<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/NCT03776149</url>
  </required_header>
  <id_info>
    <org_study_id>Pro9264</org_study_id>
    <nct_id>NCT03776149</nct_id>
  </id_info>
  <brief_title>Cardiovascular Function in Cancer Survivors</brief_title>
  <official_title>Therapeutic Role of Dietary Nitrates on Cardiovascular Function in Cancer Survivors Treated With Anthracycline Chemotherapy</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Kansas State University</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Kansas State University</source>
  <oversight_info>
    <has_dmc>No</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>
      The aim of the current project is to understand the effect of dietary nitrates (via beet-root&#xD;
      juice), on its ability to improve parameters of cardiovascular health in cancer survivors&#xD;
      with a history of anthracycline chemotherapy.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Cancer remains one of the leading causes of death in modern society, but due in part to&#xD;
      increasing rates of detection coupled with advanced therapies, of the ≈230,000 people newly&#xD;
      diagnosed with breast cancer each year, approximately 90% are expected to live beyond 5&#xD;
      years. Despite the trend in improved cancer-related mortality, breast cancer survivors are at&#xD;
      a significantly increased risk for cardiovascular disease (CVD) morbidity and mortality. As&#xD;
      such the American Heart Association has recently highlighted the immediate need to evaluate&#xD;
      changes in cardiovascular health and function in the early stages of cancer treatment.&#xD;
&#xD;
      The mechanisms of adjuvant therapies on cardiovascular function may be the result of&#xD;
      increased generation of reactive oxygen species (ROS) and altered redox status, specifically&#xD;
      the balance between nitric oxide and superoxide. As such, nitrate supplementation has been&#xD;
      shown to attenuate Doxorubicin (chemotherapy drug)-induced ventricular function in animal&#xD;
      models. These data implicate dietary nitrates as one potential therapeutic intervention that&#xD;
      could be used to improve cardiovascular health in cancer survivors.&#xD;
&#xD;
      Beetroot juice (BRJ) is a nutritional supplement that has been studied to examine potential&#xD;
      effects of dietary nitrates affecting vasodilation. The increased nitrate levels have been&#xD;
      implicated in helping increase nitric oxide bioavailability, which have been shown to improve&#xD;
      cardiovascular function in older adults and those with known cardiovascular disease. The&#xD;
      question, however, of whether or not BRJ will enhance cardiovascular function in breast&#xD;
      cancer survivors is yet to be determined.&#xD;
&#xD;
      The primary aim of the current investigation is to test the hypothesis that dietary nitrate&#xD;
      supplementation, via beet-root juice, improves parameters of cardiovascular health in cancer&#xD;
      survivors with a history of anthracycline chemotherapy treatment.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">May 10, 2018</start_date>
  <completion_date type="Actual">May 31, 2020</completion_date>
  <primary_completion_date type="Actual">May 31, 2020</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>Crossover Assignment</intervention_model>
    <intervention_model_description>This study utilizes a 7-day randomized, double-blind, placebo-controlled crossover study design, in which individuals are initially supplemented with a nitrate-rich supplement in the form of a specifically formulated beetroot juice, or nitrate-poor placebo. Individuals will then entered a 7-day washout period before entering the opposing arm of the study.</intervention_model_description>
    <primary_purpose>Supportive Care</primary_purpose>
    <masking>Double (Participant, Investigator)</masking>
    <masking_description>The supplement and placebo will be distributed to the individual by a member of the research team who is not involved with data collection or analysis.</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>Change in Left ventricular function</measure>
    <time_frame>The change between day 1 and day 21</time_frame>
    <description>Left ventricular function as measured by transthoracic echocardiography</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Change in Vascular function</measure>
    <time_frame>The change between day 1 and day 21</time_frame>
    <description>Vascular function measured as changes in arterial stiffness and endothelial function.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in Blood pressure</measure>
    <time_frame>The change between day 1 and day 21</time_frame>
    <description>Local limb blood pressure measured in millimeters of mercury (mmHg) following study interventions/arms</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">13</enrollment>
  <condition>Cancer Survivor With History of Anthracycline Chemotherapy</condition>
  <arm_group>
    <arm_group_label>Beetroot juice (dietary nitrate)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Over the 7 days preceding each testing session, participants will consume 140 ml per day of beetroot juice (Beet It (HeartBeet Ltd.), Ipswich, UK). During this time participants will be asked to abstain from use of antiseptic mouthwash as this has been shown to temporarily kill the bacteria that facilitate the reduction of nitrate to nitrite. All participants will be asked to refrain from consuming any antioxidant (e.g., Vit E or Fish Oil) supplements during the course of the study as these may impact the study findings.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Black currant juice (placebo control)</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Over the 7 days preceding each testing session, participants will consume 140 ml per day of a nitrate-depleted placebo. During this time participants will be asked to abstain from use of antiseptic mouthwash as this has been shown to temporarily kill the bacteria that facilitate the reduction of nitrate to nitrite. All participants will be asked to refrain from consuming any antioxidant (e.g., Vit E or Fish Oil) supplements during the course of the study as these may impact the study findings.</description>
  </arm_group>
  <intervention>
    <intervention_type>Dietary Supplement</intervention_type>
    <intervention_name>Beetroot juice</intervention_name>
    <description>Following randomization on day 1, subjects will consume either the nitrate or nitrate-free beverage for 7 days with outcome measurements performed on day 7. Following a 7 day washout, subjects will then consume the crossover beverage for 7 days with outcome measures performed on day 21.</description>
    <arm_group_label>Beetroot juice (dietary nitrate)</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Dietary Supplement</intervention_type>
    <intervention_name>Black currant juice</intervention_name>
    <description>Following randomization on day 1, subjects will consume either the nitrate or nitrate-free beverage for 7 days with outcome measurements performed on day 7. Following a 7 day washout, subjects will then consume the crossover beverage for 7 days with outcome measures performed on day 21.</description>
    <arm_group_label>Black currant juice (placebo control)</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  cancer survivors (at least 1 year post treatment)&#xD;
&#xD;
          -  Prior administration of anthracycline chemotherapy&#xD;
&#xD;
          -  partial/complete remission&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Unable to provide informed consent&#xD;
&#xD;
          -  Kidney disease&#xD;
&#xD;
          -  High risk of kidney stones&#xD;
&#xD;
          -  Diagnosed hemochromatosis&#xD;
&#xD;
          -  Pregnant, breast feeding, or planning to become pregnant&#xD;
&#xD;
          -  Non-English speaking&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>21 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <location>
    <facility>
      <name>Kansas State University - Clinical Integrative Physiology Laboratory</name>
      <address>
        <city>Manhattan</city>
        <state>Kansas</state>
        <zip>66506</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <reference>
    <citation>Patnaik JL, Byers T, DiGuiseppi C, Dabelea D, Denberg TD. Cardiovascular disease competes with breast cancer as the leading cause of death for older females diagnosed with breast cancer: a retrospective cohort study. Breast Cancer Res. 2011 Jun 20;13(3):R64. doi: 10.1186/bcr2901.</citation>
    <PMID>21689398</PMID>
  </reference>
  <reference>
    <citation>Mulrooney DA, Blaes AH, Duprez D. Vascular injury in cancer survivors. J Cardiovasc Transl Res. 2012 Jun;5(3):287-95. doi: 10.1007/s12265-012-9358-7. Epub 2012 Mar 29.</citation>
    <PMID>22456863</PMID>
  </reference>
  <reference>
    <citation>Chaosuwannakit N, D'Agostino R Jr, Hamilton CA, Lane KS, Ntim WO, Lawrence J, Melin SA, Ellis LR, Torti FM, Little WC, Hundley WG. Aortic stiffness increases upon receipt of anthracycline chemotherapy. J Clin Oncol. 2010 Jan 1;28(1):166-72. doi: 10.1200/JCO.2009.23.8527. Epub 2009 Nov 9.</citation>
    <PMID>19901105</PMID>
  </reference>
  <reference>
    <citation>Duquaine D, Hirsch GA, Chakrabarti A, Han Z, Kehrer C, Brook R, Joseph J, Schott A, Kalyanaraman B, Vasquez-Vivar J, Rajagopalan S. Rapid-onset endothelial dysfunction with adriamycin: evidence for a dysfunctional nitric oxide synthase. Vasc Med. 2003 May;8(2):101-7. doi: 10.1191/1358863x03vm476oa.</citation>
    <PMID>14518612</PMID>
  </reference>
  <verification_date>March 2022</verification_date>
  <study_first_submitted>May 14, 2018</study_first_submitted>
  <study_first_submitted_qc>December 13, 2018</study_first_submitted_qc>
  <study_first_posted type="Actual">December 14, 2018</study_first_posted>
  <last_update_submitted>March 30, 2022</last_update_submitted>
  <last_update_submitted_qc>March 30, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">March 31, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Kansas State University</investigator_affiliation>
    <investigator_full_name>Carl Ade, M.S., Ph.D.</investigator_full_name>
    <investigator_title>Assistant Professor</investigator_title>
  </responsible_party>
  <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/NCT03776149
org study id: Pro9264
nct id: NCT03776149
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
The aim of the current project is to understand the effect of dietary nitrates (via beet-root
      juice), on its ability to improve parameters of cardiovascular health in cancer survivors
      with a history of anthracycline chemotherapy.
Cancer remains one of the leading causes of death in modern society, but due in part to
      increasing rates of detection coupled with advanced therapies, of the ≈230,000 people newly
      diagnosed with breast cancer each year, approximately 90% are expected to live beyond 5
      years. Despite the trend in improved cancer-related mortality, breast cancer survivors are at
      a significantly increased risk for cardiovascular disease (CVD) morbidity and mortality. As
      such the American Heart Association has recently highlighted the immediate need to evaluate
      changes in cardiovascular health and function in the early stages of cancer treatment.

      The mechanisms of adjuvant therapies on cardiovascular function may be the result of
      increased generation of reactive oxygen species (ROS) and altered redox status, specifically
      the balance between nitric oxide and superoxide. As such, nitrate supplementation has been
      shown to attenuate Doxorubicin (chemotherapy drug)-induced ventricular function in animal
      models. These data implicate dietary nitrates as one potential therapeutic intervention that
      could be used to improve cardiovascular health in cancer survivors.

      Beetroot juice (BRJ) is a nutritional supplement that has been studied to examine potential
      effects of dietary nitrates affecting vasodilation. The increased nitrate levels have been
      implicated in helping increase nitric oxide bioavailability, which have been shown to improve
      cardiovascular function in older adults and those with known cardiovascular disease. The
      question, however, of whether or not BRJ will enhance cardiovascular function in breast
      cancer survivors is yet to be determined.

      The primary aim of the current investigation is to test the hypothesis that dietary nitrate
      supplementation, via beet-root juice, improves parameters of cardiovascular health in cancer
      survivors with a history of anthracycline chemotherapy treatment.
allocation: Randomized
intervention model: Crossover Assignment
intervention model description: This study utilizes a 7-day randomized, double-blind, placebo-controlled crossover study design, in which individuals are initially supplemented with a nitrate-rich supplement in the form of a specifically formulated beetroot juice, or nitrate-poor placebo. Individuals will then entered a 7-day washout period before entering the opposing arm of the study.
primary purpose: Supportive Care
masking: Double (Participant, Investigator)
masking description: The supplement and placebo will be distributed to the individual by a member of the research team who is not involved with data collection or analysis.
measure: Change in Left ventricular function
time frame: The change between day 1 and day 21
description: Left ventricular function as measured by transthoracic echocardiography
measure: Change in Vascular function
time frame: The change between day 1 and day 21
description: Vascular function measured as changes in arterial stiffness and endothelial function.
measure: Change in Blood pressure
time frame: The change between day 1 and day 21
description: Local limb blood pressure measured in millimeters of mercury (mmHg) following study interventions/arms
arm group label: Beetroot juice (dietary nitrate)
arm group type: Experimental
description: Over the 7 days preceding each testing session, participants will consume 140 ml per day of beetroot juice (Beet It (HeartBeet Ltd.), Ipswich, UK). During this time participants will be asked to abstain from use of antiseptic mouthwash as this has been shown to temporarily kill the bacteria that facilitate the reduction of nitrate to nitrite. All participants will be asked to refrain from consuming any antioxidant (e.g., Vit E or Fish Oil) supplements during the course of the study as these may impact the study findings.
arm group label: Black currant juice (placebo control)
arm group type: Placebo Comparator
description: Over the 7 days preceding each testing session, participants will consume 140 ml per day of a nitrate-depleted placebo. During this time participants will be asked to abstain from use of antiseptic mouthwash as this has been shown to temporarily kill the bacteria that facilitate the reduction of nitrate to nitrite. All participants will be asked to refrain from consuming any antioxidant (e.g., Vit E or Fish Oil) supplements during the course of the study as these may impact the study findings.
intervention type: Dietary Supplement
intervention name: Beetroot juice
description: Following randomization on day 1, subjects will consume either the nitrate or nitrate-free beverage for 7 days with outcome measurements performed on day 7. Following a 7 day washout, subjects will then consume the crossover beverage for 7 days with outcome measures performed on day 21.
arm group label: Beetroot juice (dietary nitrate)
intervention type: Dietary Supplement
intervention name: Black currant juice
description: Following randomization on day 1, subjects will consume either the nitrate or nitrate-free beverage for 7 days with outcome measurements performed on day 7. Following a 7 day washout, subjects will then consume the crossover beverage for 7 days with outcome measures performed on day 21.
arm group label: Black currant juice (placebo control)
criteria: 
gender: All
minimum age: 21 Years
maximum age: N/A
healthy volunteers: No
facility: 
country: United States
citation: Patnaik JL, Byers T, DiGuiseppi C, Dabelea D, Denberg TD. Cardiovascular disease competes with breast cancer as the leading cause of death for older females diagnosed with breast cancer: a retrospective cohort study. Breast Cancer Res. 2011 Jun 20;13(3):R64. doi: 10.1186/bcr2901.
PMID: 21689398
citation: Mulrooney DA, Blaes AH, Duprez D. Vascular injury in cancer survivors. J Cardiovasc Transl Res. 2012 Jun;5(3):287-95. doi: 10.1007/s12265-012-9358-7. Epub 2012 Mar 29.
PMID: 22456863
citation: Chaosuwannakit N, D'Agostino R Jr, Hamilton CA, Lane KS, Ntim WO, Lawrence J, Melin SA, Ellis LR, Torti FM, Little WC, Hundley WG. Aortic stiffness increases upon receipt of anthracycline chemotherapy. J Clin Oncol. 2010 Jan 1;28(1):166-72. doi: 10.1200/JCO.2009.23.8527. Epub 2009 Nov 9.
PMID: 19901105
citation: Duquaine D, Hirsch GA, Chakrabarti A, Han Z, Kehrer C, Brook R, Joseph J, Schott A, Kalyanaraman B, Vasquez-Vivar J, Rajagopalan S. Rapid-onset endothelial dysfunction with adriamycin: evidence for a dysfunctional nitric oxide synthase. Vasc Med. 2003 May;8(2):101-7. doi: 10.1191/1358863x03vm476oa.
PMID: 14518612
responsible party type: Principal Investigator
investigator affiliation: Kansas State University
investigator full name: Carl Ade, M.S., Ph.D.
investigator title: Assistant Professor
sharing ipd: No