<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/NCT03266809</url>
  </required_header>
  <id_info>
    <org_study_id>188676</org_study_id>
    <nct_id>NCT03266809</nct_id>
  </id_info>
  <brief_title>CARdiac Function Evaluation in Breast Cancer Patients</brief_title>
  <acronym>CARE-B</acronym>
  <official_title>Longitudinal Characterisation of Cardiac Function in Recently-diagnosed Breast Cancer Patients</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Swansea University</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Abertawe Bro Morgannwg University Health Board</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Swansea University</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>
  </oversight_info>
  <brief_summary>
    <textblock>
      This study will investigate the influence of systemic adjuvant/neoadjuvant therapy (SAT:&#xD;
      chemotherapy +/- anti-HER2 antibodies (trastuzumab +/- pertuzumab) on heart function/rhythm&#xD;
      and cardio-respiratory fitness in recently diagnosed breast cancer patients. In some&#xD;
      patients, SAT damages the heart (so-called 'cardiotoxicity') and this can have a serious&#xD;
      impact on the patient's quality of life and overall survival. It has also been suggested that&#xD;
      anticancer therapies may lead to repolarization abnormalities, QT prolongation and autonomic&#xD;
      dysfunction, clinically reflected by an increase in HR and a reduction in heart rate&#xD;
      variability (HRV). There is a lack of information in the literature regarding the extent and&#xD;
      time-course of changes in cardiac function, cardiac rhythm and cardio-respiratory performance&#xD;
      ('fitness') in these patients. Moreover, the differential influences of specific treatment&#xD;
      regimes (e.g. SAT or SAT plus radiotherapy) and different chemotherapy drugs on&#xD;
      cardio-respiratory performance remain unclear. A better understanding of these issues is the&#xD;
      primary aim of this study.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This study will focus on the following:&#xD;
&#xD;
        1. Cardiac function assessment: The conventional method for assessing heart function (in&#xD;
           terms of 'ejection fraction') in patients being treated for cancer uses nuclear medicine&#xD;
           (MUGA scan). MRI can also provide this information but it is not typically used for&#xD;
           cardiac function assessment in these patients. MUGA scans are typically performed before&#xD;
           chemotherapy in selected patients at higher risk of cardiotoxicity and in all cases&#xD;
           before starting anti-HER2 antibody treatment (trastuzumab, pertuzumab). Patients&#xD;
           receiving anti-HER2 antibody treatment receive repeat cardiac assessments at 3-4 month&#xD;
           intervals until the completion of treatment - it is not practical or cost-effective to&#xD;
           scan more frequently. This study will determine whether an alternative and inexpensive&#xD;
           method for monitoring heart function (Impedance Cardiography, ICG) can adequately&#xD;
           quantify changes in ejection fraction during treatment. If it can, then this technique&#xD;
           could be used more frequently during and following treatment, with the aim of&#xD;
           determining the treatment stages during which the heart is most at risk of damage. The&#xD;
           ability of ICG to dynamically characterise a relatively rapid decline in cardiac&#xD;
           function in breast cancer patients has not been established. Neither has its performance&#xD;
           been compared with MRI or MUGA in this population. This study will investigate whether&#xD;
           ICG is a sufficiently accurate and reliable alternative to MRI/MUGA for determining&#xD;
           cardiac dysfunction during and following cancer treatment.&#xD;
&#xD;
        2. Cardiac rhythm and autonomic function assessment: Heart rate variability (HRV) reflects&#xD;
           the modulation of the heart by the autonomic nervous system, and it can be quantified&#xD;
           using several different methods based on analysis of the temporal changes between&#xD;
           successive heartbeats. The development of autonomic dysfunction in breast cancer&#xD;
           patients has been shown in a few small clinical studies, but the majority of these&#xD;
           studies have considered HR rather than HRV, which is a much less robust measure of&#xD;
           autonomic function. The few studies that have used HRV analysis have demonstrated&#xD;
           significant reductions in HRV following the completion of anthracycline-based therapy.&#xD;
           Previous research on other ECG markers (e.g. QT and QRS duration) in breast cancer&#xD;
           patients has mainly focused on anthracycline-based regimes; the influence of trastuzumab&#xD;
           treatment on ECG makers has been evaluated in only two studies to date. It is still not&#xD;
           clear whether these changes can predict subsequent LV dysfunction although QT&#xD;
           variability is a possible marker of myocardial contractility and has been shown to&#xD;
           increase as a result of anthracycline therapy in breast cancer patients. This study aims&#xD;
           to characterise the impact of different treatment regimes on the temporal properties of&#xD;
           the ECG and will compare beat-to-beat QT variability and beat-to-beat T wave variability&#xD;
           in breast cancer patients receiving a range of treatment regimes.&#xD;
&#xD;
        3. Body composition and cardiorespiratory fitness assessment: This study also aims to&#xD;
           characterise the patterns of change in body composition, physical activity and&#xD;
           cardiorespiratory fitness in breast cancer patients. The study will examine whether&#xD;
           these modifiable factors might influence a patient's susceptibility to cardiac changes&#xD;
           during treatment and, in turn, how these factors are affected by treatment. Of&#xD;
           particular interest, it has been suggested that cardiorespiratory fitness (measured by&#xD;
           the rate of oxygen uptake) is impaired in breast cancer patients compared to healthy&#xD;
           controls, even seven years following the completion of treatment. Oxygen-uptake analysis&#xD;
           will be performed in this study to explore possible compensatory mechanisms for abnormal&#xD;
           pathology- or treatment-induced cardiac function in breast cancer patients. Fitness,&#xD;
           physical activity and body composition will be assessed quantitatively using a range of&#xD;
           objective techniques, including cardiopulmonary exercise testing on a cycle ergometer&#xD;
           (fitness) with breath-by-breath gas analysis (cardiorespiratory function),&#xD;
           accelerometery (activity levels) and DEXA radiography scans (body composition).&#xD;
&#xD;
      The main research questions in this study are:&#xD;
&#xD;
        1. Is the CARE-B protocol practically feasible and tolerable to early-stage breast cancer&#xD;
           patients?&#xD;
&#xD;
        2. What is the level of agreement between cardiac (ventricular) function determined using&#xD;
           cardiac MRI, MUGA and Impedance Cardiography in breast cancer patients receiving SAT?&#xD;
&#xD;
        3. Is cardiac rhythm (heart rate and QT variability) altered in breast cancer patients&#xD;
           receiving SAT?&#xD;
&#xD;
        4. Is oxygen transport and oxygen uptake into tissue altered in breast cancer patients&#xD;
           receiving SAT?&#xD;
&#xD;
        5. Does a patient's baseline physical activity, fitness and body composition affect their&#xD;
           susceptibilities to treatment-induced cardio-respiratory problems?&#xD;
&#xD;
        6. Does a patient's physical activity, physical fitness and body composition change&#xD;
           appreciably during SAT in these patients?&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">August 1, 2017</start_date>
  <completion_date type="Actual">April 1, 2020</completion_date>
  <primary_completion_date type="Actual">September 28, 2019</primary_completion_date>
  <study_type>Observational</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <observational_model>Cohort</observational_model>
    <time_perspective>Prospective</time_perspective>
  </study_design_info>
  <primary_outcome>
    <measure>Cardiac Function (stroke volume or ejection fraction)</measure>
    <time_frame>At completion of treatment, an average of 13 months</time_frame>
    <description>Cardiac function during/following treatment in breast cancer patients.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Cardiac Rhythm (heart rate variability)</measure>
    <time_frame>At completion of treatment, an average of 13 months</time_frame>
    <description>Cardiac rhythm during/following treatment in breast cancer patients.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Physical activity level (accelerometer-based activity level 'counts')</measure>
    <time_frame>At completion of treatment, an average of 13 months</time_frame>
    <description>Physical activity level during/following treatment in breast cancer patients.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cardiorespiratory function (rate of respiratory oxygen uptake)</measure>
    <time_frame>At completion of treatment, an average of 13 months</time_frame>
    <description>Cardiorespiratory function during/following treatment in breast cancer patients.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Body mass composition (from DEXA scan)</measure>
    <time_frame>At completion of treatment, an average of 13 months</time_frame>
    <description>Body fat mass and fat-free mass, and bone mineral density</description>
  </secondary_outcome>
  <number_of_groups>1</number_of_groups>
  <enrollment type="Actual">17</enrollment>
  <condition>Breast Cancer Female</condition>
  <arm_group>
    <arm_group_label>Breast Cancer Patients</arm_group_label>
    <description>Eligible participants will be women aged 18 years or over who have the following main characteristics:&#xD;
Early invasive breast cancer (stage I-III)&#xD;
Due to start SAT (adjuvant or neoadjuvant chemotherapy +/- trastuzumab +/- pertuzumab)&#xD;
WHO performance status 0-2.</description>
  </arm_group>
  <eligibility>
    <study_pop>
      <textblock>
        Women aged 18 years or older who have early invasive breast cancer and who are due to begin&#xD;
        adjuvant or neoadjuvant therapy for this condition, but who are otherwise free of major&#xD;
        cardiovascular or chronic respiratory disease and who are capable of undertaking physical&#xD;
        exercise.&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Non-Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
        Eligible participants will be women aged 18 years or over with the following&#xD;
        characteristics:&#xD;
&#xD;
          -  Early invasive breast cancer (stage I-III)&#xD;
&#xD;
          -  Due to start adjuvant or neoadjuvant therapy including either anthracycline-based&#xD;
             chemotherapy, or chemotherapy + trastuzumab +/- pertuzumab&#xD;
&#xD;
          -  WHO performance status &lt;=2&#xD;
&#xD;
          -  Absence of major cardiovascular or chronic respiratory problems, or other conditions&#xD;
             that in the opinion of the clinician would contraindicate the use of physical exercise&#xD;
             assessments&#xD;
&#xD;
          -  Absence of contraindications for MRI scans, as listed in Paragraph 3.3. Patients&#xD;
             unsuitable or unwilling to undergo MRI scans will be eligible for the study only if&#xD;
             they are planned to receive trastuzumab, since this will include LVEF monitoring with&#xD;
             MUGA scans or echocardiograms as part of routine care&#xD;
&#xD;
          -  Provision of signed informed consent.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Presence of major cardiovascular or chronic respiratory problems, or other conditions&#xD;
             that in the opinion of the clinician would contraindicate the use of treadmill&#xD;
             exercise assessments&#xD;
&#xD;
          -  Presence of contraindications for MRI scans:&#xD;
&#xD;
               -  Internal electronic devices such as neurostimulators or defibrillators&#xD;
&#xD;
               -  Replacement heart valve&#xD;
&#xD;
               -  Cardiac pacemaker&#xD;
&#xD;
               -  Intracranial vessel clips&#xD;
&#xD;
               -  Internal ear implant&#xD;
&#xD;
               -  Claustrophobia&#xD;
&#xD;
               -  Pregnancy.&#xD;
&#xD;
        MRI scans will be requested by a clinician after the exclusion of the above&#xD;
        contraindications. Patients unsuitable or unwilling to undergo MRI scans will be eligible&#xD;
        for the study only if they are planned to receive trastuzumab, since this includes LVEF&#xD;
        monitoring with MUGA scans or echocardiograms as part of routine care.&#xD;
      </textblock>
    </criteria>
    <gender>Female</gender>
    <gender_based>Yes</gender_based>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Professor Lewis</last_name>
    <role>Study Director</role>
    <affiliation>Swansea University</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Singleton Hospital</name>
      <address>
        <city>Swansea</city>
        <state>Wales</state>
        <zip>SA2 8PP</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United Kingdom</country>
  </location_countries>
  <verification_date>November 2022</verification_date>
  <study_first_submitted>August 25, 2017</study_first_submitted>
  <study_first_submitted_qc>August 29, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">August 30, 2017</study_first_posted>
  <last_update_submitted>November 29, 2022</last_update_submitted>
  <last_update_submitted_qc>November 29, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">December 1, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Swansea University</investigator_affiliation>
    <investigator_full_name>Prof Michael Lewis</investigator_full_name>
    <investigator_title>Professor</investigator_title>
  </responsible_party>
  <keyword>Cardiac function</keyword>
  <keyword>Cardio-toxicity</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Breast Neoplasms</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/NCT03266809
org study id: 188676
nct id: NCT03266809
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
This study will investigate the influence of systemic adjuvant/neoadjuvant therapy (SAT:
      chemotherapy +/- anti-HER2 antibodies (trastuzumab +/- pertuzumab) on heart function/rhythm
      and cardio-respiratory fitness in recently diagnosed breast cancer patients. In some
      patients, SAT damages the heart (so-called 'cardiotoxicity') and this can have a serious
      impact on the patient's quality of life and overall survival. It has also been suggested that
      anticancer therapies may lead to repolarization abnormalities, QT prolongation and autonomic
      dysfunction, clinically reflected by an increase in HR and a reduction in heart rate
      variability (HRV). There is a lack of information in the literature regarding the extent and
      time-course of changes in cardiac function, cardiac rhythm and cardio-respiratory performance
      ('fitness') in these patients. Moreover, the differential influences of specific treatment
      regimes (e.g. SAT or SAT plus radiotherapy) and different chemotherapy drugs on
      cardio-respiratory performance remain unclear. A better understanding of these issues is the
      primary aim of this study.
This study will focus on the following:

        1. Cardiac function assessment: The conventional method for assessing heart function (in
           terms of 'ejection fraction') in patients being treated for cancer uses nuclear medicine
           (MUGA scan). MRI can also provide this information but it is not typically used for
           cardiac function assessment in these patients. MUGA scans are typically performed before
           chemotherapy in selected patients at higher risk of cardiotoxicity and in all cases
           before starting anti-HER2 antibody treatment (trastuzumab, pertuzumab). Patients
           receiving anti-HER2 antibody treatment receive repeat cardiac assessments at 3-4 month
           intervals until the completion of treatment - it is not practical or cost-effective to
           scan more frequently. This study will determine whether an alternative and inexpensive
           method for monitoring heart function (Impedance Cardiography, ICG) can adequately
           quantify changes in ejection fraction during treatment. If it can, then this technique
           could be used more frequently during and following treatment, with the aim of
           determining the treatment stages during which the heart is most at risk of damage. The
           ability of ICG to dynamically characterise a relatively rapid decline in cardiac
           function in breast cancer patients has not been established. Neither has its performance
           been compared with MRI or MUGA in this population. This study will investigate whether
           ICG is a sufficiently accurate and reliable alternative to MRI/MUGA for determining
           cardiac dysfunction during and following cancer treatment.

        2. Cardiac rhythm and autonomic function assessment: Heart rate variability (HRV) reflects
           the modulation of the heart by the autonomic nervous system, and it can be quantified
           using several different methods based on analysis of the temporal changes between
           successive heartbeats. The development of autonomic dysfunction in breast cancer
           patients has been shown in a few small clinical studies, but the majority of these
           studies have considered HR rather than HRV, which is a much less robust measure of
           autonomic function. The few studies that have used HRV analysis have demonstrated
           significant reductions in HRV following the completion of anthracycline-based therapy.
           Previous research on other ECG markers (e.g. QT and QRS duration) in breast cancer
           patients has mainly focused on anthracycline-based regimes; the influence of trastuzumab
           treatment on ECG makers has been evaluated in only two studies to date. It is still not
           clear whether these changes can predict subsequent LV dysfunction although QT
           variability is a possible marker of myocardial contractility and has been shown to
           increase as a result of anthracycline therapy in breast cancer patients. This study aims
           to characterise the impact of different treatment regimes on the temporal properties of
           the ECG and will compare beat-to-beat QT variability and beat-to-beat T wave variability
           in breast cancer patients receiving a range of treatment regimes.

        3. Body composition and cardiorespiratory fitness assessment: This study also aims to
           characterise the patterns of change in body composition, physical activity and
           cardiorespiratory fitness in breast cancer patients. The study will examine whether
           these modifiable factors might influence a patient's susceptibility to cardiac changes
           during treatment and, in turn, how these factors are affected by treatment. Of
           particular interest, it has been suggested that cardiorespiratory fitness (measured by
           the rate of oxygen uptake) is impaired in breast cancer patients compared to healthy
           controls, even seven years following the completion of treatment. Oxygen-uptake analysis
           will be performed in this study to explore possible compensatory mechanisms for abnormal
           pathology- or treatment-induced cardiac function in breast cancer patients. Fitness,
           physical activity and body composition will be assessed quantitatively using a range of
           objective techniques, including cardiopulmonary exercise testing on a cycle ergometer
           (fitness) with breath-by-breath gas analysis (cardiorespiratory function),
           accelerometery (activity levels) and DEXA radiography scans (body composition).

      The main research questions in this study are:

        1. Is the CARE-B protocol practically feasible and tolerable to early-stage breast cancer
           patients?

        2. What is the level of agreement between cardiac (ventricular) function determined using
           cardiac MRI, MUGA and Impedance Cardiography in breast cancer patients receiving SAT?

        3. Is cardiac rhythm (heart rate and QT variability) altered in breast cancer patients
           receiving SAT?

        4. Is oxygen transport and oxygen uptake into tissue altered in breast cancer patients
           receiving SAT?

        5. Does a patient's baseline physical activity, fitness and body composition affect their
           susceptibilities to treatment-induced cardio-respiratory problems?

        6. Does a patient's physical activity, physical fitness and body composition change
           appreciably during SAT in these patients?
observational model: Cohort
time perspective: Prospective
measure: Cardiac Function (stroke volume or ejection fraction)
time frame: At completion of treatment, an average of 13 months
description: Cardiac function during/following treatment in breast cancer patients.
measure: Cardiac Rhythm (heart rate variability)
time frame: At completion of treatment, an average of 13 months
description: Cardiac rhythm during/following treatment in breast cancer patients.
measure: Physical activity level (accelerometer-based activity level 'counts')
time frame: At completion of treatment, an average of 13 months
description: Physical activity level during/following treatment in breast cancer patients.
measure: Cardiorespiratory function (rate of respiratory oxygen uptake)
time frame: At completion of treatment, an average of 13 months
description: Cardiorespiratory function during/following treatment in breast cancer patients.
measure: Body mass composition (from DEXA scan)
time frame: At completion of treatment, an average of 13 months
description: Body fat mass and fat-free mass, and bone mineral density
arm group label: Breast Cancer Patients
description: Eligible participants will be women aged 18 years or over who have the following main characteristics:
Early invasive breast cancer (stage I-III)
Due to start SAT (adjuvant or neoadjuvant chemotherapy +/- trastuzumab +/- pertuzumab)
WHO performance status 0-2.
study pop: 
sampling method: Non-Probability Sample
criteria: 
gender: Female
gender based: Yes
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Professor Lewis
role: Study Director
affiliation: Swansea University
facility: 
country: United Kingdom
responsible party type: Principal Investigator
investigator affiliation: Swansea University
investigator full name: Prof Michael Lewis
investigator title: Professor
mesh term: Breast Neoplasms
sharing ipd: No