<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/NCT03295825</url>
  </required_header>
  <id_info>
    <org_study_id>PROMPT</org_study_id>
    <nct_id>NCT03295825</nct_id>
  </id_info>
  <brief_title>Heparin Binding Protein in Early Sepsis Diagnosis</brief_title>
  <acronym>PROMPT</acronym>
  <official_title>Prospective Multi-centre Clinical Study to Assess the Clinical Validity of the Heparin Binding Protein Assay to Indicate the Presence and Outcome of Sepsis in Patients With Suspected Infection Following Emergency Department Admission</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Hellenic Institute for the Study of Sepsis</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>National and Kapodistrian University of Athens</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Aristotle University Of Thessaloniki</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Hellenic Institute for the Study of Sepsis</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>
      The primary objective of this study is to use heparin-binding protein (HBP) concentration to&#xD;
      indicate the presence, or outcome, of sepsis over 72 hours after ED admission. The secondary&#xD;
      objectives of this study are to separately evaluate the performance of HBP to predict outcome&#xD;
      in patients with suspected infection over 12-24 hours after ED admission.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The purpose of this prospective, non-interventional, multi-centre clinical study is to assess&#xD;
      the clinical validity of the Heparin Binding Protein (HBP) assay for indicating the presence,&#xD;
      or outcome, of severe sepsis (including septic shock), over 72 hours, in patients with&#xD;
      suspected infection following emergency department admission.&#xD;
&#xD;
      Sepsis is an increasingly common cause of morbidity and mortality, with approximately 150,000&#xD;
      people in Europe and 215,000 people in the US dying of severe sepsis each year. Deaths&#xD;
      attributable to sepsis continue to rise due to an increase in incidence of the disease, which&#xD;
      can be attributed to numerous factors including the aging population, the increased number of&#xD;
      immuno-compromised patients, the increased use of invasive surgery and the increased&#xD;
      incidence of microbial resistance.&#xD;
&#xD;
      The sepsis syndrome was first described in the 1992 publication by Bone et al detailing the&#xD;
      conclusions of the ACCP/SCCM Consensus Conference held in 1991, which first introduced the&#xD;
      Systemic Inflammatory Response Syndrome (SIRS) classification system. Systemic Inflammatory&#xD;
      Response Syndrome (SIRS) is considered to be present when patients have 2 or more of the&#xD;
      following clinical findings:&#xD;
&#xD;
        -  body temperature, &gt;38ºC or &lt;36ºC&#xD;
&#xD;
        -  heart rate, &gt;90 beats per minute&#xD;
&#xD;
        -  respiratory rate of &gt;20 breaths per minute or a PaCO2 of &lt;32mm Hg&#xD;
&#xD;
        -  white cell count of &gt;12,000 cells per µL or &lt;4,000 per µL, or &gt;10% immature (band) forms&#xD;
           According to the suggested definitions, sepsis is defined as SIRS plus confirmed&#xD;
           infection, severe sepsis is defined as sepsis associated with organ dysfunction,&#xD;
           hypoperfusion, or hypotension and septic shock is defined as sepsis-induced hypotension,&#xD;
           persisting despite adequate fluid resuscitation.&#xD;
&#xD;
      Diagnosis of sepsis traditionally relies on identification of the above symptoms, as well as&#xD;
      culturing techniques to confirm and identify the infection. This method of diagnosis is,&#xD;
      however, far from ideal as it has been demonstrated that SIRS criteria are poorly predictive&#xD;
      of subsequent events in the sepsis cascade and that approximately one half of severe sepsis&#xD;
      cases are culture negative. In addition, the assay time for culture-based diagnosis is 24 to&#xD;
      48 hours, where it has been shown that diagnosis of severe sepsis and septic shock as early&#xD;
      as possible is important, as each hour of delay in effective antimicrobial administration is&#xD;
      associated with an average decrease in survival of 7.6%. Although the majority of severe&#xD;
      sepsis patients receive treatment in an intensive care unit (ICU), it is estimated that up to&#xD;
      two thirds of those patients initially present to the emergency department (ED), and that&#xD;
      approximately 20% of patients with confirmed infection who present to the ED with&#xD;
      uncomplicated sepsis progress to severe sepsis or septic shock within 72 hours.&#xD;
&#xD;
      This high incidence of early progression to severe sepsis and septic shock among patients&#xD;
      presenting to the ED highlights the time-sensitive nature of diagnosis, especially in&#xD;
      patients who initially do not appear critically ill. Therefore early intervention to prevent&#xD;
      subsequent or worsening clinical deterioration is key to the successful treatment of&#xD;
      patients. However, two major impediments to the effectiveness of sepsis treatment strategies&#xD;
      are a failure to recognise the early stages of the disease and underestimation of its&#xD;
      severity, as it is difficult to determine which of the patients with signs of infection on&#xD;
      initial evaluation have, or will develop, more serious illness. Several outcome prediction&#xD;
      models, including Acute Physiology and Chronic Health Evaluation (APACHE) IV, the Simplified&#xD;
      Acute Physiology Score (SAPS) III, the Logistic Organ Dysfunction Score (LODS), and the&#xD;
      Mortality Probability Model (MPM) III have therefore been developed for use in clinical&#xD;
      practice. Moreover patients admitted in the ED with at least two of three clinical signs&#xD;
      (hypotension, tachypnea, altered mental status) are highly possible to suffer from sepsis.&#xD;
      These three clinical signs are the qSOFA score. Data from the Hellenic Sepsis Study Group put&#xD;
      into question if the qSOFA score can predict sepsis in the ED with sensitivity that exceeds&#xD;
      65% (15, 16). There is, therefore, still an unmet need for a diagnostic tool that can&#xD;
      identify those patients at risk of developing more severe disease, and although a number of&#xD;
      laboratory measures or novel sepsis biomarkers have been proposed for clinical use, there is&#xD;
      currently no single accepted biomarker or combination of biomarkers for use in patients with&#xD;
      suspected sepsis.&#xD;
&#xD;
      The recent publication by Linder et al(17) has shown that measurement of heparin binding&#xD;
      protein (HBP), also known as azurocidin or CAP37, in febrile patients presenting to the ED&#xD;
      shows a close correlation between increased plasma HBP levels and the development of severe&#xD;
      sepsis with hypotension or shock. In this prospective study of 233 febrile adult patients&#xD;
      with suspected infection, 26 were diagnosed with severe sepsis with septic shock, 44 with&#xD;
      severe sepsis without septic shock, 100 with sepsis, 43 with infection without SIRS and 20&#xD;
      with SIRS without infection. Using a cut-off of 15ng/mL, HBP showed a sensitivity in&#xD;
      diagnosing severe sepsis (with or without septic shock) of 87.1%, a specificity of 95.1%, a&#xD;
      positive predictive value (PPV) of 88.4% and a negative predictive value (NPV) of 94.5%,&#xD;
      which exceeded those values obtained for the other tested markers. Receiver-operating&#xD;
      characteristic (ROC) curves also demonstrated that HBP was the best predictor of severe&#xD;
      sepsis, with an area under the curve (AUC) value of 0.95. It is therefore hypothesised that&#xD;
      HBP may be used for the early identification of patients at risk of developing severe sepsis&#xD;
      and septic shock. In addition, it was observed that 20 of the patients with severe sepsis&#xD;
      were monitored with serial plasma sample collection during the course of the disease, and&#xD;
      that the 18 of these patients who survived had HBP levels that decreased rapidly when the&#xD;
      clinical signs improved and the blood pressures were normalised. It is therefore further&#xD;
      hypothesised that a decrease in HBP levels may be used to predict survival.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">September 22, 2017</start_date>
  <completion_date type="Actual">September 30, 2018</completion_date>
  <primary_completion_date type="Actual">June 30, 2018</primary_completion_date>
  <phase>N/A</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Diagnostic</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>ΗΒΡ for sepsis diagnosis</measure>
    <time_frame>72 hours</time_frame>
    <description>Sensitivity of ΗΒΡ for sepsis diagnosis. Every value over 90% is considered satisfactory.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Diagnostic performance of HBP for sepsis</measure>
    <time_frame>72 hours</time_frame>
    <description>Specificity, positive predictive value and negative predictive value of HBP to diagnose sepsis</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Diagnostic performance of HBP for septic shock</measure>
    <time_frame>72 hours</time_frame>
    <description>Specificity, positive predictive value and negative predictive value of HBP to diagnose septic shock</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Diagnostic performance of HBP for early death</measure>
    <time_frame>72 hours</time_frame>
    <description>Sensitivity, specificity, positive predictive value and negative predictive value of HBP to predict unfavorable outcome</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Diagnostic performance of HBP for death</measure>
    <time_frame>28 days</time_frame>
    <description>Sensitivity, specificity, positive predictive value and negative predictive value of HBP to predict unfavorable outcome</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">400</enrollment>
  <condition>Sepsis</condition>
  <condition>Infection</condition>
  <arm_group>
    <arm_group_label>Biomarker</arm_group_label>
    <arm_group_type>Other</arm_group_type>
    <description>Blood sampling</description>
  </arm_group>
  <intervention>
    <intervention_type>Diagnostic Test</intervention_type>
    <intervention_name>Biomarker</intervention_name>
    <description>Measument of heparin-binding protein in the serum of patients</description>
    <arm_group_label>Biomarker</arm_group_label>
    <other_name>Heparin Binding Protein</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Age ≥18 years&#xD;
&#xD;
          -  Male or female&#xD;
&#xD;
          -  Written informed consent&#xD;
&#xD;
          -  Suspected infection&#xD;
&#xD;
          -  Presence of at least ONE of the following:&#xD;
&#xD;
        Temperature &gt; 38°C Temperature &lt; 36°C Heart rate &gt; 90 bpm Respiratory rate &gt; 20/min Self&#xD;
        reported fever/chills&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  None&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Evangelos Giamarellos-Bourboulis, MD, PhD</last_name>
    <role>Study Chair</role>
    <affiliation>National and Kapodistrian University of Athens</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Nafplion General Hospital</name>
      <address>
        <city>Náfplio</city>
        <state>Argos</state>
        <zip>21100</zip>
        <country>Greece</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>4th Department of Internal Medicine, ATTIKON University Hospital</name>
      <address>
        <city>Athens</city>
        <state>Attiki</state>
        <zip>12462</zip>
        <country>Greece</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Department of Internal Medicine, Chalkida General Hospital</name>
      <address>
        <city>Chalkida</city>
        <zip>34100</zip>
        <country>Greece</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Department of Internal Medicine, Siros General Hospital</name>
      <address>
        <city>Ermoupolis</city>
        <zip>84100</zip>
        <country>Greece</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Department of Internal Medicine, Sparti General Hospital</name>
      <address>
        <city>Sparti</city>
        <zip>23100</zip>
        <country>Greece</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>2nd Department of Surgery, G.Gennimatas Thessaloniki General Hospital</name>
      <address>
        <city>Thessaloníki</city>
        <zip>54635</zip>
        <country>Greece</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Greece</country>
  </location_countries>
  <reference>
    <citation>Linder A, Christensson B, Herwald H, Bjorck L, Akesson P. Heparin-binding protein: an early marker of circulatory failure in sepsis. Clin Infect Dis. 2009 Oct 1;49(7):1044-50. doi: 10.1086/605563.</citation>
    <PMID>19725785</PMID>
  </reference>
  <verification_date>October 2018</verification_date>
  <study_first_submitted>September 22, 2017</study_first_submitted>
  <study_first_submitted_qc>September 25, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">September 28, 2017</study_first_posted>
  <last_update_submitted>October 20, 2018</last_update_submitted>
  <last_update_submitted_qc>October 20, 2018</last_update_submitted_qc>
  <last_update_posted type="Actual">October 23, 2018</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Heparin binding protein</keyword>
  <keyword>Mortality</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Infections</mesh_term>
    <mesh_term>Sepsis</mesh_term>
    <mesh_term>Toxemia</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Heparin</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03295825
org study id: PROMPT
nct id: NCT03295825
lead sponsor: 
collaborator: 
collaborator: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
The primary objective of this study is to use heparin-binding protein (HBP) concentration to
      indicate the presence, or outcome, of sepsis over 72 hours after ED admission. The secondary
      objectives of this study are to separately evaluate the performance of HBP to predict outcome
      in patients with suspected infection over 12-24 hours after ED admission.
The purpose of this prospective, non-interventional, multi-centre clinical study is to assess
      the clinical validity of the Heparin Binding Protein (HBP) assay for indicating the presence,
      or outcome, of severe sepsis (including septic shock), over 72 hours, in patients with
      suspected infection following emergency department admission.

      Sepsis is an increasingly common cause of morbidity and mortality, with approximately 150,000
      people in Europe and 215,000 people in the US dying of severe sepsis each year. Deaths
      attributable to sepsis continue to rise due to an increase in incidence of the disease, which
      can be attributed to numerous factors including the aging population, the increased number of
      immuno-compromised patients, the increased use of invasive surgery and the increased
      incidence of microbial resistance.

      The sepsis syndrome was first described in the 1992 publication by Bone et al detailing the
      conclusions of the ACCP/SCCM Consensus Conference held in 1991, which first introduced the
      Systemic Inflammatory Response Syndrome (SIRS) classification system. Systemic Inflammatory
      Response Syndrome (SIRS) is considered to be present when patients have 2 or more of the
      following clinical findings:

        -  body temperature, >38ºC or <36ºC

        -  heart rate, >90 beats per minute

        -  respiratory rate of >20 breaths per minute or a PaCO2 of <32mm Hg

        -  white cell count of >12,000 cells per µL or <4,000 per µL, or >10% immature (band) forms
           According to the suggested definitions, sepsis is defined as SIRS plus confirmed
           infection, severe sepsis is defined as sepsis associated with organ dysfunction,
           hypoperfusion, or hypotension and septic shock is defined as sepsis-induced hypotension,
           persisting despite adequate fluid resuscitation.

      Diagnosis of sepsis traditionally relies on identification of the above symptoms, as well as
      culturing techniques to confirm and identify the infection. This method of diagnosis is,
      however, far from ideal as it has been demonstrated that SIRS criteria are poorly predictive
      of subsequent events in the sepsis cascade and that approximately one half of severe sepsis
      cases are culture negative. In addition, the assay time for culture-based diagnosis is 24 to
      48 hours, where it has been shown that diagnosis of severe sepsis and septic shock as early
      as possible is important, as each hour of delay in effective antimicrobial administration is
      associated with an average decrease in survival of 7.6%. Although the majority of severe
      sepsis patients receive treatment in an intensive care unit (ICU), it is estimated that up to
      two thirds of those patients initially present to the emergency department (ED), and that
      approximately 20% of patients with confirmed infection who present to the ED with
      uncomplicated sepsis progress to severe sepsis or septic shock within 72 hours.

      This high incidence of early progression to severe sepsis and septic shock among patients
      presenting to the ED highlights the time-sensitive nature of diagnosis, especially in
      patients who initially do not appear critically ill. Therefore early intervention to prevent
      subsequent or worsening clinical deterioration is key to the successful treatment of
      patients. However, two major impediments to the effectiveness of sepsis treatment strategies
      are a failure to recognise the early stages of the disease and underestimation of its
      severity, as it is difficult to determine which of the patients with signs of infection on
      initial evaluation have, or will develop, more serious illness. Several outcome prediction
      models, including Acute Physiology and Chronic Health Evaluation (APACHE) IV, the Simplified
      Acute Physiology Score (SAPS) III, the Logistic Organ Dysfunction Score (LODS), and the
      Mortality Probability Model (MPM) III have therefore been developed for use in clinical
      practice. Moreover patients admitted in the ED with at least two of three clinical signs
      (hypotension, tachypnea, altered mental status) are highly possible to suffer from sepsis.
      These three clinical signs are the qSOFA score. Data from the Hellenic Sepsis Study Group put
      into question if the qSOFA score can predict sepsis in the ED with sensitivity that exceeds
      65% (15, 16). There is, therefore, still an unmet need for a diagnostic tool that can
      identify those patients at risk of developing more severe disease, and although a number of
      laboratory measures or novel sepsis biomarkers have been proposed for clinical use, there is
      currently no single accepted biomarker or combination of biomarkers for use in patients with
      suspected sepsis.

      The recent publication by Linder et al(17) has shown that measurement of heparin binding
      protein (HBP), also known as azurocidin or CAP37, in febrile patients presenting to the ED
      shows a close correlation between increased plasma HBP levels and the development of severe
      sepsis with hypotension or shock. In this prospective study of 233 febrile adult patients
      with suspected infection, 26 were diagnosed with severe sepsis with septic shock, 44 with
      severe sepsis without septic shock, 100 with sepsis, 43 with infection without SIRS and 20
      with SIRS without infection. Using a cut-off of 15ng/mL, HBP showed a sensitivity in
      diagnosing severe sepsis (with or without septic shock) of 87.1%, a specificity of 95.1%, a
      positive predictive value (PPV) of 88.4% and a negative predictive value (NPV) of 94.5%,
      which exceeded those values obtained for the other tested markers. Receiver-operating
      characteristic (ROC) curves also demonstrated that HBP was the best predictor of severe
      sepsis, with an area under the curve (AUC) value of 0.95. It is therefore hypothesised that
      HBP may be used for the early identification of patients at risk of developing severe sepsis
      and septic shock. In addition, it was observed that 20 of the patients with severe sepsis
      were monitored with serial plasma sample collection during the course of the disease, and
      that the 18 of these patients who survived had HBP levels that decreased rapidly when the
      clinical signs improved and the blood pressures were normalised. It is therefore further
      hypothesised that a decrease in HBP levels may be used to predict survival.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Diagnostic
masking: None (Open Label)
measure: ΗΒΡ for sepsis diagnosis
time frame: 72 hours
description: Sensitivity of ΗΒΡ for sepsis diagnosis. Every value over 90% is considered satisfactory.
measure: Diagnostic performance of HBP for sepsis
time frame: 72 hours
description: Specificity, positive predictive value and negative predictive value of HBP to diagnose sepsis
measure: Diagnostic performance of HBP for septic shock
time frame: 72 hours
description: Specificity, positive predictive value and negative predictive value of HBP to diagnose septic shock
measure: Diagnostic performance of HBP for early death
time frame: 72 hours
description: Sensitivity, specificity, positive predictive value and negative predictive value of HBP to predict unfavorable outcome
measure: Diagnostic performance of HBP for death
time frame: 28 days
description: Sensitivity, specificity, positive predictive value and negative predictive value of HBP to predict unfavorable outcome
arm group label: Biomarker
arm group type: Other
description: Blood sampling
intervention type: Diagnostic Test
intervention name: Biomarker
description: Measument of heparin-binding protein in the serum of patients
arm group label: Biomarker
other name: Heparin Binding Protein
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Evangelos Giamarellos-Bourboulis, MD, PhD
role: Study Chair
affiliation: National and Kapodistrian University of Athens
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
country: Greece
citation: Linder A, Christensson B, Herwald H, Bjorck L, Akesson P. Heparin-binding protein: an early marker of circulatory failure in sepsis. Clin Infect Dis. 2009 Oct 1;49(7):1044-50. doi: 10.1086/605563.
PMID: 19725785
responsible party type: Sponsor
mesh term: Infections
mesh term: Sepsis
mesh term: Toxemia
mesh term: Heparin
sharing ipd: No