<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/NCT03010410</url>
  </required_header>
  <id_info>
    <org_study_id>1040298</org_study_id>
    <nct_id>NCT03010410</nct_id>
  </id_info>
  <brief_title>Platelet Immune Responses in Aging and Influenza and Sepsis (INVACS)</brief_title>
  <official_title>Platelet Immune Responses in Aging and Influenza and Sepsis (INVACS)</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Intermountain Health Care, Inc.</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>University of Utah</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Intermountain Health Care, Inc.</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Aging is associated with immunosenescence and impaired host defense mechanisms, contributing&#xD;
      to influenza-related morbidity and mortality. Preliminary data demonstrate that the platelet&#xD;
      transcriptome is markedly different between healthy subjects and influenza patients.&#xD;
      Interferon-induced transmembrane proteins (IFITM) family members are among the transcripts&#xD;
      significantly increased in platelets during influenza and expression of IFITM-3 is impaired&#xD;
      in elderly subjects, a pattern associated with increased mortality. This study will build on&#xD;
      these data and investigate if aging influences the expression of platelet IFITM family&#xD;
      members in patients with influenza and sepsis.&#xD;
&#xD;
      This study will prospectively determine if aging alters the induction of (IFITMs) in&#xD;
      platelets from hospitalized influenza and sepsis patients. The study will also determine if&#xD;
      diminished expression of IFITM family members correlates with an increased risk of adverse&#xD;
      outcomes in older influenza and sepsis patients.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This will be a prospective observational cohort study comparing older (age≥65) and younger&#xD;
      (age&lt;65) influenza and sepsis patients.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Enrolling by invitation</last_known_status>
  <start_date type="Actual">December 21, 2014</start_date>
  <completion_date type="Anticipated">December 2019</completion_date>
  <primary_completion_date type="Anticipated">October 2019</primary_completion_date>
  <study_type>Observational</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <observational_model>Cohort</observational_model>
    <time_perspective>Prospective</time_perspective>
  </study_design_info>
  <primary_outcome>
    <measure>90 day mortality</measure>
    <time_frame>90 days</time_frame>
    <description>For the increased risk of mortality outcome, 90-day mortality will be the primary outcome variable. This will be modeled using mixed effects logistic regression, using days 0, 3, and 7 as repeated measurements. In this fashion, IFITM-3 and mortality are time-varying. A separate model will be fitted for the younger and older groups, since age group is expected to be collinear with IFITM-3 protein.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>28 day mortality</measure>
    <time_frame>28 days</time_frame>
    <description>The same sample of influenza patients will be used for mortality analysis. Based on published and unpublished data, 28-day mortality in critically-ill influenza patients admitted to ICUs ranges from 10-40%, even during non-pandemic periods. Based on these estimates, our sample size (n=75 younger and n=75 older) provides 84% power (two-sided alpha 0.05 comparison) to detect a difference in incidence of 29% and 9%, which is a conservative estimate of the difference between the younger and older groups.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Interferon-induced transmembrane protein expression in platelets</measure>
    <time_frame>24(±12) hours of diagnosis (day 0 or 1), day 3, 5, and 90</time_frame>
    <description>Recent evidence also demonstrates that IFITM-3 acts as a membrane organizer by facilitating clathrin-mediated endocytosis (CME). This membrane-organizing process allows cells to internalize molecules and viruses. CME regulates platelet membrane organization. IFITM-3 is demonstrated as necessary for host defenses against influenza virus. Moreover, with absent or reduced levels of IFITM-3, cells do not effectively restrict viral replication, an impaired response that may influence adverse clinical outcomes.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>IFITM-3 mRNA</measure>
    <time_frame>24(±12) hours of diagnosis (day 0 or 1), day 3, 5, and 90.</time_frame>
    <description>Platelet IFITM-3 protein levels have been seen to be increased in influenza patients and correlated with IFITM-3 mRNA (r2=0.33, p&lt;0.005). However, in hospitalized influenza patients, platelet IFITM-3 mRNA and protein expression was decreased in older, compared to young patients.&#xD;
It is hypothesized that influenza will induce expression of IFITM family members in platelets; IFITM's expression will be reduced in older compared to young influenza patients. This hypothesis will be tested to determine whether or not influenza induces IFITM-3 expression in human platelets and compare older and young subjects. Here, an outcome of IFITM-3 protein will be tracked in conjunction with mRNA.</description>
  </secondary_outcome>
  <number_of_groups>4</number_of_groups>
  <enrollment type="Anticipated">150</enrollment>
  <condition>Sepsis</condition>
  <condition>Influenza</condition>
  <arm_group>
    <arm_group_label>Influenza/respiratory virus pts &lt;65 yrs</arm_group_label>
    <description>Patients with a primary microbiologic diagnosis of influenza (any strain) or other routinely clinically identified respiratory viruses</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Influenza/respiratory virus pts ≥ 65 yrs</arm_group_label>
    <description>Patients with a primary microbiologic diagnosis of influenza (any strain) or other routinely clinically identified respiratory viruses</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Sepsis/septic shock patients &lt; 65 yrs</arm_group_label>
    <description>Sepsis and septic shock patients</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Sepsis/septic shock patients ≥ 65 yrs</arm_group_label>
    <description>sepsis and septic shock patients</description>
  </arm_group>
  <biospec_retention>Samples With DNA</biospec_retention>
  <biospec_descr>
    <textblock>
      The study will bank remaining platelet lysates for future assays.&#xD;
    </textblock>
  </biospec_descr>
  <eligibility>
    <study_pop>
      <textblock>
        This will be a prospective observational cohort study comparing older (age≥65) and younger&#xD;
        (age&lt;65) influenza and sepsis patients.&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Non-Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  ≥18 years old at the time of enrollment&#xD;
&#xD;
          -  Meet one of the following three main criteria:&#xD;
&#xD;
        A. INFLUENZA (AND OTHER RESPIRATORY VIRUS) PATIENTS:&#xD;
&#xD;
        Patients admitted to the intensive care unit (ICU) with a primary microbiologic diagnosis&#xD;
        of influenza (any strain) or other routinely clinically identified respiratory viruses&#xD;
        within 1 week of symptom onset. Influenza or other respiratory virus will be diagnosed&#xD;
        using an RT-PCR viral panel on a respiratory tract specimen, as is currently standard of&#xD;
        care on patients admitted to the ICUs at IMC with respiratory symptoms.&#xD;
&#xD;
        OR&#xD;
&#xD;
        B. SEPSIS PATIENTS:&#xD;
&#xD;
        Sepsis patients must have&#xD;
&#xD;
          1. Suspected or confirmed infection&#xD;
&#xD;
             AND&#xD;
&#xD;
          2. Organ dysfunction as defined by a SOFA &gt;= 2 above baseline (if no baseline data&#xD;
             available, SOFA assumed to be 0)&#xD;
&#xD;
        OR&#xD;
&#xD;
        C. SEPTIC SHOCK PATIENTS:&#xD;
&#xD;
        AFTER INFUSION OF 20ML/KG CRYSTALLOID OR EQUIVALENT, Septic shock patients must have&#xD;
&#xD;
          1. Suspected or confirmed infection&#xD;
&#xD;
             AND&#xD;
&#xD;
          2. Lactate &gt; 2 mmol/L&#xD;
&#xD;
             AND&#xD;
&#xD;
          3. Receiving vasopressors&#xD;
&#xD;
               -  All patients must be enrolled into the study within 72 hours of ICU admission&#xD;
&#xD;
        Exclusion criteria&#xD;
&#xD;
          -  Have a congenital or acquired immunodeficiency disorder (e.g., chronic variable immune&#xD;
             deficiency, agammaglobulinemia, hypogammaglobulinemia, leukocyte adhesion defects, IgA&#xD;
             deficiency, etc.)&#xD;
&#xD;
          -  Have neutropenia (&lt;1,000/mm3)&#xD;
&#xD;
          -  Have received immunosuppressant medications within the previous 30 days (e.g.,&#xD;
             prednisone or prednisone equivalent at a dose≥10mg daily for ≥14 days or any&#xD;
             cyclosporine, TNF-alpha antagonists, tacrolimus, sirolimus, interferons,&#xD;
             mycophenolate, biological agents, methotrexate, azathioprine, polyclonal/monoclonal&#xD;
             antibodies, etc.)&#xD;
&#xD;
          -  Have any history of bone marrow or organ transplantation&#xD;
&#xD;
          -  Have an active malignancy (not including non-melanoma skin cancer or localized&#xD;
             prostate cancer), or have received chemotherapy drugs within the last 6 months.&#xD;
&#xD;
          -  Have been admitted to the ICU for greater than 72 hours&#xD;
&#xD;
          -  Have a Hemoglobin level &lt;7gm/dl&#xD;
&#xD;
          -  Have clinically significant bleeding&#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>Samuel M Brown, MD MS</last_name>
    <role>Principal Investigator</role>
    <affiliation>Intermountain Health Care, Inc.</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Intermountain Medical Center</name>
      <address>
        <city>Murray</city>
        <state>Utah</state>
        <zip>84107</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>August 2019</verification_date>
  <study_first_submitted>January 3, 2017</study_first_submitted>
  <study_first_submitted_qc>January 3, 2017</study_first_submitted_qc>
  <study_first_posted type="Estimate">January 5, 2017</study_first_posted>
  <last_update_submitted>August 9, 2019</last_update_submitted>
  <last_update_submitted_qc>August 9, 2019</last_update_submitted_qc>
  <last_update_posted type="Actual">August 13, 2019</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Intermountain Health Care, Inc.</investigator_affiliation>
    <investigator_full_name>Samuel Brown</investigator_full_name>
    <investigator_title>Director, Center for Humanizing Critical Care</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Influenza, Human</mesh_term>
    <mesh_term>Sepsis</mesh_term>
    <mesh_term>Toxemia</mesh_term>
  </condition_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/NCT03010410
org study id: 1040298
nct id: NCT03010410
lead sponsor: 
collaborator: 
has dmc: No
Aging is associated with immunosenescence and impaired host defense mechanisms, contributing
      to influenza-related morbidity and mortality. Preliminary data demonstrate that the platelet
      transcriptome is markedly different between healthy subjects and influenza patients.
      Interferon-induced transmembrane proteins (IFITM) family members are among the transcripts
      significantly increased in platelets during influenza and expression of IFITM-3 is impaired
      in elderly subjects, a pattern associated with increased mortality. This study will build on
      these data and investigate if aging influences the expression of platelet IFITM family
      members in patients with influenza and sepsis.

      This study will prospectively determine if aging alters the induction of (IFITMs) in
      platelets from hospitalized influenza and sepsis patients. The study will also determine if
      diminished expression of IFITM family members correlates with an increased risk of adverse
      outcomes in older influenza and sepsis patients.
This will be a prospective observational cohort study comparing older (age≥65) and younger
      (age<65) influenza and sepsis patients.
observational model: Cohort
time perspective: Prospective
measure: 90 day mortality
time frame: 90 days
description: For the increased risk of mortality outcome, 90-day mortality will be the primary outcome variable. This will be modeled using mixed effects logistic regression, using days 0, 3, and 7 as repeated measurements. In this fashion, IFITM-3 and mortality are time-varying. A separate model will be fitted for the younger and older groups, since age group is expected to be collinear with IFITM-3 protein.
measure: 28 day mortality
time frame: 28 days
description: The same sample of influenza patients will be used for mortality analysis. Based on published and unpublished data, 28-day mortality in critically-ill influenza patients admitted to ICUs ranges from 10-40%, even during non-pandemic periods. Based on these estimates, our sample size (n=75 younger and n=75 older) provides 84% power (two-sided alpha 0.05 comparison) to detect a difference in incidence of 29% and 9%, which is a conservative estimate of the difference between the younger and older groups.
measure: Interferon-induced transmembrane protein expression in platelets
time frame: 24(±12) hours of diagnosis (day 0 or 1), day 3, 5, and 90
description: Recent evidence also demonstrates that IFITM-3 acts as a membrane organizer by facilitating clathrin-mediated endocytosis (CME). This membrane-organizing process allows cells to internalize molecules and viruses. CME regulates platelet membrane organization. IFITM-3 is demonstrated as necessary for host defenses against influenza virus. Moreover, with absent or reduced levels of IFITM-3, cells do not effectively restrict viral replication, an impaired response that may influence adverse clinical outcomes.
measure: IFITM-3 mRNA
time frame: 24(±12) hours of diagnosis (day 0 or 1), day 3, 5, and 90.
description: Platelet IFITM-3 protein levels have been seen to be increased in influenza patients and correlated with IFITM-3 mRNA (r2=0.33, p<0.005). However, in hospitalized influenza patients, platelet IFITM-3 mRNA and protein expression was decreased in older, compared to young patients.
It is hypothesized that influenza will induce expression of IFITM family members in platelets; IFITM's expression will be reduced in older compared to young influenza patients. This hypothesis will be tested to determine whether or not influenza induces IFITM-3 expression in human platelets and compare older and young subjects. Here, an outcome of IFITM-3 protein will be tracked in conjunction with mRNA.
arm group label: Influenza/respiratory virus pts <65 yrs
description: Patients with a primary microbiologic diagnosis of influenza (any strain) or other routinely clinically identified respiratory viruses
arm group label: Influenza/respiratory virus pts ≥ 65 yrs
description: Patients with a primary microbiologic diagnosis of influenza (any strain) or other routinely clinically identified respiratory viruses
arm group label: Sepsis/septic shock patients < 65 yrs
description: Sepsis and septic shock patients
arm group label: Sepsis/septic shock patients ≥ 65 yrs
description: sepsis and septic shock patients
The study will bank remaining platelet lysates for future assays.
study pop: 
sampling method: Non-Probability Sample
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Samuel M Brown, MD MS
role: Principal Investigator
affiliation: Intermountain Health Care, Inc.
facility: 
country: United States
responsible party type: Principal Investigator
investigator affiliation: Intermountain Health Care, Inc.
investigator full name: Samuel Brown
investigator title: Director, Center for Humanizing Critical Care
mesh term: Influenza, Human
mesh term: Sepsis
mesh term: Toxemia
sharing ipd: No