<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/NCT03277183</url>
  </required_header>
  <id_info>
    <org_study_id>CARA-019-16F</org_study_id>
    <secondary_id>I01CX001449</secondary_id>
    <nct_id>NCT03277183</nct_id>
  </id_info>
  <brief_title>Frequent, Low-Dose Erythropoietin A Mechanistic Approach to Mitigate Adverse Cardiovascular Effects of Erythropoietin</brief_title>
  <official_title>Frequent, Low-Dose Erythropoietin: A Mechanistic Approach to Mitigate Adverse Cardiovascular Effects of Erythropoietin Therapy in Patients With Chronic Kidney Disease</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>VA Office of Research and Development</agency>
      <agency_class>U.S. Fed</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>VA Office of Research and Development</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>Yes</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      Although several large well designed clinical trials have shown that erythropoietin which is&#xD;
      commonly used to treat anemia associated with kidney disease, increases the risk of stroke&#xD;
      and heart disease, the mechanism for this increased risk is unknown. The investigators'&#xD;
      preliminary studies show that the adverse effects of erythropoietin are from activation of&#xD;
      the heterodimeric erythropoietin/ beta common receptor which only occurs with high doses of&#xD;
      erythropoietin. The investigators propose a clinical trial of 120 patients assigned to low&#xD;
      doses of erythropoietin given more frequently or the same cumulative dose of erythropoietin&#xD;
      administered as a high dose once every two weeks and assess effects on the beta common&#xD;
      receptor activation, inflammation and vascular disease as evidence by MRI of the carotid&#xD;
      arteries.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Erythropoietin (EPO) is the most widely prescribed cytokine, yet the benefits and potential&#xD;
      side effects of different dosing regimens are poorly understood. It is now recognized that&#xD;
      erythropoietin administered at high doses to patients with chronic kidney disease, results in&#xD;
      an increased risk of morbidity and mortality from heart disease and stroke. However, the&#xD;
      mechanisms that mediate this increased risk of cardiovascular disease is not known. There are&#xD;
      two receptors for erythropoietin the homodimeric EPO receptor (EPOR) and the heterodimeric&#xD;
      beta common receptor ( CR)/EPOR. The investigators have demonstrated that activation of the&#xD;
      heterodimeric CR/EPOR only occurs with high doses of EPO. Our exciting, published,&#xD;
      preliminary data also demonstrates that the CR is in a complex with vascular endothelial&#xD;
      growth factor receptor-2 (VEGFR-2) and that high doses of EPO activate VEGFR-2 through the&#xD;
      CR, resulting in the deleterious effects of VEGFR-2 activation on the cardiovascular system.&#xD;
      This is particularly important in patients with kidney disease since they are already at a&#xD;
      high risk of cardiovascular disease. Moreover in advanced kidney disease cyanate derived from&#xD;
      the high urea levels can non-enzymatically form an amide bond with EPO. This carbamylated EPO&#xD;
      (cEPO) has no effect on hemoglobin, but still activates the heterodimeric CR/EPOR. To date&#xD;
      there have been no studies that have directly measured levels of cEPO or activation of the&#xD;
      CR/EPOR in patients with kidney disease. Our hypothesis is that the administration of&#xD;
      low-doses of EPO more frequently will result in lower levels of total and carbamylated&#xD;
      erythropoietin decreased activation of VEGFR-2 via the heterodimeric CR/EPOR and consequently&#xD;
      decreased inflammation and atherosclerosis. The investigators will directly test this&#xD;
      hypothesis by randomly allocating 120 patients with chronic kidney disease to either low-&#xD;
      dose EPO given thrice weekly or the same cumulative dose, a high-dose, administered once&#xD;
      every 2 weeks. Our hypothesis predicts that low-dose EPO will be as effective at correcting&#xD;
      anemia, but will demonstrate less progression of carotid artery plaque, as assessed by&#xD;
      non-contrast magnetic resonance imaging, as compared to the high-dose, EPO given every 2&#xD;
      weeks. To delineate how EPO affects blood vessels, the investigators will isolate endothelial&#xD;
      cells from blood vessels in 20 patients who are assigned to low-dose EPO and 20 allocated to&#xD;
      high-dose EPO. Within these cells the investigators will investigate the signaling pathways&#xD;
      that are triggered by activation of CR/EPOR. In a substudy of 20 subjects with kidney disease&#xD;
      randomized to low-dose EPO or to high-dose EPO, as well as 20 healthy controls receiving a&#xD;
      single dose of high- or low-dose EPO, the investigators will determine how kidney function&#xD;
      and dosing affects levels of total and carbamylated erythropoietin. The investigators' study&#xD;
      will not only provide us with a thorough understanding of the mechanism by which EPO mediates&#xD;
      the increased risk of atherosclerosis, but a clinical strategy to avoid the side effects of&#xD;
      EPO therapy and a tool to quantify the cardiovascular risk of EPO and newer erythropoiesis&#xD;
      stimulating agents by assessing activation of the heterodimeric CR/EPOR.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Terminated</overall_status>
  <why_stopped>
    Lack of enrollment&#xD;
  </why_stopped>
  <start_date type="Actual">November 2, 2017</start_date>
  <completion_date type="Actual">June 3, 2019</completion_date>
  <primary_completion_date type="Actual">June 3, 2019</primary_completion_date>
  <phase>Phase 4</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>
    <intervention_model_description>Patients will be randomly assigned two different erythropoietin dosing strategies. One group will be given more frequent, low-doses of EPO and the other group will be given the same, cumulative dose given every 2 weeks.</intervention_model_description>
    <primary_purpose>Prevention</primary_purpose>
    <masking>Single (Outcomes Assessor)</masking>
    <masking_description>The outcome is the progression of carotid plaque. John Forder, PhD, who will read the MRIs will be blinded to the subject and treatment group.</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>Change in Carotid Total Plaque Volume From Baseline to Approximately 1 Year, as Assessed by Non-contrast MRI</measure>
    <time_frame>1 year</time_frame>
    <description>The plaque characteristics will be analyzed by MRI-PlaqueViewTM (VP diagnostics Inc., WA). Planimetry will be performed on the image data sets, using histogram equalization to improve edge detection for plaque, arterial wall and lumen. Differences in image contrast between T1-weighted, T2-weighted, Time of Flight, and proton density will be used to characterize the plaque as fibrous, stable, or unstable.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Severity of Maximal Stenosis at Baseline and Upon Follow-up.</measure>
    <time_frame>1 year</time_frame>
    <description>The plaque characteristics will be analyzed by MRI-PlaqueViewTM (VP diagnostics Inc., WA). Planimetry will be performed on the image data sets, using histogram equalization to improve edge detection for plaque, arterial wall and lumen. Differences in image contrast between T1-weighted, T2-weighted, Time of Flight, and proton density will be used to characterize the plaque as fibrous, stable, or unstable.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Percentage of Total Plaque Area at Baseline and Upon Follow-up.</measure>
    <time_frame>1 year</time_frame>
    <description>The plaque characteristics will be analyzed by MRI-PlaqueViewTM (VP diagnostics Inc., WA). Planimetry will be performed on the image data sets, using histogram equalization to improve edge detection for plaque, arterial wall and lumen. Differences in image contrast between T1-weighted, T2-weighted, Time of Flight, and proton density will be used to characterize the plaque as fibrous, stable, or unstable.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Characteristics of Plaques (Soft or Fibrous and Stable or Unstable) at Baseline and Upon Follow-up.</measure>
    <time_frame>1 year</time_frame>
    <description>The plaque characteristics will be analyzed by MRI-PlaqueViewTM (VP diagnostics Inc., WA). Planimetry will be performed on the image data sets, using histogram equalization to improve edge detection for plaque, arterial wall and lumen. Differences in image contrast between T1-weighted, T2-weighted, Time of Flight, and proton density will be used to characterize the plaque as fibrous, stable, or unstable.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">5</enrollment>
  <condition>Anemia</condition>
  <condition>CKD</condition>
  <condition>Atherosclerosis</condition>
  <condition>Cardiovascular</condition>
  <arm_group>
    <arm_group_label>Low dose erythropoietin</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Subjects randomized to this arm will receive low-dose of EPO administered thrice weekly</description>
  </arm_group>
  <arm_group>
    <arm_group_label>High dose erythropoietin</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Subjects randomized to this arm will receive the same cumulative dose of EPO administered as a high-dose of EPO every 2 weeks</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Low dose erythropoietin</intervention_name>
    <description>Subjects randomized to this arm will receive low-dose of EPO administered thrice weekly</description>
    <arm_group_label>Low dose erythropoietin</arm_group_label>
    <other_name>Low dose</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>High dose erythropoietin</intervention_name>
    <description>Subjects randomized to this arm will receive the same cumulative dose of EPO administered as a high-dose of EPO every 2 weeks</description>
    <arm_group_label>High dose erythropoietin</arm_group_label>
    <other_name>High dose</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
        The investigators will enroll Veterans who fulfill the following criteria:&#xD;
&#xD;
          -  stage 3, 4, or 5 CKD (estimated glomerular filtration rate of less than 60 ml/min/1.73&#xD;
             m2) on at least two separate occasions greater than 3 months apart; and&#xD;
&#xD;
          -  candidates for EPO therapy as per the National Kidney Foundation's Kidney Disease&#xD;
             Outcomes Quality Initiative guidelines (hemoglobin &lt; 10 gm/dL and anemia of CKD).&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
        The investigators will exclude any Veteran who meets any of the following criteria:&#xD;
&#xD;
          1. pregnant, planning to become pregnant in the next year, or breast feeding;&#xD;
&#xD;
          2. uncontrolled hypertension (blood pressure &gt; 180/100 mm Hg despite optimal&#xD;
             antihypertensive medications);&#xD;
&#xD;
          3. active gastrointestinal bleeding (visible blood or positive tests for stool occult&#xD;
             blood accompanied by a decrease in hemoglobin);&#xD;
&#xD;
          4. likely to have EPO resistance;&#xD;
&#xD;
          5. an adverse cardiovascular event in the prior three months;&#xD;
&#xD;
          6. active or recent (within the last 3 months) severe, systemic infection;&#xD;
&#xD;
          7. active inflammatory disease such as lupus, rheumatoid arthritis, or vasculitis&#xD;
             requiring immunosuppressive or immunomodulatory medications;&#xD;
&#xD;
          8. history of solid organ transplantation;&#xD;
&#xD;
          9. expected off-dialysis survival of less than one year (as determined by the estimated&#xD;
             glomerular filtration slope and the treating physician;&#xD;
&#xD;
         10. active cancer (undergoing chemotherapy or radiation within the last 3 months) or&#xD;
             primary bone marrow disease such as myelofibrosis; or&#xD;
&#xD;
         11. a contraindication for an MRI or individuals who cannot comply with the study&#xD;
             protocol. The investigators will exclude healthy subjects that meet a, b, f, g, h, or&#xD;
             j.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Mark S. Segal, MD PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>North Florida/South Georgia Veterans Health System, Gainesville, FL</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>North Florida/South Georgia Veterans Health System, Gainesville, FL</name>
      <address>
        <city>Gainesville</city>
        <state>Florida</state>
        <zip>32608</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>July 2020</verification_date>
  <study_first_submitted>September 6, 2017</study_first_submitted>
  <study_first_submitted_qc>September 6, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">September 8, 2017</study_first_posted>
  <results_first_submitted>July 28, 2020</results_first_submitted>
  <results_first_submitted_qc>July 28, 2020</results_first_submitted_qc>
  <results_first_posted type="Actual">August 13, 2020</results_first_posted>
  <last_update_submitted>July 28, 2020</last_update_submitted>
  <last_update_submitted_qc>July 28, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">August 13, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>erythropoietin</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Atherosclerosis</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Epoetin Alfa</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <provided_document_section>
    <provided_document>
      <document_type>Study Protocol and Statistical Analysis Plan</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>April 23, 2019</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/83/NCT03277183/Prot_SAP_000.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <group_list>
        <group group_id="P1">
          <title>Low Dose Erythropoietin</title>
          <description>Subjects randomized to this arm will receive low-dose of EPO administered thrice weekly&#xD;
Low dose erythropoietin: Subjects randomized to this arm will receive low-dose of EPO administered thrice weekly</description>
        </group>
        <group group_id="P2">
          <title>High Dose Erythropoietin</title>
          <description>Subjects randomized to this arm will receive the same cumulative dose of EPO administered as a high-dose of EPO every 2 weeks&#xD;
High dose erythropoietin: Subjects randomized to this arm will receive the same cumulative dose of EPO administered as a high-dose of EPO every 2 weeks</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="3"/>
                <participants group_id="P2" count="2"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="3"/>
                <participants group_id="P2" count="2"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <population>Although baseline MRI's were performed they were not analyzed due to study termination due to lack of enrollment.</population>
      <group_list>
        <group group_id="B1">
          <title>Low Dose Erythropoietin</title>
          <description>Subjects randomized to this arm will receive low-dose of EPO administered thrice weekly&#xD;
Low dose erythropoietin: Subjects randomized to this arm will receive low-dose of EPO administered thrice weekly</description>
        </group>
        <group group_id="B2">
          <title>High Dose Erythropoietin</title>
          <description>Subjects randomized to this arm will receive the same cumulative dose of EPO administered as a high-dose of EPO every 2 weeks&#xD;
High dose erythropoietin: Subjects randomized to this arm will receive the same cumulative dose of EPO administered as a high-dose of EPO every 2 weeks</description>
        </group>
        <group group_id="B3">
          <title>Total</title>
          <description>Total of all reporting groups</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="3"/>
            <count group_id="B2" value="2"/>
            <count group_id="B3" value="5"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>&lt;=18 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Between 18 and 65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="3"/>
                  </measurement_list>
                </category>
                <category>
                  <title>&gt;=65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Age</title>
          <units>years</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="65" spread="10"/>
                    <measurement group_id="B2" value="68" spread="5"/>
                    <measurement group_id="B3" value="67" spread="8"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Sex: Female, Male</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Female</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="3"/>
                    <measurement group_id="B2" value="2"/>
                    <measurement group_id="B3" value="5"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Ethnicity (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Not Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="3"/>
                    <measurement group_id="B2" value="2"/>
                    <measurement group_id="B3" value="5"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Race (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>American Indian or Alaska Native</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Asian</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Native Hawaiian or Other Pacific Islander</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Black or African American</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="2"/>
                  </measurement_list>
                </category>
                <category>
                  <title>White</title>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="3"/>
                  </measurement_list>
                </category>
                <category>
                  <title>More than one race</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Region of Enrollment</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <title>United States</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="3"/>
                    <measurement group_id="B2" value="2"/>
                    <measurement group_id="B3" value="5"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Change in Carotid Total Plaque Volume From Baseline to Approximately 1 Year, as Assessed by Non-contrast MRI</title>
        <description>The plaque characteristics will be analyzed by MRI-PlaqueViewTM (VP diagnostics Inc., WA). Planimetry will be performed on the image data sets, using histogram equalization to improve edge detection for plaque, arterial wall and lumen. Differences in image contrast between T1-weighted, T2-weighted, Time of Flight, and proton density will be used to characterize the plaque as fibrous, stable, or unstable.</description>
        <time_frame>1 year</time_frame>
        <population>Since the study was terminated due to lack of enrollment and the paperwork to obtain the software to read the MRI was still being filled out, we did not have the software to analyze the MRI and thus there is no data to report.</population>
        <group_list>
          <group group_id="O1">
            <title>Low Dose Erythropoietin</title>
            <description>Subjects randomized to this arm will receive low-dose of EPO administered thrice weekly&#xD;
Low dose erythropoietin: Subjects randomized to this arm will receive low-dose of EPO administered thrice weekly</description>
          </group>
          <group group_id="O2">
            <title>High Dose Erythropoietin</title>
            <description>Subjects randomized to this arm will receive the same cumulative dose of EPO administered as a high-dose of EPO every 2 weeks&#xD;
High dose erythropoietin: Subjects randomized to this arm will receive the same cumulative dose of EPO administered as a high-dose of EPO every 2 weeks</description>
          </group>
        </group_list>
        <measure>
          <title>Change in Carotid Total Plaque Volume From Baseline to Approximately 1 Year, as Assessed by Non-contrast MRI</title>
          <description>The plaque characteristics will be analyzed by MRI-PlaqueViewTM (VP diagnostics Inc., WA). Planimetry will be performed on the image data sets, using histogram equalization to improve edge detection for plaque, arterial wall and lumen. Differences in image contrast between T1-weighted, T2-weighted, Time of Flight, and proton density will be used to characterize the plaque as fibrous, stable, or unstable.</description>
          <population>Since the study was terminated due to lack of enrollment and the paperwork to obtain the software to read the MRI was still being filled out, we did not have the software to analyze the MRI and thus there is no data to report.</population>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="0"/>
                <count group_id="O2" value="0"/>
              </count_list>
            </analyzed>
          </analyzed_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Severity of Maximal Stenosis at Baseline and Upon Follow-up.</title>
        <description>The plaque characteristics will be analyzed by MRI-PlaqueViewTM (VP diagnostics Inc., WA). Planimetry will be performed on the image data sets, using histogram equalization to improve edge detection for plaque, arterial wall and lumen. Differences in image contrast between T1-weighted, T2-weighted, Time of Flight, and proton density will be used to characterize the plaque as fibrous, stable, or unstable.</description>
        <time_frame>1 year</time_frame>
        <population>Since the study was terminated due to lack of enrollment and the paperwork to obtain the software to read the MRI was still being filled out, we did not have the software to analyze the MRI and thus there is no data to report.</population>
        <group_list>
          <group group_id="O1">
            <title>Low Dose Erythropoietin</title>
            <description>Subjects randomized to this arm will receive low-dose of EPO administered thrice weekly&#xD;
Low dose erythropoietin: Subjects randomized to this arm will receive low-dose of EPO administered thrice weekly</description>
          </group>
          <group group_id="O2">
            <title>High Dose Erythropoietin</title>
            <description>Subjects randomized to this arm will receive the same cumulative dose of EPO administered as a high-dose of EPO every 2 weeks&#xD;
High dose erythropoietin: Subjects randomized to this arm will receive the same cumulative dose of EPO administered as a high-dose of EPO every 2 weeks</description>
          </group>
        </group_list>
        <measure>
          <title>Severity of Maximal Stenosis at Baseline and Upon Follow-up.</title>
          <description>The plaque characteristics will be analyzed by MRI-PlaqueViewTM (VP diagnostics Inc., WA). Planimetry will be performed on the image data sets, using histogram equalization to improve edge detection for plaque, arterial wall and lumen. Differences in image contrast between T1-weighted, T2-weighted, Time of Flight, and proton density will be used to characterize the plaque as fibrous, stable, or unstable.</description>
          <population>Since the study was terminated due to lack of enrollment and the paperwork to obtain the software to read the MRI was still being filled out, we did not have the software to analyze the MRI and thus there is no data to report.</population>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="0"/>
                <count group_id="O2" value="0"/>
              </count_list>
            </analyzed>
          </analyzed_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Percentage of Total Plaque Area at Baseline and Upon Follow-up.</title>
        <description>The plaque characteristics will be analyzed by MRI-PlaqueViewTM (VP diagnostics Inc., WA). Planimetry will be performed on the image data sets, using histogram equalization to improve edge detection for plaque, arterial wall and lumen. Differences in image contrast between T1-weighted, T2-weighted, Time of Flight, and proton density will be used to characterize the plaque as fibrous, stable, or unstable.</description>
        <time_frame>1 year</time_frame>
        <population>Since the study was terminated due to lack of enrollment and the paperwork to obtain the software to read the MRI was still being filled out, we did not have the software to analyze the MRI and thus there is no data to report.</population>
        <group_list>
          <group group_id="O1">
            <title>Low Dose Erythropoietin</title>
            <description>Subjects randomized to this arm will receive low-dose of EPO administered thrice weekly&#xD;
Low dose erythropoietin: Subjects randomized to this arm will receive low-dose of EPO administered thrice weekly</description>
          </group>
          <group group_id="O2">
            <title>High Dose Erythropoietin</title>
            <description>Subjects randomized to this arm will receive the same cumulative dose of EPO administered as a high-dose of EPO every 2 weeks&#xD;
High dose erythropoietin: Subjects randomized to this arm will receive the same cumulative dose of EPO administered as a high-dose of EPO every 2 weeks</description>
          </group>
        </group_list>
        <measure>
          <title>Percentage of Total Plaque Area at Baseline and Upon Follow-up.</title>
          <description>The plaque characteristics will be analyzed by MRI-PlaqueViewTM (VP diagnostics Inc., WA). Planimetry will be performed on the image data sets, using histogram equalization to improve edge detection for plaque, arterial wall and lumen. Differences in image contrast between T1-weighted, T2-weighted, Time of Flight, and proton density will be used to characterize the plaque as fibrous, stable, or unstable.</description>
          <population>Since the study was terminated due to lack of enrollment and the paperwork to obtain the software to read the MRI was still being filled out, we did not have the software to analyze the MRI and thus there is no data to report.</population>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="0"/>
                <count group_id="O2" value="0"/>
              </count_list>
            </analyzed>
          </analyzed_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Characteristics of Plaques (Soft or Fibrous and Stable or Unstable) at Baseline and Upon Follow-up.</title>
        <description>The plaque characteristics will be analyzed by MRI-PlaqueViewTM (VP diagnostics Inc., WA). Planimetry will be performed on the image data sets, using histogram equalization to improve edge detection for plaque, arterial wall and lumen. Differences in image contrast between T1-weighted, T2-weighted, Time of Flight, and proton density will be used to characterize the plaque as fibrous, stable, or unstable.</description>
        <time_frame>1 year</time_frame>
        <population>Since the study was terminated due to lack of enrollment and the paperwork to obtain the software to read the MRI was still being filled out, we did not have the software to analyze the MRI and thus there is no data to report.</population>
        <group_list>
          <group group_id="O1">
            <title>Low Dose Erythropoietin</title>
            <description>Subjects randomized to this arm will receive low-dose of EPO administered thrice weekly&#xD;
Low dose erythropoietin: Subjects randomized to this arm will receive low-dose of EPO administered thrice weekly</description>
          </group>
          <group group_id="O2">
            <title>High Dose Erythropoietin</title>
            <description>Subjects randomized to this arm will receive the same cumulative dose of EPO administered as a high-dose of EPO every 2 weeks&#xD;
High dose erythropoietin: Subjects randomized to this arm will receive the same cumulative dose of EPO administered as a high-dose of EPO every 2 weeks</description>
          </group>
        </group_list>
        <measure>
          <title>Characteristics of Plaques (Soft or Fibrous and Stable or Unstable) at Baseline and Upon Follow-up.</title>
          <description>The plaque characteristics will be analyzed by MRI-PlaqueViewTM (VP diagnostics Inc., WA). Planimetry will be performed on the image data sets, using histogram equalization to improve edge detection for plaque, arterial wall and lumen. Differences in image contrast between T1-weighted, T2-weighted, Time of Flight, and proton density will be used to characterize the plaque as fibrous, stable, or unstable.</description>
          <population>Since the study was terminated due to lack of enrollment and the paperwork to obtain the software to read the MRI was still being filled out, we did not have the software to analyze the MRI and thus there is no data to report.</population>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="0"/>
                <count group_id="O2" value="0"/>
              </count_list>
            </analyzed>
          </analyzed_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>The time period of adverse events where for the time that each subject was enrolled in the study. No study completed the study since the study was closed prematurely.</time_frame>
      <group_list>
        <group group_id="E1">
          <title>Low Dose Erythropoietin</title>
          <description>Subjects randomized to this arm will receive low-dose of EPO administered thrice weekly&#xD;
Low dose erythropoietin: Subjects randomized to this arm will receive low-dose of EPO administered thrice weekly</description>
        </group>
        <group group_id="E2">
          <title>High Dose Erythropoietin</title>
          <description>Subjects randomized to this arm will receive the same cumulative dose of EPO administered as a high-dose of EPO every 2 weeks&#xD;
High dose erythropoietin: Subjects randomized to this arm will receive the same cumulative dose of EPO administered as a high-dose of EPO every 2 weeks</description>
        </group>
      </group_list>
      <serious_events>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, all-cause mortality</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="2"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="2"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>0</frequency_threshold>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="2"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>Principal Investigators are NOT employed by the organization sponsoring the study.</pi_employee>
      <restrictive_agreement>There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed. </restrictive_agreement>
    </certain_agreements>
    <point_of_contact>
      <name_or_title>Dr. Mark Segal</name_or_title>
      <organization>NFSGVA</organization>
      <phone>3523761611 ext 104496</phone>
      <email>mark.segal@va.gov</email>
    </point_of_contact>
  </clinical_results>
</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/NCT03277183
org study id: CARA-019-16F
secondary id: I01CX001449
nct id: NCT03277183
lead sponsor: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
is us export: Yes
Although several large well designed clinical trials have shown that erythropoietin which is
      commonly used to treat anemia associated with kidney disease, increases the risk of stroke
      and heart disease, the mechanism for this increased risk is unknown. The investigators'
      preliminary studies show that the adverse effects of erythropoietin are from activation of
      the heterodimeric erythropoietin/ beta common receptor which only occurs with high doses of
      erythropoietin. The investigators propose a clinical trial of 120 patients assigned to low
      doses of erythropoietin given more frequently or the same cumulative dose of erythropoietin
      administered as a high dose once every two weeks and assess effects on the beta common
      receptor activation, inflammation and vascular disease as evidence by MRI of the carotid
      arteries.
Erythropoietin (EPO) is the most widely prescribed cytokine, yet the benefits and potential
      side effects of different dosing regimens are poorly understood. It is now recognized that
      erythropoietin administered at high doses to patients with chronic kidney disease, results in
      an increased risk of morbidity and mortality from heart disease and stroke. However, the
      mechanisms that mediate this increased risk of cardiovascular disease is not known. There are
      two receptors for erythropoietin the homodimeric EPO receptor (EPOR) and the heterodimeric
      beta common receptor ( CR)/EPOR. The investigators have demonstrated that activation of the
      heterodimeric CR/EPOR only occurs with high doses of EPO. Our exciting, published,
      preliminary data also demonstrates that the CR is in a complex with vascular endothelial
      growth factor receptor-2 (VEGFR-2) and that high doses of EPO activate VEGFR-2 through the
      CR, resulting in the deleterious effects of VEGFR-2 activation on the cardiovascular system.
      This is particularly important in patients with kidney disease since they are already at a
      high risk of cardiovascular disease. Moreover in advanced kidney disease cyanate derived from
      the high urea levels can non-enzymatically form an amide bond with EPO. This carbamylated EPO
      (cEPO) has no effect on hemoglobin, but still activates the heterodimeric CR/EPOR. To date
      there have been no studies that have directly measured levels of cEPO or activation of the
      CR/EPOR in patients with kidney disease. Our hypothesis is that the administration of
      low-doses of EPO more frequently will result in lower levels of total and carbamylated
      erythropoietin decreased activation of VEGFR-2 via the heterodimeric CR/EPOR and consequently
      decreased inflammation and atherosclerosis. The investigators will directly test this
      hypothesis by randomly allocating 120 patients with chronic kidney disease to either low-
      dose EPO given thrice weekly or the same cumulative dose, a high-dose, administered once
      every 2 weeks. Our hypothesis predicts that low-dose EPO will be as effective at correcting
      anemia, but will demonstrate less progression of carotid artery plaque, as assessed by
      non-contrast magnetic resonance imaging, as compared to the high-dose, EPO given every 2
      weeks. To delineate how EPO affects blood vessels, the investigators will isolate endothelial
      cells from blood vessels in 20 patients who are assigned to low-dose EPO and 20 allocated to
      high-dose EPO. Within these cells the investigators will investigate the signaling pathways
      that are triggered by activation of CR/EPOR. In a substudy of 20 subjects with kidney disease
      randomized to low-dose EPO or to high-dose EPO, as well as 20 healthy controls receiving a
      single dose of high- or low-dose EPO, the investigators will determine how kidney function
      and dosing affects levels of total and carbamylated erythropoietin. The investigators' study
      will not only provide us with a thorough understanding of the mechanism by which EPO mediates
      the increased risk of atherosclerosis, but a clinical strategy to avoid the side effects of
      EPO therapy and a tool to quantify the cardiovascular risk of EPO and newer erythropoiesis
      stimulating agents by assessing activation of the heterodimeric CR/EPOR.
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: Patients will be randomly assigned two different erythropoietin dosing strategies. One group will be given more frequent, low-doses of EPO and the other group will be given the same, cumulative dose given every 2 weeks.
primary purpose: Prevention
masking: Single (Outcomes Assessor)
masking description: The outcome is the progression of carotid plaque. John Forder, PhD, who will read the MRIs will be blinded to the subject and treatment group.
measure: Change in Carotid Total Plaque Volume From Baseline to Approximately 1 Year, as Assessed by Non-contrast MRI
time frame: 1 year
description: The plaque characteristics will be analyzed by MRI-PlaqueViewTM (VP diagnostics Inc., WA). Planimetry will be performed on the image data sets, using histogram equalization to improve edge detection for plaque, arterial wall and lumen. Differences in image contrast between T1-weighted, T2-weighted, Time of Flight, and proton density will be used to characterize the plaque as fibrous, stable, or unstable.
measure: Severity of Maximal Stenosis at Baseline and Upon Follow-up.
time frame: 1 year
description: The plaque characteristics will be analyzed by MRI-PlaqueViewTM (VP diagnostics Inc., WA). Planimetry will be performed on the image data sets, using histogram equalization to improve edge detection for plaque, arterial wall and lumen. Differences in image contrast between T1-weighted, T2-weighted, Time of Flight, and proton density will be used to characterize the plaque as fibrous, stable, or unstable.
measure: Percentage of Total Plaque Area at Baseline and Upon Follow-up.
time frame: 1 year
description: The plaque characteristics will be analyzed by MRI-PlaqueViewTM (VP diagnostics Inc., WA). Planimetry will be performed on the image data sets, using histogram equalization to improve edge detection for plaque, arterial wall and lumen. Differences in image contrast between T1-weighted, T2-weighted, Time of Flight, and proton density will be used to characterize the plaque as fibrous, stable, or unstable.
measure: Characteristics of Plaques (Soft or Fibrous and Stable or Unstable) at Baseline and Upon Follow-up.
time frame: 1 year
description: The plaque characteristics will be analyzed by MRI-PlaqueViewTM (VP diagnostics Inc., WA). Planimetry will be performed on the image data sets, using histogram equalization to improve edge detection for plaque, arterial wall and lumen. Differences in image contrast between T1-weighted, T2-weighted, Time of Flight, and proton density will be used to characterize the plaque as fibrous, stable, or unstable.
arm group label: Low dose erythropoietin
arm group type: Placebo Comparator
description: Subjects randomized to this arm will receive low-dose of EPO administered thrice weekly
arm group label: High dose erythropoietin
arm group type: Experimental
description: Subjects randomized to this arm will receive the same cumulative dose of EPO administered as a high-dose of EPO every 2 weeks
intervention type: Drug
intervention name: Low dose erythropoietin
description: Subjects randomized to this arm will receive low-dose of EPO administered thrice weekly
arm group label: Low dose erythropoietin
other name: Low dose
intervention type: Drug
intervention name: High dose erythropoietin
description: Subjects randomized to this arm will receive the same cumulative dose of EPO administered as a high-dose of EPO every 2 weeks
arm group label: High dose erythropoietin
other name: High dose
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Mark S. Segal, MD PhD
role: Principal Investigator
affiliation: North Florida/South Georgia Veterans Health System, Gainesville, FL
facility: 
country: United States
responsible party type: Sponsor
mesh term: Atherosclerosis
mesh term: Epoetin Alfa
sharing ipd: No
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 