bpm in patients 6-12 months, HR< 70 bpm in patients 1-3 years of age or
      HR< 60 bpm in patients 3-18 years of age) and/or symptoms related to bradycardia or for other
      safety reasons.
allocation: N/A
intervention model: Single Group Assignment
intervention model description: Simon's two-stage design
primary purpose: Treatment
masking: None (Open Label)
measure: Heart rate in b.p.m. (mean (±SD) difference from baseline) at the end of maintenance
time frame: At the end of the two weeks maintenance period (17-29 days from enrollment)
description: To assess the response to ivabradine on heart rate after 14 days of stable therapy
measure: Heart rate in b.p.m. (mean (±SD) difference from baseline) at the end of follow-up
time frame: At the end of the 16 weeks follow-up period (129-141 days from enrollment)
description: To assess the response to ivabradine on heart rate after 16 weeks of follow-up
measure: Serum NT-proBNP in pg/mL (mean (±SD) difference from baseline) at the end of maintenance
time frame: At the end of the two weeks maintenance period (17-29 days from enrollment)
description: To assess the response to ivabradine on serum NT-proBNP levels after 14 days of stable therapy
measure: Serum NT-proBNP in pg/mL (mean (±SD) difference from baseline) at the end of follow-up
time frame: At the end of the 16 weeks follow-up period (129-141 days from enrollment)
description: To assess the response to ivabradine on serum NT-proBNP levels after 16 weeks of follow-up
measure: Correlation between heart rate and NT-proBNP value (Pearson correlation) at the end of maintenance
time frame: At the end of the two weeks maintenance period (17-29 days from enrollment)
description: To assess the correlation between heart rate and serum NT-proBNP levels after 14 days of stable therapy
measure: Correlation between heart rate and NT-proBNP value (Pearson correlation) at the end of follow-up
time frame: At the end of the 16 weeks follow-up period (129-141 days from enrollment)
description: To assess the correlation between heart rate and serum NT-proBNP levels after 16 weeks of follow-up
measure: Left ventricular function, calculated by 2D echocardiographic technique (calculation of left ventricular volume and ejection fraction - mean (±SD) difference from baseline) at the end of maintenance
time frame: At the end of the two weeks maintenance period (17-29 days from enrollment)
description: To assess EF, Left Ventricular End Diastolic Volume (LVEDV), Left Ventricular End Systolic Volume (LVESV) after 14 days of stable therapy
measure: Left ventricular function, calculated by 2D echocardiographic technique (calculation of left ventricular volume and ejection fraction - mean (±SD) difference from baseline) at the end of follow-up
time frame: At the end of the 16 weeks follow-up period (129-141 days from enrollment)
description: To assess EF, LVSV, LVDV after 16 weeks of follow-up
measure: Systolic blood pressure in mmHg (mean (±SD) difference from baseline) at the end of maintenance
time frame: At the end of the two weeks maintenance period (17-29 days from enrollment)
description: To assess the response to ivabradine on systolic blood pressure after 14 days of stable therapy
measure: Systolic blood pressure in mmHg (mean (±SD) difference from baseline) at the end of follow-up
time frame: At the end of the 16 weeks follow-up period (129-141 days from enrollment)
description: To assess the response to ivabradine on systolic blood pressure after 16 weeks of follow-up
measure: Use of inotropic drugs (number and % of patients who had to use inotropes at the end of maintenance)
time frame: At the end of the two weeks maintenance period (17-29 days from enrollment)
description: To assess the need to resort to inotropic drugs within 14 days of stable ivabradine therapy
measure: Use of inotropic drugs (number and % of patients who had to use inotropes at the end of follow-up)
time frame: At the end of the 16 weeks follow-up period (129-141 days from enrollment)
description: To assess the need to resort to inotropic drugs within 16 weeks of follow-up
measure: Number and % of dropouts at the end of maintenance
time frame: At the end of the two weeks maintenance period (17-29 days from enrollment)
description: To assess the frequency of patients who exit from the study within 14 days of stable ivabradine therapy
measure: Number and % of dropouts at the end of follow-up
time frame: At the end of the 16 weeks follow-up period (129-141 days from enrollment)
description: To assess the frequency of patients who exit from the study within 16 weeks of follow-up
measure: Time (days) from start of ivabradine therapy and new episode of acute heart failure, and/or implantation of mechanical assist device at the end of follow up
time frame: At the end of the 16 weeks follow-up period (129-141 days from enrollment)
description: To assess the period within main cardiological events would occur after the start of ivabradine therapy
arm group label: Ivabradine
arm group type: Experimental
description: Eligible patients will be given treatment with ivabradine during a titration period which will last from a minimum of 3 days to a maximum of 15 days. This will be followed by a maintenance period of another 14 days. At the end of maintenance period, primary endpoint will be assessed. After maintenance period, the patient will continue ivabradine at the same dosage during a follow-up period that will last 4 months.
intervention type: Drug
intervention name: Ivabradine 5Mg Tab
description: Initial dose of ivabradine will be:
0.02 mg/kg/dose twice daily in patients between 6-12 months 0.05 mg/kg/dose twice daily in patients between 1-3 years and 3-18 years with a weight < 40 kg 2.5 mg/day in patients between 3-18 years with weight > 40 kg During titration phase, the dose may be increased, maintained, reduced or discontinued in accordance with titration rules. The titration rules will be adjusted on the basis of age subset and of each patient's evaluation during the titration phase, whether or not the target heart rate is reached (HR ≥ 20% compared to baseline HR) and whether or not are present bradycardia (HR should be greater than predefined by a HR threshold per age subset) and/or bradycardia-related symptoms.
Maximum dose to be reached will be:
0.2 mg/kg/dose twice daily in patients between 6-12 months 0.3 mg/kg/dose twice daily in patients between 1-3 years and 3-18 years with a weight < 40 kg 15 mg/day in patients between 3-18 years, weight > 40 kg
arm group label: Ivabradine
criteria: 
gender: All
minimum age: 6 Months
maximum age: 17 Years
healthy volunteers: No
last name: Rachele Adorisio, MD
role: Principal Investigator
affiliation: Bambino Gesù Hospital and Research Institute
facility: 
country: Italy
responsible party type: Principal Investigator
investigator affiliation: Bambino Gesù Hospital and Research Institute
investigator full name: Rachele Adorisio
investigator title: MD
mesh term: Heart Failure
mesh term: Cardiomyopathies
mesh term: Cardiomyopathy, Dilated
sharing ipd: No