<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/NCT01685372</url>
  </required_header>
  <id_info>
    <org_study_id>12-0829</org_study_id>
    <nct_id>NCT01685372</nct_id>
  </id_info>
  <brief_title>Immunogenicity of Fluzone High Dose in Immunocompromised Children and Young Adults</brief_title>
  <official_title>Immunogenicity and Efficacy of High-dose Trivalent Inactivated Seasonal Influenza Vaccine (Fluzone High Dose) in Immunocompromised Children and Young Adults.</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Colorado, Denver</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Colorado Clinical &amp; Translational Sciences Institute</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>University of Colorado, Denver</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      The purpose of this study is to determine whether Fluzone High Dose increases the immune&#xD;
      response to the influenza antigens contained in the vaccine compared to standard-dose Fluzone&#xD;
      in immunocompromised children and young adults. Safety and efficacy data will also be&#xD;
      collected.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Completed</overall_status>
  <start_date>September 2012</start_date>
  <completion_date type="Actual">September 2017</completion_date>
  <primary_completion_date type="Actual">September 2015</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Prevention</primary_purpose>
    <masking>Triple (Participant, Care Provider, Investigator)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Number of Episodes of Influenza and Influenza-Like-Illness Reported in High Dose and Standard Dose Vaccination Groups</measure>
    <time_frame>up to 10 months after vaccination</time_frame>
    <description>Gathered data on influenza and influenza-like-illness during the influenza season for which the subject was vaccinated. Reported numbers of episodes of PCR-diagnosed influenza and rates of reported Influenza-Like-Illness (ILI) from Questionnaire #2 and also that were obtained from medical records. Data were categorized by the following:&#xD;
Polymerase chain reaction (PCR)-proven diagnosis of influenza performed at Children's Hospital Colorado (CHC)&#xD;
Diagnosis of influenza by non-PCR rapid-influenza test&#xD;
Diagnosis of ILI (from questionnaire #2). [Centers for Disease Control (CDC) definition of ILI: Fever ≥ 100°F AND cough or sore throat in the absence of another known cause other than influenza for the illness.]</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Number of Subjects Seroprotected at Timepoint 2 in High Dose and Standard Dose Vaccination Groups</measure>
    <time_frame>blood draw at 10-45 days post-vaccination</time_frame>
    <description>Measure hemagglutinin inhibition (HAI) on blood samples #2 for all subjects, which is the sample drawn at the &quot;peak&quot; of the immune response. Compare number of subjects who are seroprotected (reaching HAI ≥ 1:40) between the high-dose and standard-dose recipients..</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Number of Adverse Events Definitely or Possibly Related to Vaccination Reported Within 14 Days of Vaccination</measure>
    <time_frame>0-14 days after vaccination</time_frame>
    <description>Number of adverse events reported within the 14 days after vaccination by each subject within each patient group. Data collected from that reported in safety questionnaires and in Safety Diary that spanned the 14 days post-vaccination.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of Subjects With Seroconversion From T1 to T2 in the High Dose and Standard Dose Vaccine Groups</measure>
    <time_frame>10-45 days post-vaccination</time_frame>
    <description>HAI was measured on blood samples #1 and #2 for all subjects. Seroconversion is defined as a four-fold increase in antibody level between the high-dose and standard-dose recipients within each patient group was performed.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of Participants Seroprotected at Timepoint 3 in High Dose and Standard Dose Vaccination Groups</measure>
    <time_frame>at least 5 months post vaccination</time_frame>
    <description>Measure HAI on blood sample #3, drawn May-September following vaccination. Report number who still have HAI ≥ 1:40 in the high-dose and standard-dose groups.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in Disease Status From Vaccination Through June of the Following Year</measure>
    <time_frame>up to 9 months post-vaccination</time_frame>
    <description>Evaluate disease status changes reported by subject on Questionnaire #2 as well as changes reported in clinic notes over the course of the influenza season. Subjects considered &quot;worse&quot; had worsening function of transplanted organ or complications related to underlying condition (e.g. dialysis) or new diagnosis of disease considered serious by PI.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of Adverse Events Considered Definitely or Possibly Related to Vaccination Through Sept 30 of the Year Following Vaccination.</measure>
    <time_frame>(1) Date of vaccine through day 30 post-vaccine; (2) Day 31 post-vaccine through September 30 of the year following vaccine</time_frame>
    <description>Data gathered from the following&#xD;
Safety data in 1st 14 days (safety surveys and safety diary)&#xD;
Safety survey at day 30-45 regarding any unplanned health care visit or other AE during the 30 days after vaccine&#xD;
On-going passive surveillance of adverse events (AEs)/serious adverse events (SAEs) throughout course of influenza season of enrollment&#xD;
Chart review of each participant by PI through Sept 30 of the year following vaccine Data collection stopped in September following enrollment.</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Additional Measures of Immunogenicity in High Dose and Standard Dose Vaccinations</measure>
    <time_frame>10-45 days post-vaccination</time_frame>
    <description>This secondary objective was included as exploratory and we plan to add additional analyses when funding is secured. There is no anticipated date when we will have this completed. (No immunogenicity studies have been done besides HAI.) For other immunogenicity: would compare results of blood draw #1 and #2 between the high-dose and standard-dose recipients for each patient group for any of the following: antibody avidity, microneutralization, T-cell interferon, T-cell IL-2, B-cell Immunoglobulin G (IgG) and B-cell Immunoglobulin A (IgA).</description>
  </other_outcome>
  <other_outcome>
    <measure>Numbers of Subjects Who Were Both Seroprotected and Who Seroconverted at T2 and T3 After Vaccination</measure>
    <time_frame>(1) T2 measured 14-45 days post-vaccination; (2) T3 measured June 1-Sept 30 post-vaccination (end-of season), following vaccination</time_frame>
    <description>Seroprotection (HAI&gt;=1:40) and seroconversion (4-fold increase) together have been found to be a better predictor of vaccine effectiveness. Patients had to have both a 4-fold rise in HAI and have HAI&gt;=40 to be counted</description>
  </other_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">16</enrollment>
  <condition>Solid Organ Transplant Recipient (Liver, Kidney, Heart)</condition>
  <condition>Rheumatologic Disorder</condition>
  <condition>Human Immunodeficiency Virus (HIV)</condition>
  <condition>Bone Marrow Transplant (BMT)</condition>
  <condition>Dialysis</condition>
  <arm_group>
    <arm_group_label>Fluzone High Dose</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Fluzone High Dose 0.5 mL intramuscularly (IM) given once</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Fluzone</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Fluzone 0.5mL IM given once</description>
  </arm_group>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>Fluzone High Dose</intervention_name>
    <description>A single-dose of high-dose influenza vaccine will be administered to subjects randomized to this arm</description>
    <arm_group_label>Fluzone High Dose</arm_group_label>
    <other_name>high-dose influenza vaccine</other_name>
    <other_name>influenza vaccine</other_name>
  </intervention>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>Fluzone</intervention_name>
    <description>A single-dose of standard-dose influenza vaccine will be administered to subjects randomized to this arm</description>
    <arm_group_label>Fluzone</arm_group_label>
    <other_name>influenza vaccine</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Age ≥ 5 years and ≤ 35 years&#xD;
&#xD;
          -  Receiving influenza vaccination in Children's Hospital Colorado (CHC) clinic as part&#xD;
             of routine clinical care&#xD;
&#xD;
          -  Only supposed to receive one dose of influenza vaccine&#xD;
&#xD;
          -  Rheumatology patients: must be on some type of immunosuppressive or immunomodulatory&#xD;
             medication at the time of immunization and considered at least moderately&#xD;
             immunosuppressed in the opinion of the primary rheumatologist. Basic guidelines for&#xD;
             rheumatology patients: (1) Any patient receiving monoclonal antibody therapy (i.e.,&#xD;
             infliximab, etanercept, tocilizumab, anakinra) must also be taking another&#xD;
             immunosuppressive/immunomodulatory medication; (2) Patients taking steroids as&#xD;
             monotherapy must be on a dose of ≥ 2mg/kg/day OR ≥ 20mg/day; (3) Patients on&#xD;
             combination therapy where the dose of a single drug may not be very high, but the&#xD;
             combination is considered moderately or severely immunosuppressive will be eligible.&#xD;
&#xD;
          -  Bone Marrow Transplant patients: all patients in clinic eligible&#xD;
&#xD;
          -  Oncology patients: must be on some type of chemotherapy&#xD;
&#xD;
          -  Hemodialysis patients: must be on dialysis&#xD;
&#xD;
          -  Child Health Immunodeficiency Program (CHIP) patients: must have a known diagnosis of&#xD;
             HIV&#xD;
&#xD;
          -  Solid Organ Transplant patients: post-transplant, influenza vaccine recommended by&#xD;
             primary transplant physician&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Rheumatology patients: if receiving any of the monoclonal antibodies, etanercept,&#xD;
             infliximab, adalimumab, tocilizumab, atlizumab, or anakinra, must also be taking at&#xD;
             least one other immunosuppressive/immunomodulatory medication&#xD;
&#xD;
          -  Unable to come for scheduled follow-up appointments&#xD;
&#xD;
          -  History of anaphylaxis reaction to influenza vaccination in the past&#xD;
&#xD;
          -  Severe allergic reaction to any component of the vaccine, including egg protein, or&#xD;
             after previous dose of any influenza vaccine&#xD;
&#xD;
          -  History of Guillain-Barre syndrome ever in the past in the subject or in a parent or a&#xD;
             sibling of the subject&#xD;
&#xD;
          -  Allergy to latex&#xD;
&#xD;
          -  Intravenous immuneglobulin (IVIG) within in 4 weeks preceding any blood draw&#xD;
&#xD;
          -  Receiving an investigational agent as part of another study or other medical treatment&#xD;
             (investigational = not-FDA approved for any indication)&#xD;
&#xD;
          -  Subject not enrolled in other studies that prohibit him/her from enrolling in this&#xD;
             study&#xD;
&#xD;
          -  Blood draw contraindicated&#xD;
&#xD;
          -  Pregnancy&#xD;
&#xD;
          -  Breastfeeding&#xD;
&#xD;
          -  Received a polysaccharide vaccine (pneumovax) w/in 3 weeks of the vaccination&#xD;
&#xD;
          -  Absolute neutrophil count (ANC) &lt; 500/uL at the time of vaccination or could&#xD;
             potentially have ANC 500/uL during the 5 days after vaccination&#xD;
&#xD;
          -  Platelet count &lt; 50,000/uL at the time of vaccination&#xD;
&#xD;
          -  If a subject has a temperature ≥ 100.4°F at the time of enrollment, then the subject&#xD;
             must choose to not enroll or delay immunization until afebrile.&#xD;
&#xD;
          -  Receiving influenza vaccination past December 15 of influenza season.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>5 Years</minimum_age>
    <maximum_age>35 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Donna Curtis, MD, MPH</last_name>
    <role>Principal Investigator</role>
    <affiliation>Children's Hospital Colorado, University of Colorado Denver School of Medicine</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Children's Hospital Colorado</name>
      <address>
        <city>Aurora</city>
        <state>Colorado</state>
        <zip>80045</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>December 2017</verification_date>
  <study_first_submitted>August 27, 2012</study_first_submitted>
  <study_first_submitted_qc>September 13, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">September 14, 2012</study_first_posted>
  <results_first_submitted>June 30, 2017</results_first_submitted>
  <results_first_submitted_qc>October 24, 2017</results_first_submitted_qc>
  <results_first_posted type="Actual">November 30, 2017</results_first_posted>
  <disposition_first_submitted>October 24, 2016</disposition_first_submitted>
  <disposition_first_submitted_qc>October 24, 2016</disposition_first_submitted_qc>
  <disposition_first_posted type="Estimate">November 28, 2016</disposition_first_posted>
  <last_update_submitted>December 21, 2017</last_update_submitted>
  <last_update_submitted_qc>December 21, 2017</last_update_submitted_qc>
  <last_update_posted type="Actual">January 23, 2018</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>Acquired Immunodeficiency Syndrome</mesh_term>
    <mesh_term>HIV Infections</mesh_term>
    <mesh_term>Rheumatic Diseases</mesh_term>
    <mesh_term>Collagen Diseases</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Vaccines</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
    <ipd_description>There is no plan to share data at the end of the study. Data management at the close of the study will occur according to IRB and FDA regulations.</ipd_description>
  </patient_data>

  <clinical_results>

    <participant_flow>
      <recruitment_details>Study subjects were recruited over two influenza seasons, 2013-2014 and 2014-2015. Subjects were recruited from the Dialysis unit and Rheumatology clinic in 2013-2014 by referral from clinicians. Subjects were recruited by mailed letter to Solid Organ Transplant recipients in 2014-2015.</recruitment_details>
      <pre_assignment_details>In 2013-2014, 4 subjects chose not to enroll after learning more about the study. In 2014-2015, 2 subjects chose not to enroll after learning about the study. All potential subjects met pre-screening criteria. No subjects were excluded from the study by study personnel.</pre_assignment_details>
      <group_list>
        <group group_id="P1">
          <title>Fluzone High Dose</title>
          <description>A single-dose of high-dose influenza vaccine was administered to subjects randomized to this arm at T1</description>
        </group>
        <group group_id="P2">
          <title>Fluzone Standard Dose</title>
          <description>A single-dose of standard-dose influenza vaccine was administered to subjects randomized to this arm at T1</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Timepoint 1 (T1): Vaccine,1st Blood Draw</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="7"/>
                <participants group_id="P2" count="9"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="7"/>
                <participants group_id="P2" count="9"/>
              </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>
          <title>Timepoint 2 (T2): 2nd Blood Draw</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="7"/>
                <participants group_id="P2" count="9"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="7"/>
                <participants group_id="P2" count="9"/>
              </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>
          <title>Timepoint 3 (T3): 3rd Blood Draw</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="7"/>
                <participants group_id="P2" count="9"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="4"/>
                <participants group_id="P2" count="5"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="3"/>
                <participants group_id="P2" count="4"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Lost to Follow-up</title>
              <participants_list>
                <participants group_id="P1" count="3"/>
                <participants group_id="P2" count="4"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>Fluzone High Dose</title>
          <description>Fluzone High Dose 0.5 mL intramuscularly (IM) given once&#xD;
Fluzone High Dose: A single-dose of high-dose influenza vaccine will be administered to subjects randomized to this arm</description>
        </group>
        <group group_id="B2">
          <title>Fluzone Standard Dose</title>
          <description>Fluzone 0.5mL IM given once&#xD;
Fluzone: A single-dose of standard-dose influenza vaccine will be administered to subjects randomized to this arm</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="7"/>
            <count group_id="B2" value="9"/>
            <count group_id="B3" value="16"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>years</units>
          <param>Median</param>
          <dispersion>Full Range</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="15" lower_limit="9" upper_limit="18"/>
                    <measurement group_id="B2" value="15" lower_limit="10" upper_limit="23"/>
                    <measurement group_id="B3" value="15" lower_limit="9" upper_limit="23"/>
                  </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>
              <category_list>
                <category>
                  <title>Female</title>
                  <measurement_list>
                    <measurement group_id="B1" value="5"/>
                    <measurement group_id="B2" value="5"/>
                    <measurement group_id="B3" value="10"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                    <measurement group_id="B2" value="4"/>
                    <measurement group_id="B3" value="6"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Ethnicity (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                    <measurement group_id="B2" value="4"/>
                    <measurement group_id="B3" value="6"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Not Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="5"/>
                    <measurement group_id="B2" value="5"/>
                    <measurement group_id="B3" value="10"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</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_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Race (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>American Indian or Alaska Native</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>Asian</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="1"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Native Hawaiian or Other Pacific Islander</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>Black or African American</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>White</title>
                  <measurement_list>
                    <measurement group_id="B1" value="6"/>
                    <measurement group_id="B2" value="8"/>
                    <measurement group_id="B3" value="14"/>
                  </measurement_list>
                </category>
                <category>
                  <title>More than one race</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>Unknown or Not Reported</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_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Cohort</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <title>Dialysis</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="3"/>
                    <measurement group_id="B2" value="4"/>
                    <measurement group_id="B3" value="7"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Solid organ transplant</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="4"/>
                    <measurement group_id="B2" value="4"/>
                    <measurement group_id="B3" value="8"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Rheumatoloty</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Number of Episodes of Influenza and Influenza-Like-Illness Reported in High Dose and Standard Dose Vaccination Groups</title>
        <description>Gathered data on influenza and influenza-like-illness during the influenza season for which the subject was vaccinated. Reported numbers of episodes of PCR-diagnosed influenza and rates of reported Influenza-Like-Illness (ILI) from Questionnaire #2 and also that were obtained from medical records. Data were categorized by the following:&#xD;
Polymerase chain reaction (PCR)-proven diagnosis of influenza performed at Children's Hospital Colorado (CHC)&#xD;
Diagnosis of influenza by non-PCR rapid-influenza test&#xD;
Diagnosis of ILI (from questionnaire #2). [Centers for Disease Control (CDC) definition of ILI: Fever ≥ 100°F AND cough or sore throat in the absence of another known cause other than influenza for the illness.]</description>
        <time_frame>up to 10 months after vaccination</time_frame>
        <population>Row 1: Number of influenza episodes diagnosed by PCR Row 2: Number of influenza episodes diagnosed by non-PCR rapid test Row 3: Number of influenza-like-illness (ILI) episodes reported by participants from the time of vaccination through June of the following year (end of flu season).</population>
        <group_list>
          <group group_id="O1">
            <title>Fluzone High Dose</title>
            <description>Fluzone High Dose: A single-dose of high-dose influenza vaccine will be administered to subjects randomized to this arm</description>
          </group>
          <group group_id="O2">
            <title>Fluzone Standard Dose</title>
            <description>Fluzone: A single-dose of standard-dose influenza vaccine will be administered to subjects randomized to this arm</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Episodes of Influenza and Influenza-Like-Illness Reported in High Dose and Standard Dose Vaccination Groups</title>
          <description>Gathered data on influenza and influenza-like-illness during the influenza season for which the subject was vaccinated. Reported numbers of episodes of PCR-diagnosed influenza and rates of reported Influenza-Like-Illness (ILI) from Questionnaire #2 and also that were obtained from medical records. Data were categorized by the following:&#xD;
Polymerase chain reaction (PCR)-proven diagnosis of influenza performed at Children's Hospital Colorado (CHC)&#xD;
Diagnosis of influenza by non-PCR rapid-influenza test&#xD;
Diagnosis of ILI (from questionnaire #2). [Centers for Disease Control (CDC) definition of ILI: Fever ≥ 100°F AND cough or sore throat in the absence of another known cause other than influenza for the illness.]</description>
          <population>Row 1: Number of influenza episodes diagnosed by PCR Row 2: Number of influenza episodes diagnosed by non-PCR rapid test Row 3: Number of influenza-like-illness (ILI) episodes reported by participants from the time of vaccination through June of the following year (end of flu season).</population>
          <units>episodes of illness</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="7"/>
                <count group_id="O2" value="9"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Row 1: Number of Influenza diagnosed by PCR</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1"/>
                    <measurement group_id="O2" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Row 2: # of Influenza diagnosis by non-PCR test</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Row 3: Number of Influenza-like-illness</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2"/>
                    <measurement group_id="O2" value="8"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Number of Subjects Seroprotected at Timepoint 2 in High Dose and Standard Dose Vaccination Groups</title>
        <description>Measure hemagglutinin inhibition (HAI) on blood samples #2 for all subjects, which is the sample drawn at the &quot;peak&quot; of the immune response. Compare number of subjects who are seroprotected (reaching HAI ≥ 1:40) between the high-dose and standard-dose recipients..</description>
        <time_frame>blood draw at 10-45 days post-vaccination</time_frame>
        <population>All participants had blood drawn before vaccination and at timepoint 2. The influenza vaccine had the same subtypes during the two season. Data were analyzed for the 3 subtypes contained in the trivalent vaccine, H1N1, H3N2, B (Yamagata).</population>
        <group_list>
          <group group_id="O1">
            <title>Fluzone High Dose</title>
            <description>Fluzone High Dose: A single-dose of high-dose influenza vaccine will be administered to subjects randomized to this arm</description>
          </group>
          <group group_id="O2">
            <title>Fluzone Standard Dose</title>
            <description>Fluzone: A single-dose of standard-dose influenza vaccine will be administered to subjects randomized to this arm</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Subjects Seroprotected at Timepoint 2 in High Dose and Standard Dose Vaccination Groups</title>
          <description>Measure hemagglutinin inhibition (HAI) on blood samples #2 for all subjects, which is the sample drawn at the &quot;peak&quot; of the immune response. Compare number of subjects who are seroprotected (reaching HAI ≥ 1:40) between the high-dose and standard-dose recipients..</description>
          <population>All participants had blood drawn before vaccination and at timepoint 2. The influenza vaccine had the same subtypes during the two season. Data were analyzed for the 3 subtypes contained in the trivalent vaccine, H1N1, H3N2, B (Yamagata).</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="7"/>
                <count group_id="O2" value="9"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>H1N1</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="7"/>
                    <measurement group_id="O2" value="7"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>H3N2</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="7"/>
                    <measurement group_id="O2" value="9"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>B (Yamagata)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="7"/>
                    <measurement group_id="O2" value="8"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Number of Adverse Events Definitely or Possibly Related to Vaccination Reported Within 14 Days of Vaccination</title>
        <description>Number of adverse events reported within the 14 days after vaccination by each subject within each patient group. Data collected from that reported in safety questionnaires and in Safety Diary that spanned the 14 days post-vaccination.</description>
        <time_frame>0-14 days after vaccination</time_frame>
        <population>All adverse events that may have been related are included in this analysis. Events considered not-related were excluded. More information on these AEs is included in the Adverse Events section. All AEs were reviewed by the study DSMB.</population>
        <group_list>
          <group group_id="O1">
            <title>Fluzone High Dose</title>
            <description>Fluzone High Dose: A single-dose of high-dose influenza vaccine will be administered to subjects randomized to this arm</description>
          </group>
          <group group_id="O2">
            <title>Fluzone Standard Dose</title>
            <description>Fluzone: A single-dose of standard-dose influenza vaccine will be administered to subjects randomized to this arm</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Adverse Events Definitely or Possibly Related to Vaccination Reported Within 14 Days of Vaccination</title>
          <description>Number of adverse events reported within the 14 days after vaccination by each subject within each patient group. Data collected from that reported in safety questionnaires and in Safety Diary that spanned the 14 days post-vaccination.</description>
          <population>All adverse events that may have been related are included in this analysis. Events considered not-related were excluded. More information on these AEs is included in the Adverse Events section. All AEs were reviewed by the study DSMB.</population>
          <units>number of AEs reported</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="7"/>
                <count group_id="O2" value="9"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Local site reaction - grade 1</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="7"/>
                    <measurement group_id="O2" value="8"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Local site reaction - grade 2</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1"/>
                    <measurement group_id="O2" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Other AEs - Grade 1</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2"/>
                    <measurement group_id="O2" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Number of Subjects With Seroconversion From T1 to T2 in the High Dose and Standard Dose Vaccine Groups</title>
        <description>HAI was measured on blood samples #1 and #2 for all subjects. Seroconversion is defined as a four-fold increase in antibody level between the high-dose and standard-dose recipients within each patient group was performed.</description>
        <time_frame>10-45 days post-vaccination</time_frame>
        <population>All participants had blood drawn at baseline (T1) and 10-45 days after vaccination (T2). Analysis was done for the 3 influenza subtypes in the trivalent influenza vaccine. The influenza vaccine was the same in 2013-2014 and 2014-2015.</population>
        <group_list>
          <group group_id="O1">
            <title>Fluzone High Dose</title>
            <description>Fluzone High Dose: A single-dose of high-dose influenza vaccine will be administered to subjects randomized to this arm</description>
          </group>
          <group group_id="O2">
            <title>Fluzone Standard Dose</title>
            <description>Fluzone: A single-dose of standard-dose influenza vaccine will be administered to subjects randomized to this arm</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Subjects With Seroconversion From T1 to T2 in the High Dose and Standard Dose Vaccine Groups</title>
          <description>HAI was measured on blood samples #1 and #2 for all subjects. Seroconversion is defined as a four-fold increase in antibody level between the high-dose and standard-dose recipients within each patient group was performed.</description>
          <population>All participants had blood drawn at baseline (T1) and 10-45 days after vaccination (T2). Analysis was done for the 3 influenza subtypes in the trivalent influenza vaccine. The influenza vaccine was the same in 2013-2014 and 2014-2015.</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="7"/>
                <count group_id="O2" value="9"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>H1N1</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="3"/>
                    <measurement group_id="O2" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>H3N2</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="5"/>
                    <measurement group_id="O2" value="5"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>B (Yamagata)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="3"/>
                    <measurement group_id="O2" value="3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Number of Participants Seroprotected at Timepoint 3 in High Dose and Standard Dose Vaccination Groups</title>
        <description>Measure HAI on blood sample #3, drawn May-September following vaccination. Report number who still have HAI ≥ 1:40 in the high-dose and standard-dose groups.</description>
        <time_frame>at least 5 months post vaccination</time_frame>
        <population>Number of subjects seroprotected at T3 for each of the vaccine subtypes. 3 subjects in the HD group and 4 subjects in the SD group were lost-to-follow-up by T3 and not included in this analysis.</population>
        <group_list>
          <group group_id="O1">
            <title>Fluzone High Dose</title>
            <description>Fluzone High Dose: A single-dose of high-dose influenza vaccine will be administered to subjects randomized to this arm</description>
          </group>
          <group group_id="O2">
            <title>Fluzone Standard Dose</title>
            <description>Fluzone: A single-dose of standard-dose influenza vaccine will be administered to subjects randomized to this arm</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Participants Seroprotected at Timepoint 3 in High Dose and Standard Dose Vaccination Groups</title>
          <description>Measure HAI on blood sample #3, drawn May-September following vaccination. Report number who still have HAI ≥ 1:40 in the high-dose and standard-dose groups.</description>
          <population>Number of subjects seroprotected at T3 for each of the vaccine subtypes. 3 subjects in the HD group and 4 subjects in the SD group were lost-to-follow-up by T3 and not included in this analysis.</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="4"/>
                <count group_id="O2" value="5"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>H1N1</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="4"/>
                    <measurement group_id="O2" value="4"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>H3N2</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="4"/>
                    <measurement group_id="O2" value="5"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>B (Yamagata)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="4"/>
                    <measurement group_id="O2" value="5"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change in Disease Status From Vaccination Through June of the Following Year</title>
        <description>Evaluate disease status changes reported by subject on Questionnaire #2 as well as changes reported in clinic notes over the course of the influenza season. Subjects considered &quot;worse&quot; had worsening function of transplanted organ or complications related to underlying condition (e.g. dialysis) or new diagnosis of disease considered serious by PI.</description>
        <time_frame>up to 9 months post-vaccination</time_frame>
        <population>One subject in the high-dose group was originally on dialysis, but received a kidney transplant during the follow-up period. This subject was excluded from the analysis on change in baseline medical condition.</population>
        <group_list>
          <group group_id="O1">
            <title>Fluzone High Dose</title>
            <description>Fluzone High Dose: A single-dose of high-dose influenza vaccine will be administered to subjects randomized to this arm</description>
          </group>
          <group group_id="O2">
            <title>Fluzone Standard Dose</title>
            <description>Fluzone: A single-dose of standard-dose influenza vaccine will be administered to subjects randomized to this arm</description>
          </group>
        </group_list>
        <measure>
          <title>Change in Disease Status From Vaccination Through June of the Following Year</title>
          <description>Evaluate disease status changes reported by subject on Questionnaire #2 as well as changes reported in clinic notes over the course of the influenza season. Subjects considered &quot;worse&quot; had worsening function of transplanted organ or complications related to underlying condition (e.g. dialysis) or new diagnosis of disease considered serious by PI.</description>
          <population>One subject in the high-dose group was originally on dialysis, but received a kidney transplant during the follow-up period. This subject was excluded from the analysis on change in baseline medical condition.</population>
          <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="9"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Same or better</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="5"/>
                    <measurement group_id="O2" value="9"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Worse</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1"/>
                    <measurement group_id="O2" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Number of Adverse Events Considered Definitely or Possibly Related to Vaccination Through Sept 30 of the Year Following Vaccination.</title>
        <description>Data gathered from the following&#xD;
Safety data in 1st 14 days (safety surveys and safety diary)&#xD;
Safety survey at day 30-45 regarding any unplanned health care visit or other AE during the 30 days after vaccine&#xD;
On-going passive surveillance of adverse events (AEs)/serious adverse events (SAEs) throughout course of influenza season of enrollment&#xD;
Chart review of each participant by PI through Sept 30 of the year following vaccine Data collection stopped in September following enrollment.</description>
        <time_frame>(1) Date of vaccine through day 30 post-vaccine; (2) Day 31 post-vaccine through September 30 of the year following vaccine</time_frame>
        <population>Data used included: active reporting through day 30, survey at end of season, and chart review for data through Sept 30 of the year following vaccination.</population>
        <group_list>
          <group group_id="O1">
            <title>Fluzone High Dose</title>
            <description>Fluzone High Dose: A single-dose of high-dose influenza vaccine will be administered to subjects randomized to this arm</description>
          </group>
          <group group_id="O2">
            <title>Fluzone Standard Dose</title>
            <description>Fluzone: A single-dose of standard-dose influenza vaccine will be administered to subjects randomized to this arm</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Adverse Events Considered Definitely or Possibly Related to Vaccination Through Sept 30 of the Year Following Vaccination.</title>
          <description>Data gathered from the following&#xD;
Safety data in 1st 14 days (safety surveys and safety diary)&#xD;
Safety survey at day 30-45 regarding any unplanned health care visit or other AE during the 30 days after vaccine&#xD;
On-going passive surveillance of adverse events (AEs)/serious adverse events (SAEs) throughout course of influenza season of enrollment&#xD;
Chart review of each participant by PI through Sept 30 of the year following vaccine Data collection stopped in September following enrollment.</description>
          <population>Data used included: active reporting through day 30, survey at end of season, and chart review for data through Sept 30 of the year following vaccination.</population>
          <units>number of AEs reported</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="7"/>
                <count group_id="O2" value="9"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Day 0 (vaccination) through day 30</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="10"/>
                    <measurement group_id="O2" value="9"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Day 31 post-vaccination, through Sept 30</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Other Pre-specified</type>
        <title>Additional Measures of Immunogenicity in High Dose and Standard Dose Vaccinations</title>
        <description>This secondary objective was included as exploratory and we plan to add additional analyses when funding is secured. There is no anticipated date when we will have this completed. (No immunogenicity studies have been done besides HAI.) For other immunogenicity: would compare results of blood draw #1 and #2 between the high-dose and standard-dose recipients for each patient group for any of the following: antibody avidity, microneutralization, T-cell interferon, T-cell IL-2, B-cell Immunoglobulin G (IgG) and B-cell Immunoglobulin A (IgA).</description>
        <time_frame>10-45 days post-vaccination</time_frame>
      </outcome>
      <outcome>
        <type>Other Pre-specified</type>
        <title>Numbers of Subjects Who Were Both Seroprotected and Who Seroconverted at T2 and T3 After Vaccination</title>
        <description>Seroprotection (HAI&gt;=1:40) and seroconversion (4-fold increase) together have been found to be a better predictor of vaccine effectiveness. Patients had to have both a 4-fold rise in HAI and have HAI&gt;=40 to be counted</description>
        <time_frame>(1) T2 measured 14-45 days post-vaccination; (2) T3 measured June 1-Sept 30 post-vaccination (end-of season), following vaccination</time_frame>
        <population>For T3, only 4 participants in the high-dose group and 5 participants in the standard-dose group were analyzed due to loss-to-follow-up.</population>
        <group_list>
          <group group_id="O1">
            <title>Fluzone High Dose</title>
            <description>Fluzone High Dose: A single-dose of high-dose influenza vaccine will be administered to subjects randomized to this arm</description>
          </group>
          <group group_id="O2">
            <title>Fluzone Standard Dose</title>
            <description>Fluzone: A single-dose of standard-dose influenza vaccine will be administered to subjects randomized to this arm</description>
          </group>
        </group_list>
        <measure>
          <title>Numbers of Subjects Who Were Both Seroprotected and Who Seroconverted at T2 and T3 After Vaccination</title>
          <description>Seroprotection (HAI&gt;=1:40) and seroconversion (4-fold increase) together have been found to be a better predictor of vaccine effectiveness. Patients had to have both a 4-fold rise in HAI and have HAI&gt;=40 to be counted</description>
          <population>For T3, only 4 participants in the high-dose group and 5 participants in the standard-dose group were analyzed due to loss-to-follow-up.</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="7"/>
                <count group_id="O2" value="9"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>T2 - H1N1</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="7"/>
                    <count group_id="O2" value="9"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="3"/>
                    <measurement group_id="O2" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>T2 - H3N2</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="7"/>
                    <count group_id="O2" value="9"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="5"/>
                    <measurement group_id="O2" value="5"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>T2 - B (Yamagata)</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="7"/>
                    <count group_id="O2" value="9"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="3"/>
                    <measurement group_id="O2" value="3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>T3 - H1N1</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="4"/>
                    <count group_id="O2" value="5"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1"/>
                    <measurement group_id="O2" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>T3 - H3N2</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="4"/>
                    <count group_id="O2" value="5"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>T3 - B (Yamagata)</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="4"/>
                    <count group_id="O2" value="5"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1"/>
                    <measurement group_id="O2" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>AE data were collected from the date of vaccination (T1) through September 30 of the following year. AE data were collected differently over the study. At day 2-7 after vaccination, subjects were called to ask about AEs. Subjects were given a &quot;Diary&quot; to fill out for day 0-14 after vaccination, and the Diary was collected at T2. At day 30-45, subjects were given a questionnaire (in-person at T2 visit or by phone) asking about AEs and any unplanned medical visits during day 0-30 post-vaccine.</time_frame>
      <desc>In May-June after vaccination, another questionnaire was collected by phone asking about influenza and influenza-like-illness, new health conditions, changes to underlying medical condition, or new immunosuppressive treatments since enrollment. Passive AE data were collected by providing participants with contact information for the study in order to report any concerns.</desc>
      <group_list>
        <group group_id="E1">
          <title>Fluzone High Dose</title>
          <description>Fluzone High Dose: A single-dose of high-dose influenza vaccine will be administered to subjects randomized to this arm</description>
        </group>
        <group group_id="E2">
          <title>Fluzone Standard Dose</title>
          <description>Fluzone: A single-dose of standard-dose influenza vaccine will be administered to subjects randomized to this arm</description>
        </group>
      </group_list>
      <serious_events>
        <default_vocab>MedDRA (Unspecified)</default_vocab>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, all-cause mortality</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="7"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="9"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Diarrhea</sub_title>
                <description>Subject developed acute gastroenteritis 27 days after vaccination. Subject required hospitalization for rehydration and monitoring of immunosuppression levels.</description>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="7"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="9"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Bacteremia</sub_title>
                <description>Subject developed dialysis catheter insertion site infection 15 days after vaccination. Subject was admitted for IV antibiotics. No long-term sequelae. SAE was determined to be not related to the vaccine by study DSMB.</description>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="9"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>0</frequency_threshold>
        <default_vocab>MedDRA (Unspecified)</default_vocab>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="6" subjects_at_risk="7"/>
                <counts group_id="E2" subjects_affected="7" subjects_at_risk="9"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Abdominal pain</sub_title>
                <description>Abdominal pain on day after vaccination - Grade 1, possibly related</description>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="7"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="9"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Injection site reaction - pain</sub_title>
                <description>Pain at site of injection - Grade 1</description>
                <counts group_id="E1" events="6" subjects_affected="6" subjects_at_risk="7"/>
                <counts group_id="E2" events="7" subjects_affected="7" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Fatigue</sub_title>
                <description>Fatigue starting a few days after injection - Grade 1, possibly related</description>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="9"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Headache</sub_title>
                <description>Headache within 14 days of vaccination - Grade 1, possibly related</description>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="7"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="9"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Skin and subcutaneous tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Injection site reaction - induration</sub_title>
                <description>Induration at site of injection - Grade 1</description>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Injection site reaction - induration</sub_title>
                <description>Induration at site of injection - Grade 2</description>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="7"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Injection site reaction - bruising</sub_title>
                <description>Bruising at site of injection - Grade 1</description>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="7"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="9"/>
              </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>The number of participants was very low, limiting statistical analysis and limiting the ability to perform any subgroup analysis. Data at T3, were even more limited given loss-to-follow-up.</limitations_and_caveats>
    <point_of_contact>
      <name_or_title>Donna Curtis, MD, MPH</name_or_title>
      <organization>University of Colorado School of Medicine</organization>
      <phone>720-777-6981</phone>
      <email>donna.curtis@childrenscolorado.org</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/NCT01685372
org study id: 12-0829
nct id: NCT01685372
lead sponsor: 
collaborator: 
has dmc: Yes
The purpose of this study is to determine whether Fluzone High Dose increases the immune
      response to the influenza antigens contained in the vaccine compared to standard-dose Fluzone
      in immunocompromised children and young adults. Safety and efficacy data will also be
      collected.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Prevention
masking: Triple (Participant, Care Provider, Investigator)
measure: Number of Episodes of Influenza and Influenza-Like-Illness Reported in High Dose and Standard Dose Vaccination Groups
time frame: up to 10 months after vaccination
description: Gathered data on influenza and influenza-like-illness during the influenza season for which the subject was vaccinated. Reported numbers of episodes of PCR-diagnosed influenza and rates of reported Influenza-Like-Illness (ILI) from Questionnaire #2 and also that were obtained from medical records. Data were categorized by the following:
Polymerase chain reaction (PCR)-proven diagnosis of influenza performed at Children's Hospital Colorado (CHC)
Diagnosis of influenza by non-PCR rapid-influenza test
Diagnosis of ILI (from questionnaire #2). [Centers for Disease Control (CDC) definition of ILI: Fever ≥ 100°F AND cough or sore throat in the absence of another known cause other than influenza for the illness.]
measure: Number of Subjects Seroprotected at Timepoint 2 in High Dose and Standard Dose Vaccination Groups
time frame: blood draw at 10-45 days post-vaccination
description: Measure hemagglutinin inhibition (HAI) on blood samples #2 for all subjects, which is the sample drawn at the "peak" of the immune response. Compare number of subjects who are seroprotected (reaching HAI ≥ 1:40) between the high-dose and standard-dose recipients..
measure: Number of Adverse Events Definitely or Possibly Related to Vaccination Reported Within 14 Days of Vaccination
time frame: 0-14 days after vaccination
description: Number of adverse events reported within the 14 days after vaccination by each subject within each patient group. Data collected from that reported in safety questionnaires and in Safety Diary that spanned the 14 days post-vaccination.
measure: Number of Subjects With Seroconversion From T1 to T2 in the High Dose and Standard Dose Vaccine Groups
time frame: 10-45 days post-vaccination
description: HAI was measured on blood samples #1 and #2 for all subjects. Seroconversion is defined as a four-fold increase in antibody level between the high-dose and standard-dose recipients within each patient group was performed.
measure: Number of Participants Seroprotected at Timepoint 3 in High Dose and Standard Dose Vaccination Groups
time frame: at least 5 months post vaccination
description: Measure HAI on blood sample #3, drawn May-September following vaccination. Report number who still have HAI ≥ 1:40 in the high-dose and standard-dose groups.
measure: Change in Disease Status From Vaccination Through June of the Following Year
time frame: up to 9 months post-vaccination
description: Evaluate disease status changes reported by subject on Questionnaire #2 as well as changes reported in clinic notes over the course of the influenza season. Subjects considered "worse" had worsening function of transplanted organ or complications related to underlying condition (e.g. dialysis) or new diagnosis of disease considered serious by PI.
measure: Number of Adverse Events Considered Definitely or Possibly Related to Vaccination Through Sept 30 of the Year Following Vaccination.
time frame: (1) Date of vaccine through day 30 post-vaccine; (2) Day 31 post-vaccine through September 30 of the year following vaccine
description: Data gathered from the following
Safety data in 1st 14 days (safety surveys and safety diary)
Safety survey at day 30-45 regarding any unplanned health care visit or other AE during the 30 days after vaccine
On-going passive surveillance of adverse events (AEs)/serious adverse events (SAEs) throughout course of influenza season of enrollment
Chart review of each participant by PI through Sept 30 of the year following vaccine Data collection stopped in September following enrollment.
measure: Additional Measures of Immunogenicity in High Dose and Standard Dose Vaccinations
time frame: 10-45 days post-vaccination
description: This secondary objective was included as exploratory and we plan to add additional analyses when funding is secured. There is no anticipated date when we will have this completed. (No immunogenicity studies have been done besides HAI.) For other immunogenicity: would compare results of blood draw #1 and #2 between the high-dose and standard-dose recipients for each patient group for any of the following: antibody avidity, microneutralization, T-cell interferon, T-cell IL-2, B-cell Immunoglobulin G (IgG) and B-cell Immunoglobulin A (IgA).
measure: Numbers of Subjects Who Were Both Seroprotected and Who Seroconverted at T2 and T3 After Vaccination
time frame: (1) T2 measured 14-45 days post-vaccination; (2) T3 measured June 1-Sept 30 post-vaccination (end-of season), following vaccination
description: Seroprotection (HAI>=1:40) and seroconversion (4-fold increase) together have been found to be a better predictor of vaccine effectiveness. Patients had to have both a 4-fold rise in HAI and have HAI>=40 to be counted
arm group label: Fluzone High Dose
arm group type: Experimental
description: Fluzone High Dose 0.5 mL intramuscularly (IM) given once
arm group label: Fluzone
arm group type: Active Comparator
description: Fluzone 0.5mL IM given once
intervention type: Biological
intervention name: Fluzone High Dose
description: A single-dose of high-dose influenza vaccine will be administered to subjects randomized to this arm
arm group label: Fluzone High Dose
other name: high-dose influenza vaccine
other name: influenza vaccine
intervention type: Biological
intervention name: Fluzone
description: A single-dose of standard-dose influenza vaccine will be administered to subjects randomized to this arm
arm group label: Fluzone
other name: influenza vaccine
criteria: 
gender: All
minimum age: 5 Years
maximum age: 35 Years
healthy volunteers: No
last name: Donna Curtis, MD, MPH
role: Principal Investigator
affiliation: Children's Hospital Colorado, University of Colorado Denver School of Medicine
facility: 
country: United States
responsible party type: Sponsor
mesh term: Acquired Immunodeficiency Syndrome
mesh term: HIV Infections
mesh term: Rheumatic Diseases
mesh term: Collagen Diseases
mesh term: Vaccines
sharing ipd: No
ipd description: There is no plan to share data at the end of the study. Data management at the close of the study will occur according to IRB and FDA regulations.
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
limitations and caveats: The number of participants was very low, limiting statistical analysis and limiting the ability to perform any subgroup analysis. Data at T3, were even more limited given loss-to-follow-up.
point of contact: 