<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/NCT02980354</url>
  </required_header>
  <id_info>
    <org_study_id>16057</org_study_id>
    <nct_id>NCT02980354</nct_id>
  </id_info>
  <brief_title>Bayraktutan Dunhill Medical Trust EPC Study</brief_title>
  <official_title>Endothelial Progenitor Cells: Potential Biomarkers for Diagnosis and Prognosis of Ischaemic Stroke</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Nottingham</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>The Dunhill Medical Trust</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>University of Nottingham</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Stroke is a life-threatening medical condition that occurs due to a sudden disruption of&#xD;
      blood supply to the brain. Although it may affect all age groups including children, the&#xD;
      elderly are at a greater risk of having strokes. Indeed, three-quarter of all strokes are&#xD;
      seen in people over the age of 65. Unfortunately, due to short therapeutic window (4.5 h of&#xD;
      stroke onset), only 2-3% of patients can receive the currently available single medical&#xD;
      therapy with rt-PA, a clot-busting agent. As recent studies show that bone marrow-derived&#xD;
      endothelial progenitor cells, a type of stem cells, may migrate to the site of injury to&#xD;
      repair the damaged brain vessels and tissue, it is possible that their numbers and functional&#xD;
      capacity may determine the clinical outcome of stroke patients i.e. severely disabled,&#xD;
      moderately disabled or no signs at all. This study will assess these parameters in elderly&#xD;
      stroke patients compared to their age-matched stroke-free counterparts and healthy young&#xD;
      volunteers.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Ischaemic stroke develops through an interference with blood supply to the brain and&#xD;
      continues to be one of the leading causes of morbidity and mortality in the World. Global&#xD;
      medical statistics reveal that ~75% of all stroke patients are older than 65 years and that&#xD;
      the stroke occurrence more than doubles every 10 years after the age of 55 in both men and&#xD;
      women.&#xD;
&#xD;
      Although various mechanisms may alter the structure and function of the adult brain during&#xD;
      the aging process, endothelial dysfunction is regarded as the main pathology that renders&#xD;
      cerebral vessels susceptible to atherosclerosis and subsequent vascular events. Endothelial&#xD;
      dysfunction also constitutes the main cause of vascular abnormality in most lacunar strokes&#xD;
      which result from occlusion of one of the penetrating arteries deep within the brain.&#xD;
      Cortical strokes represent another common form of ischaemic stroke and develop from an&#xD;
      embolism from the heart or large arteries. As the endothelium maintains vascular balance&#xD;
      through regulation of many distinct functions like vascular permeability, tone and&#xD;
      inflammation, it is of crucial importance to preserve its integrity and function at all times&#xD;
      to prevent age- and stroke-related vascular damage.&#xD;
&#xD;
      Recent studies show that bone marrow-derived endothelial progenitor cells (EPCs) play a key&#xD;
      role in sustaining appropriate endothelial function by re-endothelialisation of blood vessels&#xD;
      in adult brain and ischaemic settings. Like embryonic angioblasts, EPCs are equipped with an&#xD;
      inherent capacity to circulate, proliferate and differentiate. Hence, the markers of&#xD;
      endothelial maturity (KDR), immaturity (CD133) and stemness (CD34) must be simultaneously&#xD;
      detected in relevant studies to identify all endothelial-committed and undifferentiated&#xD;
      cells.&#xD;
&#xD;
      It is likely that environmental changes, like oxidative stress, inflammatory responses and&#xD;
      nitric oxide availability, evoked by ischaemic injury and aging may also suppress the&#xD;
      generation and function of EPCs. As mobilisation, recruitment and homing of EPCs to sites of&#xD;
      vascular injury are mediated by various growth factors like the SDF-1 (stromal cell-derived&#xD;
      factor-1), VEGF (vascular endothelial growth factor) and GCSF (granulocyte-colony stimulating&#xD;
      factor), it is likely that the diminished expression of these factors may also negatively&#xD;
      influence the number and function of EPCs.&#xD;
&#xD;
      Interestingly, while there is little data on functional and numerical alteration of EPCs&#xD;
      during the chronic phase of stroke, current data regarding EPC levels during acute and&#xD;
      subacute phases of disease are inconsistent in that stable, increased or decreased numbers&#xD;
      have been reported as compared to healthy subjects.The time course of EPC release after acute&#xD;
      cerebral infarction also remains inconclusive.&#xD;
&#xD;
      In light of the above, the aims of the current study are to reveal whether 1- variations in&#xD;
      circulating EPC levels and/or their functional aspects may be used as markers to identify&#xD;
      ischaemic stroke subtypes and predict patients' outcome; 2- differences in EPC&#xD;
      number/function during acute, subacute or chronic phases of stroke correlate with severity&#xD;
      and functional outcome of ischaemic stroke; 3- EPC counts and function are affected by aging&#xD;
      process; and 4- levels or activity of key pathophysiological elements like VEGF, inflammatory&#xD;
      cytokines and nitric oxide, known to affect EPC count and function, differ between patients&#xD;
      with lacunar and cortical strokes and between stroke patients and healthy counterparts.&#xD;
&#xD;
      STUDY MANAGEMENT Independent outcome assessments (mRS, BI, NIHSS) will be performed on&#xD;
      admission and days 7, 30 and 90 after stroke. The laboratory procedures will be carried out&#xD;
      by a post-doctoral research fellow who will collate and analyse the data. The Chief&#xD;
      Investigator has overall responsibility for the study and shall oversee all study management.&#xD;
      The data custodian will be the Chief Investigator.&#xD;
&#xD;
      PARTICIPANT DURATION Each participant with stroke will be followed-up for 90 days from the&#xD;
      time of recruitment. Elderly and young healthy volunteers will be seen only once.&#xD;
&#xD;
      RECRUITMENT Participants will be recruited from Nottingham University Hospitals Stroke&#xD;
      Services. The initial approach will be from a member of the patient's usual care team (which&#xD;
      may include the investigators) who will inform the participant or their nominated&#xD;
      representative of all aspects pertaining to participation in the study. It will be explained&#xD;
      to the potential participant that entry into the study is entirely voluntary and that their&#xD;
      treatment and care will not be affected by their decision. It will also be explained that&#xD;
      they can withdraw at any time.&#xD;
&#xD;
      PARTICIPANT WITHDRAWAL Participants may be withdrawn from study in cases of disease&#xD;
      progression and withdrawal of consent. The participants will be made aware that this will not&#xD;
      affect their future care.&#xD;
&#xD;
      INFORMED CONSENT No patient will be recruited into the study without obtaining their written&#xD;
      informed consent. In cases of incapacity, the consent of an appropriate personal consultee&#xD;
      will be sought. The Investigator will explain the details of the study and provide a&#xD;
      Participant Information Sheet. Participants will be offered 24 hours to consider&#xD;
      participation. However, they will be allowed to consent at an earlier time, if they prefer.&#xD;
      In cases where stroke patients regain capacity, they will be re-consented for their ongoing&#xD;
      participation in the study.&#xD;
&#xD;
      STATISTICS All results including subject characteristics will be reported as means±SD.&#xD;
      Continuous variables, including age and circulating EPC level will be analysed by independent&#xD;
      t-test among groups. Circulating EPC levels at different time points (within 48 h and on days&#xD;
      7, 30 and 90 post-stroke) will be compared using the repeated measures of ANOVA. Scheffe's&#xD;
      multiple comparison will be used to analyse the intra-individual courses of parameters over&#xD;
      time. These will then be compared among patients with lacunar and cortical strokes. Multiple&#xD;
      logistic regression analyses will determine the independent impact of different predictive&#xD;
      variables on functional outcome and neurological deficits.&#xD;
&#xD;
      Sample size have been calculated to allow for failures of patient attendance on days 30 and&#xD;
      90 (~15% for each time point) and possibility of patients illness/death during the course of&#xD;
      the study (~5%).&#xD;
&#xD;
      ADVERSE EVENTS As this is not an interventional study, no adverse event is anticipated to&#xD;
      develop because of it. Adverse events of venepuncture will be dealt with according to&#xD;
      standard practice.&#xD;
&#xD;
      DATA PROTECTION The study form will only collect the minimum required information for the&#xD;
      purposes of the study. Study forms will be held securely, in a locked room, or locked&#xD;
      cupboard or cabinet. Access to the information will be limited to the study staff and&#xD;
      investigators and relevant regulatory authorities. Computer held data including the study&#xD;
      database will be held securely and password protected. All data will be stored on a secure&#xD;
      dedicated web server. Access will be restricted by user identifiers and passwords (encrypted&#xD;
      using a one way encryption method). Information about the study in the participant's medical&#xD;
      records / hospital notes will be treated confidentially in the same way as all other&#xD;
      confidential medical information. Electronic data will be backed up every 24 hours to both&#xD;
      local and remote media in encrypted format.&#xD;
&#xD;
      STUDY DATA Monitoring of study data shall include confirmation of informed consent; source&#xD;
      data verification; data storage and data transfer procedures; local quality control checks&#xD;
      and procedures, back-up and disaster recovery of any local databases and validation of data&#xD;
      manipulation. The Academic Supervisor, or where required, a nominated designee of the&#xD;
      Sponsor, shall carry out monitoring of study data as an ongoing activity.&#xD;
&#xD;
      Entries on study forms will be verified by inspection against the source data. A sample of&#xD;
      study forms (10% or as per the study risk assessment) will be checked on a regular basis for&#xD;
      verification of all entries made. In addition the subsequent capture of the data on the study&#xD;
      database will be checked. Where corrections are required these will carry a full audit trail&#xD;
      and justification. Study data and evidence of monitoring and systems audits will be made&#xD;
      available for inspection as/when required.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Recruiting</last_known_status>
  <start_date type="Actual">February 1, 2017</start_date>
  <completion_date type="Anticipated">January 2020</completion_date>
  <primary_completion_date type="Anticipated">November 2019</primary_completion_date>
  <study_type>Observational</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <observational_model>Case-Control</observational_model>
    <time_perspective>Prospective</time_perspective>
  </study_design_info>
  <primary_outcome>
    <measure>Detection of disability or dependence in the daily activities</measure>
    <time_frame>On day 90 after stroke</time_frame>
    <description>to be assessed by modified Rankin scale</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Changes in circulating EPC numbers in elderly patients with lacunar or cortical stroke</measure>
    <time_frame>within the first 48 h of stroke and on days 7, 30 and 90 after stroke</time_frame>
    <description>to be assessed by flow cytometry</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in EPC functional capacity in elderly patients with lacunar or cortical stroke</measure>
    <time_frame>within the first 48 h of stroke and on days 7, 30 and 90 after stroke</time_frame>
    <description>to be assessed by mobility, proliferation, colony forming unit and matrigel tube formation assays</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in circulating EPC numbers in stroke patients vs healthy controls</measure>
    <time_frame>patients - within the first 48 h of stroke and on days 7, 30 and 90 after stroke vs controls - once</time_frame>
    <description>to be assessed by flow cytometry</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in EPC functional capacity in stroke patients vs healthy controls</measure>
    <time_frame>patients - within the first 48 h of stroke and on days 7, 30 and 90 after stroke vs controls - once</time_frame>
    <description>to be assessed by mobility, proliferation, colony forming unit and matrigel tube formation assays</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Changes in plasma VEGF levels between stroke patients and healthy controls</measure>
    <time_frame>within the first 48 h of stroke and on days 7, 30 and 90 after stroke vs controls - once</time_frame>
    <description>VEGF levels will be reported as pg/ml.</description>
  </other_outcome>
  <other_outcome>
    <measure>Changes in plasma inflammatory cytokine levels between stroke patients and healthy controls</measure>
    <time_frame>within the first 48 h of stroke and on days 7, 30 and 90 after stroke vs controls - once</time_frame>
    <description>Levels of all cytokines (TNF-alpha, TGF-beta, MCP-1) will be reported as pg/ml.</description>
  </other_outcome>
  <other_outcome>
    <measure>Changes in EPC eNOS activity between stroke patients and healthy controls</measure>
    <time_frame>within the first 48 h of stroke and on days 7, 30 and 90 after stroke vs controls - once</time_frame>
    <description>eNOS activity in EPC homogenates will be reported as mU/mg protein.</description>
  </other_outcome>
  <number_of_groups>4</number_of_groups>
  <enrollment type="Anticipated">200</enrollment>
  <condition>Stroke</condition>
  <arm_group>
    <arm_group_label>Lacunar stroke</arm_group_label>
    <description>Blood samples will be taken from 50 patients who have been diagnosed to have lacunar stroke and are 65 years of age or above.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Cortical stroke</arm_group_label>
    <description>Blood samples will be taken from 50 patients who have been diagnosed to have cortical stroke and are 65 years of age or above.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Elderly healthy volunteers</arm_group_label>
    <description>Blood samples will be taken from 50 healthy individuals who are 65 years of age or above.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Young healthy volunteers</arm_group_label>
    <description>Blood samples will be taken from 50 healthy individuals who are between 18 and 64 years of age.</description>
  </arm_group>
  <biospec_retention>Samples Without DNA</biospec_retention>
  <biospec_descr>
    <textblock>
      plasma&#xD;
    </textblock>
  </biospec_descr>
  <eligibility>
    <study_pop>
      <textblock>
        Patients admitted to Nottingham University Hospitals Stroke Service will be recruited for&#xD;
        the study. Similar age patients' relatives, friends or carers will be recruited as&#xD;
        age-matched healthy volunteers. Staff and students working at the Clinical Sciences&#xD;
        Building (where the study will be performed) will be recruited as young healthy volunteers.&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Participants with Stroke:&#xD;
&#xD;
        Patients with anterior circulation IS and aged 65 years or older. Independence prior to&#xD;
        stroke (mRS&lt;3). Ability to give informed consent (directly or via consultee).&#xD;
&#xD;
          -  Age Matched Controls (Healthy Volunteers) Individuals aged 65 years or above. No&#xD;
             previous history of stroke. Ability to give consent to take part in the study.&#xD;
&#xD;
          -  Young Healthy Volunteers Individuals aged between 18 to 64 years of age. No previous&#xD;
             history of stroke. Ability to give consent to take part in the study.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Participants with Stroke:&#xD;
&#xD;
        Patients with posterior circulation IS and aged below 65 years of age. Patients with recent&#xD;
        recurrent IS. Patients with transient ischaemic attack or IS within the last 3 months.&#xD;
        Patients with primary intracerebral haemorrhage.&#xD;
&#xD;
          -  Age Matched Controls (Healthy Volunteers) Individuals aged below 65 years of age.&#xD;
             Previous history of stroke.&#xD;
&#xD;
          -  Young Healthy Volunteers (18-64):&#xD;
&#xD;
        Individuals aged below 18 years or are 65 years of age or above. Previous history of&#xD;
        stroke.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Ulvi Bayraktutan, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Nottingham</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Ulvi Bayraktutan, PhD</last_name>
    <phone>+44 115 8231764</phone>
    <email>ulvi.bayraktutan@nottingham.ac.uk</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Nikola Sprigg, MD</last_name>
    <phone>+44 115 8231778</phone>
    <email>nikola.sprigg@nottingham.ac.uk</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>Clinical Sciences Building, University of Nottingham</name>
      <address>
        <city>Nottingham</city>
        <zip>NG5 1PB</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Ulvi Bayraktutan, PhD</last_name>
      <phone>+44 115 8231764</phone>
      <email>ulvi.bayraktutan@nottingham.ac.uk</email>
    </contact>
  </location>
  <location>
    <facility>
      <name>Nottingham University Hospitals NHS Trust</name>
      <address>
        <city>Nottingham</city>
        <zip>NG5 1PB</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Nikola Sprigg, MD</last_name>
      <phone>+44 115 8231778</phone>
      <email>nikola.sprigg@nottingham.ac.uk</email>
    </contact>
    <contact_backup>
      <last_name>Amanda Buck</last_name>
      <phone>+44 115 8231772</phone>
      <email>amanda.buck@nottingham.ac.uk</email>
    </contact_backup>
  </location>
  <location_countries>
    <country>United Kingdom</country>
  </location_countries>
  <verification_date>April 2019</verification_date>
  <study_first_submitted>November 15, 2016</study_first_submitted>
  <study_first_submitted_qc>November 29, 2016</study_first_submitted_qc>
  <study_first_posted type="Estimate">December 2, 2016</study_first_posted>
  <last_update_submitted>April 30, 2019</last_update_submitted>
  <last_update_submitted_qc>April 30, 2019</last_update_submitted_qc>
  <last_update_posted type="Actual">May 3, 2019</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>endothelial progenitor cells, ischaemic stroke, aging</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Stroke</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>Yes</sharing_ipd>
    <ipd_description>De-identified IPD will be made available to other researchers after publication of the research findings. De-identified IPD underlying the results presented in these articles including tables, figures or supplementary material, will be shared as per the regulations of the University of Nottingham indicated on https://www.nottingham.ac.uk/fabs/rgs/research-data-management/data-sharing-and-archiving/sharing-data.aspx.</ipd_description>
    <ipd_time_frame>Data will be shared 12 months after the publication of all relevant research findings.</ipd_time_frame>
    <ipd_access_criteria>All requests regarding the data share should be directed to the chief investigator by email.</ipd_access_criteria>
    <ipd_url>https://www.nottingham.ac.uk/fabs/rgs/research-data-management/data-sharing-and-archiving/sharing-data.aspx</ipd_url>
  </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/NCT02980354
org study id: 16057
nct id: NCT02980354
lead sponsor: 
collaborator: 
has dmc: Yes
Stroke is a life-threatening medical condition that occurs due to a sudden disruption of
      blood supply to the brain. Although it may affect all age groups including children, the
      elderly are at a greater risk of having strokes. Indeed, three-quarter of all strokes are
      seen in people over the age of 65. Unfortunately, due to short therapeutic window (4.5 h of
      stroke onset), only 2-3% of patients can receive the currently available single medical
      therapy with rt-PA, a clot-busting agent. As recent studies show that bone marrow-derived
      endothelial progenitor cells, a type of stem cells, may migrate to the site of injury to
      repair the damaged brain vessels and tissue, it is possible that their numbers and functional
      capacity may determine the clinical outcome of stroke patients i.e. severely disabled,
      moderately disabled or no signs at all. This study will assess these parameters in elderly
      stroke patients compared to their age-matched stroke-free counterparts and healthy young
      volunteers.
Ischaemic stroke develops through an interference with blood supply to the brain and
      continues to be one of the leading causes of morbidity and mortality in the World. Global
      medical statistics reveal that ~75% of all stroke patients are older than 65 years and that
      the stroke occurrence more than doubles every 10 years after the age of 55 in both men and
      women.

      Although various mechanisms may alter the structure and function of the adult brain during
      the aging process, endothelial dysfunction is regarded as the main pathology that renders
      cerebral vessels susceptible to atherosclerosis and subsequent vascular events. Endothelial
      dysfunction also constitutes the main cause of vascular abnormality in most lacunar strokes
      which result from occlusion of one of the penetrating arteries deep within the brain.
      Cortical strokes represent another common form of ischaemic stroke and develop from an
      embolism from the heart or large arteries. As the endothelium maintains vascular balance
      through regulation of many distinct functions like vascular permeability, tone and
      inflammation, it is of crucial importance to preserve its integrity and function at all times
      to prevent age- and stroke-related vascular damage.

      Recent studies show that bone marrow-derived endothelial progenitor cells (EPCs) play a key
      role in sustaining appropriate endothelial function by re-endothelialisation of blood vessels
      in adult brain and ischaemic settings. Like embryonic angioblasts, EPCs are equipped with an
      inherent capacity to circulate, proliferate and differentiate. Hence, the markers of
      endothelial maturity (KDR), immaturity (CD133) and stemness (CD34) must be simultaneously
      detected in relevant studies to identify all endothelial-committed and undifferentiated
      cells.

      It is likely that environmental changes, like oxidative stress, inflammatory responses and
      nitric oxide availability, evoked by ischaemic injury and aging may also suppress the
      generation and function of EPCs. As mobilisation, recruitment and homing of EPCs to sites of
      vascular injury are mediated by various growth factors like the SDF-1 (stromal cell-derived
      factor-1), VEGF (vascular endothelial growth factor) and GCSF (granulocyte-colony stimulating
      factor), it is likely that the diminished expression of these factors may also negatively
      influence the number and function of EPCs.

      Interestingly, while there is little data on functional and numerical alteration of EPCs
      during the chronic phase of stroke, current data regarding EPC levels during acute and
      subacute phases of disease are inconsistent in that stable, increased or decreased numbers
      have been reported as compared to healthy subjects.The time course of EPC release after acute
      cerebral infarction also remains inconclusive.

      In light of the above, the aims of the current study are to reveal whether 1- variations in
      circulating EPC levels and/or their functional aspects may be used as markers to identify
      ischaemic stroke subtypes and predict patients' outcome; 2- differences in EPC
      number/function during acute, subacute or chronic phases of stroke correlate with severity
      and functional outcome of ischaemic stroke; 3- EPC counts and function are affected by aging
      process; and 4- levels or activity of key pathophysiological elements like VEGF, inflammatory
      cytokines and nitric oxide, known to affect EPC count and function, differ between patients
      with lacunar and cortical strokes and between stroke patients and healthy counterparts.

      STUDY MANAGEMENT Independent outcome assessments (mRS, BI, NIHSS) will be performed on
      admission and days 7, 30 and 90 after stroke. The laboratory procedures will be carried out
      by a post-doctoral research fellow who will collate and analyse the data. The Chief
      Investigator has overall responsibility for the study and shall oversee all study management.
      The data custodian will be the Chief Investigator.

      PARTICIPANT DURATION Each participant with stroke will be followed-up for 90 days from the
      time of recruitment. Elderly and young healthy volunteers will be seen only once.

      RECRUITMENT Participants will be recruited from Nottingham University Hospitals Stroke
      Services. The initial approach will be from a member of the patient's usual care team (which
      may include the investigators) who will inform the participant or their nominated
      representative of all aspects pertaining to participation in the study. It will be explained
      to the potential participant that entry into the study is entirely voluntary and that their
      treatment and care will not be affected by their decision. It will also be explained that
      they can withdraw at any time.

      PARTICIPANT WITHDRAWAL Participants may be withdrawn from study in cases of disease
      progression and withdrawal of consent. The participants will be made aware that this will not
      affect their future care.

      INFORMED CONSENT No patient will be recruited into the study without obtaining their written
      informed consent. In cases of incapacity, the consent of an appropriate personal consultee
      will be sought. The Investigator will explain the details of the study and provide a
      Participant Information Sheet. Participants will be offered 24 hours to consider
      participation. However, they will be allowed to consent at an earlier time, if they prefer.
      In cases where stroke patients regain capacity, they will be re-consented for their ongoing
      participation in the study.

      STATISTICS All results including subject characteristics will be reported as means±SD.
      Continuous variables, including age and circulating EPC level will be analysed by independent
      t-test among groups. Circulating EPC levels at different time points (within 48 h and on days
      7, 30 and 90 post-stroke) will be compared using the repeated measures of ANOVA. Scheffe's
      multiple comparison will be used to analyse the intra-individual courses of parameters over
      time. These will then be compared among patients with lacunar and cortical strokes. Multiple
      logistic regression analyses will determine the independent impact of different predictive
      variables on functional outcome and neurological deficits.

      Sample size have been calculated to allow for failures of patient attendance on days 30 and
      90 (~15% for each time point) and possibility of patients illness/death during the course of
      the study (~5%).

      ADVERSE EVENTS As this is not an interventional study, no adverse event is anticipated to
      develop because of it. Adverse events of venepuncture will be dealt with according to
      standard practice.

      DATA PROTECTION The study form will only collect the minimum required information for the
      purposes of the study. Study forms will be held securely, in a locked room, or locked
      cupboard or cabinet. Access to the information will be limited to the study staff and
      investigators and relevant regulatory authorities. Computer held data including the study
      database will be held securely and password protected. All data will be stored on a secure
      dedicated web server. Access will be restricted by user identifiers and passwords (encrypted
      using a one way encryption method). Information about the study in the participant's medical
      records / hospital notes will be treated confidentially in the same way as all other
      confidential medical information. Electronic data will be backed up every 24 hours to both
      local and remote media in encrypted format.

      STUDY DATA Monitoring of study data shall include confirmation of informed consent; source
      data verification; data storage and data transfer procedures; local quality control checks
      and procedures, back-up and disaster recovery of any local databases and validation of data
      manipulation. The Academic Supervisor, or where required, a nominated designee of the
      Sponsor, shall carry out monitoring of study data as an ongoing activity.

      Entries on study forms will be verified by inspection against the source data. A sample of
      study forms (10% or as per the study risk assessment) will be checked on a regular basis for
      verification of all entries made. In addition the subsequent capture of the data on the study
      database will be checked. Where corrections are required these will carry a full audit trail
      and justification. Study data and evidence of monitoring and systems audits will be made
      available for inspection as/when required.
observational model: Case-Control
time perspective: Prospective
measure: Detection of disability or dependence in the daily activities
time frame: On day 90 after stroke
description: to be assessed by modified Rankin scale
measure: Changes in circulating EPC numbers in elderly patients with lacunar or cortical stroke
time frame: within the first 48 h of stroke and on days 7, 30 and 90 after stroke
description: to be assessed by flow cytometry
measure: Changes in EPC functional capacity in elderly patients with lacunar or cortical stroke
time frame: within the first 48 h of stroke and on days 7, 30 and 90 after stroke
description: to be assessed by mobility, proliferation, colony forming unit and matrigel tube formation assays
measure: Changes in circulating EPC numbers in stroke patients vs healthy controls
time frame: patients - within the first 48 h of stroke and on days 7, 30 and 90 after stroke vs controls - once
description: to be assessed by flow cytometry
measure: Changes in EPC functional capacity in stroke patients vs healthy controls
time frame: patients - within the first 48 h of stroke and on days 7, 30 and 90 after stroke vs controls - once
description: to be assessed by mobility, proliferation, colony forming unit and matrigel tube formation assays
measure: Changes in plasma VEGF levels between stroke patients and healthy controls
time frame: within the first 48 h of stroke and on days 7, 30 and 90 after stroke vs controls - once
description: VEGF levels will be reported as pg/ml.
measure: Changes in plasma inflammatory cytokine levels between stroke patients and healthy controls
time frame: within the first 48 h of stroke and on days 7, 30 and 90 after stroke vs controls - once
description: Levels of all cytokines (TNF-alpha, TGF-beta, MCP-1) will be reported as pg/ml.
measure: Changes in EPC eNOS activity between stroke patients and healthy controls
time frame: within the first 48 h of stroke and on days 7, 30 and 90 after stroke vs controls - once
description: eNOS activity in EPC homogenates will be reported as mU/mg protein.
arm group label: Lacunar stroke
description: Blood samples will be taken from 50 patients who have been diagnosed to have lacunar stroke and are 65 years of age or above.
arm group label: Cortical stroke
description: Blood samples will be taken from 50 patients who have been diagnosed to have cortical stroke and are 65 years of age or above.
arm group label: Elderly healthy volunteers
description: Blood samples will be taken from 50 healthy individuals who are 65 years of age or above.
arm group label: Young healthy volunteers
description: Blood samples will be taken from 50 healthy individuals who are between 18 and 64 years of age.
plasma
study pop: 
sampling method: Probability Sample
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: Accepts Healthy Volunteers
last name: Ulvi Bayraktutan, PhD
role: Principal Investigator
affiliation: University of Nottingham
last name: Ulvi Bayraktutan, PhD
phone: +44 115 8231764
email: ulvi.bayraktutan@nottingham.ac.uk
last name: Nikola Sprigg, MD
phone: +44 115 8231778
email: nikola.sprigg@nottingham.ac.uk
facility: 
status: Recruiting
contact: 
facility: 
status: Recruiting
contact: 
contact backup: 
country: United Kingdom
responsible party type: Sponsor
mesh term: Stroke
sharing ipd: Yes
ipd description: De-identified IPD will be made available to other researchers after publication of the research findings. De-identified IPD underlying the results presented in these articles including tables, figures or supplementary material, will be shared as per the regulations of the University of Nottingham indicated on https://www.nottingham.ac.uk/fabs/rgs/research-data-management/data-sharing-and-archiving/sharing-data.aspx.
ipd time frame: Data will be shared 12 months after the publication of all relevant research findings.
ipd access criteria: All requests regarding the data share should be directed to the chief investigator by email.
ipd url: https://www.nottingham.ac.uk/fabs/rgs/research-data-management/data-sharing-and-archiving/sharing-data.aspx