<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/NCT02230189</url>
  </required_header>
  <id_info>
    <org_study_id>14-14224</org_study_id>
    <secondary_id>5U19AI077439</secondary_id>
    <nct_id>NCT02230189</nct_id>
  </id_info>
  <brief_title>Study of the Inflammation and Airway Changes That Occur After Exposure to Allergen in Asthmatics</brief_title>
  <acronym>ACE</acronym>
  <official_title>Mechanistic Study of Epithelial miRNAs and T-cell Recruitment Dynamics That Occur After Allergen Challenge in Patients With Asthma.</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Prescott Woodruff</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>National Institute of Allergy and Infectious Diseases (NIAID)</agency>
      <agency_class>NIH</agency_class>
    </collaborator>
  </sponsors>
  <source>University of California, San Francisco</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      This protocol describes a single site mechanistic study to investigate microRNAs (miRNAs)&#xD;
      that are differentially expressed in the airway epithelium of patients with asthma at&#xD;
      baseline and in response to allergen challenge. We hypothesize that allergen exposure&#xD;
      enhances airway smooth muscle contractility and epithelial cell mRNA/miRNA production as a&#xD;
      consequence of locally increased T-cell derived cytokine production. The study will involve&#xD;
      three visits over the course of approximately 14 days. At Visit 1, participants will be&#xD;
      characterized in detail with lung function testing, methacholine challenge testing, and&#xD;
      allergen skin prick testing. At Visit 2, participants will undergo bronchoscopy with&#xD;
      segmental allergen administration of either cat or dust mite standardized allergen extract.&#xD;
      At Visit 3 (either 24 hours later or 7 days later), bronchoscopy will be performed to collect&#xD;
      airway samples including bronchoalveolar lavage (BAL), epithelial brushings and endobronchial&#xD;
      biopsies. Sample analysis will include measurement of miRNA and mRNA expression in epithelial&#xD;
      brushings (RNAseq and qPCR); analysis of cell surface markers on BAL cells and blood cells;&#xD;
      and collection of endobronchial biopsies for immunostaining of immune cells localization,&#xD;
      immunoblotting of smooth cell protein phosphorylation, analysis of mucin content and smooth&#xD;
      muscle cell subculture. A total of 38 subjects (26 asthmatics with stable or well-controlled&#xD;
      asthma, 6 allergic non-asthmatics and 6 non-allergic non-asthmatics) will complete the study.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">March 2015</start_date>
  <completion_date type="Actual">January 2020</completion_date>
  <primary_completion_date type="Actual">January 2020</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <intervention_model_description>Single group before and after administration of allergen</intervention_model_description>
    <primary_purpose>Basic Science</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Difference in Expression of Epithelial miRNAs (in Read Counts) 24 Hours After Allergen-challenge as Compared to 24 Hours After Diluent Challenge in Participants With Allergic Asthma</measure>
    <time_frame>24 hours</time_frame>
    <description>For each participant with Allergic Asthma, a baseline airway epithelial brushing was performed, allergen was instilled into one segment of the lung, and diluent (control) was instilled into another segment. Both segments were brushed for epithelial cells 24 hours later. After processing brushes to RNA and generating RNA sequencing data, the RNA transcript read counts for each gene underwent variance stabilized log normalization. Then we built a regression model which estimated the difference in miRNA read count in the allergen challenged as compared to the baseline sample and the difference in miRNA read count in the diluent challenged segment as compared to baseline for each participant. The change from baseline read count for each miRNA in the allergen samples was compared to the change in the diluent samples and statistical significance was assessed using the unadjusted p-value(&lt;0.05). The direction of change does not have clinical significance; this was a mechanistic study.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Difference in Expression of Epithelial miRNAs (in Read Counts) 7 Days After Allergen-challenge as Compared to 7 Days After Diluent Challenge</measure>
    <time_frame>7 days</time_frame>
    <description>For each participant with Allergic Asthma, a baseline airway epithelial brushing was performed, allergen was instilled into one segment of the lung, and diluent (control) was instilled into another segment. Both segments were brushed for epithelial cells 7 days later. After processing the brushes to RNA and generating RNA sequencing data, the RNA transcript read counts for each gene underwent variance stabilized log normalization. Then we built a regression model which estimated the difference in miRNA read count in the allergen challenged as compared to the baseline sample and the difference in miRNA read count in the diluent challenged segment as compared to baseline for each participant. The change from baseline read count for each miRNA in the allergen samples was compared to the change in the diluent samples and statistical significance was assessed using the unadjusted p-value(&lt;0.05). The direction of change does not have clinical significance; this was a mechanistic study.</description>
  </primary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">28</enrollment>
  <condition>Asthma</condition>
  <arm_group>
    <arm_group_label>Allergen challenge subjects</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Intervention: Segmental airway allergen challenge&#xD;
Three types of subjects are studied in this arm:&#xD;
1) Volunteers with neither asthma nor allergy (as established by skin prick testing); 2) Volunteers with allergy (as established by skin prick testing) but without asthma; and 3) Volunteers with both asthma and allergy (as established by skin prick testing)</description>
  </arm_group>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>Segmental airway allergen challenge</intervention_name>
    <arm_group_label>Allergen challenge subjects</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>Bronchoscopy</intervention_name>
    <arm_group_label>Allergen challenge subjects</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Diagnostic Test</intervention_type>
    <intervention_name>Methacholine challenge test</intervention_name>
    <arm_group_label>Allergen challenge subjects</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Diagnostic Test</intervention_type>
    <intervention_name>Spirometry</intervention_name>
    <arm_group_label>Allergen challenge subjects</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Diagnostic Test</intervention_type>
    <intervention_name>Allergen skin prick test</intervention_name>
    <arm_group_label>Allergen challenge subjects</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Allergic/Non-Asthmatic subjects and Allergic/Asthmatic subjects&#xD;
&#xD;
        Inclusion Criteria:&#xD;
&#xD;
          -  Positive skin test to dust mite or cat allergen&#xD;
&#xD;
        Non-Allergic/Non-Asthmatic subjects&#xD;
&#xD;
        Inclusion Criteria:&#xD;
&#xD;
          -  Negative skin test to panel of 12 allergens, including dust mite and cat allergen&#xD;
&#xD;
        All groups&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  History of intubation for asthma exacerbation&#xD;
&#xD;
          -  Use of Xolair (omalizumab) within the last 6 months&#xD;
&#xD;
          -  Immunotherapy with cat or dust mite extract now or in the past 5 years&#xD;
&#xD;
          -  ≥ 10 pack-years smoking or any smoking in the past year&#xD;
&#xD;
          -  Other lung diseases, such as sarcoidosis, bronchiectasis or active lung infection&#xD;
&#xD;
          -  History of dermatographia&#xD;
&#xD;
          -  History of anaphylaxis to cat allergen&#xD;
&#xD;
          -  Participation in another research study involving a drug or biologic during the past&#xD;
             30 days&#xD;
&#xD;
          -  Presence of past or current medical problems/other factors that may pose additional&#xD;
             risks from participation or influence study results, as determined per study&#xD;
             investigator&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>50 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Prescott G Woodruff, MD, MPH</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of California, San Francisco</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>University of California, San Francisco</name>
      <address>
        <city>San Francisco</city>
        <state>California</state>
        <zip>94143</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <link>
    <url>http://acrc.ucsf.edu/</url>
    <description>UCSF Airway Clinical Research Center</description>
  </link>
  <verification_date>July 2022</verification_date>
  <study_first_submitted>August 28, 2014</study_first_submitted>
  <study_first_submitted_qc>August 29, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">September 3, 2014</study_first_posted>
  <results_first_submitted>April 26, 2022</results_first_submitted>
  <results_first_submitted_qc>July 19, 2022</results_first_submitted_qc>
  <results_first_posted type="Actual">August 16, 2022</results_first_posted>
  <disposition_first_submitted>January 29, 2021</disposition_first_submitted>
  <disposition_first_submitted_qc>January 29, 2021</disposition_first_submitted_qc>
  <disposition_first_posted type="Actual">February 2, 2021</disposition_first_posted>
  <last_update_submitted>July 19, 2022</last_update_submitted>
  <last_update_submitted_qc>July 19, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">August 16, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor-Investigator</responsible_party_type>
    <investigator_affiliation>University of California, San Francisco</investigator_affiliation>
    <investigator_full_name>Prescott Woodruff</investigator_full_name>
    <investigator_title>Professor of Medicine</investigator_title>
  </responsible_party>
  <keyword>Asthma</keyword>
  <keyword>Allergen challenge</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Asthma</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Methacholine Chloride</mesh_term>
  </intervention_browse>
  <provided_document_section>
    <provided_document>
      <document_type>Study Protocol and Statistical Analysis Plan</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>August 1, 2014</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/89/NCT02230189/Prot_SAP_000.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <group_list>
        <group group_id="P1">
          <title>Allergic Asthmatics(AA)</title>
          <description>Volunteers with both asthma and allergy (as established by skin prick testing)</description>
        </group>
        <group group_id="P2">
          <title>Allergic Non-Asthmatics(ANA)</title>
          <description>Volunteers with allergy (as established by skin prick testing) but without asthma;</description>
        </group>
        <group group_id="P3">
          <title>Non-Allergic Non-Asthmatics(NANA)</title>
          <description>Volunteers with neither asthma nor allergy (as established by skin prick testing)</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="22"/>
                <participants group_id="P2" count="2"/>
                <participants group_id="P3" count="4"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="17"/>
                <participants group_id="P2" count="2"/>
                <participants group_id="P3" count="3"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="5"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="1"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Withdrawal by Subject</title>
              <participants_list>
                <participants group_id="P1" count="3"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="1"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Lost to Follow-up</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Physician Decision</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>Allergic Non-asthmatics(ANA)</title>
          <description>) Volunteers with allergy (as established by skin prick testing) but without asthma</description>
        </group>
        <group group_id="B2">
          <title>Non-allergic Non-asthmatics(NANA)</title>
          <description>Volunteers with neither asthma nor allergy (as established by skin prick testing)</description>
        </group>
        <group group_id="B3">
          <title>Allergic Asthmatics(AA)</title>
          <description>Volunteers with both asthma and allergy (as established by skin prick testing)</description>
        </group>
        <group group_id="B4">
          <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="2"/>
            <count group_id="B2" value="3"/>
            <count group_id="B3" value="17"/>
            <count group_id="B4" value="22"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>&lt;=18 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="1"/>
                    <measurement group_id="B4" value="1"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Between 18 and 65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                    <measurement group_id="B2" value="3"/>
                    <measurement group_id="B3" value="16"/>
                    <measurement group_id="B4" value="21"/>
                  </measurement_list>
                </category>
                <category>
                  <title>&gt;=65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Age</title>
          <units>years</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="29.5" spread="2.12"/>
                    <measurement group_id="B2" value="29" spread="5"/>
                    <measurement group_id="B3" value="29.7" spread="7.15"/>
                    <measurement group_id="B4" value="29.5" spread="9.268"/>
                  </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="1"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="11"/>
                    <measurement group_id="B4" value="13"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                    <measurement group_id="B2" value="2"/>
                    <measurement group_id="B3" value="6"/>
                    <measurement group_id="B4" value="9"/>
                  </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="1"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="4"/>
                    <measurement group_id="B4" value="5"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Not Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                    <measurement group_id="B2" value="3"/>
                    <measurement group_id="B3" value="13"/>
                    <measurement group_id="B4" value="17"/>
                  </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 group_id="B4" 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 group_id="B4" 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="3"/>
                    <measurement group_id="B4" value="4"/>
                  </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="1"/>
                    <measurement group_id="B4" value="1"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Black or African American</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="2"/>
                    <measurement group_id="B4" value="3"/>
                  </measurement_list>
                </category>
                <category>
                  <title>White</title>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="8"/>
                    <measurement group_id="B4" value="11"/>
                  </measurement_list>
                </category>
                <category>
                  <title>More than one race</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="0"/>
                  </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="3"/>
                    <measurement group_id="B4" value="3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Region of Enrollment</title>
          <units>participants</units>
          <param>Number</param>
          <class_list>
            <class>
              <title>United States</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                    <measurement group_id="B2" value="3"/>
                    <measurement group_id="B3" value="17"/>
                    <measurement group_id="B4" value="22"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>FEV1</title>
          <units>liters</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="4.52" spread="1.71"/>
                    <measurement group_id="B2" value="4.22" spread="0.397"/>
                    <measurement group_id="B3" value="3.38" spread="0.789"/>
                    <measurement group_id="B4" value="3.6" spread="0.864"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Difference in Expression of Epithelial miRNAs (in Read Counts) 24 Hours After Allergen-challenge as Compared to 24 Hours After Diluent Challenge in Participants With Allergic Asthma</title>
        <description>For each participant with Allergic Asthma, a baseline airway epithelial brushing was performed, allergen was instilled into one segment of the lung, and diluent (control) was instilled into another segment. Both segments were brushed for epithelial cells 24 hours later. After processing brushes to RNA and generating RNA sequencing data, the RNA transcript read counts for each gene underwent variance stabilized log normalization. Then we built a regression model which estimated the difference in miRNA read count in the allergen challenged as compared to the baseline sample and the difference in miRNA read count in the diluent challenged segment as compared to baseline for each participant. The change from baseline read count for each miRNA in the allergen samples was compared to the change in the diluent samples and statistical significance was assessed using the unadjusted p-value(&lt;0.05). The direction of change does not have clinical significance; this was a mechanistic study.</description>
        <time_frame>24 hours</time_frame>
        <population>Our pre-specified primary outcome was limited to Allergic Asthmatics only. The rationale for this is that participants without allergy or asthma do not respond to Allergen Challenge and therefore the changes in miRNA are uninformative.</population>
        <group_list>
          <group group_id="O1">
            <title>Allergen Challenge Subjects</title>
            <description>Intervention: Segmental airway allergen challenge&#xD;
In this arm, we studied volunteers with both asthma and allergy (as established by skin prick testing)&#xD;
Biological/Vaccine: Segmental airway allergen challenge Procedure/Surgery: Bronchoscopy Diagnostic Test: Methacholine challenge test Diagnostic Test: Spirometry Diagnostic Test: Allergen skin prick test</description>
          </group>
          <group group_id="O2">
            <title>Diluent Challenge Subjects</title>
            <description>Intervention: Segmental airway diluent challenge&#xD;
In this arm, we studied volunteers with both asthma and allergy (as established by skin prick testing).</description>
          </group>
        </group_list>
        <measure>
          <title>Difference in Expression of Epithelial miRNAs (in Read Counts) 24 Hours After Allergen-challenge as Compared to 24 Hours After Diluent Challenge in Participants With Allergic Asthma</title>
          <description>For each participant with Allergic Asthma, a baseline airway epithelial brushing was performed, allergen was instilled into one segment of the lung, and diluent (control) was instilled into another segment. Both segments were brushed for epithelial cells 24 hours later. After processing brushes to RNA and generating RNA sequencing data, the RNA transcript read counts for each gene underwent variance stabilized log normalization. Then we built a regression model which estimated the difference in miRNA read count in the allergen challenged as compared to the baseline sample and the difference in miRNA read count in the diluent challenged segment as compared to baseline for each participant. The change from baseline read count for each miRNA in the allergen samples was compared to the change in the diluent samples and statistical significance was assessed using the unadjusted p-value(&lt;0.05). The direction of change does not have clinical significance; this was a mechanistic study.</description>
          <population>Our pre-specified primary outcome was limited to Allergic Asthmatics only. The rationale for this is that participants without allergy or asthma do not respond to Allergen Challenge and therefore the changes in miRNA are uninformative.</population>
          <units>Normalized log2 copy number</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="12"/>
                <count group_id="O2" value="12"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>miR4521</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="7.33" spread="0.79"/>
                    <measurement group_id="O2" value="6.74" spread="0.43"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>miR107</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="9.63" spread="0.61"/>
                    <measurement group_id="O2" value="9.01" spread="0.98"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>miR891a</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="7.02" spread="0.64"/>
                    <measurement group_id="O2" value="6.56" spread="0.46"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>miR363</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="9.55" spread="1.16"/>
                    <measurement group_id="O2" value="8.77" spread="1.07"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>miR1248</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="7.02" spread="0.31"/>
                    <measurement group_id="O2" value="7.21" spread="0.48"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>miR944</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="7.12" spread="0.19"/>
                    <measurement group_id="O2" value="7.27" spread="0.36"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>miR6806</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="6.63" spread="0.22"/>
                    <measurement group_id="O2" value="6.35" spread="0.13"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>miR103a</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="12.05" spread="0.38"/>
                    <measurement group_id="O2" value="11.7" spread="0.48"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>miR454-5p</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="6.77" spread="0.16"/>
                    <measurement group_id="O2" value="6.57" spread="0.28"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>miR320e</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="6.57" spread="0.16"/>
                    <measurement group_id="O2" value="6.69" spread="0.24"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>miR181a</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="8.29" spread="0.33"/>
                    <measurement group_id="O2" value="8.83" spread="0.86"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>miR130b</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="6.72" spread="0.17"/>
                    <measurement group_id="O2" value="6.5" spread="0.33"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>miR365a</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="6.4" spread="0.14"/>
                    <measurement group_id="O2" value="6.55" spread="0.21"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>miR135b</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="6.65" spread="0.22"/>
                    <measurement group_id="O2" value="6.43" spread="0.19"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>miR1273h</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="6.53" spread="0.24"/>
                    <measurement group_id="O2" value="6.62" spread="0.33"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>miR3177</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="6.79" spread="0.26"/>
                    <measurement group_id="O2" value="6.88" spread="0.27"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>miR4521</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.010</p_value>
            <method>t-test, 2 sided</method>
            <param_type>Mean Difference (Net)</param_type>
            <param_value>2.11</param_value>
            <ci_n_sides>2-Sided</ci_n_sides>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>miR107</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.010</p_value>
            <method>t-test, 2 sided</method>
            <param_type>Mean Difference (Net)</param_type>
            <param_value>0.56</param_value>
            <ci_n_sides>2-Sided</ci_n_sides>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>miR-891a</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.018</p_value>
            <method>t-test, 2 sided</method>
            <param_type>Mean Difference (Net)</param_type>
            <param_value>2.57</param_value>
            <ci_n_sides>2-Sided</ci_n_sides>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>miR363</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.021</p_value>
            <method>t-test, 2 sided</method>
            <param_type>Mean Difference (Net)</param_type>
            <param_value>0.88</param_value>
            <ci_n_sides>2-Sided</ci_n_sides>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>miR1248</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.028</p_value>
            <method>t-test, 2 sided</method>
            <param_type>Mean Difference (Net)</param_type>
            <param_value>-1</param_value>
            <ci_n_sides>2-Sided</ci_n_sides>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>miR944</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.033</p_value>
            <method>t-test, 2 sided</method>
            <param_type>Mean Difference (Net)</param_type>
            <param_value>-0.85</param_value>
            <ci_n_sides>2-Sided</ci_n_sides>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>miR6806</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.034</p_value>
            <method>t-test, 2 sided</method>
            <param_type>Mean Difference (Net)</param_type>
            <param_value>2.13</param_value>
            <ci_n_sides>2-Sided</ci_n_sides>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>miR103a</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.036</p_value>
            <method>t-test, 2 sided</method>
            <param_type>Mean Difference (Net)</param_type>
            <param_value>0.39</param_value>
            <ci_n_sides>2-Sided</ci_n_sides>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>miR454</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.037</p_value>
            <method>t-test, 2 sided</method>
            <param_type>Mean Difference (Net)</param_type>
            <param_value>1.69</param_value>
            <ci_n_sides>2-Sided</ci_n_sides>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>miR320e</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.041</p_value>
            <method>t-test, 2 sided</method>
            <param_type>Mean Difference (Net)</param_type>
            <param_value>-1.13</param_value>
            <ci_n_sides>2-Sided</ci_n_sides>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>miR181a</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.043</p_value>
            <method>t-test, 2 sided</method>
            <param_type>Mean Difference (Net)</param_type>
            <param_value>-0.55</param_value>
            <ci_n_sides>2-Sided</ci_n_sides>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>miR130b</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.044</p_value>
            <method>t-test, 2 sided</method>
            <param_type>Mean Difference (Net)</param_type>
            <param_value>1.95</param_value>
            <ci_n_sides>2-Sided</ci_n_sides>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>miR365a</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.044</p_value>
            <method>t-test, 2 sided</method>
            <param_type>Mean Difference (Net)</param_type>
            <param_value>-2.18</param_value>
            <ci_n_sides>2-Sided</ci_n_sides>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>miR135b</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.047</p_value>
            <method>t-test, 2 sided</method>
            <param_type>Mean Difference (Net)</param_type>
            <param_value>2.06</param_value>
            <ci_n_sides>2-Sided</ci_n_sides>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>miR1273h</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.048</p_value>
            <method>t-test, 2 sided</method>
            <param_type>Mean Difference (Net)</param_type>
            <param_value>-2.35</param_value>
            <ci_n_sides>2-Sided</ci_n_sides>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>miR3177</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.048</p_value>
            <method>t-test, 2 sided</method>
            <param_type>Mean Difference (Net)</param_type>
            <param_value>-1.31</param_value>
            <ci_n_sides>2-Sided</ci_n_sides>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Difference in Expression of Epithelial miRNAs (in Read Counts) 7 Days After Allergen-challenge as Compared to 7 Days After Diluent Challenge</title>
        <description>For each participant with Allergic Asthma, a baseline airway epithelial brushing was performed, allergen was instilled into one segment of the lung, and diluent (control) was instilled into another segment. Both segments were brushed for epithelial cells 7 days later. After processing the brushes to RNA and generating RNA sequencing data, the RNA transcript read counts for each gene underwent variance stabilized log normalization. Then we built a regression model which estimated the difference in miRNA read count in the allergen challenged as compared to the baseline sample and the difference in miRNA read count in the diluent challenged segment as compared to baseline for each participant. The change from baseline read count for each miRNA in the allergen samples was compared to the change in the diluent samples and statistical significance was assessed using the unadjusted p-value(&lt;0.05). The direction of change does not have clinical significance; this was a mechanistic study.</description>
        <time_frame>7 days</time_frame>
        <population>Our pre-specified primary outcome was limited to Allergic Asthmatics only. The rationale for this is that participants without allergy or asthma do not respond to Allergen Challenge and therefore the changes in miRNA are uninformative.</population>
        <group_list>
          <group group_id="O1">
            <title>Allergen Challenge Segment</title>
            <description>Intervention: Segmental airway allergen challenge&#xD;
In this arm, we studied volunteers with both asthma and allergy (as established by skin prick testing)&#xD;
Biological/Vaccine: Segmental airway allergen challenge Procedure/Surgery: Bronchoscopy Diagnostic Test: Methacholine challenge test Diagnostic Test: Spirometry Diagnostic Test: Allergen skin prick test</description>
          </group>
          <group group_id="O2">
            <title>Diluent Challenge Segment</title>
            <description>Intervention: Segmental airway diluent challenge&#xD;
In this arm, we studied volunteers with both asthma and allergy (as established by skin prick testing).</description>
          </group>
        </group_list>
        <measure>
          <title>Difference in Expression of Epithelial miRNAs (in Read Counts) 7 Days After Allergen-challenge as Compared to 7 Days After Diluent Challenge</title>
          <description>For each participant with Allergic Asthma, a baseline airway epithelial brushing was performed, allergen was instilled into one segment of the lung, and diluent (control) was instilled into another segment. Both segments were brushed for epithelial cells 7 days later. After processing the brushes to RNA and generating RNA sequencing data, the RNA transcript read counts for each gene underwent variance stabilized log normalization. Then we built a regression model which estimated the difference in miRNA read count in the allergen challenged as compared to the baseline sample and the difference in miRNA read count in the diluent challenged segment as compared to baseline for each participant. The change from baseline read count for each miRNA in the allergen samples was compared to the change in the diluent samples and statistical significance was assessed using the unadjusted p-value(&lt;0.05). The direction of change does not have clinical significance; this was a mechanistic study.</description>
          <population>Our pre-specified primary outcome was limited to Allergic Asthmatics only. The rationale for this is that participants without allergy or asthma do not respond to Allergen Challenge and therefore the changes in miRNA are uninformative.</population>
          <units>Normalized log2 copy number</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="4"/>
                <count group_id="O2" value="4"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>miR6510</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="7.74" spread="0.57"/>
                    <measurement group_id="O2" value="9.2" spread="0.81"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>miR3605</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="5.92" spread="0.61"/>
                    <measurement group_id="O2" value="6.9" spread="0.8"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>miR3912</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="5.03" spread="0.53"/>
                    <measurement group_id="O2" value="5.83" spread="0.61"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>miR15b</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="6.76" spread="0.33"/>
                    <measurement group_id="O2" value="6.09" spread="0.39"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>miR127</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="7.06" spread="0.8"/>
                    <measurement group_id="O2" value="8.54" spread="1.73"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>miR146a</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="14.14" spread="1.19"/>
                    <measurement group_id="O2" value="12.73" spread="0.8"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>miR449b</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="9.99" spread="0.54"/>
                    <measurement group_id="O2" value="8.84" spread="0.88"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>miR21-5p</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="18.02" spread="0.33"/>
                    <measurement group_id="O2" value="17" spread="0.82"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>miR6842</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="6.83" spread="0.37"/>
                    <measurement group_id="O2" value="7.67" spread="0.44"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>miR142-5p</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="7.68" spread="0.38"/>
                    <measurement group_id="O2" value="6.93" spread="0.66"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>miR21</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="7.97" spread="0.49"/>
                    <measurement group_id="O2" value="6.83" spread="0.99"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>miR493</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="5.03" spread="0.31"/>
                    <measurement group_id="O2" value="5.66" spread="0.67"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>miR193a</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="6.66" spread="0.99"/>
                    <measurement group_id="O2" value="7.46" spread="0.72"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>miR149</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="9.98" spread="0.42"/>
                    <measurement group_id="O2" value="10.95" spread="0.4"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>miR449a</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="12.46" spread="0.56"/>
                    <measurement group_id="O2" value="11.36" spread="0.95"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>miR6511a</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="5.58" spread="0.66"/>
                    <measurement group_id="O2" value="6.46" spread="0.56"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>miR6843</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="5.99" spread="0.11"/>
                    <measurement group_id="O2" value="6.8" spread="0.67"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>miR671</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="8.53" spread="0.87"/>
                    <measurement group_id="O2" value="9.3" spread="0.73"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>miR6503</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="4.93" spread="0.19"/>
                    <measurement group_id="O2" value="5.56" spread="0.59"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>miR450b</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="6.05" spread="0.4"/>
                    <measurement group_id="O2" value="5.35" spread="0.52"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>miR485</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="5.08" spread="0.62"/>
                    <measurement group_id="O2" value="5.68" spread="0.72"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>miR6806</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="5.22" spread="0.38"/>
                    <measurement group_id="O2" value="5.85" spread="0.43"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>miR3182</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="5.92" spread="0.2"/>
                    <measurement group_id="O2" value="5.68" spread="0.97"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>miR142-3p</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="7.58" spread="0.21"/>
                    <measurement group_id="O2" value="6.72" spread="0.91"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>miR320d</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="6.48" spread="0.33"/>
                    <measurement group_id="O2" value="7.09" spread="0.72"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>miR3928</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="5.95" spread="0.3"/>
                    <measurement group_id="O2" value="5.24" spread="0.49"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>miR744</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="5.6" spread="0.58"/>
                    <measurement group_id="O2" value="5.1" spread="0.47"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>miR206</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="5.67" spread="1.06"/>
                    <measurement group_id="O2" value="5.18" spread="0.61"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>miR30e</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="11.3" spread="0.29"/>
                    <measurement group_id="O2" value="10.36" spread="0.7"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>miR4500</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="6.21" spread="0.41"/>
                    <measurement group_id="O2" value="5.61" spread="0.22"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>miR125a</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="13.66" spread="1.47"/>
                    <measurement group_id="O2" value="14.55" spread="1.18"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>miR99b</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="13.78" spread="0.31"/>
                    <measurement group_id="O2" value="14.33" spread="0.4"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>miR1</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="5.86" spread="0.76"/>
                    <measurement group_id="O2" value="5.17" spread="0.49"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>miR146b</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="14.13" spread="0.38"/>
                    <measurement group_id="O2" value="14.72" spread="0.76"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>miR1255a</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="5.21" spread="0.54"/>
                    <measurement group_id="O2" value="5.79" spread="0.67"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>miR223</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="9.9" spread="0.6"/>
                    <measurement group_id="O2" value="8.9" spread="1.08"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>miR642a</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="7.8" spread="0.56"/>
                    <measurement group_id="O2" value="8.32" spread="0.22"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>miR548ae</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="5.86" spread="0.24"/>
                    <measurement group_id="O2" value="5.23" spread="0.4"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>miR146b-3p</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="7.9" spread="0.35"/>
                    <measurement group_id="O2" value="8.58" spread="0.31"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>miR877</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="5.13" spread="0.42"/>
                    <measurement group_id="O2" value="5.66" spread="0.39"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>miR181a</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="8.25" spread="0.32"/>
                    <measurement group_id="O2" value="8.74" spread="0.58"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>miR4467</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="5.17" spread="0.47"/>
                    <measurement group_id="O2" value="5.56" spread="0.92"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>miR1249</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="5.05" spread="0.35"/>
                    <measurement group_id="O2" value="5.62" spread="0.44"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>miR766</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="5.59" spread="0.63"/>
                    <measurement group_id="O2" value="4.98" spread="0.3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>miR29c</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="7.93" spread="0.56"/>
                    <measurement group_id="O2" value="7.09" spread="0.78"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>miR370</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="5.77" spread="0.76"/>
                    <measurement group_id="O2" value="6.51" spread="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>miR6510</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.0</p_value>
            <method>t-test, 2 sided</method>
            <param_type>Mean Difference (Net)</param_type>
            <param_value>-1.83</param_value>
            <ci_n_sides>2-Sided</ci_n_sides>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>miR3605</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0</p_value>
            <method>t-test, 2 sided</method>
            <param_type>Mean Difference (Net)</param_type>
            <param_value>-2.09</param_value>
            <ci_n_sides>2-Sided</ci_n_sides>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>miR3912</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0</p_value>
            <method>t-test, 2 sided</method>
            <param_type>Mean Difference (Net)</param_type>
            <param_value>-5.75</param_value>
            <ci_n_sides>2-Sided</ci_n_sides>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>miR15b</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0</p_value>
            <method>t-test, 2 sided</method>
            <param_type>Median Difference (Net)</param_type>
            <param_value>1.93</param_value>
            <ci_n_sides>2-Sided</ci_n_sides>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>miR127</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0</p_value>
            <method>t-test, 2 sided</method>
            <param_type>Mean Difference (Net)</param_type>
            <param_value>-2.35</param_value>
            <ci_n_sides>2-Sided</ci_n_sides>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>miR146a</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0</p_value>
            <method>t-test, 2 sided</method>
            <param_type>Mean Difference (Net)</param_type>
            <param_value>1.59</param_value>
            <ci_n_sides>2-Sided</ci_n_sides>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>miR449b</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0</p_value>
            <method>t-test, 2 sided</method>
            <param_type>Mean Difference (Net)</param_type>
            <param_value>1.21</param_value>
            <ci_n_sides>2-Sided</ci_n_sides>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>miR21-5p</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.01</p_value>
            <method>t-test, 2 sided</method>
            <param_type>Mean Difference (Net)</param_type>
            <param_value>0.85</param_value>
            <ci_n_sides>2-Sided</ci_n_sides>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>miR6842</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.01</p_value>
            <method>t-test, 2 sided</method>
            <param_type>Mean Difference (Net)</param_type>
            <param_value>-1.29</param_value>
            <ci_n_sides>2-Sided</ci_n_sides>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>miR142-5p</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.01</p_value>
            <method>t-test, 2 sided</method>
            <param_type>Mean Difference (Net)</param_type>
            <param_value>1.24</param_value>
            <ci_n_sides>2-Sided</ci_n_sides>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>miR21</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.01</p_value>
            <method>t-test, 2 sided</method>
            <param_type>Mean Difference (Net)</param_type>
            <param_value>1.67</param_value>
            <ci_n_sides>2-Sided</ci_n_sides>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>miR493</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.01</p_value>
            <method>t-test, 2 sided</method>
            <param_type>Mean Difference (Net)</param_type>
            <param_value>-4.24</param_value>
            <ci_n_sides>2-Sided</ci_n_sides>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>miR193a</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.01</p_value>
            <method>t-test, 2 sided</method>
            <param_type>Mean Difference (Net)</param_type>
            <param_value>-1.46</param_value>
            <ci_n_sides>2-Sided</ci_n_sides>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>miR149</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.01</p_value>
            <method>t-test, 2 sided</method>
            <param_type>Mean Difference (Net)</param_type>
            <param_value>-0.89</param_value>
            <ci_n_sides>2-Sided</ci_n_sides>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>miR449a</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.01</p_value>
            <method>t-test, 2 sided</method>
            <param_type>Mean Difference (Net)</param_type>
            <param_value>1.06</param_value>
            <ci_n_sides>2-Sided</ci_n_sides>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>miR6511a</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.01</p_value>
            <method>t-test, 2 sided</method>
            <param_type>Mean Difference (Net)</param_type>
            <param_value>-2.1</param_value>
            <ci_n_sides>2-Sided</ci_n_sides>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>miR6843</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.01</p_value>
            <method>t-test, 2 sided</method>
            <param_type>Mean Difference (Net)</param_type>
            <param_value>-1.59</param_value>
            <ci_n_sides>2-Sided</ci_n_sides>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>miR671</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.01</p_value>
            <method>t-test, 2 sided</method>
            <param_type>Mean Difference (Net)</param_type>
            <param_value>-0.95</param_value>
            <ci_n_sides>2-Sided</ci_n_sides>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>miR6503</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.02</p_value>
            <method>t-test, 2 sided</method>
            <param_type>Mean Difference (Net)</param_type>
            <param_value>-4.65</param_value>
            <ci_n_sides>2-Sided</ci_n_sides>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>miR450b</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.02</p_value>
            <method>t-test, 2 sided</method>
            <param_type>Mean Difference (Net)</param_type>
            <param_value>2.84</param_value>
            <ci_n_sides>2-Sided</ci_n_sides>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>miR485</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.02</p_value>
            <method>t-test, 2 sided</method>
            <param_type>Mean Difference (Net)</param_type>
            <param_value>-4.92</param_value>
            <ci_n_sides>2-Sided</ci_n_sides>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>miR6806</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.02</p_value>
            <method>t-test, 2 sided</method>
            <param_type>Mean Difference (Net)</param_type>
            <param_value>-2.49</param_value>
            <ci_n_sides>2-Sided</ci_n_sides>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>miR3182</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.02</p_value>
            <method>t-test, 2 sided</method>
            <param_type>Mean Difference (Net)</param_type>
            <param_value>2.18</param_value>
            <ci_n_sides>2-Sided</ci_n_sides>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>miR142-3p</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.02</p_value>
            <method>t-test, 2 sided</method>
            <param_type>Mean Difference (Net)</param_type>
            <param_value>1.28</param_value>
            <ci_n_sides>2-Sided</ci_n_sides>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>miR320d</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.02</p_value>
            <method>t-test, 2 sided</method>
            <param_type>Mean Difference (Net)</param_type>
            <param_value>-1.23</param_value>
            <ci_n_sides>2-Sided</ci_n_sides>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>miR3928</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.02</p_value>
            <method>t-test, 2 sided</method>
            <param_type>Mean Difference (Net)</param_type>
            <param_value>2.73</param_value>
            <ci_n_sides>2-Sided</ci_n_sides>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>miR744</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.02</p_value>
            <method>t-test, 2 sided</method>
            <param_type>Mean Difference (Net)</param_type>
            <param_value>4.59</param_value>
            <ci_n_sides>2-Sided</ci_n_sides>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>miR206</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.02</p_value>
            <method>t-test, 2 sided</method>
            <param_type>Median Difference (Net)</param_type>
            <param_value>3.42</param_value>
            <ci_n_sides>2-Sided</ci_n_sides>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>miR30e</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.03</p_value>
            <method>t-test, 2 sided</method>
            <param_type>Mean Difference (Net)</param_type>
            <param_value>0.9</param_value>
            <ci_n_sides>2-Sided</ci_n_sides>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>miR4500</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.03</p_value>
            <method>t-test, 2 sided</method>
            <param_type>Mean Difference (Net)</param_type>
            <param_value>1.52</param_value>
            <ci_n_sides>2-Sided</ci_n_sides>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>miR125a</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.03</p_value>
            <method>t-test, 2 sided</method>
            <param_type>Mean Difference (Net)</param_type>
            <param_value>-0.98</param_value>
            <ci_n_sides>2-Sided</ci_n_sides>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>miR99b</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.03</p_value>
            <method>t-test, 2 sided</method>
            <param_type>Mean Difference (Net)</param_type>
            <param_value>-0.6</param_value>
            <ci_n_sides>2-Sided</ci_n_sides>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>miR1</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.03</p_value>
            <method>t-test, 2 sided</method>
            <param_type>Mean Difference (Net)</param_type>
            <param_value>2.67</param_value>
            <ci_n_sides>2-Sided</ci_n_sides>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>miR146b</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.03</p_value>
            <method>t-test, 2 sided</method>
            <param_type>Mean Difference (Net)</param_type>
            <param_value>-0.77</param_value>
            <ci_n_sides>2-Sided</ci_n_sides>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>miR1255a</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.03</p_value>
            <method>t-test, 2 sided</method>
            <param_type>Mean Difference (Net)</param_type>
            <param_value>-3.17</param_value>
            <ci_n_sides>2-Sided</ci_n_sides>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>miR223</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.03</p_value>
            <method>t-test, 2 sided</method>
            <param_type>Mean Difference (Net)</param_type>
            <param_value>1.02</param_value>
            <ci_n_sides>2-Sided</ci_n_sides>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>miR642a</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.03</p_value>
            <method>t-test, 2 sided</method>
            <param_type>Mean Difference (Net)</param_type>
            <param_value>-0.78</param_value>
            <ci_n_sides>2-Sided</ci_n_sides>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>miR548ae</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.4</p_value>
            <method>t-test, 2 sided</method>
            <param_type>Mean Difference (Net)</param_type>
            <param_value>2.17</param_value>
            <ci_n_sides>2-Sided</ci_n_sides>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>miR146b</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.04</p_value>
            <method>t-test, 2 sided</method>
            <param_type>Mean Difference (Net)</param_type>
            <param_value>-0.79</param_value>
            <ci_n_sides>2-Sided</ci_n_sides>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>miR877</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.04</p_value>
            <method>t-test, 2 sided</method>
            <param_type>Mean Difference (Net)</param_type>
            <param_value>-2.52</param_value>
            <ci_n_sides>2-Sided</ci_n_sides>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>miR181a</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.04</p_value>
            <method>t-test, 2 sided</method>
            <param_type>Mean Difference (Net)</param_type>
            <param_value>-0.69</param_value>
            <ci_n_sides>2-Sided</ci_n_sides>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>miR4467</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.04</p_value>
            <method>t-test, 2 sided</method>
            <param_type>Mean Difference (Net)</param_type>
            <param_value>-3.4</param_value>
            <ci_n_sides>2-Sided</ci_n_sides>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>miR1249</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.04</p_value>
            <method>t-test, 2 sided</method>
            <param_type>Mean Difference (Net)</param_type>
            <param_value>-2.48</param_value>
            <ci_n_sides>2-Sided</ci_n_sides>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>miR766</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.04</p_value>
            <method>t-test, 2 sided</method>
            <param_type>Mean Difference (Net)</param_type>
            <param_value>3.87</param_value>
            <ci_n_sides>2-Sided</ci_n_sides>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>miR29c</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.048</p_value>
            <method>t-test, 2 sided</method>
            <param_type>Mean Difference (Net)</param_type>
            <param_value>1.07</param_value>
            <ci_n_sides>2-Sided</ci_n_sides>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>miR370</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>-1.75</p_value>
            <method>t-test, 2 sided</method>
            <param_type>Mean Difference (Net)</param_type>
            <param_value>-1.75</param_value>
            <ci_n_sides>2-Sided</ci_n_sides>
          </analysis>
        </analysis_list>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>Adverse event data were prospectively collected from the first visit until 48 hours after the last study visit in all participants and until the resolution of any potential adverse event reported by a subject after a study procedure, up to 6 months.</time_frame>
      <group_list>
        <group group_id="E1">
          <title>Allergic Asthmatics(AA)</title>
          <description>Volunteers with both asthma and allergy (as established by skin prick testing)</description>
        </group>
        <group group_id="E2">
          <title>Allergic Non-Asthmatics(ANA)</title>
          <description>Volunteers with allergy (as established by skin prick testing) but without asthma;</description>
        </group>
        <group group_id="E3">
          <title>Non-Allergic Non-Asthmatics(NANA)</title>
          <description>Volunteers with neither asthma nor allergy (as established by skin prick testing)</description>
        </group>
      </group_list>
      <serious_events>
        <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="22"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="22"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="4"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Pregnancy, puerperium and perinatal conditions</title>
            <event_list>
              <event>
                <sub_title>Pregnancy identified during study enrollment</sub_title>
                <description>Participant was not pregnant upon enrollment (confirmed via urine pregnancy test). Participant later notified study team of pregnancy and was withdrawn prior to Visit 2 and Visit 3 bronchoscopies. Event was reported to sponsor and medical monitor.</description>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="22"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="4"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>3</frequency_threshold>
        <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="2" subjects_at_risk="22"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="4"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Increased systolic blood pressure post-bronchoscopy</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="22"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>Respiratory infection post-bronchoscopy</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="22"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="4"/>
              </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>
    <point_of_contact>
      <name_or_title>PI: Prescott G. Woodruff, MD, MPH</name_or_title>
      <organization>University of California, San Francisco</organization>
      <phone>415-514-2061</phone>
      <email>prescott.woodruff@ucsf.edu</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/NCT02230189
org study id: 14-14224
secondary id: 5U19AI077439
nct id: NCT02230189
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
This protocol describes a single site mechanistic study to investigate microRNAs (miRNAs)
      that are differentially expressed in the airway epithelium of patients with asthma at
      baseline and in response to allergen challenge. We hypothesize that allergen exposure
      enhances airway smooth muscle contractility and epithelial cell mRNA/miRNA production as a
      consequence of locally increased T-cell derived cytokine production. The study will involve
      three visits over the course of approximately 14 days. At Visit 1, participants will be
      characterized in detail with lung function testing, methacholine challenge testing, and
      allergen skin prick testing. At Visit 2, participants will undergo bronchoscopy with
      segmental allergen administration of either cat or dust mite standardized allergen extract.
      At Visit 3 (either 24 hours later or 7 days later), bronchoscopy will be performed to collect
      airway samples including bronchoalveolar lavage (BAL), epithelial brushings and endobronchial
      biopsies. Sample analysis will include measurement of miRNA and mRNA expression in epithelial
      brushings (RNAseq and qPCR); analysis of cell surface markers on BAL cells and blood cells;
      and collection of endobronchial biopsies for immunostaining of immune cells localization,
      immunoblotting of smooth cell protein phosphorylation, analysis of mucin content and smooth
      muscle cell subculture. A total of 38 subjects (26 asthmatics with stable or well-controlled
      asthma, 6 allergic non-asthmatics and 6 non-allergic non-asthmatics) will complete the study.
allocation: N/A
intervention model: Single Group Assignment
intervention model description: Single group before and after administration of allergen
primary purpose: Basic Science
masking: None (Open Label)
measure: Difference in Expression of Epithelial miRNAs (in Read Counts) 24 Hours After Allergen-challenge as Compared to 24 Hours After Diluent Challenge in Participants With Allergic Asthma
time frame: 24 hours
description: For each participant with Allergic Asthma, a baseline airway epithelial brushing was performed, allergen was instilled into one segment of the lung, and diluent (control) was instilled into another segment. Both segments were brushed for epithelial cells 24 hours later. After processing brushes to RNA and generating RNA sequencing data, the RNA transcript read counts for each gene underwent variance stabilized log normalization. Then we built a regression model which estimated the difference in miRNA read count in the allergen challenged as compared to the baseline sample and the difference in miRNA read count in the diluent challenged segment as compared to baseline for each participant. The change from baseline read count for each miRNA in the allergen samples was compared to the change in the diluent samples and statistical significance was assessed using the unadjusted p-value(<0.05). The direction of change does not have clinical significance; this was a mechanistic study.
measure: Difference in Expression of Epithelial miRNAs (in Read Counts) 7 Days After Allergen-challenge as Compared to 7 Days After Diluent Challenge
time frame: 7 days
description: For each participant with Allergic Asthma, a baseline airway epithelial brushing was performed, allergen was instilled into one segment of the lung, and diluent (control) was instilled into another segment. Both segments were brushed for epithelial cells 7 days later. After processing the brushes to RNA and generating RNA sequencing data, the RNA transcript read counts for each gene underwent variance stabilized log normalization. Then we built a regression model which estimated the difference in miRNA read count in the allergen challenged as compared to the baseline sample and the difference in miRNA read count in the diluent challenged segment as compared to baseline for each participant. The change from baseline read count for each miRNA in the allergen samples was compared to the change in the diluent samples and statistical significance was assessed using the unadjusted p-value(<0.05). The direction of change does not have clinical significance; this was a mechanistic study.
arm group label: Allergen challenge subjects
arm group type: Experimental
description: Intervention: Segmental airway allergen challenge
Three types of subjects are studied in this arm:
1) Volunteers with neither asthma nor allergy (as established by skin prick testing); 2) Volunteers with allergy (as established by skin prick testing) but without asthma; and 3) Volunteers with both asthma and allergy (as established by skin prick testing)
intervention type: Biological
intervention name: Segmental airway allergen challenge
arm group label: Allergen challenge subjects
intervention type: Procedure
intervention name: Bronchoscopy
arm group label: Allergen challenge subjects
intervention type: Diagnostic Test
intervention name: Methacholine challenge test
arm group label: Allergen challenge subjects
intervention type: Diagnostic Test
intervention name: Spirometry
arm group label: Allergen challenge subjects
intervention type: Diagnostic Test
intervention name: Allergen skin prick test
arm group label: Allergen challenge subjects
criteria: 
gender: All
minimum age: 18 Years
maximum age: 50 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Prescott G Woodruff, MD, MPH
role: Principal Investigator
affiliation: University of California, San Francisco
facility: 
country: United States
url: http://acrc.ucsf.edu/
description: UCSF Airway Clinical Research Center
responsible party type: Sponsor-Investigator
investigator affiliation: University of California, San Francisco
investigator full name: Prescott Woodruff
investigator title: Professor of Medicine
mesh term: Asthma
mesh term: Methacholine Chloride
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 