<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/NCT03810911</url>
  </required_header>
  <id_info>
    <org_study_id>NEPH-005-18S</org_study_id>
    <secondary_id>052387</secondary_id>
    <nct_id>NCT03810911</nct_id>
  </id_info>
  <brief_title>Mechanisms of EPO-induced Hypertension</brief_title>
  <acronym>EPIC</acronym>
  <official_title>Mechanisms of Erythropoietin Induced Hypertension</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>
      The investigators hypothesize that compared to untreated controls, erythropoietin (EPO)&#xD;
      therapy in anemic patients with chronic kidney disease will raise diastolic blood pressure&#xD;
      (BP). The magnitude of increase in diastolic BP at 12 weeks after treatment will be related&#xD;
      to two factors. First, endothelial dysfunction and worsening of endothelial function from&#xD;
      baseline to 4 weeks and second, the change of forearm blood flow in response to breathing&#xD;
      oxygen and the change in this measure from baseline to 4 weeks. Study procedures include&#xD;
      fasting blood draws, ambulatory blood pressure, urine collection, and forearm blood flow&#xD;
      tests. The study hopes to accrue 160 subjects.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Hypertension is a common but frequently overlooked and underreported adverse effect of&#xD;
      erythropoietin (EPO) therapy. Recent trials have noted substantial cardiovascular risks&#xD;
      associated with normalization of hemoglobin. The risk of strokes is strongly related to&#xD;
      poorly controlled hypertension. Blood pressure was not measured the way it usually is in&#xD;
      hypertension trials, so the investigators cannot be completely confident that the risk of&#xD;
      strokes in this large randomized trial was not related to EPO-induced hypertension. New&#xD;
      therapies, such as hypoxia-inducible factor (HIF) stabilizers are on the horizon but it&#xD;
      remains to be seen whether these new drugs would have a lower or a higher risk for&#xD;
      hypertension compared to EPO. Accordingly, understanding the mechanism of EPO-induced&#xD;
      hypertension is urgent. The investigators hypothesize that compared to untreated controls,&#xD;
      EPO therapy in anemic patients with chronic kidney disease (CKD) will raise diastolic blood&#xD;
      pressure. The magnitude of increase in diastolic BP at 12 weeks after treatment will be&#xD;
      related to endothelial dysfunction and worsening of endothelial function from baseline to 4&#xD;
      weeks. If the investigators understood the time course, the magnitude, and the mechanisms of&#xD;
      EPO-induced hypertension (EIH) the investigators will better be able to design studies to&#xD;
      compare the vascular effects of EPO and HIF stabilizers in the future. Thus, this study has&#xD;
      the potential of improving the investigators' understanding of a common side effect of EPO by&#xD;
      precisely quantifying the magnitude of BP change, its effects on endothelial function, and&#xD;
      discovering the biomarkers of these adverse effects. Thus, the investigators can in the&#xD;
      future robustly compare these effects of EPO with HIF stabilizers. This study is innovative&#xD;
      because it will focus on the potential mechanisms by which EPO induces an increase in BP. The&#xD;
      time-course and magnitude of change in BP will be assessed using the gold-standard&#xD;
      measurement of 24 hour ambulatory BP recordings. The more frequent clinic BP recordings using&#xD;
      validated methods will better allow us to track changes in BP over time. The investigators'&#xD;
      lab is uniquely qualified to carry out these experiments due to a large experience with such&#xD;
      types of studies. The investigators will examine endothelial function using a reference&#xD;
      method -- that of flow-mediated dilatation -- which is established in the investigators'&#xD;
      laboratory. The investigators will directly test the hypothesis whether endothelial function&#xD;
      is responsible for the BP increase.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">January 4, 2021</start_date>
  <completion_date type="Anticipated">July 31, 2025</completion_date>
  <primary_completion_date type="Anticipated">December 31, 2024</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Sequential Assignment</intervention_model>
    <intervention_model_description>All subjects will receive darbepoetin during the study. One group, the immediate start group, will receive the drug the day of randomization. The other group, the delayed start group, will receive the drug 12 weeks later.</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
    <masking_description>The groups are randomized not the study drug. The groups will be known by both the participant and the investigator.</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>Change in diastolic blood pressure in EPO treated patients compared to delayed start controls</measure>
    <time_frame>Baseline to 12 weeks</time_frame>
    <description>In the delayed start group (the control group), the investigators will measure the change in diastolic blood pressure from 0 weeks to 12 weeks compared to the change in diastolic BP from 0 to 12 weeks in the immediate start group.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Change in flow mediated dilatation (FMD)</measure>
    <time_frame>Baseline to 4 weeks</time_frame>
    <description>Those treated with EPO compared to the delayed start group. The hypothesis being tested is that EPO will cause impairment in endothelial function.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Predictors of change in flow mediated dilatation (FMD)</measure>
    <time_frame>Baseline to 4 weeks</time_frame>
    <description>A multivariable model will be created to predict the change in FMD from baseline to 4 w. Model 1 will have an indicator variable of those treated with EPO compared to time controls (this is outcome 2 essentially). Model 2 will have the following predictors of this change in addition: baseline values of urine albumin/creat ratio, asymmetric dimethylarginine (ADMA), urine nitrate and nitrite, renin, aldosterone, and plasma endothelin-1. Model 3 will include all the variables in Model 1 and 2 and also include change from baseline to 4 weeks in the same variables reported in Model 2.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Change in systolic blood pressure in EPO treated patients</measure>
    <time_frame>Baseline to 12 weeks</time_frame>
    <description>In the delayed start group (the control group), the investigators will measure the change in systolic blood pressure change from 0 weeks to 12 weeks compared to the change in systolic BP from 0 to 12 weeks in the immediate start group.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Between group change in hypertension status</measure>
    <time_frame>Baseline to 12 weeks</time_frame>
    <description>Worsening of hypertension at any time point will be defined as either an increase in blood pressure medication, an increase in seated clinic diastolic blood pressure by greater than or equal to 10 mmHg or systolic blood pressure increase of greater than or equal to 20 mmHg. Between-group change in hypertension status from baseline to 12 weeks will be compared in the immediate start and delayed start groups.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Within group change in hypertension status</measure>
    <time_frame>baseline to 12 weeks vs 12 weeks to 24 weeks</time_frame>
    <description>Worsening of hypertension at any time point will be defined as either an increase in blood pressure medication, an increase in seated clinic diastolic blood pressure by greater than or equal to 10 mmHg or systolic blood pressure increase of greater than or equal to 20 mmHg. Within-group change in hypertension status from 12 weeks to 24 weeks will be compared to the control period of 0 weeks to 12 weeks in the delayed start group.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">160</enrollment>
  <condition>Chronic Kidney Disease</condition>
  <condition>Blood Pressure</condition>
  <condition>Anemia</condition>
  <arm_group>
    <arm_group_label>Early start</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Participants given study drug immediately at randomization</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Delayed start</arm_group_label>
    <arm_group_type>No Intervention</arm_group_type>
    <description>Participants given study drugs 12 weeks after randomization</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Darbepoetin</intervention_name>
    <description>Used to treat anemia. In the group labeled no intervention, the intervention is simply delayed 12 weeks after randomization as noted in the description.</description>
    <arm_group_label>Early start</arm_group_label>
    <other_name>EPO</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Stage 3 or 4 chronic kidney disease&#xD;
&#xD;
          -  Controlled hypertension with 24 hour ambulatory blood pressure monitoring less than&#xD;
             140/90 mmHg at baseline and treatment with at least 1 antihypertensive medication&#xD;
&#xD;
          -  Hemoglobin between 8 and 10 g/dL&#xD;
&#xD;
          -  No treatment with erythropoiesis-stimulating agents (ESA) within 3 previous months&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Need for packed red blood cells (RBC) transfusion in the previous 2 months&#xD;
&#xD;
          -  Myocardial infarction, stroke or hospitalization for heart failure in the past 2&#xD;
             months&#xD;
&#xD;
          -  In the assessment of the investigator, have hematologic, inflammatory, infectious, or&#xD;
             other conditions that might interfere with the erythropoietic response&#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>Rajiv Agarwal, MD MBBS</last_name>
    <role>Principal Investigator</role>
    <affiliation>Richard L. Roudebush VA Medical Center, Indianapolis, IN</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Rajiv Agarwal, MD MBBS</last_name>
    <phone>(317) 988-2241</phone>
    <email>ragarwal@iu.edu</email>
  </overall_contact>
  <location>
    <facility>
      <name>Richard L. Roudebush VA Medical Center, Indianapolis, IN</name>
      <address>
        <city>Indianapolis</city>
        <state>Indiana</state>
        <zip>46202-2803</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Rajiv Agarwal, MD MBBS</last_name>
      <phone>317-988-2241</phone>
      <email>ragarwal@iu.edu</email>
    </contact>
    <investigator>
      <last_name>Rajiv Agarwal, MD MBBS</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>January 2023</verification_date>
  <study_first_submitted>January 7, 2019</study_first_submitted>
  <study_first_submitted_qc>January 16, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">January 22, 2019</study_first_posted>
  <last_update_submitted>January 24, 2023</last_update_submitted>
  <last_update_submitted_qc>January 24, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">January 26, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Flow mediated dilatation</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Kidney Diseases</mesh_term>
    <mesh_term>Renal Insufficiency, Chronic</mesh_term>
    <mesh_term>Hypertension</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Darbepoetin alfa</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03810911
org study id: NEPH-005-18S
secondary id: 052387
nct id: NCT03810911
lead sponsor: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
is us export: Yes
The investigators hypothesize that compared to untreated controls, erythropoietin (EPO)
      therapy in anemic patients with chronic kidney disease will raise diastolic blood pressure
      (BP). The magnitude of increase in diastolic BP at 12 weeks after treatment will be related
      to two factors. First, endothelial dysfunction and worsening of endothelial function from
      baseline to 4 weeks and second, the change of forearm blood flow in response to breathing
      oxygen and the change in this measure from baseline to 4 weeks. Study procedures include
      fasting blood draws, ambulatory blood pressure, urine collection, and forearm blood flow
      tests. The study hopes to accrue 160 subjects.
Hypertension is a common but frequently overlooked and underreported adverse effect of
      erythropoietin (EPO) therapy. Recent trials have noted substantial cardiovascular risks
      associated with normalization of hemoglobin. The risk of strokes is strongly related to
      poorly controlled hypertension. Blood pressure was not measured the way it usually is in
      hypertension trials, so the investigators cannot be completely confident that the risk of
      strokes in this large randomized trial was not related to EPO-induced hypertension. New
      therapies, such as hypoxia-inducible factor (HIF) stabilizers are on the horizon but it
      remains to be seen whether these new drugs would have a lower or a higher risk for
      hypertension compared to EPO. Accordingly, understanding the mechanism of EPO-induced
      hypertension is urgent. The investigators hypothesize that compared to untreated controls,
      EPO therapy in anemic patients with chronic kidney disease (CKD) will raise diastolic blood
      pressure. The magnitude of increase in diastolic BP at 12 weeks after treatment will be
      related to endothelial dysfunction and worsening of endothelial function from baseline to 4
      weeks. If the investigators understood the time course, the magnitude, and the mechanisms of
      EPO-induced hypertension (EIH) the investigators will better be able to design studies to
      compare the vascular effects of EPO and HIF stabilizers in the future. Thus, this study has
      the potential of improving the investigators' understanding of a common side effect of EPO by
      precisely quantifying the magnitude of BP change, its effects on endothelial function, and
      discovering the biomarkers of these adverse effects. Thus, the investigators can in the
      future robustly compare these effects of EPO with HIF stabilizers. This study is innovative
      because it will focus on the potential mechanisms by which EPO induces an increase in BP. The
      time-course and magnitude of change in BP will be assessed using the gold-standard
      measurement of 24 hour ambulatory BP recordings. The more frequent clinic BP recordings using
      validated methods will better allow us to track changes in BP over time. The investigators'
      lab is uniquely qualified to carry out these experiments due to a large experience with such
      types of studies. The investigators will examine endothelial function using a reference
      method -- that of flow-mediated dilatation -- which is established in the investigators'
      laboratory. The investigators will directly test the hypothesis whether endothelial function
      is responsible for the BP increase.
allocation: Randomized
intervention model: Sequential Assignment
intervention model description: All subjects will receive darbepoetin during the study. One group, the immediate start group, will receive the drug the day of randomization. The other group, the delayed start group, will receive the drug 12 weeks later.
primary purpose: Treatment
masking: None (Open Label)
masking description: The groups are randomized not the study drug. The groups will be known by both the participant and the investigator.
measure: Change in diastolic blood pressure in EPO treated patients compared to delayed start controls
time frame: Baseline to 12 weeks
description: In the delayed start group (the control group), the investigators will measure the change in diastolic blood pressure from 0 weeks to 12 weeks compared to the change in diastolic BP from 0 to 12 weeks in the immediate start group.
measure: Change in flow mediated dilatation (FMD)
time frame: Baseline to 4 weeks
description: Those treated with EPO compared to the delayed start group. The hypothesis being tested is that EPO will cause impairment in endothelial function.
measure: Predictors of change in flow mediated dilatation (FMD)
time frame: Baseline to 4 weeks
description: A multivariable model will be created to predict the change in FMD from baseline to 4 w. Model 1 will have an indicator variable of those treated with EPO compared to time controls (this is outcome 2 essentially). Model 2 will have the following predictors of this change in addition: baseline values of urine albumin/creat ratio, asymmetric dimethylarginine (ADMA), urine nitrate and nitrite, renin, aldosterone, and plasma endothelin-1. Model 3 will include all the variables in Model 1 and 2 and also include change from baseline to 4 weeks in the same variables reported in Model 2.
measure: Change in systolic blood pressure in EPO treated patients
time frame: Baseline to 12 weeks
description: In the delayed start group (the control group), the investigators will measure the change in systolic blood pressure change from 0 weeks to 12 weeks compared to the change in systolic BP from 0 to 12 weeks in the immediate start group.
measure: Between group change in hypertension status
time frame: Baseline to 12 weeks
description: Worsening of hypertension at any time point will be defined as either an increase in blood pressure medication, an increase in seated clinic diastolic blood pressure by greater than or equal to 10 mmHg or systolic blood pressure increase of greater than or equal to 20 mmHg. Between-group change in hypertension status from baseline to 12 weeks will be compared in the immediate start and delayed start groups.
measure: Within group change in hypertension status
time frame: baseline to 12 weeks vs 12 weeks to 24 weeks
description: Worsening of hypertension at any time point will be defined as either an increase in blood pressure medication, an increase in seated clinic diastolic blood pressure by greater than or equal to 10 mmHg or systolic blood pressure increase of greater than or equal to 20 mmHg. Within-group change in hypertension status from 12 weeks to 24 weeks will be compared to the control period of 0 weeks to 12 weeks in the delayed start group.
arm group label: Early start
arm group type: Active Comparator
description: Participants given study drug immediately at randomization
arm group label: Delayed start
arm group type: No Intervention
description: Participants given study drugs 12 weeks after randomization
intervention type: Drug
intervention name: Darbepoetin
description: Used to treat anemia. In the group labeled no intervention, the intervention is simply delayed 12 weeks after randomization as noted in the description.
arm group label: Early start
other name: EPO
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Rajiv Agarwal, MD MBBS
role: Principal Investigator
affiliation: Richard L. Roudebush VA Medical Center, Indianapolis, IN
last name: Rajiv Agarwal, MD MBBS
phone: (317) 988-2241
email: ragarwal@iu.edu
facility: 
status: Recruiting
contact: 
investigator: 
country: United States
responsible party type: Sponsor
mesh term: Kidney Diseases
mesh term: Renal Insufficiency, Chronic
mesh term: Hypertension
mesh term: Darbepoetin alfa
sharing ipd: No