<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/NCT02993198</url>
  </required_header>
  <id_info>
    <org_study_id>STU00200675</org_study_id>
    <nct_id>NCT02993198</nct_id>
  </id_info>
  <brief_title>A Prospective Study of Breast Cancer Patients With Abnormal Strain Imaging</brief_title>
  <official_title>A Prospective Study of Early Stage Breast Cancer Patients With Abnormal Myocardial Deformation Treated With Anthracycline and/or Trastuzumab and Pertuzumab-based Cancer Therapy</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Northwestern University</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Northwestern University</source>
  <brief_summary>
    <textblock>
      The Cardio-Oncology program at Northwestern offers care to cancer patients who develop&#xD;
      cardiac toxicities from chemotherapy. Breast cancer patients with the tumor marker for HER2&#xD;
      necessitate treatment with anthracycline and/or trastuzumab and pertuzumab-based&#xD;
      chemotherapies, which are known to cause cardiac toxicities. Breast cancer patients will&#xD;
      undergo a &quot;cardio-oncology echocardiogram&quot; which incorporates advanced left ventricular&#xD;
      assessment by utilizing deformation or strain imaging during chemotherapy treatment for&#xD;
      surveillance of cardiac toxicities. The aims of this project are:&#xD;
&#xD;
        1. To create a registry of both clinical, and echocardiographic variables, biomarkers, and&#xD;
           genetic analysis that will be used to develop a risk model to predict LV dysfunction in&#xD;
           early stage breast cancer patients undergoing chemotherapy with anthracycline and/or&#xD;
           trastuzumab and pertuzumab-based chemotherapy regimens.&#xD;
&#xD;
        2. To propose a new management algorithm for initiation of prophylactic beta-blocker&#xD;
           therapy for early stage breast cancer patients with preclinical cardiac toxicities&#xD;
           demonstrated by strain parameters.&#xD;
&#xD;
        3. To determine if initiation of prophylactic beta-blocker therapy in patients with early&#xD;
           cardiac toxicity can delay or prevent a drop in LV EF and the development of clinical&#xD;
           heart failure.&#xD;
&#xD;
        4. To explore serial measurements of a suite of novel biomarkers during ongoing anticancer&#xD;
           treatment that are presumed but not yet proven to be predictive of cardiac dysfunction&#xD;
           in women with breast cancer.&#xD;
&#xD;
        5. To identify DNA biomarkers of predilection to cardiotoxicity.&#xD;
&#xD;
        6. To generate hiPSC to validate markers predictive of cardiotoxicity.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      150 patients will be prospectively consented/screened. Over the course of the study, 30&#xD;
      patients are expected to develop abnormal strain with a normal EF &gt; 53%. They will be&#xD;
      randomized in 1:1 fashion to open label carvedilol vs. no treatment.&#xD;
&#xD;
      All consenting patients will receive a baseline echocardiogram and blood draw for biomarkers&#xD;
      and genetic testing. Patients will be followed with echocardiograms at 3 month intervals for&#xD;
      12 months, until completion of trastuzumab/pertuzumab therapy.&#xD;
&#xD;
      Based on echocardiogram findings, patient will fall into four study arms (A, B, C, D).&#xD;
      Patients in Arm A (normal EF and normal strain) and Arm D (decrease in EF &gt; 10%, to a value&#xD;
      &lt;53%) will receive current standard of care treatment and will be followed in a registry arm.&#xD;
      Arms B and C will comprise of 30 patients with normal EF who develop preclinical cardiac&#xD;
      dysfunction, as defined as a change in global longitudinal strain of &gt; 15% from baseline&#xD;
      strain) or &lt; -15% absolute longitudinal strain will be prospectively assigned 1:1 to receive&#xD;
      prophylactic carvedilol (Arm B) vs. no treatment (Arm C). Prophylactic carvedilol will be&#xD;
      initiated at the starting dose of 3.125 mg PO BID and titrated based on blood pressure and&#xD;
      heart rate.&#xD;
&#xD;
      Patients will be seen every 3 weeks during the titration phase at their chemotherapy&#xD;
      appointments. At each visit, vitals and symptoms will be assessed for dizziness and&#xD;
      side-effects from carvedilol. If patient complains of dizziness or HR &lt; 50 bpm, or SBP &lt; 100&#xD;
      mmHg, then the dose titration should stop and the dose should be reduced to the dose at the&#xD;
      last increased increment. If there is a &gt; 10% decrease in EF to a value &lt; 53% on the next&#xD;
      echocardiogram, then standard heart failure therapy will be initiated (beta-blocker and/or&#xD;
      ace-inhibitors) and chemotherapy will be held as per standard of care. If patients require&#xD;
      other standard of care treatments for heart failure, such as diuretic therapy or aldosterone&#xD;
      antagonists, then this will also be initiated. At this point, these patients will be&#xD;
      considered to have met the study endpoint. However, if there is an improvement or no change&#xD;
      in strain and EF, then patients will continue with cardiac surveillance with an echo at 3&#xD;
      month intervals. Patients who have been assigned to receive prophylactic carvedilol will&#xD;
      continue treatment for duration of chemotherapy up to 1 year. Prophylactic carvedilol will be&#xD;
      stopped at the completion of study.&#xD;
&#xD;
      A biomarker substudy will be conducted on 100 patients. These patients will have labs drawn&#xD;
      every at ten time points, baseline and every 6 weeks for 12 months, and 1 year&#xD;
      post-chemotherapy. A separate blood draw for generation of hiPSC and DNA testing would be&#xD;
      done for 100 patients. The blood collection will coincide with the patient's chemotherapy&#xD;
      infusions with trastuzumab. These biomarkers will allow for further characterization of&#xD;
      patients at risk for developing CTRCD.&#xD;
&#xD;
      A &quot;cardio-oncology&quot; echocardiogram will include standard 2D M-mode and Doppler&#xD;
      echocardiography, 2D strain imaging, and 3D LV volume. This data will be processed on-line or&#xD;
      off-line within 24 hours of completion of the echocardiogram to determine randomization.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Active, not recruiting</overall_status>
  <start_date>April 2015</start_date>
  <completion_date type="Anticipated">December 2024</completion_date>
  <primary_completion_date type="Anticipated">December 2024</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>Prevention</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Change in Global Longitudinal Strain</measure>
    <time_frame>1 year</time_frame>
    <description>Improvement or stability in strain from baseline (i.e., increase in strain or decrease by no more than 3%).</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Number of cancer treatments</measure>
    <time_frame>1 year</time_frame>
    <description>Rate of cancer treatments held for decrement in EF &gt; 10% among groups.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">134</enrollment>
  <condition>HER2 Positive Breast Cancer</condition>
  <condition>Cardiovascular Abnormalities</condition>
  <arm_group>
    <arm_group_label>Prophylactic Carvedilol</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Carvedilol 3.125 mg by mouth every 12 hours, titrated to a max dose of 25 mg by mouth every 12 hours, depending on blood pressure and heart rate, until completion of study.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>No Therapy</arm_group_label>
    <arm_group_type>No Intervention</arm_group_type>
    <description>Standard of care monitoring without prophylactic treatment.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Carvedilol</intervention_name>
    <arm_group_label>Prophylactic Carvedilol</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Patients &gt; 18 years of age with HER2-overexpressing early stage breast cancer (Stages&#xD;
             I - III)&#xD;
&#xD;
          2. Pathology report must include HER2 expression, estrogen and progesterone receptor&#xD;
             status&#xD;
&#xD;
          3. Normal LV function (EF &gt; 53%) on baseline echocardiogram&#xD;
&#xD;
          4. NYHA functional class I-II (no symptoms, dyspnea with more than 2 blocks)&#xD;
&#xD;
          5. Scheduled to receive treatment with anthracycline and/or trastuzumab and&#xD;
             pertuzumab-based regimens&#xD;
&#xD;
          6. Patients with a history of HTN, hyperlipidemia, diabetes, mild CAD, mild valvular&#xD;
             disease are permitted&#xD;
&#xD;
          7. Patients on concomitant cardiac medications other than beta-blockers (BB) or&#xD;
             ace-inhibitors (ACE) therapy are permitted. Other non-cardiac medications are not&#xD;
             prohibited.&#xD;
&#xD;
          8. Women of childbearing potential and sexually active men and women should use effective&#xD;
             contraception.&#xD;
&#xD;
          9. Patients must have a signed informed consent prior to registration&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. LV dysfunction (EF &lt; 53%)&#xD;
&#xD;
          2. New York Heart Association (NYHA) functional class III-IV (heart failure symptoms at&#xD;
             less than 2 blocks to advanced symptoms at rest)&#xD;
&#xD;
             a. NYHA Classification: I - No limitations to activity II - Slight limitation to&#xD;
             ordinary activity, no symptoms at rest III - Marked limitation to less than ordinary&#xD;
             activity, no symptoms at rest IV - Inability to carry out activity without symptoms,&#xD;
             symptoms at rest&#xD;
&#xD;
          3. Pre-existing cardiac disease (moderate-severe coronary artery disease, moderate-severe&#xD;
             valvular heart disease, constrictive/restrictive cardiomyopathies)&#xD;
&#xD;
          4. Metastatic breast cancer&#xD;
&#xD;
          5. Patients who have ever taken BB/ACE therapy are excluded.&#xD;
&#xD;
          6. 2nd and 3rd degree AV block&#xD;
&#xD;
          7. Sick sinus syndrome&#xD;
&#xD;
          8. Patients with severe bradycardia (&lt; 50 bpm) or severe hypotension (SBP &lt; 85 mmHg)&#xD;
&#xD;
          9. Severe liver dysfunction defined as Child-Turcotte-Pugh class B &amp; C (significant&#xD;
             functional compromise - decompensated disease)&#xD;
&#xD;
         10. Moderate-severe Asthma&#xD;
&#xD;
         11. Hypersensitivity to beta-blockers&#xD;
&#xD;
         12. Patients who are pregnant/lactating are not eligible&#xD;
&#xD;
         13. Unwilling to consent/assent to blood donation&#xD;
      </textblock>
    </criteria>
    <gender>Female</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <location>
    <facility>
      <name>Northwestern University</name>
      <address>
        <city>Chicago</city>
        <state>Illinois</state>
        <zip>60611</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>April 2023</verification_date>
  <study_first_submitted>December 2, 2016</study_first_submitted>
  <study_first_submitted_qc>December 12, 2016</study_first_submitted_qc>
  <study_first_posted type="Estimate">December 15, 2016</study_first_posted>
  <last_update_submitted>May 19, 2023</last_update_submitted>
  <last_update_submitted_qc>May 19, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">May 22, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Northwestern University</investigator_affiliation>
    <investigator_full_name>Nausheen Akhter</investigator_full_name>
    <investigator_title>Assistant Professor of Medicine</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Breast Neoplasms</mesh_term>
    <mesh_term>Cardiovascular Abnormalities</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/NCT02993198
org study id: STU00200675
nct id: NCT02993198
lead sponsor: 
The Cardio-Oncology program at Northwestern offers care to cancer patients who develop
      cardiac toxicities from chemotherapy. Breast cancer patients with the tumor marker for HER2
      necessitate treatment with anthracycline and/or trastuzumab and pertuzumab-based
      chemotherapies, which are known to cause cardiac toxicities. Breast cancer patients will
      undergo a "cardio-oncology echocardiogram" which incorporates advanced left ventricular
      assessment by utilizing deformation or strain imaging during chemotherapy treatment for
      surveillance of cardiac toxicities. The aims of this project are:

        1. To create a registry of both clinical, and echocardiographic variables, biomarkers, and
           genetic analysis that will be used to develop a risk model to predict LV dysfunction in
           early stage breast cancer patients undergoing chemotherapy with anthracycline and/or
           trastuzumab and pertuzumab-based chemotherapy regimens.

        2. To propose a new management algorithm for initiation of prophylactic beta-blocker
           therapy for early stage breast cancer patients with preclinical cardiac toxicities
           demonstrated by strain parameters.

        3. To determine if initiation of prophylactic beta-blocker therapy in patients with early
           cardiac toxicity can delay or prevent a drop in LV EF and the development of clinical
           heart failure.

        4. To explore serial measurements of a suite of novel biomarkers during ongoing anticancer
           treatment that are presumed but not yet proven to be predictive of cardiac dysfunction
           in women with breast cancer.

        5. To identify DNA biomarkers of predilection to cardiotoxicity.

        6. To generate hiPSC to validate markers predictive of cardiotoxicity.
150 patients will be prospectively consented/screened. Over the course of the study, 30
      patients are expected to develop abnormal strain with a normal EF > 53%. They will be
      randomized in 1:1 fashion to open label carvedilol vs. no treatment.

      All consenting patients will receive a baseline echocardiogram and blood draw for biomarkers
      and genetic testing. Patients will be followed with echocardiograms at 3 month intervals for
      12 months, until completion of trastuzumab/pertuzumab therapy.

      Based on echocardiogram findings, patient will fall into four study arms (A, B, C, D).
      Patients in Arm A (normal EF and normal strain) and Arm D (decrease in EF > 10%, to a value
      <53%) will receive current standard of care treatment and will be followed in a registry arm.
      Arms B and C will comprise of 30 patients with normal EF who develop preclinical cardiac
      dysfunction, as defined as a change in global longitudinal strain of > 15% from baseline
      strain) or < -15% absolute longitudinal strain will be prospectively assigned 1:1 to receive
      prophylactic carvedilol (Arm B) vs. no treatment (Arm C). Prophylactic carvedilol will be
      initiated at the starting dose of 3.125 mg PO BID and titrated based on blood pressure and
      heart rate.

      Patients will be seen every 3 weeks during the titration phase at their chemotherapy
      appointments. At each visit, vitals and symptoms will be assessed for dizziness and
      side-effects from carvedilol. If patient complains of dizziness or HR < 50 bpm, or SBP < 100
      mmHg, then the dose titration should stop and the dose should be reduced to the dose at the
      last increased increment. If there is a > 10% decrease in EF to a value < 53% on the next
      echocardiogram, then standard heart failure therapy will be initiated (beta-blocker and/or
      ace-inhibitors) and chemotherapy will be held as per standard of care. If patients require
      other standard of care treatments for heart failure, such as diuretic therapy or aldosterone
      antagonists, then this will also be initiated. At this point, these patients will be
      considered to have met the study endpoint. However, if there is an improvement or no change
      in strain and EF, then patients will continue with cardiac surveillance with an echo at 3
      month intervals. Patients who have been assigned to receive prophylactic carvedilol will
      continue treatment for duration of chemotherapy up to 1 year. Prophylactic carvedilol will be
      stopped at the completion of study.

      A biomarker substudy will be conducted on 100 patients. These patients will have labs drawn
      every at ten time points, baseline and every 6 weeks for 12 months, and 1 year
      post-chemotherapy. A separate blood draw for generation of hiPSC and DNA testing would be
      done for 100 patients. The blood collection will coincide with the patient's chemotherapy
      infusions with trastuzumab. These biomarkers will allow for further characterization of
      patients at risk for developing CTRCD.

      A "cardio-oncology" echocardiogram will include standard 2D M-mode and Doppler
      echocardiography, 2D strain imaging, and 3D LV volume. This data will be processed on-line or
      off-line within 24 hours of completion of the echocardiogram to determine randomization.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Prevention
masking: None (Open Label)
measure: Change in Global Longitudinal Strain
time frame: 1 year
description: Improvement or stability in strain from baseline (i.e., increase in strain or decrease by no more than 3%).
measure: Number of cancer treatments
time frame: 1 year
description: Rate of cancer treatments held for decrement in EF > 10% among groups.
arm group label: Prophylactic Carvedilol
arm group type: Experimental
description: Carvedilol 3.125 mg by mouth every 12 hours, titrated to a max dose of 25 mg by mouth every 12 hours, depending on blood pressure and heart rate, until completion of study.
arm group label: No Therapy
arm group type: No Intervention
description: Standard of care monitoring without prophylactic treatment.
intervention type: Drug
intervention name: Carvedilol
arm group label: Prophylactic Carvedilol
criteria: 
gender: Female
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
facility: 
country: United States
responsible party type: Principal Investigator
investigator affiliation: Northwestern University
investigator full name: Nausheen Akhter
investigator title: Assistant Professor of Medicine
mesh term: Breast Neoplasms
mesh term: Cardiovascular Abnormalities
mesh term: Carvedilol