<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/NCT01700036</url>
  </required_header>
  <id_info>
    <org_study_id>umcc 2012.043</org_study_id>
    <secondary_id>HUM 67889</secondary_id>
    <nct_id>NCT01700036</nct_id>
  </id_info>
  <brief_title>A Pilot Study of Alpha-1-Antitrypsin (AAT) in Steroid Refractory Acute Graft vs Host Disease</brief_title>
  <official_title>A Pilot Study of Alpha-1-Antitrypsin (AAT) in Steroid Refractory Acute Graft vs Host Disease</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Michigan Rogel Cancer Center</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>CSL Behring</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
    <collaborator>
      <agency>The Leukemia and Lymphoma Society</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>University of Michigan Rogel Cancer Center</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      This clinical trial will study the safety and efficacy of using the drug Zemaira, an Alpha&#xD;
      1-Antitrypsin (AAT) medication (also known as an Alpha1-Proteinase Inhibitor [Human]) for the&#xD;
      treatment of steroid refractory GVHD.&#xD;
&#xD;
      For bone marrow transplant patients, the most common, serious complication is Graft vs Host&#xD;
      Disease (GVHD), which at its most severe is a life-threatening, complication and a&#xD;
      significant cause of treatment related death, following stem cell transplantation. GVHD is a&#xD;
      major obstacle to the overall success of transplant treatment, a strategy that would&#xD;
      otherwise provide the possibility of a cure for patients with blood cancers or severe blood&#xD;
      disorders. GVHD primarily affects the skin, gut, and liver of the recipient, and involves the&#xD;
      interaction of the recipient's (the host's) cells and tissues with the donor's immune system&#xD;
      cells that see the host tissues as foreign, and attack the host's cells resulting in tissue&#xD;
      and organ damage.&#xD;
&#xD;
      The severity of acute GvHD ranges from mild to severe, and for patients who don't respond to&#xD;
      steroid therapy, the complication is nearly always fatal, either from organ damage or&#xD;
      opportunistic infection as a consequence of high dose, steroid treatments.&#xD;
&#xD;
      There is currently no known effective therapy for patients with acute graft vs host disease&#xD;
      that's refractory (nonresponsive) to steroid therapy. As stated earlier,the overwhelming&#xD;
      majority of these patients may ultimately die from infection. The incidence of acute GvHD&#xD;
      that requires intervention, is higher for unrelated donor transplants, the most common&#xD;
      treatment option available, and therefore, these patients are at higher risk for treatment&#xD;
      related complications from GVHD. Approximately 20,000 unrelated donor transplants are&#xD;
      performed each year. The magnitude of this problem then is significant for patients who&#xD;
      otherwise might be cured of their blood cancer or disease.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Completed</overall_status>
  <start_date>July 2013</start_date>
  <completion_date type="Actual">October 26, 2018</completion_date>
  <primary_completion_date type="Actual">October 2016</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>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Percentage of Patients That Respond to Treatment</measure>
    <time_frame>4 weeks</time_frame>
    <description>To estimate the proportion of patients with steroid refractory acute Graft vs Host Disease) GvHD who respond (achieve either PR or CR) to Alpha-1 Antitrypsin (AAT) at a dose of 60mg/kg twice weekly for 8 doses&#xD;
Partial Response (PR) is defined as a decrease of at least one grade in the severity of GVHD without deterioration of any organ systems by d28 of therapy.&#xD;
Complete Response (CR) is defined as the resolution of all manifestations of GVHD by d28 of treatment. All organs must have a Stage 0.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Percentage of Patients Who Achieve a Complete Response to Treatment</measure>
    <time_frame>4 weeks</time_frame>
    <description>To estimate the proportion of patients in complete remission without additional therapy at four weeks after the last dose of AAT&#xD;
Complete remission is defined as the resolution of all manifestations of GVHD by d28 of treatment. All organs must have a Stage 0.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Percentage of Patients With Documented Infection</measure>
    <time_frame>30 days</time_frame>
    <description>To estimate the incidence of infection during and following treatment of steroid refractory acute GVHD with AAT</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>The Percentage of Patients Alive at 6 Months for Patients in CR or PR</measure>
    <time_frame>6 months</time_frame>
    <description>Survival at 6 months in patients receiving AAT treatment for steroid refractory acute GVHD for patients that achieved a CR or PR.&#xD;
Partial Response (PR) is defined as a decrease of at least one grade in the severity of GVHD without deterioration of any organ systems by d28 of therapy.&#xD;
Complete Response (CR) is defined as the resolution of all manifestations of GVHD by d28 of treatment. All organs must have a Stage 0.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Mean Fold Change in Plasma Biomarkers</measure>
    <time_frame>Baseline, 2 weeks, and 4 weeks</time_frame>
    <description>The fold change in levels of plasma biomarkers IL-6, TNF-alpha and ST2 will be measured pre-treatment and after the administration of AAT treatment for steroid refractory GvHD.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Mean Plasma Levels for Alpha-1-Antitrypsin (AAT)</measure>
    <time_frame>4 weeks</time_frame>
    <description>Plasma levels of Alpha-1-Antitrypsin(AAT)will be measured.</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">40</enrollment>
  <condition>Graft vs Host Disease</condition>
  <arm_group>
    <arm_group_label>Treatment arm</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Alpha-1-Antitrypsin (AAT) for the treatment of Steroid Refractory Acute Graft vs Host Disease.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Alpha-1-Antitrypsin (AAT)</intervention_name>
    <description>AAT (Zemaira) will be administered at a dose of 60mg/kg (actual weight) on D1, 4, 8, 12, 16, 20, 24, and 28. A second course of treatment will not be given.</description>
    <arm_group_label>Treatment arm</arm_group_label>
    <other_name>Zemaira</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Age &gt;18 years&#xD;
&#xD;
          -  Patients must have clinical evidence* of steroid-refractory acute Graft vs Host&#xD;
             Disease (any organ) defined as one of the following:&#xD;
&#xD;
               -  No change or progression in the stage of skin GvHD after at least 1 week of&#xD;
                  2mg/kg/day methylprednisolone (or po equivalent)&#xD;
&#xD;
               -  lack of response of visceral (liver, GI) GvHD despite treatment with 2mg/kg/day&#xD;
                  methylprednisolone for at least 72h.&#xD;
&#xD;
               -  progression of visceral GvHD despite treatment with 2mg/kg/day methylprednisolone&#xD;
                  for at least 48h&#xD;
&#xD;
               -  visceral GvHD progressing to stage 4 after 24h of 2mg/kg/d methylprednisolone&#xD;
&#xD;
               -  Patients with protracted acute GvHD who have not responded to at least 0.5mg/kg/d&#xD;
                  of prednisone are considered eligible.&#xD;
&#xD;
          -  Ability to understand and the willingness to sign a written informed consent document.&#xD;
&#xD;
          -  * As GvHD is a clinical diagnosis, and patients will have already been initiated on&#xD;
             steroid therapy at the discretion of the attending physician, tissue confirmation of&#xD;
             refractory GvHD by biopsy is not required for entry to this study. It is anticipated&#xD;
             that most, but not all, patients will have undergone tissue confirmation of the&#xD;
             initial diagnosis of GvHD; however lack of tissue confirmation for this clinical&#xD;
             syndrome is not exclusionary.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  As patients with steroid refractory acute GvHD are quite ill with multiple abnormal&#xD;
             labs and organ dysfunction, there are no explicit laboratory values or degree of organ&#xD;
             dysfunction that specifically preclude enrollment on this study. Baseline lab studies&#xD;
             will be obtained and followed throughout this trial as the standard of care for&#xD;
             patients with GvHD.&#xD;
&#xD;
          -  Pregnancy or Nursing Mother&#xD;
&#xD;
          -  Vasopressor requirement&#xD;
&#xD;
          -  Patients may not be receiving any other investigational agents for the treatment of&#xD;
             GvHD at time of study entry or at any time while on study or be on another&#xD;
             investigational agent that can impact on the primary clinical outcome analyses or has&#xD;
             known pharmacodynamics or pharmacokinetic effects on AAT.&#xD;
&#xD;
          -  Patients with known antibodies to IgA&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Pavan Reddy, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Michigan Rogel Cancer Center</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Dana-Farber Cancer Institute</name>
      <address>
        <city>Boston</city>
        <state>Massachusetts</state>
        <zip>02215</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Michigan Cancer Center</name>
      <address>
        <city>Ann Arbor</city>
        <state>Michigan</state>
        <zip>48109</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>October 2018</verification_date>
  <study_first_submitted>October 2, 2012</study_first_submitted>
  <study_first_submitted_qc>October 3, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">October 4, 2012</study_first_posted>
  <results_first_submitted>November 2, 2017</results_first_submitted>
  <results_first_submitted_qc>December 5, 2017</results_first_submitted_qc>
  <results_first_posted type="Actual">January 5, 2018</results_first_posted>
  <last_update_submitted>October 29, 2018</last_update_submitted>
  <last_update_submitted_qc>October 29, 2018</last_update_submitted_qc>
  <last_update_posted type="Actual">November 27, 2018</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Alpha 1-Antitrypsin Deficiency</mesh_term>
    <mesh_term>Graft vs Host Disease</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Alpha 1-Antitrypsin</mesh_term>
    <mesh_term>Protein C Inhibitor</mesh_term>
  </intervention_browse>

  <clinical_results>

    <participant_flow>
      <group_list>
        <group group_id="P1">
          <title>Treatment Arm</title>
          <description>Alpha-1-Antitrypsin (AAT) for the treatment of Steroid Refractory Acute Graft vs Host Disease.&#xD;
Alpha-1-Antitrypsin (AAT): AAT (Zemaira) will be administered at a dose of 60mg/kg (actual weight) on D1, 4, 8, 12, 16, 20, 24, and 28. A second course of treatment will not be given.</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="40"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="40"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>Treatment Arm</title>
          <description>Alpha-1-Antitrypsin (AAT) for the treatment of Steroid Refractory Acute Graft vs Host Disease.&#xD;
Alpha-1-Antitrypsin (AAT): AAT (Zemaira) will be administered at a dose of 60mg/kg (actual weight) on D1, 4, 8, 12, 16, 20, 24, and 28. A second course of treatment will not be given.</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="40"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>years</units>
          <param>Median</param>
          <dispersion>Full Range</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="59" lower_limit="18" upper_limit="70"/>
                  </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="13"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="27"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Percentage of Patients That Respond to Treatment</title>
        <description>To estimate the proportion of patients with steroid refractory acute Graft vs Host Disease) GvHD who respond (achieve either PR or CR) to Alpha-1 Antitrypsin (AAT) at a dose of 60mg/kg twice weekly for 8 doses&#xD;
Partial Response (PR) is defined as a decrease of at least one grade in the severity of GVHD without deterioration of any organ systems by d28 of therapy.&#xD;
Complete Response (CR) is defined as the resolution of all manifestations of GVHD by d28 of treatment. All organs must have a Stage 0.</description>
        <time_frame>4 weeks</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Treatment Arm</title>
            <description>Alpha-1-Antitrypsin (AAT): AAT (Zemaira) will be administered at a dose of 60mg/kg (actual weight) on D1, 4, 8, 12, 16, 20, 24, and 28.</description>
          </group>
        </group_list>
        <measure>
          <title>Percentage of Patients That Respond to Treatment</title>
          <description>To estimate the proportion of patients with steroid refractory acute Graft vs Host Disease) GvHD who respond (achieve either PR or CR) to Alpha-1 Antitrypsin (AAT) at a dose of 60mg/kg twice weekly for 8 doses&#xD;
Partial Response (PR) is defined as a decrease of at least one grade in the severity of GVHD without deterioration of any organ systems by d28 of therapy.&#xD;
Complete Response (CR) is defined as the resolution of all manifestations of GVHD by d28 of treatment. All organs must have a Stage 0.</description>
          <units>percentage of patients</units>
          <param>Number</param>
          <dispersion>95% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="40"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="65" lower_limit="48" upper_limit="79"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Percentage of Patients Who Achieve a Complete Response to Treatment</title>
        <description>To estimate the proportion of patients in complete remission without additional therapy at four weeks after the last dose of AAT&#xD;
Complete remission is defined as the resolution of all manifestations of GVHD by d28 of treatment. All organs must have a Stage 0.</description>
        <time_frame>4 weeks</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Treatment Arm</title>
            <description>Alpha-1-Antitrypsin (AAT): AAT (Zemaira) will be administered at a dose of 60mg/kg (actual weight) on D1, 4, 8, 12, 16, 20, 24, and 28.</description>
          </group>
        </group_list>
        <measure>
          <title>Percentage of Patients Who Achieve a Complete Response to Treatment</title>
          <description>To estimate the proportion of patients in complete remission without additional therapy at four weeks after the last dose of AAT&#xD;
Complete remission is defined as the resolution of all manifestations of GVHD by d28 of treatment. All organs must have a Stage 0.</description>
          <units>percentage of patients</units>
          <param>Number</param>
          <dispersion>95% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="40"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="35" lower_limit="21" upper_limit="52"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Percentage of Patients With Documented Infection</title>
        <description>To estimate the incidence of infection during and following treatment of steroid refractory acute GVHD with AAT</description>
        <time_frame>30 days</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Treatment Arm</title>
            <description>Alpha-1-Antitrypsin (AAT): AAT (Zemaira) will be administered at a dose of 60mg/kg (actual weight) on D1, 4, 8, 12, 16, 20, 24, and 28.</description>
          </group>
        </group_list>
        <measure>
          <title>Percentage of Patients With Documented Infection</title>
          <description>To estimate the incidence of infection during and following treatment of steroid refractory acute GVHD with AAT</description>
          <units>percentage of patients</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="40"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="32.5"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>The Percentage of Patients Alive at 6 Months for Patients in CR or PR</title>
        <description>Survival at 6 months in patients receiving AAT treatment for steroid refractory acute GVHD for patients that achieved a CR or PR.&#xD;
Partial Response (PR) is defined as a decrease of at least one grade in the severity of GVHD without deterioration of any organ systems by d28 of therapy.&#xD;
Complete Response (CR) is defined as the resolution of all manifestations of GVHD by d28 of treatment. All organs must have a Stage 0.</description>
        <time_frame>6 months</time_frame>
        <population>40 patients were enrolled and 26 patients achieved a CR or PR.</population>
        <group_list>
          <group group_id="O1">
            <title>Treatment Arm</title>
            <description>Alpha-1-Antitrypsin (AAT): AAT (Zemaira) will be administered at a dose of 60mg/kg (actual weight) on D1, 4, 8, 12, 16, 20, 24, and 28.</description>
          </group>
        </group_list>
        <measure>
          <title>The Percentage of Patients Alive at 6 Months for Patients in CR or PR</title>
          <description>Survival at 6 months in patients receiving AAT treatment for steroid refractory acute GVHD for patients that achieved a CR or PR.&#xD;
Partial Response (PR) is defined as a decrease of at least one grade in the severity of GVHD without deterioration of any organ systems by d28 of therapy.&#xD;
Complete Response (CR) is defined as the resolution of all manifestations of GVHD by d28 of treatment. All organs must have a Stage 0.</description>
          <population>40 patients were enrolled and 26 patients achieved a CR or PR.</population>
          <units>percentage of patients</units>
          <param>Number</param>
          <dispersion>95% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="26"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="50" lower_limit="34" upper_limit="73"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Mean Fold Change in Plasma Biomarkers</title>
        <description>The fold change in levels of plasma biomarkers IL-6, TNF-alpha and ST2 will be measured pre-treatment and after the administration of AAT treatment for steroid refractory GvHD.</description>
        <time_frame>Baseline, 2 weeks, and 4 weeks</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Treatment Arm</title>
            <description>Alpha-1-Antitrypsin (AAT): AAT (Zemaira) will be administered at a dose of 60mg/kg (actual weight) on D1, 4, 8, 12, 16, 20, 24, and 28.</description>
          </group>
        </group_list>
        <measure>
          <title>Mean Fold Change in Plasma Biomarkers</title>
          <description>The fold change in levels of plasma biomarkers IL-6, TNF-alpha and ST2 will be measured pre-treatment and after the administration of AAT treatment for steroid refractory GvHD.</description>
          <units>fold change from baseline</units>
          <param>Mean</param>
          <dispersion>Standard Error</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="40"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>IL-6 Fold Change at 2 weeks</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="6.3" spread="3.6"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>IL-6 Fold Change at 4 weeks</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="4" spread="1.9"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>TNF-alpha Fold Change at 2 weeks</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1.7" spread="0.8"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>TNF-alpha Fold Change at 4 weeks</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1.1" spread="0.2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>ST2 Fold Change at 2 weeks</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1.2" spread="0.4"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>ST2 Fold Change at 4 weeks</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1.5" spread="0.7"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Mean Plasma Levels for Alpha-1-Antitrypsin (AAT)</title>
        <description>Plasma levels of Alpha-1-Antitrypsin(AAT)will be measured.</description>
        <time_frame>4 weeks</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Treatment Arm</title>
            <description>Alpha-1-Antitrypsin (AAT): AAT (Zemaira) will be administered at a dose of 60mg/kg (actual weight) on D1, 4, 8, 12, 16, 20, 24, and 28.</description>
          </group>
        </group_list>
        <measure>
          <title>Mean Plasma Levels for Alpha-1-Antitrypsin (AAT)</title>
          <description>Plasma levels of Alpha-1-Antitrypsin(AAT)will be measured.</description>
          <units>mg/dl</units>
          <param>Mean</param>
          <dispersion>Standard Error</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="40"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>AAT levels at two weeks</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="196.8" spread="11.91"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>AAT levels at 4 weeks</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="214.8" spread="18.62"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>Patients will be followed for adverse events for 30 days after the last dose of the study drug.</time_frame>
      <group_list>
        <group group_id="E1">
          <title>Treatment Arm</title>
          <description>Alpha-1-Antitrypsin (AAT): AAT (Zemaira) will be administered at a dose of 60mg/kg (actual weight) on D1, 4, 8, 12, 16, 20, 24, and 28.</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="8" subjects_at_risk="40"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="11" subjects_at_risk="40"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Blood and lymphatic system disorders</title>
            <event_list>
              <event>
                <sub_title>Disseminated intravascular coagulation</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="40"/>
              </event>
              <event>
                <sub_title>Thrombotic thrombocytopenic purpura</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="40"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Colitis</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="40"/>
              </event>
              <event>
                <sub_title>Lower gastrointestinal hemorrhage</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="40"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Multi-organ failure</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="40"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Immune system disorders</title>
            <event_list>
              <event>
                <sub_title>Immune system disorder</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="40"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Bladder infection</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="40"/>
              </event>
              <event>
                <sub_title>Hepatic infection</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="40"/>
              </event>
              <event>
                <sub_title>Infection</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="40"/>
              </event>
              <event>
                <sub_title>Sepsis</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="40"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>Blood bilirubin increased</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="40"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Neoplasms benign, malignant and unspecified (incl cysts and polyps)</title>
            <event_list>
              <event>
                <sub_title>Neoplasms benign, malignant and unspecified</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="40"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Hypoxia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="40"/>
              </event>
              <event>
                <sub_title>Respiratory failure</sub_title>
                <counts group_id="E1" events="4" subjects_affected="3" subjects_at_risk="40"/>
              </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="31" subjects_at_risk="40"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Blood and lymphatic system disorders</title>
            <event_list>
              <event>
                <sub_title>Anemia</sub_title>
                <counts group_id="E1" events="4" subjects_affected="4" subjects_at_risk="40"/>
              </event>
              <event>
                <sub_title>Disseminated intravascular coagulation</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="40"/>
              </event>
              <event>
                <sub_title>Thrombotic thrombocytopenic purpura</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="40"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Cardiac disorders</title>
            <event_list>
              <event>
                <sub_title>Atrial fibrillation</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="40"/>
              </event>
              <event>
                <sub_title>Sinus bradycardia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="40"/>
              </event>
              <event>
                <sub_title>Sinus tachycardia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="40"/>
              </event>
              <event>
                <sub_title>Supraventricular tachycardia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="40"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Abdominal pain</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="40"/>
              </event>
              <event>
                <sub_title>Ascites</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="40"/>
              </event>
              <event>
                <sub_title>Colitis</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="40"/>
              </event>
              <event>
                <sub_title>Diarrhea</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="40"/>
              </event>
              <event>
                <sub_title>Gastrointestinal disorder</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="40"/>
              </event>
              <event>
                <sub_title>Lower gastrointestinal hemorrhage</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="40"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Fever</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="40"/>
              </event>
              <event>
                <sub_title>Multi-organ failure</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="40"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Immune system disorders</title>
            <event_list>
              <event>
                <sub_title>Immune system disorder</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="40"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Bladder infection</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="40"/>
              </event>
              <event>
                <sub_title>Device related infection</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="40"/>
              </event>
              <event>
                <sub_title>Enterocolitis infectious</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="40"/>
              </event>
              <event>
                <sub_title>Hepatic infection</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="40"/>
              </event>
              <event>
                <sub_title>Infection</sub_title>
                <counts group_id="E1" events="16" subjects_affected="11" subjects_at_risk="40"/>
              </event>
              <event>
                <sub_title>Kidney infection</sub_title>
                <counts group_id="E1" events="2" subjects_affected="1" subjects_at_risk="40"/>
              </event>
              <event>
                <sub_title>Lung infection</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="40"/>
              </event>
              <event>
                <sub_title>Mucosal infection</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="40"/>
              </event>
              <event>
                <sub_title>Sepsis</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="40"/>
              </event>
              <event>
                <sub_title>Skin infection</sub_title>
                <counts group_id="E1" events="3" subjects_affected="2" subjects_at_risk="40"/>
              </event>
              <event>
                <sub_title>Urinary tract infection</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="40"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Injury, poisoning and procedural complications</title>
            <event_list>
              <event>
                <sub_title>Spinal fracture</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="40"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>Alanine aminotransferase increased</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="40"/>
              </event>
              <event>
                <sub_title>Blood bilirubin increased</sub_title>
                <counts group_id="E1" events="6" subjects_affected="6" subjects_at_risk="40"/>
              </event>
              <event>
                <sub_title>Lymphocyte count decreased</sub_title>
                <counts group_id="E1" events="6" subjects_affected="5" subjects_at_risk="40"/>
              </event>
              <event>
                <sub_title>Lymphocyte count increased</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="40"/>
              </event>
              <event>
                <sub_title>Neutrophil count decreased</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="40"/>
              </event>
              <event>
                <sub_title>Platelet count decreased</sub_title>
                <counts group_id="E1" events="7" subjects_affected="5" subjects_at_risk="40"/>
              </event>
              <event>
                <sub_title>White blood cell decreased</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="40"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Metabolism and nutrition disorders</title>
            <event_list>
              <event>
                <sub_title>Anorexia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="40"/>
              </event>
              <event>
                <sub_title>Hyperglycemia</sub_title>
                <counts group_id="E1" events="7" subjects_affected="7" subjects_at_risk="40"/>
              </event>
              <event>
                <sub_title>Hyperkalemia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="40"/>
              </event>
              <event>
                <sub_title>Hypoalbuminemia</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="40"/>
              </event>
              <event>
                <sub_title>Hyponatremia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="40"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Generalized muscle weakness</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="40"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Neoplasms benign, malignant and unspecified (incl cysts and polyps)</title>
            <event_list>
              <event>
                <sub_title>Neoplasms benign, malignant and unspecified</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="40"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Encephalopathy</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="40"/>
              </event>
              <event>
                <sub_title>Nervous system disorder</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="40"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Psychiatric disorders</title>
            <event_list>
              <event>
                <sub_title>Delirium</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="40"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Renal and urinary disorders</title>
            <event_list>
              <event>
                <sub_title>Acute kidney injury</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="40"/>
              </event>
              <event>
                <sub_title>Hematuria</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="40"/>
              </event>
              <event>
                <sub_title>Urinary retention</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="40"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Dyspnea</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="40"/>
              </event>
              <event>
                <sub_title>Hypoxia</sub_title>
                <counts group_id="E1" events="4" subjects_affected="4" subjects_at_risk="40"/>
              </event>
              <event>
                <sub_title>Pneumonitis</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="40"/>
              </event>
              <event>
                <sub_title>Respiratory failure</sub_title>
                <counts group_id="E1" events="4" subjects_affected="3" subjects_at_risk="40"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Skin and subcutaneous tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Rash maculo-papular</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="40"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Vascular disorders</title>
            <event_list>
              <event>
                <sub_title>Hypertension</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="40"/>
              </event>
              <event>
                <sub_title>Hypotension</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="40"/>
              </event>
              <event>
                <sub_title>Thromboembolic event</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="40"/>
              </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>Dr. Pavan Reddy, MD</name_or_title>
      <organization>University of Michigan Cancer Center</organization>
      <phone>734-936-8785</phone>
      <email>reddypr@umich.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/NCT01700036
org study id: umcc 2012.043
secondary id: HUM 67889
nct id: NCT01700036
lead sponsor: 
collaborator: 
collaborator: 
has dmc: Yes
This clinical trial will study the safety and efficacy of using the drug Zemaira, an Alpha
      1-Antitrypsin (AAT) medication (also known as an Alpha1-Proteinase Inhibitor [Human]) for the
      treatment of steroid refractory GVHD.

      For bone marrow transplant patients, the most common, serious complication is Graft vs Host
      Disease (GVHD), which at its most severe is a life-threatening, complication and a
      significant cause of treatment related death, following stem cell transplantation. GVHD is a
      major obstacle to the overall success of transplant treatment, a strategy that would
      otherwise provide the possibility of a cure for patients with blood cancers or severe blood
      disorders. GVHD primarily affects the skin, gut, and liver of the recipient, and involves the
      interaction of the recipient's (the host's) cells and tissues with the donor's immune system
      cells that see the host tissues as foreign, and attack the host's cells resulting in tissue
      and organ damage.

      The severity of acute GvHD ranges from mild to severe, and for patients who don't respond to
      steroid therapy, the complication is nearly always fatal, either from organ damage or
      opportunistic infection as a consequence of high dose, steroid treatments.

      There is currently no known effective therapy for patients with acute graft vs host disease
      that's refractory (nonresponsive) to steroid therapy. As stated earlier,the overwhelming
      majority of these patients may ultimately die from infection. The incidence of acute GvHD
      that requires intervention, is higher for unrelated donor transplants, the most common
      treatment option available, and therefore, these patients are at higher risk for treatment
      related complications from GVHD. Approximately 20,000 unrelated donor transplants are
      performed each year. The magnitude of this problem then is significant for patients who
      otherwise might be cured of their blood cancer or disease.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Percentage of Patients That Respond to Treatment
time frame: 4 weeks
description: To estimate the proportion of patients with steroid refractory acute Graft vs Host Disease) GvHD who respond (achieve either PR or CR) to Alpha-1 Antitrypsin (AAT) at a dose of 60mg/kg twice weekly for 8 doses
Partial Response (PR) is defined as a decrease of at least one grade in the severity of GVHD without deterioration of any organ systems by d28 of therapy.
Complete Response (CR) is defined as the resolution of all manifestations of GVHD by d28 of treatment. All organs must have a Stage 0.
measure: Percentage of Patients Who Achieve a Complete Response to Treatment
time frame: 4 weeks
description: To estimate the proportion of patients in complete remission without additional therapy at four weeks after the last dose of AAT
Complete remission is defined as the resolution of all manifestations of GVHD by d28 of treatment. All organs must have a Stage 0.
measure: Percentage of Patients With Documented Infection
time frame: 30 days
description: To estimate the incidence of infection during and following treatment of steroid refractory acute GVHD with AAT
measure: The Percentage of Patients Alive at 6 Months for Patients in CR or PR
time frame: 6 months
description: Survival at 6 months in patients receiving AAT treatment for steroid refractory acute GVHD for patients that achieved a CR or PR.
Partial Response (PR) is defined as a decrease of at least one grade in the severity of GVHD without deterioration of any organ systems by d28 of therapy.
Complete Response (CR) is defined as the resolution of all manifestations of GVHD by d28 of treatment. All organs must have a Stage 0.
measure: Mean Fold Change in Plasma Biomarkers
time frame: Baseline, 2 weeks, and 4 weeks
description: The fold change in levels of plasma biomarkers IL-6, TNF-alpha and ST2 will be measured pre-treatment and after the administration of AAT treatment for steroid refractory GvHD.
measure: Mean Plasma Levels for Alpha-1-Antitrypsin (AAT)
time frame: 4 weeks
description: Plasma levels of Alpha-1-Antitrypsin(AAT)will be measured.
arm group label: Treatment arm
arm group type: Experimental
description: Alpha-1-Antitrypsin (AAT) for the treatment of Steroid Refractory Acute Graft vs Host Disease.
intervention type: Drug
intervention name: Alpha-1-Antitrypsin (AAT)
description: AAT (Zemaira) will be administered at a dose of 60mg/kg (actual weight) on D1, 4, 8, 12, 16, 20, 24, and 28. A second course of treatment will not be given.
arm group label: Treatment arm
other name: Zemaira
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Pavan Reddy, MD
role: Principal Investigator
affiliation: University of Michigan Rogel Cancer Center
facility: 
facility: 
country: United States
responsible party type: Sponsor
mesh term: Alpha 1-Antitrypsin Deficiency
mesh term: Graft vs Host Disease
mesh term: Alpha 1-Antitrypsin
mesh term: Protein C Inhibitor
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 