<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/NCT01723371</url>
  </required_header>
  <id_info>
    <org_study_id>1000031903</org_study_id>
    <nct_id>NCT01723371</nct_id>
  </id_info>
  <brief_title>Beta Blockers for Treatment of Pulmonary Arterial Hypertension in Children</brief_title>
  <official_title>Beta Blockers for Treatment of Pulmonary Arterial Hypertension in Children</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>The Hospital for Sick Children</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>The Hospital for Sick Children</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      This study will determine the safety and feasibility of using a β-blocker (in this case&#xD;
      carvedilol) in the treatment of pediatric patients with Left Heart Failure (LHF) in children&#xD;
      with Pulmonary Arterial Hypertension (PAH). Carvedilol affects the nervous system, the same&#xD;
      system that is highly activated in response to stress in patients with PAH. Each patient is&#xD;
      administered a dosage of carvedilol, according to their weight. This dosage is increased&#xD;
      incrementally over the span of the study, if the patient responds well to the drug. The study&#xD;
      will determine whether the potential adverse side effects of carvedilol outweigh the possible&#xD;
      positive results in reducing LHF. The hypothesis of this study predicts that carvedilol will&#xD;
      have positive effects in treating LHF, similar to their use in treatment of Right Heart&#xD;
      Failure (RHF). This is a single-centered pilot study. Each patient will be studied for&#xD;
      approximately 31 weeks.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Withdrawn</overall_status>
  <why_stopped>
    Due to lack of enrollment.&#xD;
  </why_stopped>
  <start_date>September 2012</start_date>
  <primary_completion_date type="Actual">September 2015</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>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Incidence of Adverse Events</measure>
    <time_frame>Throughout study (Baseline to week 31)</time_frame>
    <description>-Incidence of major adverse effects defined as bradycardia, hypotension, and syncope, worsening of symptoms, disease state and death</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Improvement in the six minute walk test (6MWT) and cardiopulmonary exercise testing (CPX)</measure>
    <time_frame>Change over 6 months</time_frame>
    <description>This will be measured by the difference in walking distance in the 6MWT and peak oxygen consumption in the CPX, between the baseline condition before the study and after 6 months with maintenance dose of carvedilol.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Improvement in echocardiogram and magnetic resonance imaging (MRI) parameters</measure>
    <time_frame>Change over 6 months</time_frame>
    <description>The echocardiogram will be a subjective assessment of the right valve (RV) fractional area of change through TAPSE. The MRI will measure the RV ejection fraction. Both indicators will measure the different between the baseline condition before the study and after 6 months with maintenance dose of carvedilol.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Feasibility of carvedilol</measure>
    <time_frame>Baseline, Week 0, 2, 3, 4, 5, 6, 10, 18, 22, 30, 31</time_frame>
    <description>Proportion of patients achieving target maintenance dose of carvedilol&#xD;
Proportion of patients requiring dose adjustment due to bradycardia and/or hypertension&#xD;
Proportion of patients stopping treatment with carvedilol due to serious adverse events</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">0</enrollment>
  <condition>Pulmonary Arterial Hypertension</condition>
  <arm_group>
    <arm_group_label>Carvedilol</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Carvedilol</intervention_name>
    <description>Carvedilol will be administered orally. The initial dose of carvedilol will be 0.05mg/kg/day divided into 2 doses. After two weeks, at subsequent weekly study visits, the dose of carvedilol will be increased incrementally to 0.1mg/kg in Week 2, 0.2mg/kg in Week 3, 0.4mg/kg in Week 4, 0.6mg/kg in Week 5, and 0.8mg/kg in Week 6, when the target dose of 0.8mg/kg/day (if weight is less than 62.5kg) or 50mg/day (if weight is greater than 62.5kg) is achieved. This dosage, assuming no adverse effects, will be maintained between Weeks 6 and 30 of the study. After the maintenance period from Week 6 to 30, patients will be weaned over 5 to 7 days or continued on a non-study drug supply.</description>
    <arm_group_label>Carvedilol</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Patients must be ≥ 8 and ≤ 17.5 years of age at the time of study enrollment.&#xD;
&#xD;
          -  Patients must have a mean pulmonary artery pressure of greater than 25mmHg at rest in&#xD;
             a setting of normal pulmonary arterial wedge pressure of 15mmHg or less with a PVR&#xD;
             index greater than 3 Woods units•m2 at last hemodynamic study.&#xD;
&#xD;
          -  Patients must be diagnosed with any of the following:Idiopathic PAH (IPAH), PAH&#xD;
             associated with repaired congenital heart disease, PAH associated with minor&#xD;
             congenital heart disease (small interventricular communication, small interarterial&#xD;
             communication, small ductus arteriosis)&#xD;
&#xD;
          -  Patients must be clinically stable (i.e. no treatment changes) for the last 3 months&#xD;
&#xD;
          -  Patients must have no or minimal evidence of fluid overload or volume depletion judged&#xD;
             by clinical evaluation (with or without diuretic treatment)&#xD;
&#xD;
          -  Written informed consent&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Patients who are unable to perform a six minute walk test (6MWT)&#xD;
&#xD;
          -  Patients with a known history of pulmonary hypertension secondary to venoocclusive&#xD;
             disease and/or capillary hemangiomatosis; pulmonary hypertensions owing to left heart&#xD;
             disease&#xD;
&#xD;
          -  Patients who have previously received treatment with an intravenous positive inotropic&#xD;
             agent in the last 3 months&#xD;
&#xD;
          -  Patients who are currently receiving β-blockers&#xD;
&#xD;
          -  Patients with a known history of reactive airways disease (bronchial asthma or relate&#xD;
             bronchospastic conditions)&#xD;
&#xD;
          -  Patients with chronic obstructive pulmonary disease (COPD)&#xD;
&#xD;
          -  Patients with a known history of adverse reaction to β-blockers&#xD;
&#xD;
          -  Patients with a heart block on ECG or resting heart rate &lt; 60 bpm&#xD;
&#xD;
          -  Patients with systemic hypotension (below 5th percentile for age) are not eligible as&#xD;
             follows: 1-10 years old: systolic blood pressure defined as &lt; [70 + (2 x age in&#xD;
             years)] mmHg; Older than 10 years: systolic blood pressure &lt; 90 mmHg&#xD;
&#xD;
          -  Patients with coagulopathy (INR &lt; 1.5 or platelet count &lt;50,000/mm3)&#xD;
&#xD;
          -  Patients with a known history of severe hepatic impairment (defined by the presence of&#xD;
             ascites, esophageal varices, jaundice or spider angiomata)&#xD;
&#xD;
          -  Patients with severe renal insufficiency (defined as creatinine clearance &lt; 30&#xD;
             mL/min/m2)&#xD;
&#xD;
          -  Patients with a known malignancy or other co-morbidity expected to limit survival or&#xD;
             to limit the ability to complete the study&#xD;
&#xD;
          -  Patients with trisomy 21&#xD;
&#xD;
          -  Patients with a known history of sick sinus syndrome&#xD;
&#xD;
          -  Patients with a known history of moderate or severe primary obstructive valvular heart&#xD;
             disease&#xD;
&#xD;
          -  Patients with a known history of diabetes&#xD;
&#xD;
          -  Female patients who are pregnant of breast-feeding&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>8 Years</minimum_age>
    <maximum_age>17 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Mark Friedberg, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>The Hospital for Sick Children</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>The Hospital for Sick Children</name>
      <address>
        <city>Toronto</city>
        <state>Ontario</state>
        <zip>M5G 1X8</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Canada</country>
  </location_countries>
  <verification_date>December 2015</verification_date>
  <study_first_submitted>October 31, 2012</study_first_submitted>
  <study_first_submitted_qc>November 5, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">November 7, 2012</study_first_posted>
  <last_update_submitted>December 30, 2015</last_update_submitted>
  <last_update_submitted_qc>December 30, 2015</last_update_submitted_qc>
  <last_update_posted type="Estimate">December 31, 2015</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>The Hospital for Sick Children</investigator_affiliation>
    <investigator_full_name>Mark Friedberg</investigator_full_name>
    <investigator_title>Staff Cardiologist</investigator_title>
  </responsible_party>
  <keyword>Pulmonary Arterial Hypertension (PAH</keyword>
  <keyword>Pediatrics</keyword>
  <keyword>Right Heart Failure (RHF)</keyword>
  <keyword>Carvedilol</keyword>
  <keyword>Beta-blockers</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Pulmonary Arterial Hypertension</mesh_term>
    <mesh_term>Familial Primary Pulmonary Hypertension</mesh_term>
    <mesh_term>Hypertension</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Carvedilol</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/NCT01723371
org study id: 1000031903
nct id: NCT01723371
lead sponsor: 
has dmc: No
This study will determine the safety and feasibility of using a β-blocker (in this case
      carvedilol) in the treatment of pediatric patients with Left Heart Failure (LHF) in children
      with Pulmonary Arterial Hypertension (PAH). Carvedilol affects the nervous system, the same
      system that is highly activated in response to stress in patients with PAH. Each patient is
      administered a dosage of carvedilol, according to their weight. This dosage is increased
      incrementally over the span of the study, if the patient responds well to the drug. The study
      will determine whether the potential adverse side effects of carvedilol outweigh the possible
      positive results in reducing LHF. The hypothesis of this study predicts that carvedilol will
      have positive effects in treating LHF, similar to their use in treatment of Right Heart
      Failure (RHF). This is a single-centered pilot study. Each patient will be studied for
      approximately 31 weeks.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Incidence of Adverse Events
time frame: Throughout study (Baseline to week 31)
description: -Incidence of major adverse effects defined as bradycardia, hypotension, and syncope, worsening of symptoms, disease state and death
measure: Improvement in the six minute walk test (6MWT) and cardiopulmonary exercise testing (CPX)
time frame: Change over 6 months
description: This will be measured by the difference in walking distance in the 6MWT and peak oxygen consumption in the CPX, between the baseline condition before the study and after 6 months with maintenance dose of carvedilol.
measure: Improvement in echocardiogram and magnetic resonance imaging (MRI) parameters
time frame: Change over 6 months
description: The echocardiogram will be a subjective assessment of the right valve (RV) fractional area of change through TAPSE. The MRI will measure the RV ejection fraction. Both indicators will measure the different between the baseline condition before the study and after 6 months with maintenance dose of carvedilol.
measure: Feasibility of carvedilol
time frame: Baseline, Week 0, 2, 3, 4, 5, 6, 10, 18, 22, 30, 31
description: Proportion of patients achieving target maintenance dose of carvedilol
Proportion of patients requiring dose adjustment due to bradycardia and/or hypertension
Proportion of patients stopping treatment with carvedilol due to serious adverse events
arm group label: Carvedilol
arm group type: Experimental
intervention type: Drug
intervention name: Carvedilol
description: Carvedilol will be administered orally. The initial dose of carvedilol will be 0.05mg/kg/day divided into 2 doses. After two weeks, at subsequent weekly study visits, the dose of carvedilol will be increased incrementally to 0.1mg/kg in Week 2, 0.2mg/kg in Week 3, 0.4mg/kg in Week 4, 0.6mg/kg in Week 5, and 0.8mg/kg in Week 6, when the target dose of 0.8mg/kg/day (if weight is less than 62.5kg) or 50mg/day (if weight is greater than 62.5kg) is achieved. This dosage, assuming no adverse effects, will be maintained between Weeks 6 and 30 of the study. After the maintenance period from Week 6 to 30, patients will be weaned over 5 to 7 days or continued on a non-study drug supply.
arm group label: Carvedilol
criteria: 
gender: All
minimum age: 8 Years
maximum age: 17 Years
healthy volunteers: No
last name: Mark Friedberg, MD
role: Principal Investigator
affiliation: The Hospital for Sick Children
facility: 
country: Canada
responsible party type: Principal Investigator
investigator affiliation: The Hospital for Sick Children
investigator full name: Mark Friedberg
investigator title: Staff Cardiologist
mesh term: Pulmonary Arterial Hypertension
mesh term: Familial Primary Pulmonary Hypertension
mesh term: Hypertension
mesh term: Carvedilol