<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/NCT03037281</url>
  </required_header>
  <id_info>
    <org_study_id>0554</org_study_id>
    <nct_id>NCT03037281</nct_id>
  </id_info>
  <brief_title>Release of Nociceptin From Granulocytes in Sepsis</brief_title>
  <official_title>Does the Release Profile of Nociceptin From Immunocytes Differ in Healthy Volunteers and Critically Ill Patients With Sepsis?</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Leicester</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>The Royal College of Anaesthetists</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>University Hospitals, Leicester</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>University of Leicester</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      Nociceptin is a protein found in the body, with a number of functions in the central nervous&#xD;
      system, blood vessels and the gut. There is evidence that it may have a role in controlling&#xD;
      the immune response to infection, and may act as a link between the brain and immune system.&#xD;
&#xD;
      In infection, or after surgery, there is an increase in nociceptin, and subjects greater&#xD;
      elevations of nociceptin have a poorer outcome. There is evidence that cells of the immune&#xD;
      system may produce nociceptin, although it is not yet known which cells are capable of&#xD;
      producing it, and what &quot;switches on&quot; production.&#xD;
&#xD;
      This study aims to determine&#xD;
&#xD;
        1. Which cells of the immune system can produce nociceptin&#xD;
&#xD;
        2. If there is a difference in the ability to produce nociceptin between healthy volunteers&#xD;
           and patients with severe infections&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">April 7, 2016</start_date>
  <completion_date type="Actual">June 30, 2019</completion_date>
  <primary_completion_date type="Actual">June 30, 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>Proportion of Responsive Biosensor Cells Responding to Granulocyte Addition in the Presence and Absence of NOP Antagonist</measure>
    <time_frame>Day 1</time_frame>
    <description>Measure of N/OFQ presence in granulocytes and associated supernatant</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Granulocyte Count</measure>
    <time_frame>Day 1</time_frame>
    <description>Count of the number of neutrophils in the original sample</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Mortality In-hospital, at 30 Days</measure>
    <time_frame>30 days</time_frame>
    <description>All cause mortality at 30 days</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Time to ICU Discharge (or Death if on ICU)</measure>
    <time_frame>Time to ICU discharge (or death if on ICU)</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Time to Death or Discharge</measure>
    <time_frame>Number of days between admission and death or discharge from hospital</time_frame>
    <description>Time to death or discharge (days)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Acute Physiology and Chronic Health Evaluation (APACHE-2) Score</measure>
    <time_frame>Day 1</time_frame>
    <description>The Acute Physiology and Chronic Health Evaluation (APACHE-2) score for the patient.&#xD;
APACHE 2 is an international standard,12 variable score from 0-71 reflecting disease severity in the critically unwell during the first 24 hours of illness. The score is a combined measure of illness severity (acute physiology), and background chronic health factors. Increased score represents increased predicted mortality.&#xD;
Variables recorded include AaDO2 or PaO2 (depending on FiO2), temperature, mean arterial pressure, blood pH, heart rate, respiratory rate, serum sodium, serum potassium, creatinine, hematocrit, white blood cell count, Glasgow Coma Scale&#xD;
Knaus WA, Draper EA, Wagner DP, Zimmerman JE (1985). &quot;APACHE II: a severity of disease classification system&quot;. Critical Care Medicine. 13 (10): 818-29</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Sequential Organ Failure Assessment (SOFA) Score</measure>
    <time_frame>Day 1</time_frame>
    <description>The Sequential Organ Failure Assessment (SOFA) score for the patient, a score predictive of mortality in sepsis for intensive care patients based on respiratory, cardiovascular, hepatic, coagulation, renal and neurological function (each scored 0-4, with a maximum overall score of 24). The worst (most deranged) physiological values for the first 24 hours are used. A higher score predicts increased mortality. The mortality breakdown for each sofa score range is - SOFA 0-6 (&lt;10% mortality), 7-9 (15-20%), 10-12 (40-50%), 13-14 (50 - 60%), 15 (&gt; 80%), 16 to 24 (&gt; 90%)</description>
  </secondary_outcome>
  <number_of_groups>2</number_of_groups>
  <enrollment type="Actual">14</enrollment>
  <condition>Sepsis</condition>
  <condition>Septic Shock</condition>
  <condition>Sepsis Syndrome</condition>
  <condition>Severe Sepsis</condition>
  <arm_group>
    <arm_group_label>Septic</arm_group_label>
    <description>Patients admitted to the intensive care unit with a diagnosis of sepsis. For the purposes of this study, patients must have a diagnosis of sepsis; SIRS (2 of pulse &gt;90, WCC, BP, Oxygen(Dellinger et al., 2013)) with microbiological evidence of infection (positive blood culture, urine dipstick, compatible history or examination, radiographic evidence)</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Healthy volunteers</arm_group_label>
    <description>Healthy volunteers will be approached within the Department of Cardiovascular Sciences, and provided with the PIS, with consent taken by one of the investigating team.</description>
  </arm_group>
  <intervention>
    <intervention_type>Diagnostic Test</intervention_type>
    <intervention_name>Septic</intervention_name>
    <description>30mls of blood will be sampled by venepuncture, or sampled from indwelling lines (in the case of septic patients on intensive care). Blood will be sampled using standard techniques, and transferred to EDTA containing blood bottles, and undergo processing immediately.</description>
    <arm_group_label>Healthy volunteers</arm_group_label>
    <arm_group_label>Septic</arm_group_label>
    <other_name>Healthy volunteers</other_name>
  </intervention>
  <eligibility>
    <study_pop>
      <textblock>
        Healthy volunteers - Adults, staff or students at the Univesity of Leicester, with no&#xD;
        significant comorbidity Septic patients - Adult patients admitted to the adult intensive&#xD;
        care unit, Leicester Royal Infirmary, with a diagnosis of sepsis&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Non-Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  For septic patients;&#xD;
&#xD;
               1. Participant is willing and able to give informed consent for participation in the&#xD;
                  study, or if lacking capacity, a next of kin or advocate is willing and able to&#xD;
                  give assent for participation in the study. Must be able to read and understand&#xD;
                  English.&#xD;
&#xD;
               2. Male or Female, aged 18 years or above.&#xD;
&#xD;
               3. Diagnosed with sepsis and admitted to the intensive care unit.&#xD;
&#xD;
               4. Able (in the Investigators opinion) and willing to comply with all study&#xD;
                  requirements.&#xD;
&#xD;
               5. Willing to allow his or her General Practitioner and consultant, if appropriate,&#xD;
                  to be notified of participation in the study.&#xD;
&#xD;
        Healthy Volunteers;&#xD;
&#xD;
          1. Participant is willing and able to give informed consent for participation in the&#xD;
             study. Must be able to read and understand English.&#xD;
&#xD;
          2. Male or Female, aged 18 years or above and be&#xD;
&#xD;
          3. In good health.&#xD;
&#xD;
          4. Have had no course of medication, whether prescribed or over-the-counter, in the four&#xD;
             weeks before first study dose and no individual doses in the final two weeks other&#xD;
             than mild analgesia, vitamins and mineral supplements or, for females, oral&#xD;
             contraceptives&#xD;
&#xD;
          5. Able (in the Investigators opinion) and willing to comply with all study requirements.&#xD;
&#xD;
          6. Willing to allow his or her General Practitioner and consultant, if appropriate, to be&#xD;
             notified of participation in the study.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  1. Conditions which may make phlebotomy hazardous to the participant (such as&#xD;
             significant bleeding disorders or anaemia, or allergy), or to the investigator (blood&#xD;
             viral infection).&#xD;
&#xD;
             2. Any significant disease or disorder which, in the opinion of the Investigator, may&#xD;
             either put the participants at risk because of participation in the study, or may&#xD;
             influence the result of the study, or the participant's ability to participate in the&#xD;
             study.&#xD;
&#xD;
             3. Participants who have participated in another research study involving an&#xD;
             investigational product in the past 12 weeks.&#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>Christopher P Hebbes, BSc</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Leicester</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Leicester Royal Infirmary</name>
      <address>
        <city>Leicester</city>
        <state>Leicestershire</state>
        <zip>LE1 5WW</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Leicester</name>
      <address>
        <city>Leicester</city>
        <state>Leicestershire</state>
        <zip>LE2 7LX</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United Kingdom</country>
  </location_countries>
  <verification_date>April 2019</verification_date>
  <study_first_submitted>January 25, 2017</study_first_submitted>
  <study_first_submitted_qc>January 30, 2017</study_first_submitted_qc>
  <study_first_posted type="Estimate">January 31, 2017</study_first_posted>
  <results_first_submitted>September 1, 2020</results_first_submitted>
  <results_first_submitted_qc>December 10, 2020</results_first_submitted_qc>
  <results_first_posted type="Actual">January 6, 2021</results_first_posted>
  <last_update_submitted>December 10, 2020</last_update_submitted>
  <last_update_submitted_qc>December 10, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">January 6, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Sepsis</mesh_term>
    <mesh_term>Toxemia</mesh_term>
    <mesh_term>Systemic Inflammatory Response Syndrome</mesh_term>
  </condition_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>June 25, 2018</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/81/NCT03037281/Prot_SAP_000.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <group_list>
        <group group_id="P1">
          <title>Septic</title>
          <description>Patients admitted to the intensive care unit with a diagnosis of sepsis. For the purposes of this study, patients must have a diagnosis of sepsis; SIRS (2 of pulse &gt;90, WCC, BP, Oxygen(Dellinger et al., 2013)) with microbiological evidence of infection (positive blood culture, urine dipstick, compatible history or examination, radiographic evidence)&#xD;
Septic: 30mls of blood will be sampled by venepuncture, or sampled from indwelling lines (in the case of septic patients on intensive care). Blood will be sampled using standard techniques, and transferred to EDTA containing blood bottles, and undergo processing immediately.</description>
        </group>
        <group group_id="P2">
          <title>Healthy Volunteers</title>
          <description>Healthy volunteers will be approached within the Department of Cardiovascular Sciences, and provided with the PIS, with consent taken by one of the investigating team.&#xD;
Septic: 30mls of blood will be sampled by venepuncture, or sampled from indwelling lines (in the case of septic patients on intensive care). Blood will be sampled using standard techniques, and transferred to EDTA containing blood bottles, and undergo processing immediately.</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="6"/>
                <participants group_id="P2" count="8"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="6"/>
                <participants group_id="P2" count="8"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>Septic</title>
          <description>Patients admitted to the intensive care unit with a diagnosis of sepsis. For the purposes of this study, patients must have a diagnosis of sepsis; SIRS (2 of pulse &gt;90, WCC, BP, Oxygen(Dellinger et al., 2013)) with microbiological evidence of infection (positive blood culture, urine dipstick, compatible history or examination, radiographic evidence)&#xD;
Septic: 30mls of blood will be sampled by venepuncture, or sampled from indwelling lines (in the case of septic patients on intensive care). Blood will be sampled using standard techniques, and transferred to EDTA containing blood bottles, and undergo processing immediately.</description>
        </group>
        <group group_id="B2">
          <title>Healthy Volunteers</title>
          <description>Healthy volunteers will be approached within the Department of Cardiovascular Sciences, and provided with the PIS, with consent taken by one of the investigating team.&#xD;
Septic: 30mls of blood will be sampled by venepuncture, or sampled from indwelling lines (in the case of septic patients on intensive care). Blood will be sampled using standard techniques, and transferred to EDTA containing blood bottles, and undergo processing immediately.</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="6"/>
            <count group_id="B2" value="8"/>
            <count group_id="B3" value="14"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="6"/>
                    <count group_id="B2" value="8"/>
                    <count group_id="B3" value="14"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <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="1"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="1"/>
                  </measurement_list>
                </category>
                <category>
                  <title>&gt;=65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="5"/>
                    <measurement group_id="B2" value="8"/>
                    <measurement group_id="B3" value="13"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Age</title>
          <units>years</units>
          <param>Mean</param>
          <dispersion>Full Range</dispersion>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="6"/>
                    <count group_id="B2" value="8"/>
                    <count group_id="B3" value="14"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="75.5" lower_limit="55" upper_limit="85"/>
                    <measurement group_id="B2" value="34.5" lower_limit="26" upper_limit="47"/>
                    <measurement group_id="B3" value="52" lower_limit="26" upper_limit="85"/>
                  </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>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="6"/>
                    <count group_id="B2" value="8"/>
                    <count group_id="B3" value="14"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <title>Female</title>
                  <measurement_list>
                    <measurement group_id="B1" value="3"/>
                    <measurement group_id="B2" value="6"/>
                    <measurement group_id="B3" value="9"/>
                  </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>Race and Ethnicity Not Collected</title>
          <population>Race and Ethnicity were not collected from any participant.</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="0"/>
                    <count group_id="B2" value="0"/>
                    <count group_id="B3" value="0"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <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>Number</param>
          <class_list>
            <class>
              <title>United Kingdom</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="6"/>
                    <count group_id="B2" value="8"/>
                    <count group_id="B3" value="14"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="6"/>
                    <measurement group_id="B2" value="8"/>
                    <measurement group_id="B3" value="14"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Proportion of Responsive Biosensor Cells Responding to Granulocyte Addition in the Presence and Absence of NOP Antagonist</title>
        <description>Measure of N/OFQ presence in granulocytes and associated supernatant</description>
        <time_frame>Day 1</time_frame>
        <population>Biosensor cells</population>
        <group_list>
          <group group_id="O1">
            <title>Septic</title>
            <description>Patients admitted to the intensive care unit with a diagnosis of sepsis. For the purposes of this study, patients must have a diagnosis of sepsis; SIRS (2 of pulse &gt;90, WCC, BP, Oxygen(Dellinger et al., 2013)) with microbiological evidence of infection (positive blood culture, urine dipstick, compatible history or examination, radiographic evidence)&#xD;
Septic: 30mls of blood will be sampled by venepuncture, or sampled from indwelling lines (in the case of septic patients on intensive care). Blood will be sampled using standard techniques, and transferred to EDTA containing blood bottles, and undergo processing immediately.</description>
          </group>
          <group group_id="O2">
            <title>Septic (+NOP Antagonist SB612111)</title>
            <description>Cells harvested from patients with sepsis, treated in an environment containing the NOP antagonist SB612111</description>
          </group>
          <group group_id="O3">
            <title>Septic (N/OFQ Control)</title>
            <description>Control treatment of biosensor cells with N/OFQ as a control</description>
          </group>
          <group group_id="O4">
            <title>Healthy Volunteers</title>
            <description>Healthy volunteers will be approached within the Department of Cardiovascular Sciences, and provided with the PIS, with consent taken by one of the investigating team.&#xD;
Septic: 30mls of blood will be sampled by venepuncture, or sampled from indwelling lines (in the case of septic patients on intensive care). Blood will be sampled using standard techniques, and transferred to EDTA containing blood bottles, and undergo processing immediately.</description>
          </group>
          <group group_id="O5">
            <title>Healthy Volunteers (+NOP Antagonist SB612111)</title>
            <description>Cells harvested from healthy volunteers in an environment containing the NOP antagonist SB612111</description>
          </group>
          <group group_id="O6">
            <title>Healthy Volunteers (N/OFQ Control)</title>
            <description>Cells taken from healthy volunteers treated with N/OFQ as a control</description>
          </group>
        </group_list>
        <measure>
          <title>Proportion of Responsive Biosensor Cells Responding to Granulocyte Addition in the Presence and Absence of NOP Antagonist</title>
          <description>Measure of N/OFQ presence in granulocytes and associated supernatant</description>
          <population>Biosensor cells</population>
          <units>mean % responsive biosensor cells</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <units_analyzed>Biosensor cells</units_analyzed>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="6"/>
                <count group_id="O2" value="6"/>
                <count group_id="O3" value="6"/>
                <count group_id="O4" value="8"/>
                <count group_id="O5" value="8"/>
                <count group_id="O6" value="8"/>
              </count_list>
            </analyzed>
            <analyzed>
              <units>Biosensor cells</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="138"/>
                <count group_id="O2" value="40"/>
                <count group_id="O3" value="258"/>
                <count group_id="O4" value="210"/>
                <count group_id="O5" value="184"/>
                <count group_id="O6" value="410"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Eosinophils</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="34.25907426" spread="26.36477836"/>
                    <measurement group_id="O2" value="5.882352941" spread="NA">Insufficient number of responsive cells as a fraction of overall number of cells extracted to allow SD to be calculated.</measurement>
                    <measurement group_id="O3" value="44.17193917" spread="30.09734468"/>
                    <measurement group_id="O4" value="25.13095238" spread="31.52494693"/>
                    <measurement group_id="O5" value="17.86976912" spread="14.33561565"/>
                    <measurement group_id="O6" value="39.97303622" spread="32.13672569"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Neutrophils</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="25.73232323" spread="25.95276607"/>
                    <measurement group_id="O2" value="8.712121212" spread="0.535686955"/>
                    <measurement group_id="O3" value="48.66792929" spread="37.86453531"/>
                    <measurement group_id="O4" value="32.34442641" spread="22.5667298"/>
                    <measurement group_id="O5" value="12.87518038" spread="20.00326171"/>
                    <measurement group_id="O6" value="17.06777597" spread="15.88672067"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Granulocyte Count</title>
        <description>Count of the number of neutrophils in the original sample</description>
        <time_frame>Day 1</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Septic</title>
            <description>Patients admitted to the intensive care unit with a diagnosis of sepsis. For the purposes of this study, patients must have a diagnosis of sepsis; SIRS (2 of pulse &gt;90, WCC, BP, Oxygen(Dellinger et al., 2013)) with microbiological evidence of infection (positive blood culture, urine dipstick, compatible history or examination, radiographic evidence)&#xD;
Septic: 30mls of blood will be sampled by venepuncture, or sampled from indwelling lines (in the case of septic patients on intensive care). Blood will be sampled using standard techniques, and transferred to EDTA containing blood bottles, and undergo processing immediately.</description>
          </group>
          <group group_id="O2">
            <title>Healthy Volunteers</title>
            <description>Healthy volunteers will be approached within the Department of Cardiovascular Sciences, and provided with the PIS, with consent taken by one of the investigating team.&#xD;
Septic: 30mls of blood will be sampled by venepuncture, or sampled from indwelling lines (in the case of septic patients on intensive care). Blood will be sampled using standard techniques, and transferred to EDTA containing blood bottles, and undergo processing immediately.</description>
          </group>
        </group_list>
        <measure>
          <title>Granulocyte Count</title>
          <description>Count of the number of neutrophils in the original sample</description>
          <units>x10^7 cells ml-1</units>
          <param>Mean</param>
          <dispersion>Full Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="6"/>
                <count group_id="O2" value="8"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Neutrophils</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="5.07" lower_limit="3.33" upper_limit="6.4"/>
                    <measurement group_id="O2" value="2.05" lower_limit="0.94" upper_limit="3.4"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Eosinophils</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.98" lower_limit="0.4" upper_limit="1.9"/>
                    <measurement group_id="O2" value="1.61" lower_limit="0.53" upper_limit="2.44"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Mortality In-hospital, at 30 Days</title>
        <description>All cause mortality at 30 days</description>
        <time_frame>30 days</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Septic</title>
            <description>Patients admitted to the intensive care unit with a diagnosis of sepsis. For the purposes of this study, patients must have a diagnosis of sepsis; SIRS (2 of pulse &gt;90, WCC, BP, Oxygen(Dellinger et al., 2013)) with microbiological evidence of infection (positive blood culture, urine dipstick, compatible history or examination, radiographic evidence)&#xD;
Septic: 30mls of blood will be sampled by venepuncture, or sampled from indwelling lines (in the case of septic patients on intensive care). Blood will be sampled using standard techniques, and transferred to EDTA containing blood bottles, and undergo processing immediately.</description>
          </group>
          <group group_id="O2">
            <title>Healthy Volunteers</title>
            <description>Healthy volunteers will be approached within the Department of Cardiovascular Sciences, and provided with the PIS, with consent taken by one of the investigating team.&#xD;
Septic: 30mls of blood will be sampled by venepuncture, or sampled from indwelling lines (in the case of septic patients on intensive care). Blood will be sampled using standard techniques, and transferred to EDTA containing blood bottles, and undergo processing immediately.</description>
          </group>
        </group_list>
        <measure>
          <title>Mortality In-hospital, at 30 Days</title>
          <description>All cause mortality at 30 days</description>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="6"/>
                <count group_id="O2" value="8"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="3"/>
                    <measurement group_id="O2" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Time to ICU Discharge (or Death if on ICU)</title>
        <time_frame>Time to ICU discharge (or death if on ICU)</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Septic</title>
            <description>Patients admitted to the intensive care unit with a diagnosis of sepsis. For the purposes of this study, patients must have a diagnosis of sepsis; SIRS (2 of pulse &gt;90, WCC, BP, Oxygen(Dellinger et al., 2013)) with microbiological evidence of infection (positive blood culture, urine dipstick, compatible history or examination, radiographic evidence)&#xD;
Septic: 30mls of blood will be sampled by venepuncture, or sampled from indwelling lines (in the case of septic patients on intensive care). Blood will be sampled using standard techniques, and transferred to EDTA containing blood bottles, and undergo processing immediately.</description>
          </group>
        </group_list>
        <measure>
          <title>Time to ICU Discharge (or Death if on ICU)</title>
          <units>days</units>
          <param>Median</param>
          <dispersion>Full Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="4"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="7.5" lower_limit="3" upper_limit="24"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Time to Death or Discharge</title>
        <description>Time to death or discharge (days)</description>
        <time_frame>Number of days between admission and death or discharge from hospital</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Septic</title>
            <description>Patients admitted to the intensive care unit with a diagnosis of sepsis. For the purposes of this study, patients must have a diagnosis of sepsis; SIRS (2 of pulse &gt;90, WCC, BP, Oxygen(Dellinger et al., 2013)) with microbiological evidence of infection (positive blood culture, urine dipstick, compatible history or examination, radiographic evidence)&#xD;
Septic: 30mls of blood will be sampled by venepuncture, or sampled from indwelling lines (in the case of septic patients on intensive care). Blood will be sampled using standard techniques, and transferred to EDTA containing blood bottles, and undergo processing immediately.</description>
          </group>
        </group_list>
        <measure>
          <title>Time to Death or Discharge</title>
          <description>Time to death or discharge (days)</description>
          <units>days</units>
          <param>Median</param>
          <dispersion>Full Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="6"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="17.5" lower_limit="3" upper_limit="59"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Acute Physiology and Chronic Health Evaluation (APACHE-2) Score</title>
        <description>The Acute Physiology and Chronic Health Evaluation (APACHE-2) score for the patient.&#xD;
APACHE 2 is an international standard,12 variable score from 0-71 reflecting disease severity in the critically unwell during the first 24 hours of illness. The score is a combined measure of illness severity (acute physiology), and background chronic health factors. Increased score represents increased predicted mortality.&#xD;
Variables recorded include AaDO2 or PaO2 (depending on FiO2), temperature, mean arterial pressure, blood pH, heart rate, respiratory rate, serum sodium, serum potassium, creatinine, hematocrit, white blood cell count, Glasgow Coma Scale&#xD;
Knaus WA, Draper EA, Wagner DP, Zimmerman JE (1985). &quot;APACHE II: a severity of disease classification system&quot;. Critical Care Medicine. 13 (10): 818-29</description>
        <time_frame>Day 1</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Septic</title>
            <description>Patients admitted to the intensive care unit with a diagnosis of sepsis. For the purposes of this study, patients must have a diagnosis of sepsis; SIRS (2 of pulse &gt;90, WCC, BP, Oxygen(Dellinger et al., 2013)) with microbiological evidence of infection (positive blood culture, urine dipstick, compatible history or examination, radiographic evidence)&#xD;
Septic: 30mls of blood will be sampled by venepuncture, or sampled from indwelling lines (in the case of septic patients on intensive care). Blood will be sampled using standard techniques, and transferred to EDTA containing blood bottles, and undergo processing immediately.</description>
          </group>
        </group_list>
        <measure>
          <title>Acute Physiology and Chronic Health Evaluation (APACHE-2) Score</title>
          <description>The Acute Physiology and Chronic Health Evaluation (APACHE-2) score for the patient.&#xD;
APACHE 2 is an international standard,12 variable score from 0-71 reflecting disease severity in the critically unwell during the first 24 hours of illness. The score is a combined measure of illness severity (acute physiology), and background chronic health factors. Increased score represents increased predicted mortality.&#xD;
Variables recorded include AaDO2 or PaO2 (depending on FiO2), temperature, mean arterial pressure, blood pH, heart rate, respiratory rate, serum sodium, serum potassium, creatinine, hematocrit, white blood cell count, Glasgow Coma Scale&#xD;
Knaus WA, Draper EA, Wagner DP, Zimmerman JE (1985). &quot;APACHE II: a severity of disease classification system&quot;. Critical Care Medicine. 13 (10): 818-29</description>
          <units>score on a scale</units>
          <param>Mean</param>
          <dispersion>Full Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="6"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="19.8" lower_limit="6" upper_limit="31"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Sequential Organ Failure Assessment (SOFA) Score</title>
        <description>The Sequential Organ Failure Assessment (SOFA) score for the patient, a score predictive of mortality in sepsis for intensive care patients based on respiratory, cardiovascular, hepatic, coagulation, renal and neurological function (each scored 0-4, with a maximum overall score of 24). The worst (most deranged) physiological values for the first 24 hours are used. A higher score predicts increased mortality. The mortality breakdown for each sofa score range is - SOFA 0-6 (&lt;10% mortality), 7-9 (15-20%), 10-12 (40-50%), 13-14 (50 - 60%), 15 (&gt; 80%), 16 to 24 (&gt; 90%)</description>
        <time_frame>Day 1</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Septic</title>
            <description>Patients admitted to the intensive care unit with a diagnosis of sepsis. For the purposes of this study, patients must have a diagnosis of sepsis; SIRS (2 of pulse &gt;90, WCC, BP, Oxygen(Dellinger et al., 2013)) with microbiological evidence of infection (positive blood culture, urine dipstick, compatible history or examination, radiographic evidence)&#xD;
Septic: 30mls of blood will be sampled by venepuncture, or sampled from indwelling lines (in the case of septic patients on intensive care). Blood will be sampled using standard techniques, and transferred to EDTA containing blood bottles, and undergo processing immediately.</description>
          </group>
        </group_list>
        <measure>
          <title>Sequential Organ Failure Assessment (SOFA) Score</title>
          <description>The Sequential Organ Failure Assessment (SOFA) score for the patient, a score predictive of mortality in sepsis for intensive care patients based on respiratory, cardiovascular, hepatic, coagulation, renal and neurological function (each scored 0-4, with a maximum overall score of 24). The worst (most deranged) physiological values for the first 24 hours are used. A higher score predicts increased mortality. The mortality breakdown for each sofa score range is - SOFA 0-6 (&lt;10% mortality), 7-9 (15-20%), 10-12 (40-50%), 13-14 (50 - 60%), 15 (&gt; 80%), 16 to 24 (&gt; 90%)</description>
          <units>score on a scale</units>
          <param>Mean</param>
          <dispersion>Full Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="6"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="9.33" lower_limit="5" upper_limit="12"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>30 days</time_frame>
      <group_list>
        <group group_id="E1">
          <title>Septic</title>
          <description>Patients admitted to the intensive care unit with a diagnosis of sepsis. For the purposes of this study, patients must have a diagnosis of sepsis; SIRS (2 of pulse &gt;90, WCC, BP, Oxygen(Dellinger et al., 2013)) with microbiological evidence of infection (positive blood culture, urine dipstick, compatible history or examination, radiographic evidence)&#xD;
Septic: 30mls of blood will be sampled by venepuncture, or sampled from indwelling lines (in the case of septic patients on intensive care). Blood will be sampled using standard techniques, and transferred to EDTA containing blood bottles, and undergo processing immediately.</description>
        </group>
        <group group_id="E2">
          <title>Healthy Volunteers</title>
          <description>Healthy volunteers will be approached within the Department of Cardiovascular Sciences, and provided with the PIS, with consent taken by one of the investigating team.&#xD;
Septic: 30mls of blood will be sampled by venepuncture, or sampled from indwelling lines (in the case of septic patients on intensive care). Blood will be sampled using standard techniques, and transferred to EDTA containing blood bottles, and undergo processing immediately.</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="3" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="8"/>
              </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="6"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="8"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>All Principal Investigators ARE 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>
    <limitations_and_caveats>Technical problems with both measurement and immunocyte extraction contributed to high variability with the assay and inconsistencies.Small numbers of subjects recruited precluded robust statistical analysis.Basophil extraction very low - not viable.</limitations_and_caveats>
    <point_of_contact>
      <name_or_title>Dr Christopher Hebbes</name_or_title>
      <organization>University of Leicester</organization>
      <phone>0116 252 2522</phone>
      <email>christopher.hebbes@le.ac.uk</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/NCT03037281
org study id: 0554
nct id: NCT03037281
lead sponsor: 
collaborator: 
collaborator: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
Nociceptin is a protein found in the body, with a number of functions in the central nervous
      system, blood vessels and the gut. There is evidence that it may have a role in controlling
      the immune response to infection, and may act as a link between the brain and immune system.

      In infection, or after surgery, there is an increase in nociceptin, and subjects greater
      elevations of nociceptin have a poorer outcome. There is evidence that cells of the immune
      system may produce nociceptin, although it is not yet known which cells are capable of
      producing it, and what "switches on" production.

      This study aims to determine

        1. Which cells of the immune system can produce nociceptin

        2. If there is a difference in the ability to produce nociceptin between healthy volunteers
           and patients with severe infections
observational model: Case-Control
time perspective: Prospective
measure: Proportion of Responsive Biosensor Cells Responding to Granulocyte Addition in the Presence and Absence of NOP Antagonist
time frame: Day 1
description: Measure of N/OFQ presence in granulocytes and associated supernatant
measure: Granulocyte Count
time frame: Day 1
description: Count of the number of neutrophils in the original sample
measure: Mortality In-hospital, at 30 Days
time frame: 30 days
description: All cause mortality at 30 days
measure: Time to ICU Discharge (or Death if on ICU)
time frame: Time to ICU discharge (or death if on ICU)
measure: Time to Death or Discharge
time frame: Number of days between admission and death or discharge from hospital
description: Time to death or discharge (days)
measure: Acute Physiology and Chronic Health Evaluation (APACHE-2) Score
time frame: Day 1
description: The Acute Physiology and Chronic Health Evaluation (APACHE-2) score for the patient.
APACHE 2 is an international standard,12 variable score from 0-71 reflecting disease severity in the critically unwell during the first 24 hours of illness. The score is a combined measure of illness severity (acute physiology), and background chronic health factors. Increased score represents increased predicted mortality.
Variables recorded include AaDO2 or PaO2 (depending on FiO2), temperature, mean arterial pressure, blood pH, heart rate, respiratory rate, serum sodium, serum potassium, creatinine, hematocrit, white blood cell count, Glasgow Coma Scale
Knaus WA, Draper EA, Wagner DP, Zimmerman JE (1985). "APACHE II: a severity of disease classification system". Critical Care Medicine. 13 (10): 818-29
measure: Sequential Organ Failure Assessment (SOFA) Score
time frame: Day 1
description: The Sequential Organ Failure Assessment (SOFA) score for the patient, a score predictive of mortality in sepsis for intensive care patients based on respiratory, cardiovascular, hepatic, coagulation, renal and neurological function (each scored 0-4, with a maximum overall score of 24). The worst (most deranged) physiological values for the first 24 hours are used. A higher score predicts increased mortality. The mortality breakdown for each sofa score range is - SOFA 0-6 (<10% mortality), 7-9 (15-20%), 10-12 (40-50%), 13-14 (50 - 60%), 15 (> 80%), 16 to 24 (> 90%)
arm group label: Septic
description: Patients admitted to the intensive care unit with a diagnosis of sepsis. For the purposes of this study, patients must have a diagnosis of sepsis; SIRS (2 of pulse >90, WCC, BP, Oxygen(Dellinger et al., 2013)) with microbiological evidence of infection (positive blood culture, urine dipstick, compatible history or examination, radiographic evidence)
arm group label: Healthy volunteers
description: Healthy volunteers will be approached within the Department of Cardiovascular Sciences, and provided with the PIS, with consent taken by one of the investigating team.
intervention type: Diagnostic Test
intervention name: Septic
description: 30mls of blood will be sampled by venepuncture, or sampled from indwelling lines (in the case of septic patients on intensive care). Blood will be sampled using standard techniques, and transferred to EDTA containing blood bottles, and undergo processing immediately.
arm group label: Healthy volunteers
arm group label: Septic
other name: Healthy volunteers
study pop: 
sampling method: Non-Probability Sample
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: Accepts Healthy Volunteers
last name: Christopher P Hebbes, BSc
role: Principal Investigator
affiliation: University of Leicester
facility: 
facility: 
country: United Kingdom
responsible party type: Sponsor
mesh term: Sepsis
mesh term: Toxemia
mesh term: Systemic Inflammatory Response Syndrome
sharing ipd: No
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
limitations and caveats: Technical problems with both measurement and immunocyte extraction contributed to high variability with the assay and inconsistencies.Small numbers of subjects recruited precluded robust statistical analysis.Basophil extraction very low - not viable.
point of contact: 