<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/NCT02226848</url>
  </required_header>
  <id_info>
    <org_study_id>140174</org_study_id>
    <secondary_id>14-N-0174</secondary_id>
    <nct_id>NCT02226848</nct_id>
  </id_info>
  <brief_title>Effect of Recombinant Erythropoietin on Numbers of Circulating Endothelial Progenitor Cells in People With Persistent Symptoms During the Subacute Period After Traumatic Brain Injury</brief_title>
  <official_title>Effect of Administration of Recombinant Erythropoietin on Numbers of Circulating Endothelial Progenitor Cells in Patients With Persistent Symptoms During the Subacute Period After TBI</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>National Institute of Neurological Disorders and Stroke (NINDS)</agency>
      <agency_class>NIH</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>National Institutes of Health Clinical Center (CC)</source>
  <brief_summary>
    <textblock>
      Background:&#xD;
&#xD;
      - Traumatic brain injury (TBI) injures blood vessels in the brain. Endothelial progenitor&#xD;
      cells (EPCs) help the body form new blood vessels. The drug erythropoietin (EPO) helps the&#xD;
      body make more blood cells and might help make blood vessels. Researchers want to see if EPO&#xD;
      helps people with TBI.&#xD;
&#xD;
      Objective:&#xD;
&#xD;
      - To see whether erythropoietin increases the number of endothelial progenitor cells&#xD;
      circulating in the blood and changes reactivity of brain vessels.&#xD;
&#xD;
      Eligibility:&#xD;
&#xD;
      - Adults age 18 70 who had a TBI 3 7 days ago and still have symptoms.&#xD;
&#xD;
      Design:&#xD;
&#xD;
        -  Participants will be screened with medical history and blood tests. Vital signs will be&#xD;
           taken.&#xD;
&#xD;
        -  Visit 1:&#xD;
&#xD;
        -  Medical history, physical exam, and blood sample.&#xD;
&#xD;
        -  Neuropsychological tests of memory, attention, and thinking. These include written and&#xD;
           spoken questions, tests on paper or computer, and simple actions.&#xD;
&#xD;
        -  Magnetic resonance imaging (MRI) scan with carbon dioxide. Participants will lie on a&#xD;
           table that slides in and out of a metal cylinder. For part of the scan, participants&#xD;
           will wear a breathing mask like a snorkel and wear a nose clip.&#xD;
&#xD;
        -  Study drug or placebo injection under the skin of the arm, leg, or buttock.&#xD;
&#xD;
        -  Visits 2, 3, and 4 will be 1 week apart.&#xD;
&#xD;
        -  Blood sample.&#xD;
&#xD;
        -  Review of TBI symptoms and any drug side effects.&#xD;
&#xD;
        -  Study drug or placebo injection under the skin.&#xD;
&#xD;
        -  Visit 5 will be 1 week after visit 4. Visit 6 will be 6 months after participants start&#xD;
           the study.&#xD;
&#xD;
        -  Blood sample.&#xD;
&#xD;
        -  Review of TBI symptoms and any drug side effects.&#xD;
&#xD;
        -  Neuropsychological tests.&#xD;
&#xD;
        -  MRI with carbon dioxide.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Objective&#xD;
&#xD;
      Traumatic brain injury (TBI) is the leading cause of death and disability in people under age&#xD;
      45 in industrialized countries 5;6. Significant numbers of US veterans from the wars in Iraq&#xD;
      and Afghanistan return with TBI7. However, to date, there are no specific neuroprotective&#xD;
      treatment options with proven clinical efficacy 8. Erythropoietin (EPO) is approved by the&#xD;
      FDA to treat anemia and has comprehensive preclinical data supporting its neuroprotective and&#xD;
      neuroregenerative efficacy following traumatic (TBI) and a wide range of other acquired brain&#xD;
      insults. Injury to small and medium-sized cerebral blood vessels is a well recognized&#xD;
      consequence of TBI. EPO increases production of endothelial progenitor cells (EPCs) 4;9 and&#xD;
      promotes angiogenesis and neovascularization after TBI. EPO also promotes neurogenesis and&#xD;
      improves functional recovery in animals after experimental stroke10-12 and TBI.13;14&#xD;
      Neovascularization is coupled with neurogenesis, and augmentation of both processes by EPO&#xD;
      may result in lessened cognitive deficits. Neovascularization by EPO may prevent&#xD;
      post-traumatic deficits in cerebrovascular reactivity (CVR), which can be measured&#xD;
      noninvasively using magnetic resonance imaging (MRI).&#xD;
&#xD;
      This proposal is for a randomized, placebo-controlled pilot clinical trial designed to obtain&#xD;
      data on the effects of EPO in humans with persistent post-concussive symptoms after TBI. The&#xD;
      primary objective is to evaluate effect of 4 week administration of recombinant&#xD;
      erythropoietin on numbers of circulating endothelial progenitor cells in patients with&#xD;
      persistent symptoms during the subacute period after TBI. This information will guide the&#xD;
      design of a future definitive study.&#xD;
&#xD;
      Study Population&#xD;
&#xD;
      The study population will include 30 males and females with persistent post-concussive&#xD;
      symptoms continuing up to 7 days after TBI. Participants will be military service members or&#xD;
      civilians presenting as outpatients for clinical management of TBI or post-concussive&#xD;
      symptoms at the Center for Neuroscience and Regenerative Medicine (CNRM)-affiliated&#xD;
      hospitals. These include the Walter Reed National Military Medical Center (WRNMMC), Suburban&#xD;
      Hospital (SH), and Washington Hospital Center (WHC).&#xD;
&#xD;
      Design&#xD;
&#xD;
      Participants will be referred to the NIH Clinical Center (CC) from participating hospitals or&#xD;
      will be recruited by advertisements through CNRM Recruitment core to receive EPO or placebo.&#xD;
      Telephone screening will be carried out to determine tentative eligibility. At the baseline&#xD;
      visit, participants will be screened, consented and randomized 2:1 to receive either EPO or&#xD;
      placebo with a dose of 40,000 IU EPO subcutaneously (s.c.) (n=20) once weekly for 4 weeks or&#xD;
      placebo (n=10). Each participant will have 6 outpatient visits (visits 1-6) performed at the&#xD;
      NIH CC. Placebo or active drug will be administered s.c. based on the randomization at visits&#xD;
      1-4; blood will be collected for EPC assays and safety laboratory measurements during each&#xD;
      visit. Brain MRI and neuropsychological tests will be performed during visit 1 (before&#xD;
      administering EPO or placebo), and visit 5 (one week after final drug administration) and&#xD;
      visit 6 (6 months after study enrollment).&#xD;
&#xD;
      Outcome Measures&#xD;
&#xD;
      Primary outcome:&#xD;
&#xD;
        1. . Effect of 4 weeks of EPO administration on numbers of circulating EPCs in patients&#xD;
           with persistent symptoms during the subacute period after TBI (within subject&#xD;
           comparison).&#xD;
&#xD;
           Secondary outcomes:&#xD;
&#xD;
        2. . Comparison of the change of numbers of circulating EPC s between EPO and placebo&#xD;
           groups.&#xD;
&#xD;
        3. . Effect of 4 weeks of EPO administration on MRI biomarkers of TBI recovery (such as CVR&#xD;
           on hypercapnia and global and regional brain volumes by MRI).&#xD;
&#xD;
        4. . Effect of 4 weeks of EPO administration on plasma biomarkers of angiogenesis and&#xD;
           inflammation, such as stem cell factor (SCF), vascular endothelial growth factor (VEGF),&#xD;
           stromal-derived factor (SDF-1 ); and matrix metalloproteinase-9 (MMP-9).&#xD;
&#xD;
        5. . Effect of 4 weeks of placebo administration on numbers of circulating EPCs in patients&#xD;
           with persistent symptoms during the subacute period after TBI.&#xD;
&#xD;
           Tertiary outcome:&#xD;
&#xD;
        6. . Relationship between EPC levels at baseline and after 4 weeks and neuropsychological&#xD;
           performance following TBI.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Withdrawn</overall_status>
  <start_date>August 15, 2014</start_date>
  <completion_date type="Actual">May 31, 2017</completion_date>
  <primary_completion_date type="Actual">May 31, 2017</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>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
  </study_design_info>
  <primary_outcome>
    <measure>Effect of 4 weeks of EPO administration on numbers of circulating EPCs in patients with persistent symptons during the subacute period after TBI.</measure>
    <time_frame>4 weeks</time_frame>
  </primary_outcome>
  <secondary_outcome>
    <measure>Safety of 4 weeks of EPO administration to TBI participants</measure>
    <time_frame>4 weeks</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Effect of 4 weeks of EPO administration on MRI biomarkers of TBI recovery</measure>
    <time_frame>4 weeks</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Effect of 4 weeks of EPO administration on biomarkers</measure>
    <time_frame>4 weeks</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Relationship between EPC levels at baseline after 4 weeks and neuropsychological performance following TBI.</measure>
    <time_frame>Baseline</time_frame>
  </secondary_outcome>
  <enrollment type="Actual">0</enrollment>
  <condition>Traumatic Brain Injury</condition>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Erythropoeitin</intervention_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        -  INCLUSION CRITERIA:&#xD;
&#xD;
               1. Age 18 - 70 years, inclusive&#xD;
&#xD;
               2. History of having sustained a TBI greater than or equal to 3 days and less than&#xD;
                  or equal to 7 days prior to enrollment. This evidence will be any one of the&#xD;
                  following:&#xD;
&#xD;
                    1. GCS 3 - 12 on first presentation to medical attention&#xD;
&#xD;
                    2. Post-traumatic amnesia &gt; 24 hours&#xD;
&#xD;
                    3. TBI-related abnormality on neuroimaging (either CT or MRI)&#xD;
&#xD;
               3. Persistent post-concussive symptoms, according to the DSM-IV Research Criteria&#xD;
                  for Post- Concussional Disorder.&#xD;
&#xD;
                    1. Three of more of the following symptoms, which started shortly after the&#xD;
                       trauma and persist for at least up to the time of enrollment:&#xD;
&#xD;
                         -  Fatigueability&#xD;
&#xD;
                         -  Disordered sleep&#xD;
&#xD;
                         -  Headache&#xD;
&#xD;
                         -  Vertigo or dizziness&#xD;
&#xD;
                         -  Irritability or aggression&#xD;
&#xD;
                         -  Anxiety, depression, or affective instability&#xD;
&#xD;
                         -  Changes in personality (e.g., social or sexual inappropriateness)&#xD;
&#xD;
                         -  Apathy or lack of spontaneity&#xD;
&#xD;
                    2. Symptoms had their onset after trauma, or there is a significant worsening&#xD;
                       or preexisting symptoms after trauma.&#xD;
&#xD;
               4. Ability to read, write, and speak English&#xD;
&#xD;
               5. Ability to give consent by the participant himself&#xD;
&#xD;
               6. Willingness of women of childbearing potential to use effective contraception&#xD;
                  during this study and until 2 weeks after they have completed the study drug (EPO&#xD;
                  or placebo).&#xD;
&#xD;
        Effective methods of contraception for this study include:&#xD;
&#xD;
          -  hormonal contraception (birth control pills, injected hormones or vaginal ring),&#xD;
&#xD;
          -  intrauterine device,&#xD;
&#xD;
          -  barrier methods (condom or diaphragm) combined with spermicide,&#xD;
&#xD;
          -  surgical sterilization (hysterectomy, tubal ligation), or vasectomy in a partner.&#xD;
&#xD;
        EXCLUSION CRITERIA:&#xD;
&#xD;
          1. Contraindication to EPO therapy:&#xD;
&#xD;
               1. Known allergy to EPO, hypersensitivity to mammalian cell-derived products, or&#xD;
                  hypersensitivity to albumin&#xD;
&#xD;
               2. Serum hemoglobin &gt; 16 g/dL in a male patient or &gt; 14 g/dL in a female patient; or&#xD;
                  a platelet count &gt; 400,000/mm3 or serum hemoglobin &lt; 10 g/dL in either a male or&#xD;
                  female patient&#xD;
&#xD;
               3. liver or kidney disease; the former will be operationally defined as a serum&#xD;
                  bilirubin &gt; 4 mg/dL, alkaline phosphatase (AP) &gt; 250 U/L, aspartate&#xD;
                  aminotransferase (SGOT, AST) &gt; 150 U/L, alanine aminotransferase (SGPT, ALT) &gt;150&#xD;
                  U/L, or Moderately decreased GFR 30-59 ml/min/1.73m2&#xD;
&#xD;
               4. Pregnancy or lactating; note that a negative pregnancy test will be required if&#xD;
                  the patient is a female of childbearing potential&#xD;
&#xD;
          2. Use of EPO one month prior to the randomization&#xD;
&#xD;
          3. Suspicion of a coagulation disorder associated with bleeding (PTT&gt;45 or INR&gt;1.7,&#xD;
             spontaneously out of normal range)&#xD;
&#xD;
          4. Pre-existing and active major disabling psychiatric disorder (e.g., schizophrenia or&#xD;
             bipolar disorder), or other neurological disease (epilepsy, multiple sclerosis,&#xD;
             developmental disorder) not related to TBI&#xD;
&#xD;
          5. History of heart disease or heart attack, congestive heart failure, stroke, venous&#xD;
             thromboembolism.&#xD;
&#xD;
          6. History of disorders that predispose to coagulation (e.g. polycythemia vera, essential&#xD;
             thrombocytosis, or thrombotic thrombocytopenic purpura).&#xD;
&#xD;
          7. Uncontrolled hypertension, defined as above 140/90 mm Hg in three measurements in two&#xD;
             separate visits despite antihypertensive therapy. Antihypertensive therapy is allowed,&#xD;
             including agents such as thiazide diuretics, ACE inhibitors, beta-blockers, calcium&#xD;
             channel blockers, alpha-blockers, or a centrally acting alpha agonists.&#xD;
&#xD;
          8. Known malignant conditions, e.g., melanoma, breast, brain, lung tumor or prostate&#xD;
             cancer&#xD;
&#xD;
          9. Terminal medical diagnosis consistent with survival &lt; 1 year&#xD;
&#xD;
         10. Planned surgical procedure during duration of the study (if emergency surgery needed,&#xD;
             EPO administration will be stopped, but the patient will remain in the study according&#xD;
             to the intention to treat principles).&#xD;
&#xD;
         11. Current use of Coumadin or other blood thinners (e.g. Pradaxa, Heparin, Lovenox)&#xD;
&#xD;
             ASA, Plavix or Aggrenox are not a contraindication&#xD;
&#xD;
         12. Any history of previous deep venous thrombosis (DVT), pulmonary embolization (PE), or&#xD;
             other thromboembolic event&#xD;
&#xD;
         13. Current participation in other interventional clinical trial&#xD;
&#xD;
         14. Current use of iron supplements&#xD;
&#xD;
         15. Evidence of penetrating brain injury&#xD;
&#xD;
         16. Contraindication to MRI scanning&#xD;
&#xD;
         17. No adherence to use of effective method of contraception for females of childbearing&#xD;
             potential for time from enrollment to the study until 2 weeks after completion of the&#xD;
             study drug (EPO or placebo)&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>70 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Eric M Wassermann, M.D.</last_name>
    <role>Principal Investigator</role>
    <affiliation>National Institute of Neurological Disorders and Stroke (NINDS)</affiliation>
  </overall_official>
  <removed_countries>
    <country>United States</country>
  </removed_countries>
  <verification_date>May 31, 2017</verification_date>
  <study_first_submitted>August 26, 2014</study_first_submitted>
  <study_first_submitted_qc>August 26, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">August 27, 2014</study_first_posted>
  <last_update_submitted>July 3, 2018</last_update_submitted>
  <last_update_submitted_qc>July 3, 2018</last_update_submitted_qc>
  <last_update_posted type="Actual">July 5, 2018</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Endothelial Progenitor Cells</keyword>
  <keyword>Angiogenesis</keyword>
  <keyword>Traumatic Brain Injury</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Brain Injuries</mesh_term>
    <mesh_term>Brain Injuries, Traumatic</mesh_term>
  </condition_browse>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT02226848
org study id: 140174
secondary id: 14-N-0174
nct id: NCT02226848
lead sponsor: 
Background:

      - Traumatic brain injury (TBI) injures blood vessels in the brain. Endothelial progenitor
      cells (EPCs) help the body form new blood vessels. The drug erythropoietin (EPO) helps the
      body make more blood cells and might help make blood vessels. Researchers want to see if EPO
      helps people with TBI.

      Objective:

      - To see whether erythropoietin increases the number of endothelial progenitor cells
      circulating in the blood and changes reactivity of brain vessels.

      Eligibility:

      - Adults age 18 70 who had a TBI 3 7 days ago and still have symptoms.

      Design:

        -  Participants will be screened with medical history and blood tests. Vital signs will be
           taken.

        -  Visit 1:

        -  Medical history, physical exam, and blood sample.

        -  Neuropsychological tests of memory, attention, and thinking. These include written and
           spoken questions, tests on paper or computer, and simple actions.

        -  Magnetic resonance imaging (MRI) scan with carbon dioxide. Participants will lie on a
           table that slides in and out of a metal cylinder. For part of the scan, participants
           will wear a breathing mask like a snorkel and wear a nose clip.

        -  Study drug or placebo injection under the skin of the arm, leg, or buttock.

        -  Visits 2, 3, and 4 will be 1 week apart.

        -  Blood sample.

        -  Review of TBI symptoms and any drug side effects.

        -  Study drug or placebo injection under the skin.

        -  Visit 5 will be 1 week after visit 4. Visit 6 will be 6 months after participants start
           the study.

        -  Blood sample.

        -  Review of TBI symptoms and any drug side effects.

        -  Neuropsychological tests.

        -  MRI with carbon dioxide.
Objective

      Traumatic brain injury (TBI) is the leading cause of death and disability in people under age
      45 in industrialized countries 5;6. Significant numbers of US veterans from the wars in Iraq
      and Afghanistan return with TBI7. However, to date, there are no specific neuroprotective
      treatment options with proven clinical efficacy 8. Erythropoietin (EPO) is approved by the
      FDA to treat anemia and has comprehensive preclinical data supporting its neuroprotective and
      neuroregenerative efficacy following traumatic (TBI) and a wide range of other acquired brain
      insults. Injury to small and medium-sized cerebral blood vessels is a well recognized
      consequence of TBI. EPO increases production of endothelial progenitor cells (EPCs) 4;9 and
      promotes angiogenesis and neovascularization after TBI. EPO also promotes neurogenesis and
      improves functional recovery in animals after experimental stroke10-12 and TBI.13;14
      Neovascularization is coupled with neurogenesis, and augmentation of both processes by EPO
      may result in lessened cognitive deficits. Neovascularization by EPO may prevent
      post-traumatic deficits in cerebrovascular reactivity (CVR), which can be measured
      noninvasively using magnetic resonance imaging (MRI).

      This proposal is for a randomized, placebo-controlled pilot clinical trial designed to obtain
      data on the effects of EPO in humans with persistent post-concussive symptoms after TBI. The
      primary objective is to evaluate effect of 4 week administration of recombinant
      erythropoietin on numbers of circulating endothelial progenitor cells in patients with
      persistent symptoms during the subacute period after TBI. This information will guide the
      design of a future definitive study.

      Study Population

      The study population will include 30 males and females with persistent post-concussive
      symptoms continuing up to 7 days after TBI. Participants will be military service members or
      civilians presenting as outpatients for clinical management of TBI or post-concussive
      symptoms at the Center for Neuroscience and Regenerative Medicine (CNRM)-affiliated
      hospitals. These include the Walter Reed National Military Medical Center (WRNMMC), Suburban
      Hospital (SH), and Washington Hospital Center (WHC).

      Design

      Participants will be referred to the NIH Clinical Center (CC) from participating hospitals or
      will be recruited by advertisements through CNRM Recruitment core to receive EPO or placebo.
      Telephone screening will be carried out to determine tentative eligibility. At the baseline
      visit, participants will be screened, consented and randomized 2:1 to receive either EPO or
      placebo with a dose of 40,000 IU EPO subcutaneously (s.c.) (n=20) once weekly for 4 weeks or
      placebo (n=10). Each participant will have 6 outpatient visits (visits 1-6) performed at the
      NIH CC. Placebo or active drug will be administered s.c. based on the randomization at visits
      1-4; blood will be collected for EPC assays and safety laboratory measurements during each
      visit. Brain MRI and neuropsychological tests will be performed during visit 1 (before
      administering EPO or placebo), and visit 5 (one week after final drug administration) and
      visit 6 (6 months after study enrollment).

      Outcome Measures

      Primary outcome:

        1. . Effect of 4 weeks of EPO administration on numbers of circulating EPCs in patients
           with persistent symptoms during the subacute period after TBI (within subject
           comparison).

           Secondary outcomes:

        2. . Comparison of the change of numbers of circulating EPC s between EPO and placebo
           groups.

        3. . Effect of 4 weeks of EPO administration on MRI biomarkers of TBI recovery (such as CVR
           on hypercapnia and global and regional brain volumes by MRI).

        4. . Effect of 4 weeks of EPO administration on plasma biomarkers of angiogenesis and
           inflammation, such as stem cell factor (SCF), vascular endothelial growth factor (VEGF),
           stromal-derived factor (SDF-1 ); and matrix metalloproteinase-9 (MMP-9).

        5. . Effect of 4 weeks of placebo administration on numbers of circulating EPCs in patients
           with persistent symptoms during the subacute period after TBI.

           Tertiary outcome:

        6. . Relationship between EPC levels at baseline and after 4 weeks and neuropsychological
           performance following TBI.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
measure: Effect of 4 weeks of EPO administration on numbers of circulating EPCs in patients with persistent symptons during the subacute period after TBI.
time frame: 4 weeks
measure: Safety of 4 weeks of EPO administration to TBI participants
time frame: 4 weeks
measure: Effect of 4 weeks of EPO administration on MRI biomarkers of TBI recovery
time frame: 4 weeks
measure: Effect of 4 weeks of EPO administration on biomarkers
time frame: 4 weeks
measure: Relationship between EPC levels at baseline after 4 weeks and neuropsychological performance following TBI.
time frame: Baseline
intervention type: Drug
intervention name: Erythropoeitin
criteria: 
gender: All
minimum age: 18 Years
maximum age: 70 Years
healthy volunteers: No
last name: Eric M Wassermann, M.D.
role: Principal Investigator
affiliation: National Institute of Neurological Disorders and Stroke (NINDS)
country: United States
responsible party type: Sponsor
mesh term: Brain Injuries
mesh term: Brain Injuries, Traumatic