<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/NCT03008915</url>
  </required_header>
  <id_info>
    <org_study_id>AAAP9855</org_study_id>
    <nct_id>NCT03008915</nct_id>
  </id_info>
  <brief_title>Targeting Pulmonary Perfusion in Alpha-1 Antitrypsin Deficiency</brief_title>
  <official_title>Targeting Pulmonary Perfusion in Alpha-1 Antitrypsin Deficiency</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Columbia University</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Alpha-1 Foundation</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Stony Wold-Herbert Fund, Inc.</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Columbia University</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      The aim of this study is to test whether aspirin improves endothelial function in alpha-1&#xD;
      antitrypsin deficiency-associated lung disease, measured by pulmonary microvascular blood&#xD;
      flow on magnetic resonance imaging (MRI) and with apoptotic endothelial microparticles.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Emphysema is a common type of lung disease in patients with alpha-1 antitrypsin deficiency&#xD;
      (AATD). Emphysema refers to destruction of the fine network of air spaces and blood vessels&#xD;
      in the lung, and results in what looks like &quot;holes&quot; in the lung. Emphysema is associated with&#xD;
      an increased risk of death but currently no medications, except for replacement of alpha-1&#xD;
      antitrypsin (AAT), have been shown to treat emphysema.&#xD;
&#xD;
      The study plans to enroll subjects with alpha-1 antitrypsin deficiency-associated lung&#xD;
      disease (PiZZ phenotype) to perform a cross-over randomized controlled trial (RCT) of aspirin&#xD;
      compared to placebo to test the hypotheses that aspirin is effective in improving blood flow&#xD;
      in the lungs and reducing damage to the endothelial cells. Subjects will be randomized to&#xD;
      receive aspirin or placebo for 2 weeks. There will be a 2-week washout period, then the&#xD;
      participant will be crossed over to receive the other treatment (those who received aspirin&#xD;
      first will receive the placebo and those who received the placebo first will receive&#xD;
      aspirin).&#xD;
&#xD;
      Participants who are on alpha-1 replacement therapy who have had fewer than 2 exacerbations&#xD;
      in the last year will be asked whether they are interested in a withdrawal study. For this&#xD;
      second part of the study, eligible and willing participants will be asked to stop their&#xD;
      alpha-1 replacement therapy for 5 weeks and come in for a 4th study visit. This will allow&#xD;
      AAT levels to drop briefly to those seen in the absence of AAT augmentation.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">January 2017</start_date>
  <completion_date type="Actual">October 2020</completion_date>
  <primary_completion_date type="Actual">July 2018</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Crossover Assignment</intervention_model>
    <primary_purpose>Other</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Pulmonary Microvascular Blood Flow, Mean</measure>
    <time_frame>2 weeks</time_frame>
    <description>Pulmonary microvascular blood flow is measured on contrast-enhanced MRI, limited to blood flow in the 2cm periphery of the lung</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Endothelial Microparticles</measure>
    <time_frame>2 weeks</time_frame>
    <description>Endothelial microparticles (EMPs) are vesicles shed from endothelial plasma membranes into the circulation in response to endothelial cell perturbation. CD31+ is a measure of apoptotic endothelial microparticles, CD62+ (P-selectin) is a measure of endothelial activation, and Annexin V/CD31+ is a more specific marker of endothelial cell apoptosis.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Endothelial Microparticles</measure>
    <time_frame>5 weeks</time_frame>
    <description>Endothelial microparticles (EMPs) are vesicles shed from endothelial plasma membranes into the circulation in response to endothelial cell perturbation. CD31+ is a measure of apoptotic endothelial microparticles, CD62+ (P-selectin) is a measure of endothelial activation, and Annexin V/CD31+ is a more specific marker of endothelial cell apoptosis.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pulmonary Microvascular Blood Flow, Mean</measure>
    <time_frame>5 weeks</time_frame>
    <description>Pulmonary microvascular blood flow is measured on contrast-enhanced MRI in the peripheral 2cm of the lung.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">15</enrollment>
  <condition>Alpha-1 Antitrypsin Deficiency</condition>
  <condition>Emphysema</condition>
  <condition>Chronic Obstructive Pulmonary Disease</condition>
  <arm_group>
    <arm_group_label>Aspirin first then placebo</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Aspirin 81mg for 2 weeks followed by a washout period and then placebo for 2 weeks</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo first then aspirin</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Placebo for 2 weeks followed by a washout period and then aspirin 81mg for 2 weeks</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Aspirin</intervention_name>
    <description>81mg aspirin taken once per day in the morning</description>
    <arm_group_label>Aspirin first then placebo</arm_group_label>
    <arm_group_label>Placebo first then aspirin</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>placebo taken once per day in the morning</description>
    <arm_group_label>Aspirin first then placebo</arm_group_label>
    <arm_group_label>Placebo first then aspirin</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Withdrawal from alpha1 antitrypsin replacement therapy</intervention_name>
    <description>After the completion of the randomization to aspirin and placebo, participants who are on alpha1 replacement therapy are asked to withhold their usual alpha1 antitrypsin replacement therapy for 5 weeks. This is not randomized.</description>
    <arm_group_label>Aspirin first then placebo</arm_group_label>
    <arm_group_label>Placebo first then aspirin</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Alpha-1 antitrypsin deficiency (PiZZ genotype)&#xD;
&#xD;
          -  40 years of age or older&#xD;
&#xD;
          -  Evidence of emphysema on CT scan as read by a Radiologist&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Platelet count &lt; 150,000/dL, history of intracranial hemorrhage or severe GI bleed,&#xD;
             use of systemic anticoagulant, physician prescribed use of antiplatelet drug&#xD;
             (including aspirin and P2Y12 receptor inhibitors), or known severe liver disease&#xD;
&#xD;
          -  Immunosuppression by use of medications (including oral prednisone), or those with&#xD;
             immunomodulatory disease (organ transplantation, autoimmune conditions or&#xD;
             actively-treated malignancy)&#xD;
&#xD;
          -  Known atrial fibrillation or left ventricular (LV) systolic heart failure&#xD;
&#xD;
          -  Contraindication to MRI, including pregnancy, weight &gt; 300 lbs (due to weight limits&#xD;
             of the machine), those with pacemakers, aneurysm clips, cochlear implants or other&#xD;
             implanted electronic devices, or severe claustrophobia;&#xD;
&#xD;
          -  Chronic renal insufficiency (estimated GFR &lt; 45 L/min/1.73 m2 or self report) due to&#xD;
             slightly increased risk of nephrogenic systemic fibrosis from gadolinium&#xD;
             administration and aspirin-related renal insufficiency&#xD;
&#xD;
          -  Exacerbation of respiratory symptoms within the previous 6 weeks, such as that&#xD;
             requiring hospitalization, oral prednisone or antibiotics to control symptoms.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>40 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Carrie Aaron, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Columbia University</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Columbia University</name>
      <address>
        <city>New York</city>
        <state>New York</state>
        <zip>10032</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>January 2021</verification_date>
  <study_first_submitted>December 22, 2016</study_first_submitted>
  <study_first_submitted_qc>December 30, 2016</study_first_submitted_qc>
  <study_first_posted type="Estimate">January 4, 2017</study_first_posted>
  <results_first_submitted>November 30, 2020</results_first_submitted>
  <results_first_submitted_qc>January 28, 2021</results_first_submitted_qc>
  <results_first_posted type="Actual">February 17, 2021</results_first_posted>
  <disposition_first_submitted>July 30, 2019</disposition_first_submitted>
  <disposition_first_submitted_qc>January 30, 2020</disposition_first_submitted_qc>
  <disposition_first_posted type="Actual">February 7, 2020</disposition_first_posted>
  <last_update_submitted>January 28, 2021</last_update_submitted>
  <last_update_submitted_qc>January 28, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">February 17, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Columbia University</investigator_affiliation>
    <investigator_full_name>Carrie Aaron</investigator_full_name>
    <investigator_title>Assistant Professor of Medicine</investigator_title>
  </responsible_party>
  <keyword>alpha-1 antitrypsin deficiency</keyword>
  <keyword>Emphysema</keyword>
  <keyword>chronic obstructive pulmonary disease</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Alpha 1-Antitrypsin Deficiency</mesh_term>
    <mesh_term>Lung Diseases</mesh_term>
    <mesh_term>Lung Diseases, Obstructive</mesh_term>
    <mesh_term>Pulmonary Disease, Chronic Obstructive</mesh_term>
    <mesh_term>Pulmonary Emphysema</mesh_term>
    <mesh_term>Emphysema</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Aspirin</mesh_term>
    <mesh_term>Alpha 1-Antitrypsin</mesh_term>
    <mesh_term>Protein C Inhibitor</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <provided_document_section>
    <provided_document>
      <document_type>Study Protocol and Statistical Analysis Plan</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>April 11, 2017</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/15/NCT03008915/Prot_SAP_000.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <group_list>
        <group group_id="P1">
          <title>Aspirin First, Then Placebo</title>
          <description>Aspirin 81mg for 2 weeks followed by a washout period and then placebo for 2 weeks&#xD;
Aspirin: 81mg aspirin taken once per day in the morning&#xD;
Placebo: placebo taken once per day in the morning&#xD;
Withdrawal from alpha1 antitrypsin replacement therapy: After the completion of the randomization to aspirin and placebo, participants who are on alpha1 replacement therapy are asked to withhold their usual alpha1 antitrypsin replacement therapy for 5 weeks. This is not randomized.</description>
        </group>
        <group group_id="P2">
          <title>Placebo First, Then Aspirin</title>
          <description>Placebo for 2 weeks followed by a washout period and then aspirin 81mg for 2 weeks&#xD;
Aspirin: 81mg aspirin taken once per day in the morning&#xD;
Placebo: placebo taken once per day in the morning&#xD;
Withdrawal from alpha1 antitrypsin replacement therapy: After the completion of the randomization to aspirin and placebo, participants who are on alpha1 replacement therapy are asked to withhold their usual alpha1 antitrypsin replacement therapy for 5 weeks. This is not randomized.</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Treatment 1</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="8"/>
                <participants group_id="P2" count="7"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="8"/>
                <participants group_id="P2" count="6"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" 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="0"/>
                <participants group_id="P2" count="1"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
        <period>
          <title>Treatment 2</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="8"/>
                <participants group_id="P2" count="6"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="8"/>
                <participants group_id="P2" count="6"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <population>All participants</population>
      <group_list>
        <group group_id="B1">
          <title>Overall Study</title>
          <description>Baseline characteristics reported for all 15 participants in the crossover study.</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="15"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>years</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="15"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="55.6" spread="7.9"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Sex: Female, Male</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="15"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <title>Female</title>
                  <measurement_list>
                    <measurement group_id="B1" value="5"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="10"/>
                  </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>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="15"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <title>Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Not Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="15"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" 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>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="15"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <title>American Indian or Alaska Native</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Asian</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Native Hawaiian or Other Pacific Islander</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Black or African American</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>White</title>
                  <measurement_list>
                    <measurement group_id="B1" value="15"/>
                  </measurement_list>
                </category>
                <category>
                  <title>More than one race</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Region of Enrollment</title>
          <units>participants</units>
          <param>Number</param>
          <class_list>
            <class>
              <title>United States</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="15"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="15"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Smoking status</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="15"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <title>Former smoker</title>
                  <measurement_list>
                    <measurement group_id="B1" value="9"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Never smoker</title>
                  <measurement_list>
                    <measurement group_id="B1" value="6"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>FEV1/FVC ratio</title>
          <units>percent</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="15"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="44.0" spread="13.0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Percent emphysema, -950 HU</title>
          <population>1 participant withdrew before CT scan</population>
          <units>percent</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="14"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="21.2" spread="9.8"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Pulmonary Microvascular Blood Flow, Mean</title>
        <description>Pulmonary microvascular blood flow is measured on contrast-enhanced MRI, limited to blood flow in the 2cm periphery of the lung</description>
        <time_frame>2 weeks</time_frame>
        <population>Due to errors in acquisition of MRI, a number of participants had uninterpretable scans. 13 participants had MRIs interpretable for PMBF on placebo, and 7 on aspirin. Altogether, there were 6 participants with paired results from the two scans.</population>
        <group_list>
          <group group_id="O1">
            <title>Aspirin</title>
            <description>Assessment on aspirin 81mg for 2 weeks.</description>
          </group>
          <group group_id="O2">
            <title>Placebo</title>
            <description>Assessment on placebo for 2 weeks.</description>
          </group>
        </group_list>
        <measure>
          <title>Pulmonary Microvascular Blood Flow, Mean</title>
          <description>Pulmonary microvascular blood flow is measured on contrast-enhanced MRI, limited to blood flow in the 2cm periphery of the lung</description>
          <population>Due to errors in acquisition of MRI, a number of participants had uninterpretable scans. 13 participants had MRIs interpretable for PMBF on placebo, and 7 on aspirin. Altogether, there were 6 participants with paired results from the two scans.</population>
          <units>mL blood/minute per 100mL lung</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="6"/>
                <count group_id="O2" value="6"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="36.9" spread="13.0"/>
                    <measurement group_id="O2" value="35.1" spread="15.4"/>
                  </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>The null hypothesis is that there is no difference between measures on aspirin and placebo.</groups_desc>
            <non_inferiority_type>Other</non_inferiority_type>
            <non_inferiority_desc>Paired t-test for participants with measures on both aspirin and placebo.</non_inferiority_desc>
            <p_value>0.692</p_value>
            <method>t-test, 2 sided</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Endothelial Microparticles</title>
        <description>Endothelial microparticles (EMPs) are vesicles shed from endothelial plasma membranes into the circulation in response to endothelial cell perturbation. CD31+ is a measure of apoptotic endothelial microparticles, CD62+ (P-selectin) is a measure of endothelial activation, and Annexin V/CD31+ is a more specific marker of endothelial cell apoptosis.</description>
        <time_frame>2 weeks</time_frame>
        <population>Due to lab closure and technician availability, only the first 3 participants had EMPs measured.</population>
        <group_list>
          <group group_id="O1">
            <title>Aspirin</title>
            <description>Assessment on aspirin 81mg for 2 weeks.</description>
          </group>
          <group group_id="O2">
            <title>Placebo</title>
            <description>Assessment on placebo for 2 weeks.</description>
          </group>
        </group_list>
        <measure>
          <title>Endothelial Microparticles</title>
          <description>Endothelial microparticles (EMPs) are vesicles shed from endothelial plasma membranes into the circulation in response to endothelial cell perturbation. CD31+ is a measure of apoptotic endothelial microparticles, CD62+ (P-selectin) is a measure of endothelial activation, and Annexin V/CD31+ is a more specific marker of endothelial cell apoptosis.</description>
          <population>Due to lab closure and technician availability, only the first 3 participants had EMPs measured.</population>
          <units>EMPs/uL</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="3"/>
                <count group_id="O2" value="2"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>CD31+</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="749.0" spread="231.1"/>
                    <measurement group_id="O2" value="821.5" spread="3.5"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>CD62+</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1357.3" spread="469.6"/>
                    <measurement group_id="O2" value="596" spread="287.1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Annexin V, CD31+</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="145.0" spread="62.8"/>
                    <measurement group_id="O2" value="317.0" spread="210.7"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Endothelial Microparticles</title>
        <description>Endothelial microparticles (EMPs) are vesicles shed from endothelial plasma membranes into the circulation in response to endothelial cell perturbation. CD31+ is a measure of apoptotic endothelial microparticles, CD62+ (P-selectin) is a measure of endothelial activation, and Annexin V/CD31+ is a more specific marker of endothelial cell apoptosis.</description>
        <time_frame>5 weeks</time_frame>
        <population>Only 2 participants had EMPs measured on placebo and 2 off AAT replacement therapy, only 1 participant had EMPs measured at both time points.</population>
        <group_list>
          <group group_id="O1">
            <title>Off Alpha-1 Replacement Therapy</title>
            <description>Assessment after 5 weeks off alpha-1 replacement therapy</description>
          </group>
          <group group_id="O2">
            <title>Placebo</title>
            <description>Assessment on placebo for 2 weeks.</description>
          </group>
        </group_list>
        <measure>
          <title>Endothelial Microparticles</title>
          <description>Endothelial microparticles (EMPs) are vesicles shed from endothelial plasma membranes into the circulation in response to endothelial cell perturbation. CD31+ is a measure of apoptotic endothelial microparticles, CD62+ (P-selectin) is a measure of endothelial activation, and Annexin V/CD31+ is a more specific marker of endothelial cell apoptosis.</description>
          <population>Only 2 participants had EMPs measured on placebo and 2 off AAT replacement therapy, only 1 participant had EMPs measured at both time points.</population>
          <units>EMPs/uL</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="2"/>
                <count group_id="O2" value="2"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>CD31+</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="996.0" spread="408.7"/>
                    <measurement group_id="O2" value="821.5" spread="3.5"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>CD62+</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="3681.5" spread="3806.4"/>
                    <measurement group_id="O2" value="596.0" spread="287.1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Annexin V, CD31+</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="146.0" spread="186.7"/>
                    <measurement group_id="O2" value="317.0" spread="210.7"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Pulmonary Microvascular Blood Flow, Mean</title>
        <description>Pulmonary microvascular blood flow is measured on contrast-enhanced MRI in the peripheral 2cm of the lung.</description>
        <time_frame>5 weeks</time_frame>
        <population>2 participants who completed the withdrawal phase had MRIs interpretable for PMBF on placebo and off AAT replacement therapy, data for the other 2 participants was uninterpretable for at least 1 of the 2 scans.</population>
        <group_list>
          <group group_id="O1">
            <title>Off Alpha-1 Replacement Therapy</title>
            <description>Assessment after 5 weeks off alpha-1 replacement therapy</description>
          </group>
          <group group_id="O2">
            <title>Placebo</title>
            <description>Assessment on placebo for 2 weeks.</description>
          </group>
        </group_list>
        <measure>
          <title>Pulmonary Microvascular Blood Flow, Mean</title>
          <description>Pulmonary microvascular blood flow is measured on contrast-enhanced MRI in the peripheral 2cm of the lung.</description>
          <population>2 participants who completed the withdrawal phase had MRIs interpretable for PMBF on placebo and off AAT replacement therapy, data for the other 2 participants was uninterpretable for at least 1 of the 2 scans.</population>
          <units>mL blood/minute per 100mL lung</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="2"/>
                <count group_id="O2" value="13"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="35.5" spread="2.6"/>
                    <measurement group_id="O2" value="35.1" spread="11.0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>During the course of the study, typically this was 6 weeks, but up to 11 weeks for those also withheld their alpha-1 antitrypsin replacement therapy.</time_frame>
      <group_list>
        <group group_id="E1">
          <title>Aspirin</title>
          <description>Assessment on aspirin 81mg for 2 weeks.</description>
        </group>
        <group group_id="E2">
          <title>Placebo</title>
          <description>Assessment on placebo for 2 weeks.</description>
        </group>
      </group_list>
      <serious_events>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, all-cause mortality</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="14"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="14"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="15"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>0</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="0" subjects_at_risk="14"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="15"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Vascular disorders</title>
            <event_list>
              <event>
                <sub_title>Syncope</sub_title>
                <description>Patient developed syncope during spirometry/</description>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="14"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="15"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>Principal Investigators are NOT 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>Dr. Carrie Pistenmaa</name_or_title>
      <organization>Columbia University</organization>
      <phone>212-342-4162</phone>
      <email>cp2346@&quot;at&quot;cumc.columbia.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/NCT03008915
org study id: AAAP9855
nct id: NCT03008915
lead sponsor: 
collaborator: 
collaborator: 
has dmc: Yes
The aim of this study is to test whether aspirin improves endothelial function in alpha-1
      antitrypsin deficiency-associated lung disease, measured by pulmonary microvascular blood
      flow on magnetic resonance imaging (MRI) and with apoptotic endothelial microparticles.
Emphysema is a common type of lung disease in patients with alpha-1 antitrypsin deficiency
      (AATD). Emphysema refers to destruction of the fine network of air spaces and blood vessels
      in the lung, and results in what looks like "holes" in the lung. Emphysema is associated with
      an increased risk of death but currently no medications, except for replacement of alpha-1
      antitrypsin (AAT), have been shown to treat emphysema.

      The study plans to enroll subjects with alpha-1 antitrypsin deficiency-associated lung
      disease (PiZZ phenotype) to perform a cross-over randomized controlled trial (RCT) of aspirin
      compared to placebo to test the hypotheses that aspirin is effective in improving blood flow
      in the lungs and reducing damage to the endothelial cells. Subjects will be randomized to
      receive aspirin or placebo for 2 weeks. There will be a 2-week washout period, then the
      participant will be crossed over to receive the other treatment (those who received aspirin
      first will receive the placebo and those who received the placebo first will receive
      aspirin).

      Participants who are on alpha-1 replacement therapy who have had fewer than 2 exacerbations
      in the last year will be asked whether they are interested in a withdrawal study. For this
      second part of the study, eligible and willing participants will be asked to stop their
      alpha-1 replacement therapy for 5 weeks and come in for a 4th study visit. This will allow
      AAT levels to drop briefly to those seen in the absence of AAT augmentation.
allocation: Randomized
intervention model: Crossover Assignment
primary purpose: Other
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
measure: Pulmonary Microvascular Blood Flow, Mean
time frame: 2 weeks
description: Pulmonary microvascular blood flow is measured on contrast-enhanced MRI, limited to blood flow in the 2cm periphery of the lung
measure: Endothelial Microparticles
time frame: 2 weeks
description: Endothelial microparticles (EMPs) are vesicles shed from endothelial plasma membranes into the circulation in response to endothelial cell perturbation. CD31+ is a measure of apoptotic endothelial microparticles, CD62+ (P-selectin) is a measure of endothelial activation, and Annexin V/CD31+ is a more specific marker of endothelial cell apoptosis.
measure: Endothelial Microparticles
time frame: 5 weeks
description: Endothelial microparticles (EMPs) are vesicles shed from endothelial plasma membranes into the circulation in response to endothelial cell perturbation. CD31+ is a measure of apoptotic endothelial microparticles, CD62+ (P-selectin) is a measure of endothelial activation, and Annexin V/CD31+ is a more specific marker of endothelial cell apoptosis.
measure: Pulmonary Microvascular Blood Flow, Mean
time frame: 5 weeks
description: Pulmonary microvascular blood flow is measured on contrast-enhanced MRI in the peripheral 2cm of the lung.
arm group label: Aspirin first then placebo
arm group type: Active Comparator
description: Aspirin 81mg for 2 weeks followed by a washout period and then placebo for 2 weeks
arm group label: Placebo first then aspirin
arm group type: Placebo Comparator
description: Placebo for 2 weeks followed by a washout period and then aspirin 81mg for 2 weeks
intervention type: Drug
intervention name: Aspirin
description: 81mg aspirin taken once per day in the morning
arm group label: Aspirin first then placebo
arm group label: Placebo first then aspirin
intervention type: Drug
intervention name: Placebo
description: placebo taken once per day in the morning
arm group label: Aspirin first then placebo
arm group label: Placebo first then aspirin
intervention type: Other
intervention name: Withdrawal from alpha1 antitrypsin replacement therapy
description: After the completion of the randomization to aspirin and placebo, participants who are on alpha1 replacement therapy are asked to withhold their usual alpha1 antitrypsin replacement therapy for 5 weeks. This is not randomized.
arm group label: Aspirin first then placebo
arm group label: Placebo first then aspirin
criteria: 
gender: All
minimum age: 40 Years
maximum age: N/A
healthy volunteers: No
last name: Carrie Aaron, MD
role: Principal Investigator
affiliation: Columbia University
facility: 
country: United States
responsible party type: Principal Investigator
investigator affiliation: Columbia University
investigator full name: Carrie Aaron
investigator title: Assistant Professor of Medicine
mesh term: Alpha 1-Antitrypsin Deficiency
mesh term: Lung Diseases
mesh term: Lung Diseases, Obstructive
mesh term: Pulmonary Disease, Chronic Obstructive
mesh term: Pulmonary Emphysema
mesh term: Emphysema
mesh term: Aspirin
mesh term: Alpha 1-Antitrypsin
mesh term: Protein C Inhibitor
sharing ipd: No
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 