<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/NCT03277898</url>
  </required_header>
  <id_info>
    <org_study_id>H17-00563</org_study_id>
    <nct_id>NCT03277898</nct_id>
  </id_info>
  <brief_title>Aerobic Exercise and Cognitive Functioning in Women With Breast Cancer</brief_title>
  <acronym>ACTIVATE</acronym>
  <official_title>Aerobic Exercise and Cognitive Functioning in Women With Breast Cancer: the ACTIVATE Trial</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of British Columbia</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Canadian Cancer Society (CCS)</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Avon Foundation</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>University of Ottawa</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>British Columbia Cancer Agency</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>University of British Columbia</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>
      In Canada, approximately 68 women are diagnosed with breast cancer every day.&#xD;
      Chemotherapy-related cognitive changes (CRCC) are reported by up to 75% of breast cancer&#xD;
      survivors during treatment and symptoms persist in 35% of survivors after treatment. Women&#xD;
      report that CRCC negatively impacts their everyday functioning and substantially reduces&#xD;
      their overall quality of life. Effective clinical interventions to manage CRCC are elusive.&#xD;
      As a result, breast cancer survivors typically receive little to no advice on how to prevent&#xD;
      or manage CRCC. Aerobic exercise is a type of physical activity that uses large muscle&#xD;
      groups, is rhythmic in nature, and can be sustained for at least 10 minutes (e.g., walking,&#xD;
      jogging, indoor cycling). It has been associated with improved quality of life in breast&#xD;
      cancer survivors. It also holds great promise as an intervention to prevent or mitigate CRCC.&#xD;
      However, there is limited evidence from experimental studies to confirm this. Therefore, the&#xD;
      primary aim of this trial is to evaluate the impact of a supervised aerobic exercise&#xD;
      intervention on CRCC in women diagnosed with early-stage breast cancer. Recruited women will&#xD;
      be randomized into one of two groups: (1) aerobic exercise during chemotherapy, or (2) usual&#xD;
      care during chemotherapy and the aerobic exercise post-chemotherapy (i.e., wait-list control&#xD;
      group). This study will test several novel hypotheses, including whether exercise during&#xD;
      chemotherapy can prevent and/or mitigate CRCC and its negative impact on quality of life&#xD;
      among women with breast cancer, and whether the timing of the exercise intervention matters&#xD;
      (i.e., exercise during versus after chemotherapy). The results of this study aim to address&#xD;
      the concerns of women affected by CRCC who are currently lacking available evidence-based&#xD;
      treatment options, as well as oncology care providers' need to have options to recommend to&#xD;
      their patients to prevent or manage CRCC.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The purpose of this study is to evaluate the impact of an aerobic exercise intervention on&#xD;
      CRCC in women diagnosed with breast cancer who undergo chemotherapy. The specific objectives&#xD;
      are to:&#xD;
&#xD;
        1. Test the effect of aerobic exercise during chemotherapy (EX) compared to a usual care&#xD;
           wait-list control group (exercise after chemotherapy; UC) on CRCC as assessed by&#xD;
           neuropsychological tests and self-report;&#xD;
&#xD;
        2. Test the effect of EX compared to UC on:&#xD;
&#xD;
             1. Global measures of brain structure and functioning including brain volume in&#xD;
                regions associated with working memory and response inhibition, white matter&#xD;
                integrity (i.e., fractional anisotropy, mean diffusivity), and neural functioning&#xD;
                using magnetic resonance imaging (MRI);&#xD;
&#xD;
             2. Overall global brain network organization and improved regional brain network&#xD;
                organization and neural functioning in areas underlying attention and working&#xD;
                memory (i.e., dorso-lateral prefrontal cortex, superior temporal region and&#xD;
                posterior parietal cortex) using electroencephalography (EEG; Vancouver site only;&#xD;
                see Methods).&#xD;
&#xD;
        3. Assess if the timing of the exercise intervention (i.e., during chemotherapy versus&#xD;
           after chemotherapy) moderates the effects on CRCC by examining the effects of the&#xD;
           intervention at 1-year post start of chemotherapy.&#xD;
&#xD;
      It is hypothesized that:&#xD;
&#xD;
        1. At the end of chemotherapy, EX group will perform better than UC group on&#xD;
           neuropsychological tests and will self-report better cognitive functioning;&#xD;
&#xD;
        2. At the end of chemotherapy, EX group will have maintained measures of brain structure&#xD;
           and functioning as assessed by MRI scans and EEG (Vancouver site only) compared to UC&#xD;
           group who will have significant changes in both;&#xD;
&#xD;
        3. At 1-year post the start of chemotherapy, EX group will have better outcomes compared to&#xD;
           the UC group.&#xD;
&#xD;
      This is a two-arm, two-centre RCT. The two arms are:&#xD;
&#xD;
        1. Aerobic exercise intervention during chemotherapy (EX);&#xD;
&#xD;
        2. Usual care during chemotherapy and aerobic exercise after chemotherapy (i.e., usual care&#xD;
           wait-list control group; UC).&#xD;
&#xD;
      Recruitment:&#xD;
&#xD;
      84 women diagnosed with breast cancer will be recruited across the two sites. The primary&#xD;
      method of recruitment will be through printed postings and oncologist referral at the two&#xD;
      main clinical sites: British Columbia Cancer Agency-Vancouver (BCCA) and The Ottawa Hospital&#xD;
      (TOH). We anticipate our target of 84 patients will be reached in 30 months (combined site&#xD;
      rate of 2-3 participants per month).&#xD;
&#xD;
      Outcomes will be assessed at:&#xD;
&#xD;
        1. Pre-chemotherapy (baseline, week 0);&#xD;
&#xD;
        2. Mid-chemotherapy (approximately 6-9 weeks post-baseline);&#xD;
&#xD;
        3. End of chemotherapy (approximately 12-18 weeks post-baseline);&#xD;
&#xD;
        4. Follow-up and post-usual care wait-list control group receiving the intervention&#xD;
           (approximately 24-34 weeks post-baseline);&#xD;
&#xD;
        5. 1-year follow-up (52 weeks post-baseline).&#xD;
&#xD;
      Optional neuroimaging and EEG will be completed in a sub-set of participants at each site who&#xD;
      are interested, eligible, and consent to additional assessments at these time points:&#xD;
&#xD;
        1. Pre-chemotherapy (baseline, week 0);&#xD;
&#xD;
        2. End of chemotherapy (approximately 12-18 weeks post-baseline);&#xD;
&#xD;
        3. 1-year follow-up (52 weeks post-baseline).&#xD;
&#xD;
      Intervention:&#xD;
&#xD;
      After obtaining informed consent, each participant will be scheduled for a baseline&#xD;
      assessment (week 0). After baseline assessments, participants will be randomized. For the EX&#xD;
      group, the intervention will be delivered concurrent with participants' chemotherapy regimen&#xD;
      (lasting approximately 12-18 weeks). The intervention will be progressive aerobic exercise.&#xD;
      The intervention is based on prior protocols used by the study team among women during&#xD;
      treatment or who have completed treatment. Participants will complete three supervised 20-40&#xD;
      minute aerobic exercise sessions each week. Home-based exercise will be introduced in week 3.&#xD;
      For the home-based sessions, participants will be asked to complete at least 1 session per&#xD;
      week of 30 minutes of aerobic exercise (an activity of their choosing; e.g., walking).&#xD;
&#xD;
      Data Analysis:&#xD;
&#xD;
      Changes in objective and self-reported cognitive functioning will be analyzed based on&#xD;
      repeated measures analysis of variance with fixed terms for treatment, time, and a treatment&#xD;
      by time interaction. Clinically important baseline differences between the study arms will be&#xD;
      included as covariates in all analyses. Correlation in repeated measures on the same&#xD;
      individual over time will be accounted for by explicitly modeling the covariance matrix, with&#xD;
      the best-fitting covariance structure decided using likelihood ratio tests and information&#xD;
      criteria. The difference between the experimental and control arms at end of chemotherapy&#xD;
      (primary comparison) will be calculated as adjusted least square mean difference in change&#xD;
      from baseline, together with 95% confidence intervals. All tests will be evaluated at the&#xD;
      two-sided 5% level of significance. SAS v.9.3 will be used for all analyses. Additional&#xD;
      adjusted analyses will be carried out using potential covariates.&#xD;
&#xD;
      To explore changes in brain structure and functioning, data will be analyzed with SPM12 (VBM&#xD;
      and CONN toolboxes) and FSL (FMRIB Software Library v5.0). Following respective&#xD;
      post-processing procedures, pre- and post- intervention measurement comparisons will be&#xD;
      conducted using voxel-wise statistical repeated-measures analyses, appropriate to each MRI&#xD;
      technique (for example, FA, MD for the DTI data, seed-to-voxel functional connectivity for&#xD;
      the fMRI data, as well as both whole brain and region of interest analyses of each fMRI&#xD;
      task). Statistical maps will be inspected at p &lt; 0.05 levels, corrected for multiple&#xD;
      comparisons. To test the effect of aerobic exercise during chemotherapy compared to&#xD;
      post-chemotherapy on outcomes 1-year after enrolment, the models as described above will&#xD;
      additionally include the response at 1-year follow-up and the contrast of interest will be&#xD;
      the difference in change from baseline (week 0) to 1-year post start of chemotherapy (week&#xD;
      52).&#xD;
&#xD;
      The sustainability of the intervention will be examined in each arm by testing the change in&#xD;
      response from immediately post-intervention to week 52, together with a 95% confidence&#xD;
      interval.&#xD;
&#xD;
      EEG signal processing will be completed using EEG time series from 27 locations to construct&#xD;
      the brain connectivity networks. The network graphs will be computed for each subject using&#xD;
      the false discovery rate controlled PC (PCFDR) algorithm, which is a statistical model that&#xD;
      tests the conditional dependence/independence between any two regions based on all other&#xD;
      brain regions. Partial correlation will be used to evaluate the conditional independence,&#xD;
      which estimates the directed interactions between any two brain regions after removing the&#xD;
      effects of all other brain areas. The FDR threshold will be set at a 5% level. Graph Theory&#xD;
      Analysis will use the &quot;Brain Connectivity Toolbox&quot; running Matlab (Natick, MA) to carry out&#xD;
      the graph theoretical based analysis. Traditional graph theoretical calculations will be used&#xD;
      to characterize different features of the network of interest such as density, global&#xD;
      efficiency, modularity and small-worldness.&#xD;
&#xD;
      Justification:&#xD;
&#xD;
      CRCC, or &quot;chemo brain&quot;, is common among women diagnosed with breast cancer, significantly&#xD;
      impacts everyday life, and diminishes quality of life. Women with breast cancer described&#xD;
      their chemo brain symptoms as &quot;frustrating&quot;, &quot;upsetting&quot; and for some &quot;frightening&quot;. In&#xD;
      addition, women with breast cancer may be unable to return to their previous occupational,&#xD;
      family and social activities, or do so only with significant additional mental effort. As a&#xD;
      result the high prevalence of chemo brain in women with breast cancer has a large economic&#xD;
      burden due to demand of health care resources and lost work-force productivity. Women with&#xD;
      breast cancer also report a general frustration in the response of the medical community,&#xD;
      either due to lack of acknowledgement of their symptoms or the fact that intervention&#xD;
      strategies are limited. Furthermore, there is limited information to guide health care&#xD;
      professionals with regards to clinical guidelines for the management of chemo brain and&#xD;
      health care professionals report that they do not consider themselves adequately&#xD;
      knowledgeable to address chemo brain.&#xD;
&#xD;
      This study will test if exercise during chemotherapy can mitigate chemo brain and its&#xD;
      negative impact on quality of life among women diagnosed with breast cancer, which if shown&#xD;
      to be effective, will have profound effects on the lives of those with chemo brain as well as&#xD;
      their family members and clinicians who currently have a lack of treatment options available.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Recruiting</last_known_status>
  <start_date type="Actual">November 1, 2017</start_date>
  <completion_date type="Anticipated">January 1, 2022</completion_date>
  <primary_completion_date type="Anticipated">May 1, 2021</primary_completion_date>
  <phase>N/A</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>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Change with treatment and maintenance post-treatment in objective neuropsychology test battery composite score</measure>
    <time_frame>Pre-chemotherapy (baseline, week 0), end of chemotherapy (12-18 weeks post-baseline), follow-up/post-usual care group receiving intervention (24-34 weeks post-baseline), 1-year follow-up (52 weeks post-baseline)</time_frame>
    <description>A neuropsychological test battery. The tests are as follows: WAIS-IV (Digit-Symbol Coding, Letter-Number-Sequencing), Auditory Consonant Trigrams Test, Brief Visuospatial Memory Test Revised, Controlled Oral Word Association Test, Hopkins Verbal Learning Test-Revised, and Trail Making Test A&amp;B. Alternate forms will be used, with the exception of the WAIS-IV tests, the Controlled Oral Word Association Test, and Trail Making A&amp;B. These tests are combined to form a composite score called the COGSUM.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Change with treatment and maintenance post-treatment in self-reported cognitive function and impact on quality of life</measure>
    <time_frame>Pre-chemotherapy (baseline, week 0), mid-chemotherapy (week 6-9), end of chemotherapy (12-18 weeks post-baseline), follow-up/post-usual care group receiving intervention (24-34 weeks post-baseline), 1-year follow-up (52 weeks post-baseline).</time_frame>
    <description>The Functional Assessment of Cancer Therapy (FACT)-Cognitive (Cog) Version 3</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change with treatment and maintenance post-treatment in self-reported cognitive function</measure>
    <time_frame>Pre-chemotherapy (baseline, week 0), mid-chemotherapy (week 6-9), end of chemotherapy (12-18 weeks post-baseline), follow-up/post-usual care group receiving intervention (24-34 weeks post-baseline),1-year follow-up (52 weeks post-baseline).</time_frame>
    <description>The Patient-Reported Outcomes Measurement Information System Applied Cognition short form</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change with treatment and maintenance post-treatment in brain function and structure</measure>
    <time_frame>Pre-chemotherapy (baseline, week 0), end of chemotherapy (12-18 weeks post-baseline), 1-year follow-up (52 weeks post-baseline).</time_frame>
    <description>Magnetic resonance imaging (MRI) assessment including a resting state fMRI procedure, a diffusion tensor imaging sequence, and three fMRI tasks (i.e., Letter N-Back and Word List Recognition Task).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change with treatment and maintenance post-treatment in electrical activity of the brain</measure>
    <time_frame>Pre-chemotherapy (baseline, week 0), end of chemotherapy (12-18 weeks post-baseline), 1-year follow-up (52 weeks post-baseline).</time_frame>
    <description>Electroencephalogram (EEG) will be performed including five minutes of resting data and 20 minutes during a computerized task.</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Change with treatment and maintenance post-treatment in aerobic fitness</measure>
    <time_frame>Pre-chemotherapy (baseline, week 0), end of chemotherapy (12-18 weeks post-baseline), follow-up (24-34 weeks post-baseline; UC participants only), 1-year follow-up (52 weeks post-baseline).</time_frame>
    <description>Aerobic capacity (VO2peak) will be measured with a maximal cardiopulmonary test using a metabolic cart (PARVO Medics).</description>
  </other_outcome>
  <other_outcome>
    <measure>Change with treatment and maintenance post-treatment in resting blood pressure</measure>
    <time_frame>Pre-chemotherapy (baseline, week 0), end of chemotherapy (12-18 weeks post-baseline), follow-up (24-34 weeks post-baseline; UC participants only), 1-year follow-up (52 weeks post-baseline).</time_frame>
    <description>Resting blood pressure (mmHg), measured in duplicate on non-surgical side using a blood pressure monitor.</description>
  </other_outcome>
  <other_outcome>
    <measure>Change with treatment and maintenance post-treatment in body composition</measure>
    <time_frame>Pre-chemotherapy (baseline, week 0), end of chemotherapy (12-18 weeks post-baseline), follow-up (24-34 weeks post-baseline; UC participants only), 1-year follow-up (52 weeks post-baseline).</time_frame>
    <description>Height (using a stadiometer) and weight (using a standard scale)</description>
  </other_outcome>
  <other_outcome>
    <measure>Socio-demographic information</measure>
    <time_frame>Pre-chemotherapy (baseline, week 0)</time_frame>
    <description>Brief self-reported socio-demographic</description>
  </other_outcome>
  <other_outcome>
    <measure>Medical characteristics</measure>
    <time_frame>Through study completion, an average of 1 year</time_frame>
    <description>Measures will be extracted from participants' medical records at the Vancouver-BCCA and TOH (as appropriate). In particular, the following medical information will be extracted: cancer disease stage, treatment factors (i.e., type, timing, and dosage of all treatments including surgery/ies and adjuvant treatment(s)), and list of prescribed medications</description>
  </other_outcome>
  <other_outcome>
    <measure>Change in exercise behaviour</measure>
    <time_frame>Pre-chemotherapy (baseline, week 0), end of chemotherapy (12-18 weeks post-baseline), follow-up and post-usual care wait-list control group receiving the intervention (24-34 weeks post-baseline), and 1-year follow-up (52 weeks)</time_frame>
    <description>Modified version of the Leisure Time Exercise Questionnaire</description>
  </other_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">84</enrollment>
  <condition>Breast Neoplasms</condition>
  <arm_group>
    <arm_group_label>Aerobic Exercise</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Participants will complete three supervised aerobic exercise sessions each week using the treadmill, stationary bicycle or elliptical training for the duration of their chemotherapy (12-18 weeks). Aerobic exercise will be performed for 20-40 minutes at 50-75% of heart rate reserve. Participants will wear heart rate monitors during all supervised sessions (Polar Electro Inc., Lake Success, NY) and will be provided with target heart rates that will be individualized using their baseline (i.e., week 0) assessment data. Home-based exercise will be introduced in week 3. For the home-based sessions, participants will be asked to complete at least 1 session per week of 30 minutes of aerobic exercise (an activity of their choosing; e.g., walking).</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Usual Care (Wait-list Control)</arm_group_label>
    <arm_group_type>Other</arm_group_type>
    <description>Participants randomly assigned to UC group will be advised to continue with their regular activities of daily living. Following their chemotherapy, the UC group will receive the exercise intervention (lasting 12 weeks).</description>
  </arm_group>
  <intervention>
    <intervention_type>Behavioral</intervention_type>
    <intervention_name>Aerobic Exercise</intervention_name>
    <description>Three weekly moderate-vigorous intensity supervised aerobic exercise training for the duration of adjuvant chemotherapy. Home-based exercise will also be introduced in week 3 of the intervention.</description>
    <arm_group_label>Aerobic Exercise</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Behavioral</intervention_type>
    <intervention_name>Usual Care (Wait-list Control)</intervention_name>
    <description>Three weekly moderate-vigorous intensity supervised aerobic exercise training starting upon adjuvant chemotherapy completion. Home-based exercise will also be introduced in week 3 of the intervention.</description>
    <arm_group_label>Usual Care (Wait-list Control)</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Diagnosed with stage I-III breast cancer;&#xD;
&#xD;
          -  Scheduled to receive adjuvant or neoadjuvant chemotherapy;&#xD;
&#xD;
          -  Able to speak and understand English in order to complete the study outcome measures;&#xD;
&#xD;
          -  Approval of medical oncologist to participate in the exercise intervention&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Having previously received chemotherapy or radiation therapy;&#xD;
&#xD;
          -  Score &lt;24 at baseline on the Montreal Cognitive Assessment (MoCA; indicating moderate&#xD;
             to severe cognitive impairment);&#xD;
&#xD;
          -  Having received a diagnosis of severe anxiety or mood disorder within the past year;&#xD;
&#xD;
          -  Having a medical condition that could impact cognition (e.g., prior head injury,&#xD;
             substance use disorder);&#xD;
&#xD;
          -  Currently meeting American College of Sports Medicine (ACSM) aerobic exercise&#xD;
             guidelines for cancer survivors in the 3 months prior to enrolment;&#xD;
&#xD;
          -  Body mass index ≥45 kg/m2;&#xD;
&#xD;
          -  Mobility issues that require a mobility aid or that prevent exercise on a bike,&#xD;
             treadmill, or elliptical (e.g., orthopedic injury, severe arthritis).&#xD;
&#xD;
        Additional Inclusion/Exclusion Criteria: During the screening process, patients will be&#xD;
        informed that they can participate in additional optional assessments (i.e., MRI and EEG&#xD;
        (Vancouver site only for EEG)&#xD;
&#xD;
        Additional inclusion criteria for MRI:&#xD;
&#xD;
          -  Right-handedness, because language is lateralized and has been shown to be left side&#xD;
             dominant (for right handers) during MRI tasks;&#xD;
&#xD;
          -  Able to read, understand, and provide informed consent in English for the additional&#xD;
             assessments.&#xD;
&#xD;
        Additional exclusion criteria for MRI are:&#xD;
&#xD;
          -  Metal implants (e.g., pacemaker) or metal dental work (aside from fillings) that would&#xD;
             preclude scanning;&#xD;
&#xD;
          -  Claustrophobia;&#xD;
&#xD;
          -  Poor eyesight (not correctable with contact lenses) that precludes viewing stimuli&#xD;
             presented in the scanner;&#xD;
&#xD;
          -  Lower back pain that would preclude a person from lying relatively still for one hour;&#xD;
&#xD;
          -  Breast tissue expander(s) inserted in the surgery site.&#xD;
      </textblock>
    </criteria>
    <gender>Female</gender>
    <minimum_age>19 Years</minimum_age>
    <maximum_age>70 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Kristin L Campbell, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Department of Physical Therapy</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Aaliya Merali-Dewji, MSc</last_name>
    <phone>604-827-1914</phone>
    <email>aaliya.merali@ubc.ca</email>
  </overall_contact>
  <location>
    <facility>
      <name>Breast Cancer Training Center, 614 W. 8th Ave</name>
      <address>
        <city>Vancouver</city>
        <state>British Columbia</state>
        <zip>V5Z 1C8</zip>
        <country>Canada</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Aaliya Merali-Dewji, MSc</last_name>
      <phone>604-872-4527</phone>
      <email>aaliya.merali@ubc.ca</email>
    </contact>
  </location>
  <location>
    <facility>
      <name>Clinical Exercise Physiology Lab</name>
      <address>
        <city>Vancouver</city>
        <state>British Columbia</state>
        <zip>V6T 1Z3</zip>
        <country>Canada</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Aaliya Merali-Dewji, MSc</last_name>
      <phone>6048271914</phone>
      <email>aaliya.merali@ubc.ca</email>
    </contact>
    <investigator>
      <last_name>Kristin L Campbell, BScPT, PhD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>School of Human Kinetics - University of Ottawa</name>
      <address>
        <city>Ottawa</city>
        <state>Ontario</state>
        <country>Canada</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Nicole Giouridis</last_name>
      <email>ngiourid@uottawa.ca</email>
    </contact>
  </location>
  <location>
    <facility>
      <name>School of Human Kinetics - University of Ottawa</name>
      <address>
        <city>Ottawa</city>
        <state>Ontario</state>
        <country>Canada</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Jennifer Brunet, PhD</last_name>
      <email>jennifer.brunet@uottawa.ca</email>
    </contact>
  </location>
  <location_countries>
    <country>Canada</country>
  </location_countries>
  <verification_date>February 2021</verification_date>
  <study_first_submitted>August 3, 2017</study_first_submitted>
  <study_first_submitted_qc>September 6, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">September 11, 2017</study_first_posted>
  <last_update_submitted>February 8, 2021</last_update_submitted>
  <last_update_submitted_qc>February 8, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">February 11, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>University of British Columbia</investigator_affiliation>
    <investigator_full_name>Kristin Campbell</investigator_full_name>
    <investigator_title>Associate Professor</investigator_title>
  </responsible_party>
  <keyword>Breast Neoplasms</keyword>
  <keyword>Exercise* OR &quot;Aerobic Exercise&quot;</keyword>
  <keyword>Cognitive Function*</keyword>
  <keyword>&quot;Antineoplastic therapy&quot; OR &quot;Antineoplastic agent&quot;</keyword>
  <keyword>Chemotherapy, Adjuvant</keyword>
  <keyword>Chemotherapy, Neoadjuvant</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Breast Neoplasms</mesh_term>
  </condition_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/NCT03277898
org study id: H17-00563
nct id: NCT03277898
lead sponsor: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
In Canada, approximately 68 women are diagnosed with breast cancer every day.
      Chemotherapy-related cognitive changes (CRCC) are reported by up to 75% of breast cancer
      survivors during treatment and symptoms persist in 35% of survivors after treatment. Women
      report that CRCC negatively impacts their everyday functioning and substantially reduces
      their overall quality of life. Effective clinical interventions to manage CRCC are elusive.
      As a result, breast cancer survivors typically receive little to no advice on how to prevent
      or manage CRCC. Aerobic exercise is a type of physical activity that uses large muscle
      groups, is rhythmic in nature, and can be sustained for at least 10 minutes (e.g., walking,
      jogging, indoor cycling). It has been associated with improved quality of life in breast
      cancer survivors. It also holds great promise as an intervention to prevent or mitigate CRCC.
      However, there is limited evidence from experimental studies to confirm this. Therefore, the
      primary aim of this trial is to evaluate the impact of a supervised aerobic exercise
      intervention on CRCC in women diagnosed with early-stage breast cancer. Recruited women will
      be randomized into one of two groups: (1) aerobic exercise during chemotherapy, or (2) usual
      care during chemotherapy and the aerobic exercise post-chemotherapy (i.e., wait-list control
      group). This study will test several novel hypotheses, including whether exercise during
      chemotherapy can prevent and/or mitigate CRCC and its negative impact on quality of life
      among women with breast cancer, and whether the timing of the exercise intervention matters
      (i.e., exercise during versus after chemotherapy). The results of this study aim to address
      the concerns of women affected by CRCC who are currently lacking available evidence-based
      treatment options, as well as oncology care providers' need to have options to recommend to
      their patients to prevent or manage CRCC.
The purpose of this study is to evaluate the impact of an aerobic exercise intervention on
      CRCC in women diagnosed with breast cancer who undergo chemotherapy. The specific objectives
      are to:

        1. Test the effect of aerobic exercise during chemotherapy (EX) compared to a usual care
           wait-list control group (exercise after chemotherapy; UC) on CRCC as assessed by
           neuropsychological tests and self-report;

        2. Test the effect of EX compared to UC on:

             1. Global measures of brain structure and functioning including brain volume in
                regions associated with working memory and response inhibition, white matter
                integrity (i.e., fractional anisotropy, mean diffusivity), and neural functioning
                using magnetic resonance imaging (MRI);

             2. Overall global brain network organization and improved regional brain network
                organization and neural functioning in areas underlying attention and working
                memory (i.e., dorso-lateral prefrontal cortex, superior temporal region and
                posterior parietal cortex) using electroencephalography (EEG; Vancouver site only;
                see Methods).

        3. Assess if the timing of the exercise intervention (i.e., during chemotherapy versus
           after chemotherapy) moderates the effects on CRCC by examining the effects of the
           intervention at 1-year post start of chemotherapy.

      It is hypothesized that:

        1. At the end of chemotherapy, EX group will perform better than UC group on
           neuropsychological tests and will self-report better cognitive functioning;

        2. At the end of chemotherapy, EX group will have maintained measures of brain structure
           and functioning as assessed by MRI scans and EEG (Vancouver site only) compared to UC
           group who will have significant changes in both;

        3. At 1-year post the start of chemotherapy, EX group will have better outcomes compared to
           the UC group.

      This is a two-arm, two-centre RCT. The two arms are:

        1. Aerobic exercise intervention during chemotherapy (EX);

        2. Usual care during chemotherapy and aerobic exercise after chemotherapy (i.e., usual care
           wait-list control group; UC).

      Recruitment:

      84 women diagnosed with breast cancer will be recruited across the two sites. The primary
      method of recruitment will be through printed postings and oncologist referral at the two
      main clinical sites: British Columbia Cancer Agency-Vancouver (BCCA) and The Ottawa Hospital
      (TOH). We anticipate our target of 84 patients will be reached in 30 months (combined site
      rate of 2-3 participants per month).

      Outcomes will be assessed at:

        1. Pre-chemotherapy (baseline, week 0);

        2. Mid-chemotherapy (approximately 6-9 weeks post-baseline);

        3. End of chemotherapy (approximately 12-18 weeks post-baseline);

        4. Follow-up and post-usual care wait-list control group receiving the intervention
           (approximately 24-34 weeks post-baseline);

        5. 1-year follow-up (52 weeks post-baseline).

      Optional neuroimaging and EEG will be completed in a sub-set of participants at each site who
      are interested, eligible, and consent to additional assessments at these time points:

        1. Pre-chemotherapy (baseline, week 0);

        2. End of chemotherapy (approximately 12-18 weeks post-baseline);

        3. 1-year follow-up (52 weeks post-baseline).

      Intervention:

      After obtaining informed consent, each participant will be scheduled for a baseline
      assessment (week 0). After baseline assessments, participants will be randomized. For the EX
      group, the intervention will be delivered concurrent with participants' chemotherapy regimen
      (lasting approximately 12-18 weeks). The intervention will be progressive aerobic exercise.
      The intervention is based on prior protocols used by the study team among women during
      treatment or who have completed treatment. Participants will complete three supervised 20-40
      minute aerobic exercise sessions each week. Home-based exercise will be introduced in week 3.
      For the home-based sessions, participants will be asked to complete at least 1 session per
      week of 30 minutes of aerobic exercise (an activity of their choosing; e.g., walking).

      Data Analysis:

      Changes in objective and self-reported cognitive functioning will be analyzed based on
      repeated measures analysis of variance with fixed terms for treatment, time, and a treatment
      by time interaction. Clinically important baseline differences between the study arms will be
      included as covariates in all analyses. Correlation in repeated measures on the same
      individual over time will be accounted for by explicitly modeling the covariance matrix, with
      the best-fitting covariance structure decided using likelihood ratio tests and information
      criteria. The difference between the experimental and control arms at end of chemotherapy
      (primary comparison) will be calculated as adjusted least square mean difference in change
      from baseline, together with 95% confidence intervals. All tests will be evaluated at the
      two-sided 5% level of significance. SAS v.9.3 will be used for all analyses. Additional
      adjusted analyses will be carried out using potential covariates.

      To explore changes in brain structure and functioning, data will be analyzed with SPM12 (VBM
      and CONN toolboxes) and FSL (FMRIB Software Library v5.0). Following respective
      post-processing procedures, pre- and post- intervention measurement comparisons will be
      conducted using voxel-wise statistical repeated-measures analyses, appropriate to each MRI
      technique (for example, FA, MD for the DTI data, seed-to-voxel functional connectivity for
      the fMRI data, as well as both whole brain and region of interest analyses of each fMRI
      task). Statistical maps will be inspected at p < 0.05 levels, corrected for multiple
      comparisons. To test the effect of aerobic exercise during chemotherapy compared to
      post-chemotherapy on outcomes 1-year after enrolment, the models as described above will
      additionally include the response at 1-year follow-up and the contrast of interest will be
      the difference in change from baseline (week 0) to 1-year post start of chemotherapy (week
      52).

      The sustainability of the intervention will be examined in each arm by testing the change in
      response from immediately post-intervention to week 52, together with a 95% confidence
      interval.

      EEG signal processing will be completed using EEG time series from 27 locations to construct
      the brain connectivity networks. The network graphs will be computed for each subject using
      the false discovery rate controlled PC (PCFDR) algorithm, which is a statistical model that
      tests the conditional dependence/independence between any two regions based on all other
      brain regions. Partial correlation will be used to evaluate the conditional independence,
      which estimates the directed interactions between any two brain regions after removing the
      effects of all other brain areas. The FDR threshold will be set at a 5% level. Graph Theory
      Analysis will use the "Brain Connectivity Toolbox" running Matlab (Natick, MA) to carry out
      the graph theoretical based analysis. Traditional graph theoretical calculations will be used
      to characterize different features of the network of interest such as density, global
      efficiency, modularity and small-worldness.

      Justification:

      CRCC, or "chemo brain", is common among women diagnosed with breast cancer, significantly
      impacts everyday life, and diminishes quality of life. Women with breast cancer described
      their chemo brain symptoms as "frustrating", "upsetting" and for some "frightening". In
      addition, women with breast cancer may be unable to return to their previous occupational,
      family and social activities, or do so only with significant additional mental effort. As a
      result the high prevalence of chemo brain in women with breast cancer has a large economic
      burden due to demand of health care resources and lost work-force productivity. Women with
      breast cancer also report a general frustration in the response of the medical community,
      either due to lack of acknowledgement of their symptoms or the fact that intervention
      strategies are limited. Furthermore, there is limited information to guide health care
      professionals with regards to clinical guidelines for the management of chemo brain and
      health care professionals report that they do not consider themselves adequately
      knowledgeable to address chemo brain.

      This study will test if exercise during chemotherapy can mitigate chemo brain and its
      negative impact on quality of life among women diagnosed with breast cancer, which if shown
      to be effective, will have profound effects on the lives of those with chemo brain as well as
      their family members and clinicians who currently have a lack of treatment options available.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Change with treatment and maintenance post-treatment in objective neuropsychology test battery composite score
time frame: Pre-chemotherapy (baseline, week 0), end of chemotherapy (12-18 weeks post-baseline), follow-up/post-usual care group receiving intervention (24-34 weeks post-baseline), 1-year follow-up (52 weeks post-baseline)
description: A neuropsychological test battery. The tests are as follows: WAIS-IV (Digit-Symbol Coding, Letter-Number-Sequencing), Auditory Consonant Trigrams Test, Brief Visuospatial Memory Test Revised, Controlled Oral Word Association Test, Hopkins Verbal Learning Test-Revised, and Trail Making Test A&B. Alternate forms will be used, with the exception of the WAIS-IV tests, the Controlled Oral Word Association Test, and Trail Making A&B. These tests are combined to form a composite score called the COGSUM.
measure: Change with treatment and maintenance post-treatment in self-reported cognitive function and impact on quality of life
time frame: Pre-chemotherapy (baseline, week 0), mid-chemotherapy (week 6-9), end of chemotherapy (12-18 weeks post-baseline), follow-up/post-usual care group receiving intervention (24-34 weeks post-baseline), 1-year follow-up (52 weeks post-baseline).
description: The Functional Assessment of Cancer Therapy (FACT)-Cognitive (Cog) Version 3
measure: Change with treatment and maintenance post-treatment in self-reported cognitive function
time frame: Pre-chemotherapy (baseline, week 0), mid-chemotherapy (week 6-9), end of chemotherapy (12-18 weeks post-baseline), follow-up/post-usual care group receiving intervention (24-34 weeks post-baseline),1-year follow-up (52 weeks post-baseline).
description: The Patient-Reported Outcomes Measurement Information System Applied Cognition short form
measure: Change with treatment and maintenance post-treatment in brain function and structure
time frame: Pre-chemotherapy (baseline, week 0), end of chemotherapy (12-18 weeks post-baseline), 1-year follow-up (52 weeks post-baseline).
description: Magnetic resonance imaging (MRI) assessment including a resting state fMRI procedure, a diffusion tensor imaging sequence, and three fMRI tasks (i.e., Letter N-Back and Word List Recognition Task).
measure: Change with treatment and maintenance post-treatment in electrical activity of the brain
time frame: Pre-chemotherapy (baseline, week 0), end of chemotherapy (12-18 weeks post-baseline), 1-year follow-up (52 weeks post-baseline).
description: Electroencephalogram (EEG) will be performed including five minutes of resting data and 20 minutes during a computerized task.
measure: Change with treatment and maintenance post-treatment in aerobic fitness
time frame: Pre-chemotherapy (baseline, week 0), end of chemotherapy (12-18 weeks post-baseline), follow-up (24-34 weeks post-baseline; UC participants only), 1-year follow-up (52 weeks post-baseline).
description: Aerobic capacity (VO2peak) will be measured with a maximal cardiopulmonary test using a metabolic cart (PARVO Medics).
measure: Change with treatment and maintenance post-treatment in resting blood pressure
time frame: Pre-chemotherapy (baseline, week 0), end of chemotherapy (12-18 weeks post-baseline), follow-up (24-34 weeks post-baseline; UC participants only), 1-year follow-up (52 weeks post-baseline).
description: Resting blood pressure (mmHg), measured in duplicate on non-surgical side using a blood pressure monitor.
measure: Change with treatment and maintenance post-treatment in body composition
time frame: Pre-chemotherapy (baseline, week 0), end of chemotherapy (12-18 weeks post-baseline), follow-up (24-34 weeks post-baseline; UC participants only), 1-year follow-up (52 weeks post-baseline).
description: Height (using a stadiometer) and weight (using a standard scale)
measure: Socio-demographic information
time frame: Pre-chemotherapy (baseline, week 0)
description: Brief self-reported socio-demographic
measure: Medical characteristics
time frame: Through study completion, an average of 1 year
description: Measures will be extracted from participants' medical records at the Vancouver-BCCA and TOH (as appropriate). In particular, the following medical information will be extracted: cancer disease stage, treatment factors (i.e., type, timing, and dosage of all treatments including surgery/ies and adjuvant treatment(s)), and list of prescribed medications
measure: Change in exercise behaviour
time frame: Pre-chemotherapy (baseline, week 0), end of chemotherapy (12-18 weeks post-baseline), follow-up and post-usual care wait-list control group receiving the intervention (24-34 weeks post-baseline), and 1-year follow-up (52 weeks)
description: Modified version of the Leisure Time Exercise Questionnaire
arm group label: Aerobic Exercise
arm group type: Experimental
description: Participants will complete three supervised aerobic exercise sessions each week using the treadmill, stationary bicycle or elliptical training for the duration of their chemotherapy (12-18 weeks). Aerobic exercise will be performed for 20-40 minutes at 50-75% of heart rate reserve. Participants will wear heart rate monitors during all supervised sessions (Polar Electro Inc., Lake Success, NY) and will be provided with target heart rates that will be individualized using their baseline (i.e., week 0) assessment data. Home-based exercise will be introduced in week 3. For the home-based sessions, participants will be asked to complete at least 1 session per week of 30 minutes of aerobic exercise (an activity of their choosing; e.g., walking).
arm group label: Usual Care (Wait-list Control)
arm group type: Other
description: Participants randomly assigned to UC group will be advised to continue with their regular activities of daily living. Following their chemotherapy, the UC group will receive the exercise intervention (lasting 12 weeks).
intervention type: Behavioral
intervention name: Aerobic Exercise
description: Three weekly moderate-vigorous intensity supervised aerobic exercise training for the duration of adjuvant chemotherapy. Home-based exercise will also be introduced in week 3 of the intervention.
arm group label: Aerobic Exercise
intervention type: Behavioral
intervention name: Usual Care (Wait-list Control)
description: Three weekly moderate-vigorous intensity supervised aerobic exercise training starting upon adjuvant chemotherapy completion. Home-based exercise will also be introduced in week 3 of the intervention.
arm group label: Usual Care (Wait-list Control)
criteria: 
gender: Female
minimum age: 19 Years
maximum age: 70 Years
healthy volunteers: No
last name: Kristin L Campbell, PhD
role: Principal Investigator
affiliation: Department of Physical Therapy
last name: Aaliya Merali-Dewji, MSc
phone: 604-827-1914
email: aaliya.merali@ubc.ca
facility: 
status: Recruiting
contact: 
facility: 
status: Recruiting
contact: 
investigator: 
facility: 
status: Recruiting
contact: 
facility: 
status: Recruiting
contact: 
country: Canada
responsible party type: Principal Investigator
investigator affiliation: University of British Columbia
investigator full name: Kristin Campbell
investigator title: Associate Professor
mesh term: Breast Neoplasms