<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/NCT01731691</url>
  </required_header>
  <id_info>
    <org_study_id>Prolastin-C in HIV disease</org_study_id>
    <nct_id>NCT01731691</nct_id>
  </id_info>
  <brief_title>Safety and Efficacy of (α1Proteinase Inhibitor, α1PI) in HIV Disease</brief_title>
  <official_title>Safety and Efficacy of Prolastin®-C (α1Proteinase Inhibitor, α1PI) in Human Immunodeficiency Virus-Infected Subjects</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Institute for Human Genetics and Biochemistry</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>AIDS Community Research Initiative of America</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Grifols Biologicals, LLC</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>Institute for Human Genetics and Biochemistry</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      Our primary objective is to further characterize the mechanism by which alpha-1PI regulates&#xD;
      CD4 counts.&#xD;
&#xD;
      HIV-1 infected patients will be initiated on PROLASTIN®-C (Alpha-1 Proteinase Inhibitor&#xD;
      [Human], Grifols Biotherapeutics Inc.) or placebo. Uninfected volunteers will be untreated&#xD;
      and will be monitored for comparison.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This study protocol is designed to investigate the benefit of a well-tolerated, FDA approved&#xD;
      biological product that has been extensively used in a different patient population.&#xD;
&#xD;
      For more than 20 years, α1proteinase inhibitor (α1PI or α1antitrypsin) therapy has been the&#xD;
      standard treatment for people with insufficient α1PI blood levels. This disorder, also known&#xD;
      as α1antitrypsin deficiency, was previously thought to be caused only as an inherited trait&#xD;
      due to the gene PIzz. Recent evidence shows that it can also be an acquired disease.&#xD;
      Specifically, individuals with HIV-1 disease have been found to have severely low α1PI blood&#xD;
      levels (Bristow et al., 2001; Bristow et al., 2010; Bristow et al., 2012). Many people with&#xD;
      the inherited version of α1PI deficiency eventually develop emphysema, and among individuals&#xD;
      with HIV-1 disease, 90% have acquired α1PI deficiency. Whether they go on to develop&#xD;
      emphysema is still unresolved.&#xD;
&#xD;
      HIV-1 infected individuals are the first patient population identified so far in which severe&#xD;
      α1PI deficiency is acquired through infection rather than being inherited.&#xD;
&#xD;
      It was found that a decrease in α1PI blood levels is directly correlated to a decrease in CD4&#xD;
      lymphocytes (Bristow et al., 2001; Bristow et al., 2012): In a pilot study to determine&#xD;
      whether α1PI therapy might benefit the CD4 counts in HIV-1 infected patients&#xD;
      (Clinicaltrials.gov NCT01370018), HIV-1 patients with infection-related α1PI deficiency&#xD;
      received weekly α1PI therapy (120mg/kg) for a period of 8 weeks and results were compared&#xD;
      with those of patients having the inherited version of α1PI deficiency who were&#xD;
      simultaneously receiving weekly α1PI therapy (60mg/kg). None of the patients in the study had&#xD;
      ever previously received α1PI therapy. It was found that CD4 cells rose to normal levels&#xD;
      following 2 weeks of intravenous α1PI therapy with no adverse effects observed in the HIV-1&#xD;
      patients (n=3) or the control group of HIV-1 uninfected, α1PI deficiency patients (n=2). The&#xD;
      new crop of CD4 cells were functional, capable of fighting infection, and appeared to be&#xD;
      generated from bone marrow-derived stem cells (Bristow et al., 2010). As a bonus, it was&#xD;
      found in the HIV-1 patients that LDL levels (bad cholesterol) decreased and HDL levels (good&#xD;
      cholesterol) increased {Bristow et al., in review).&#xD;
&#xD;
      The information gained from the initial pilot study will be incorporated into this study&#xD;
      design to further characterize the mechanism of lymphocyte renewal and to increase the number&#xD;
      of patients observed. Only minor modifications to the pilot protocol are proposed including&#xD;
      the sample size, addition of volunteers not receiving therapy, and a double-blind design: Ten&#xD;
      (10) HIV-1 infected patients will be dosed with PROLASTIN®-C (Grifols Therapeutics Inc.),&#xD;
      five (5) will be dosed with placebo, and five (5) uninfected volunteers not receiving therapy&#xD;
      will be monitored.&#xD;
&#xD;
      It has been observed that CD4 counts and cholesterol levels are correlated and that there is&#xD;
      cyclic variation in individuals with and without HIV. To examine whether there are&#xD;
      differences due to HIV infection in cyclic variation of CD4 counts, cholesterol levels, and&#xD;
      other values monitored during this study, five (5) volunteers, who do not have HIV, will be&#xD;
      included in the study for blood collection only.&#xD;
&#xD;
      In a previous study, we determined that in individuals with abnormally low active α1PI&#xD;
      levels, CD4 counts exhibit sinusoidal cycling with 23 day periodicity. Wave form appearance&#xD;
      of CD4 cells with a peak every 23 days is a pattern that is indicative of adult thymopoiesis.&#xD;
      We showed that in response to α1PI therapy, HIV infected and uninfected individuals exhibited&#xD;
      an increased CD4 counts axis of oscillation, but no change in periodicity. In contrast, one&#xD;
      uninfected individual who was not receiving therapy, exhibited no change in the axis of&#xD;
      oscillation, but periodicity was 27 days. Human adult thymopoiesis is not well characterized,&#xD;
      and based on these results, we have two hypotheses.&#xD;
&#xD;
      One hypothesis is that in response to α1PI therapy, thymopoiesis will increase, manifested by&#xD;
      an increased axis of oscillation and increased numbers of recent thymic emigrants. In the&#xD;
      proposed study, we will perform weekly TREC analysis which measures recent thymic emigrants&#xD;
      and is definitive for thymopoiesis. We will test whether the changes in TREC numbers&#xD;
      corresponds with changes in the CD4 counts axis of oscillation in HIV infected individuals&#xD;
      receiving α1PI therapy as compared with HIV infected individuals with abnormally low active&#xD;
      α1PI levels not on α1PI therapy, and HIV uninfected individuals with normal active α1PI&#xD;
      levels not on α1PI therapy.&#xD;
&#xD;
      The second hypothesis is that in individuals with abnormally low active α1PI levels, the&#xD;
      periodicity of CD4 counts is shorter than in individuals with normal active α1PI levels.&#xD;
      Although we will measure periodicity in only 5 individuals with normal active α1PI levels and&#xD;
      15 with abnormal active α1PI levels, this will allow us to determine whether active α1PI is a&#xD;
      linear determinate of periodicity or whether there are other variables that regulate&#xD;
      periodicity. In an 8-week study, only 2 periods can be observed. Thus, following an 8-week&#xD;
      regimen of therapy, one study subject may be asked to continue for a second 8-week regimen of&#xD;
      therapy to allow the observation of 5 periods.&#xD;
&#xD;
      In addition to these two primary hypotheses regarding CD4 counts, we have found that HDL and&#xD;
      LDL levels are linearly dependent on the balance of active and inactive α1PI levels&#xD;
      (manuscript in review). This phenomenon is due the transport of HDL and LDL by CD4 cells. We&#xD;
      found that in HIV infected individuals with abnormally low active α1PI and abnormally high&#xD;
      inactive α1PI, HDL and LDL increased or decreased differently from individuals with normal&#xD;
      active α1PI. Based on these results, our hypothesis is that in HIV infected individuals with&#xD;
      abnormally low active α1PI receiving α1PI therapy, LDL levels will decrease and HDL levels&#xD;
      will increase as active α1PI levels increase in contrast to HIV uninfected individuals with&#xD;
      normal active α1PI levels not on therapy and in contrast to HIV infected individuals with&#xD;
      abnormally low active α1PI levels not on therapy.&#xD;
&#xD;
      Prolastin-C treatment will be given weekly for eight (8) to sixteen (16) weeks by intravenous&#xD;
      infusion. Blood will be collected immediately prior to each infusion. As in the previous&#xD;
      study, complete blood count, lymphocyte phenotype, extended lymphocyte phenotype, lymphocyte&#xD;
      function; HIV-1 viral load, lipid levels, blood chemistry, and markers of inflammation will&#xD;
      be measured. The present study will also include measurements for HIV-1 tropism and markers&#xD;
      for recent thymic emigrants.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Terminated</overall_status>
  <why_stopped>
    Blinded review of the data suggested no significant diferences in outcomes.&#xD;
  </why_stopped>
  <start_date type="Actual">April 2012</start_date>
  <completion_date type="Actual">July 2014</completion_date>
  <primary_completion_date type="Actual">July 2014</primary_completion_date>
  <phase>Phase 2/Phase 3</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Basic Science</primary_purpose>
    <masking>Triple (Participant, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>CD4 Counts</measure>
    <time_frame>9 weeks after initiation of treatment</time_frame>
    <description>It has been observed that CD4 counts and cholesterol levels are correlated and that there is cyclic variation in individuals with and without HIV.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>CD8</measure>
    <time_frame>9 weeks after initiation of treatment</time_frame>
    <description>It has been observed that CD4 counts and cholesterol levels are correlated and that there is cyclic variation in individuals with and without HIV.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>CD4/CD8 Ratio</measure>
    <time_frame>9 weeks after initiation of treatment</time_frame>
    <description>It has been observed that CD4 counts and cholesterol levels are correlated and that there is cyclic variation in individuals with and without HIV.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Alpha-1 Proteinase Inhibitor</measure>
    <time_frame>weekly for 8 weeks</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>sj/betaTrec Ratio</measure>
    <time_frame>weekly for 8 weeks</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>High Density Lipoprotein (HDL)</measure>
    <time_frame>weekly for 8 weeks</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>Low Density Lipoprotein (LDL)</measure>
    <time_frame>weekly for 8 weeks</time_frame>
  </primary_outcome>
  <number_of_arms>3</number_of_arms>
  <enrollment type="Actual">12</enrollment>
  <condition>HIV Disease</condition>
  <arm_group>
    <arm_group_label>α1 Proteinase Inhibitor in HIV disease</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>α1Proteinase Inhibitor (120mg/kg Prolastin-C) weekly for 8 weeks</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo in HIV disease</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Placebos weekly for 8 weeks</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Uninfected controls</arm_group_label>
    <arm_group_type>No Intervention</arm_group_type>
    <description>Blood collection only for 8 weeks</description>
  </arm_group>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>α1 Proteinase Inhibitor</intervention_name>
    <description>Prolastin-C treatment in HIV disease will be compared with placebo treatment in HIV disease and no treatment in uninfected volunteers.</description>
    <arm_group_label>α1 Proteinase Inhibitor in HIV disease</arm_group_label>
    <other_name>Prolastin</other_name>
    <other_name>Prolastin-C</other_name>
    <other_name>Zemaira</other_name>
    <other_name>Glassia</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebos</intervention_name>
    <description>Placebo treatment in HIV disease will be compared with Prolastin-C treatment in HIV disease and no treatment in uninfected volunteers.</description>
    <arm_group_label>Placebo in HIV disease</arm_group_label>
    <other_name>Saline</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. HIV-1 patients must have confirmed HIV-1 disease, diagnosed using the standard&#xD;
             criteria and be on antiretroviral therapy. Uninfected volunteers will be age and&#xD;
             gender matched.&#xD;
&#xD;
          2. HIV-1 patients must have measurable disease, defined as HIV-1 infected patients on&#xD;
             antiretroviral therapy with undetectable HIV RNA (&lt;1000 HIV RNA copies/ml) and CD4&#xD;
             counts more than 200 and less than 600 cells/uL.&#xD;
&#xD;
          3. Not have previously received α1PI augmentation therapy&#xD;
&#xD;
          4. Age at least 18 years and under 65 years&#xD;
&#xD;
          5. Capacity for and commitment to attend all protocol scheduled visits at ACRIA&#xD;
&#xD;
          6. Life expectancy of greater than 5 years&#xD;
&#xD;
          7. Patients must have lab values within the limits defined below:&#xD;
&#xD;
               -  WBC &gt;4,1000/uL&#xD;
&#xD;
               -  ANC &gt;1,000/uL&#xD;
&#xD;
               -  platelets &gt;100,000//uL&#xD;
&#xD;
               -  total bilirubin 2-12 mg/dL&#xD;
&#xD;
               -  AST(SGOT)/ALT(SGPT) &lt; or = 2.5 X upper limit of normal&#xD;
&#xD;
               -  creatinine Male : 0.50-1.30 mg/dL Female: 0.40-1.20 mg/dL&#xD;
&#xD;
          8. HIV-1 patients must have active α1PI below 11 uM (normal is 18-53 uM)&#xD;
&#xD;
          9. HIV-1 patients must have one year history (prior to the study) with CD4+ lymphocytes&#xD;
             at levels greater than 200 and less than 400 cells/uL&#xD;
&#xD;
         10. HIV-1 patients must have absence of symptoms suggestive of HIV-1 disease progression&#xD;
&#xD;
         11. HIV-1 patients must have adequate suppression of virus (&lt;400 HIV RNA/mL)&#xD;
&#xD;
         12. HIV-1 patients must have a history of compliance with antiretroviral medication based&#xD;
             on undetectable virus levels&#xD;
&#xD;
         13. No evidence of malignancy&#xD;
&#xD;
         14. The effects of Prolastin-C on the developing human fetus at the recommended&#xD;
             therapeutic dose are unknown: At any time throughout the study, from the signing of&#xD;
             the informed consent form until after the last study visit, all female and male&#xD;
             subjects who are biologically capable of having children must agree and commit to use&#xD;
             a reliable method of birth control.&#xD;
&#xD;
         15. Ability to understand and the willingness to sign a written informed consent document&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Recent illness that will prevent the patient from participating in required study&#xD;
             activities&#xD;
&#xD;
          2. Patients receiving other investigational agents&#xD;
&#xD;
          3. Patients with known malignancies&#xD;
&#xD;
          4. History of allergic reactions attributed to compounds of similar chemical or biologic&#xD;
             composition to Prolastin-C&#xD;
&#xD;
          5. IgA deficient patients&#xD;
&#xD;
          6. Patients with ≥1000 HIV-1 RNA copies/ mL&#xD;
&#xD;
          7. Patients with &gt;600 CD4 cells/uL&#xD;
&#xD;
          8. Uncontrolled illness including, but not limited to, ongoing or active infection,&#xD;
             myeloid dysplastic syndrome, anemia, bone marrow failure, DiGeorge Syndrome, thymic&#xD;
             disorders, or psychiatric illness/social situations that would limit compliance with&#xD;
             study requirements&#xD;
&#xD;
          9. Pregnant and breastfeeding women&#xD;
&#xD;
         10. Refusal to give informed consent&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>65 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Cynthia Bristow, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Institute for Human Genetics and Biochemistry</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>ACRIA</name>
      <address>
        <city>New York</city>
        <state>New York</state>
        <zip>10018</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <reference>
    <citation>Bristow CL, Babayeva MA, LaBrunda M, Mullen MP, Winston R. alpha1Proteinase inhibitor regulates CD4+ lymphocyte levels and is rate limiting in HIV-1 disease. PLoS One. 2012;7(2):e31383. doi: 10.1371/journal.pone.0031383. Epub 2012 Feb 17.</citation>
    <PMID>22363634</PMID>
  </reference>
  <reference>
    <citation>Bristow CL, Patel H, Arnold RR. Self antigen prognostic for human immunodeficiency virus disease progression. Clin Diagn Lab Immunol. 2001 Sep;8(5):937-42. doi: 10.1128/CDLI.8.5.937-942.2001.</citation>
    <PMID>11527807</PMID>
  </reference>
  <results_reference>
    <citation>Bristow CL, Ferrando-Martinez S, Ruiz-Mateos E, Leal M, Winston R. Development of Immature CD4+CD8+T Cells Into Mature CD4+ T Cells Requires Alpha-1 Antitrypsin as Observed by Treatment in HIV-1 Infected and Uninfected Controls. Front Cell Dev Biol. 2019 Nov 21;7:278. doi: 10.3389/fcell.2019.00278. eCollection 2019.</citation>
    <PMID>31824943</PMID>
  </results_reference>
  <verification_date>August 2020</verification_date>
  <study_first_submitted>November 19, 2012</study_first_submitted>
  <study_first_submitted_qc>November 21, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">November 22, 2012</study_first_posted>
  <results_first_submitted>April 13, 2017</results_first_submitted>
  <results_first_submitted_qc>August 22, 2020</results_first_submitted_qc>
  <results_first_posted type="Actual">August 31, 2020</results_first_posted>
  <last_update_submitted>August 22, 2020</last_update_submitted>
  <last_update_submitted_qc>August 22, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">August 31, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Institute for Human Genetics and Biochemistry</investigator_affiliation>
    <investigator_full_name>Cynthia L Bristow, PhD</investigator_full_name>
    <investigator_title>Principal Investigator</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Acquired Immunodeficiency Syndrome</mesh_term>
    <mesh_term>HIV Infections</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Protease Inhibitors</mesh_term>
    <mesh_term>Alpha 1-Antitrypsin</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
    <ipd_description>Incomplete data was made available to the PI.</ipd_description>
  </patient_data>

  <clinical_results>

    <participant_flow>
      <recruitment_details>Volunteers were recruited by ACRIA by placing advertisements in neighborhood publications. A total of 227 patients were interviewed as potential candidates. The first study candidate was screened on January 14, 2013 and the first HIV+ subject was randomized (treatment/placebo) on April 25, 2013.</recruitment_details>
      <pre_assignment_details>Of the 21 potential subjects screened, 12 (57%) reached the baseline visit. All 12 were enrolled and all completed the study.</pre_assignment_details>
      <group_list>
        <group group_id="P1">
          <title>α1 Proteinase Inhibitor in HIV Disease</title>
          <description>α1Proteinase Inhibitor (120mg/kg Prolastin-C) weekly for 8 weeks&#xD;
α1 Proteinase Inhibitor: Prolastin-C treatment in HIV disease will be compared with placebo treatment in HIV disease and no treatment in uninfected volunteers.</description>
        </group>
        <group group_id="P2">
          <title>Placebo in HIV Disease</title>
          <description>Placebos weekly for 8 weeks&#xD;
Placebos: Placebo treatment in HIV disease will be compared with Prolastin-C treatment in HIV disease and no treatment in uninfected volunteers.</description>
        </group>
        <group group_id="P3">
          <title>Uninfected Controls</title>
          <description>Blood collection only for 8 weeks</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="3"/>
                <participants group_id="P2" count="5"/>
                <participants group_id="P3" count="4"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="3"/>
                <participants group_id="P2" count="5"/>
                <participants group_id="P3" count="4"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>α1 Proteinase Inhibitor in HIV Disease</title>
          <description>α1Proteinase Inhibitor (120mg/kg Prolastin-C) weekly for 8 weeks&#xD;
α1 Proteinase Inhibitor: Prolastin-C treatment in HIV disease will be compared with placebo treatment in HIV disease and no treatment in uninfected volunteers.&#xD;
The subjects in the HIV+ groups (Prolastin-C and Placebo) were not comparable to those in the HIV- group.</description>
        </group>
        <group group_id="B2">
          <title>Placebo in HIV Disease</title>
          <description>Placebos weekly for 8 weeks&#xD;
Placebos: Placebo treatment in HIV disease will be compared with Prolastin-C treatment in HIV disease and no treatment in uninfected volunteers.&#xD;
The subjects in the HIV+ groups (Prolastin-C and Placebo) were not comparable to those in the HIV- group.</description>
        </group>
        <group group_id="B3">
          <title>Uninfected Controls</title>
          <description>Blood collection only for 8 weeks&#xD;
The subjects in the HIV+ groups (Prolastin-C and Placebo) were not comparable to those in the HIV- group.</description>
        </group>
        <group group_id="B4">
          <title>Total</title>
          <description>Total of all reporting groups</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="3"/>
            <count group_id="B2" value="5"/>
            <count group_id="B3" value="4"/>
            <count group_id="B4" value="12"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>&lt;=18 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Between 18 and 65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="3"/>
                    <measurement group_id="B2" value="5"/>
                    <measurement group_id="B3" value="4"/>
                    <measurement group_id="B4" value="12"/>
                  </measurement_list>
                </category>
                <category>
                  <title>&gt;=65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Age</title>
          <units>years</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="54" spread="5"/>
                    <measurement group_id="B2" value="52" spread="7"/>
                    <measurement group_id="B3" value="32" spread="10"/>
                    <measurement group_id="B4" value="46" spread="13"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Sex: Female, Male</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Female</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="1"/>
                    <measurement group_id="B4" value="3"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                    <measurement group_id="B2" value="4"/>
                    <measurement group_id="B3" value="3"/>
                    <measurement group_id="B4" value="9"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Ethnicity (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="2"/>
                    <measurement group_id="B3" value="2"/>
                    <measurement group_id="B4" value="4"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Not Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="3"/>
                    <measurement group_id="B2" value="3"/>
                    <measurement group_id="B3" value="2"/>
                    <measurement group_id="B4" value="8"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Region of Enrollment</title>
          <units>participants</units>
          <param>Number</param>
          <class_list>
            <class>
              <title>United States</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="3"/>
                    <measurement group_id="B2" value="5"/>
                    <measurement group_id="B3" value="4"/>
                    <measurement group_id="B4" value="12"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>CD4</title>
          <units>cells/uL</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="365" spread="116"/>
                    <measurement group_id="B2" value="438" spread="108"/>
                    <measurement group_id="B3" value="651" spread="239"/>
                    <measurement group_id="B4" value="491" spread="193"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>CD8</title>
          <units>cells/uL</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="958" spread="340"/>
                    <measurement group_id="B2" value="872" spread="271"/>
                    <measurement group_id="B3" value="324" spread="53"/>
                    <measurement group_id="B4" value="711" spread="363"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>CD4/CD8 Ratio</title>
          <units>Ratio</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="0.42" spread="0.17"/>
                    <measurement group_id="B2" value="0.53" spread="0.18"/>
                    <measurement group_id="B3" value="2.00" spread="0.58"/>
                    <measurement group_id="B4" value="0.99" spread="0.82"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>α1 Proteinase Inhibitor</title>
          <description>Measured as active concentration, not as the traditional total concentration.</description>
          <units>uM</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="14" spread="4"/>
                    <measurement group_id="B2" value="12" spread="6"/>
                    <measurement group_id="B3" value="21" spread="10"/>
                    <measurement group_id="B4" value="15" spread="8"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>HDL</title>
          <units>mg/dL</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="55" spread="14"/>
                    <measurement group_id="B2" value="65" spread="14"/>
                    <measurement group_id="B3" value="58" spread="10"/>
                    <measurement group_id="B4" value="60" spread="12"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>LDL</title>
          <units>mg/dL</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="89" spread="1.5"/>
                    <measurement group_id="B2" value="83" spread="16"/>
                    <measurement group_id="B3" value="83" spread="20"/>
                    <measurement group_id="B4" value="85" spread="14"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>CD4 Counts</title>
        <description>It has been observed that CD4 counts and cholesterol levels are correlated and that there is cyclic variation in individuals with and without HIV.</description>
        <time_frame>9 weeks after initiation of treatment</time_frame>
        <group_list>
          <group group_id="O1">
            <title>α1 Proteinase Inhibitor in HIV Disease</title>
            <description>α1Proteinase Inhibitor (120mg/kg Prolastin-C) weekly for 8 weeks&#xD;
α1 Proteinase Inhibitor: Prolastin-C treatment in HIV disease will be compared with placebo treatment in HIV disease and no treatment in uninfected volunteers.&#xD;
The subjects in the HIV+ groups (Prolastin-C and Placebo) were not comparable to those in the HIV- group.</description>
          </group>
          <group group_id="O2">
            <title>Placebo in HIV Disease</title>
            <description>Placebos weekly for 8 weeks&#xD;
Placebos: Placebo treatment in HIV disease will be compared with Prolastin-C treatment in HIV disease and no treatment in uninfected volunteers.&#xD;
The subjects in the HIV+ groups (Prolastin-C and Placebo) were not comparable to those in the HIV- group.</description>
          </group>
          <group group_id="O3">
            <title>Uninfected Controls</title>
            <description>Blood collection only for 8 weeks&#xD;
The subjects in the HIV+ groups (Prolastin-C and Placebo) were not comparable to those in the HIV- group.</description>
          </group>
        </group_list>
        <measure>
          <title>CD4 Counts</title>
          <description>It has been observed that CD4 counts and cholesterol levels are correlated and that there is cyclic variation in individuals with and without HIV.</description>
          <units>cells/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="5"/>
                <count group_id="O3" value="4"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="326" spread="103"/>
                    <measurement group_id="O2" value="437" spread="180"/>
                    <measurement group_id="O3" value="649" spread="141"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>CD8</title>
        <description>It has been observed that CD4 counts and cholesterol levels are correlated and that there is cyclic variation in individuals with and without HIV.</description>
        <time_frame>9 weeks after initiation of treatment</time_frame>
        <group_list>
          <group group_id="O1">
            <title>α1 Proteinase Inhibitor in HIV Disease</title>
            <description>α1Proteinase Inhibitor (120mg/kg Prolastin-C) weekly for 8 weeks&#xD;
α1 Proteinase Inhibitor: Prolastin-C treatment in HIV disease will be compared with placebo treatment in HIV disease and no treatment in uninfected volunteers.</description>
          </group>
          <group group_id="O2">
            <title>Placebo in HIV Disease</title>
            <description>Placebos weekly for 8 weeks&#xD;
Placebos: Placebo treatment in HIV disease will be compared with Prolastin-C treatment in HIV disease and no treatment in uninfected volunteers.</description>
          </group>
          <group group_id="O3">
            <title>Uninfected Controls</title>
            <description>Blood collection only for 8 weeks</description>
          </group>
        </group_list>
        <measure>
          <title>CD8</title>
          <description>It has been observed that CD4 counts and cholesterol levels are correlated and that there is cyclic variation in individuals with and without HIV.</description>
          <units>cells/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="5"/>
                <count group_id="O3" value="4"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="848" spread="202"/>
                    <measurement group_id="O2" value="946" spread="365"/>
                    <measurement group_id="O3" value="302" spread="61"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>CD4/CD8 Ratio</title>
        <description>It has been observed that CD4 counts and cholesterol levels are correlated and that there is cyclic variation in individuals with and without HIV.</description>
        <time_frame>9 weeks after initiation of treatment</time_frame>
        <group_list>
          <group group_id="O1">
            <title>α1 Proteinase Inhibitor in HIV Disease</title>
            <description>α1Proteinase Inhibitor (120mg/kg Prolastin-C) weekly for 8 weeks&#xD;
α1 Proteinase Inhibitor: Prolastin-C treatment in HIV disease will be compared with placebo treatment in HIV disease and no treatment in uninfected volunteers.</description>
          </group>
          <group group_id="O2">
            <title>Placebo in HIV Disease</title>
            <description>Placebos weekly for 8 weeks&#xD;
Placebos: Placebo treatment in HIV disease will be compared with Prolastin-C treatment in HIV disease and no treatment in uninfected volunteers.</description>
          </group>
          <group group_id="O3">
            <title>Uninfected Controls</title>
            <description>Blood collection only for 8 weeks</description>
          </group>
        </group_list>
        <measure>
          <title>CD4/CD8 Ratio</title>
          <description>It has been observed that CD4 counts and cholesterol levels are correlated and that there is cyclic variation in individuals with and without HIV.</description>
          <units>Ratio</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="5"/>
                <count group_id="O3" value="4"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.41" spread="0.18"/>
                    <measurement group_id="O2" value="0.48" spread="0.14"/>
                    <measurement group_id="O3" value="2.20" spread="0.55"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Alpha-1 Proteinase Inhibitor</title>
        <time_frame>weekly for 8 weeks</time_frame>
        <group_list>
          <group group_id="O1">
            <title>α1 Proteinase Inhibitor in HIV Disease</title>
            <description>α1Proteinase Inhibitor (120mg/kg Prolastin-C) weekly for 8 weeks&#xD;
α1 Proteinase Inhibitor: Prolastin-C treatment in HIV disease will be compared with placebo treatment in HIV disease and no treatment in uninfected volunteers.</description>
          </group>
          <group group_id="O2">
            <title>Placebo in HIV Disease</title>
            <description>Placebos weekly for 8 weeks&#xD;
Placebos: Placebo treatment in HIV disease will be compared with Prolastin-C treatment in HIV disease and no treatment in uninfected volunteers.</description>
          </group>
          <group group_id="O3">
            <title>Uninfected Controls</title>
            <description>Blood collection only for 8 weeks</description>
          </group>
        </group_list>
        <measure>
          <title>Alpha-1 Proteinase Inhibitor</title>
          <units>micromol</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="5"/>
                <count group_id="O3" value="4"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="13.7" spread="3.4"/>
                    <measurement group_id="O2" value="13.6" spread="4.1"/>
                    <measurement group_id="O3" value="19" spread="9.5"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>sj/betaTrec Ratio</title>
        <time_frame>weekly for 8 weeks</time_frame>
        <group_list>
          <group group_id="O1">
            <title>α1 Proteinase Inhibitor in HIV Disease</title>
            <description>α1Proteinase Inhibitor (120mg/kg Prolastin-C) weekly for 8 weeks&#xD;
α1 Proteinase Inhibitor: Prolastin-C treatment in HIV disease will be compared with placebo treatment in HIV disease and no treatment in uninfected volunteers.</description>
          </group>
          <group group_id="O2">
            <title>Placebo in HIV Disease</title>
            <description>Placebos weekly for 8 weeks&#xD;
Placebos: Placebo treatment in HIV disease will be compared with Prolastin-C treatment in HIV disease and no treatment in uninfected volunteers.</description>
          </group>
          <group group_id="O3">
            <title>Uninfected Controls</title>
            <description>Blood collection only for 8 weeks</description>
          </group>
        </group_list>
        <measure>
          <title>sj/betaTrec Ratio</title>
          <units>sj/beta ratio</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="5"/>
                <count group_id="O3" value="4"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="353.52" spread="353.54"/>
                    <measurement group_id="O2" value="271.19" spread="414.34"/>
                    <measurement group_id="O3" value="375.96" spread="357.81"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>High Density Lipoprotein (HDL)</title>
        <time_frame>weekly for 8 weeks</time_frame>
        <group_list>
          <group group_id="O1">
            <title>α1 Proteinase Inhibitor in HIV Disease</title>
            <description>α1Proteinase Inhibitor (120mg/kg Prolastin-C) weekly for 8 weeks&#xD;
α1 Proteinase Inhibitor: Prolastin-C treatment in HIV disease will be compared with placebo treatment in HIV disease and no treatment in uninfected volunteers.</description>
          </group>
          <group group_id="O2">
            <title>Placebo in HIV Disease</title>
            <description>Placebos weekly for 8 weeks&#xD;
Placebos: Placebo treatment in HIV disease will be compared with Prolastin-C treatment in HIV disease and no treatment in uninfected volunteers.</description>
          </group>
          <group group_id="O3">
            <title>Uninfected Controls</title>
            <description>Blood collection only for 8 weeks</description>
          </group>
        </group_list>
        <measure>
          <title>High Density Lipoprotein (HDL)</title>
          <units>mg/dL</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="5"/>
                <count group_id="O3" value="4"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="49.29" spread="6.21"/>
                    <measurement group_id="O2" value="63.14" spread="14.51"/>
                    <measurement group_id="O3" value="61.13" spread="10.40"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Low Density Lipoprotein (LDL)</title>
        <time_frame>weekly for 8 weeks</time_frame>
        <group_list>
          <group group_id="O1">
            <title>α1 Proteinase Inhibitor in HIV Disease</title>
            <description>α1Proteinase Inhibitor (120mg/kg Prolastin-C) weekly for 8 weeks&#xD;
α1 Proteinase Inhibitor: Prolastin-C treatment in HIV disease will be compared with placebo treatment in HIV disease and no treatment in uninfected volunteers.</description>
          </group>
          <group group_id="O2">
            <title>Placebo in HIV Disease</title>
            <description>Placebos weekly for 8 weeks&#xD;
Placebos: Placebo treatment in HIV disease will be compared with Prolastin-C treatment in HIV disease and no treatment in uninfected volunteers.</description>
          </group>
          <group group_id="O3">
            <title>Uninfected Controls</title>
            <description>Blood collection only for 8 weeks</description>
          </group>
        </group_list>
        <measure>
          <title>Low Density Lipoprotein (LDL)</title>
          <units>mg/dL</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="5"/>
                <count group_id="O3" value="4"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="90.67" spread="9.21"/>
                    <measurement group_id="O2" value="77.23" spread="25.19"/>
                    <measurement group_id="O3" value="75.19" spread="15.32"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>9 weeks from initiation of therapy</time_frame>
      <desc>Zero patients experienced adverse events including in any of the following outcomes: death, a life-threatening adverse event, inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant incapacity or substantial disruption of the ability to conduct normal functions, or a congenital anomaly/birth defect. Zero adverse events resulted in life-threatening incidents or hospitalization or jeopardized the participant.</desc>
      <group_list>
        <group group_id="E1">
          <title>α1 Proteinase Inhibitor in HIV Disease</title>
          <description>α1Proteinase Inhibitor (120mg/kg Prolastin-C) weekly for 8 weeks&#xD;
α1 Proteinase Inhibitor: Prolastin-C treatment in HIV disease will be compared with placebo treatment in HIV disease and no treatment in uninfected volunteers.</description>
        </group>
        <group group_id="E2">
          <title>Placebo in HIV Disease</title>
          <description>Placebos weekly for 8 weeks&#xD;
Placebos: Placebo treatment in HIV disease will be compared with Prolastin-C treatment in HIV disease and no treatment in uninfected volunteers.</description>
        </group>
        <group group_id="E3">
          <title>Uninfected Controls</title>
          <description>Blood collection only for 8 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="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="4"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>0</frequency_threshold>
        <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="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="4"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>All Principal Investigators ARE employed by the organization sponsoring the study.</pi_employee>
      <restrictive_agreement>There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed. </restrictive_agreement>
    </certain_agreements>
    <limitations_and_caveats>Early termination leading to small numbers of subjects analyzed; Technical problems with measurement leading to unreliable or uninterpretable data.</limitations_and_caveats>
    <point_of_contact>
      <name_or_title>Dr. Cynthia L. Bristow</name_or_title>
      <organization>Institute for Human Genetics and Biochemistry</organization>
      <phone>631-444-6238</phone>
      <email>cynthia.bristow@stonybrook.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/NCT01731691
org study id: Prolastin-C in HIV disease
nct id: NCT01731691
lead sponsor: 
collaborator: 
collaborator: 
has dmc: No
is fda regulated drug: Yes
is fda regulated device: No
is us export: No
Our primary objective is to further characterize the mechanism by which alpha-1PI regulates
      CD4 counts.

      HIV-1 infected patients will be initiated on PROLASTIN®-C (Alpha-1 Proteinase Inhibitor
      [Human], Grifols Biotherapeutics Inc.) or placebo. Uninfected volunteers will be untreated
      and will be monitored for comparison.
This study protocol is designed to investigate the benefit of a well-tolerated, FDA approved
      biological product that has been extensively used in a different patient population.

      For more than 20 years, α1proteinase inhibitor (α1PI or α1antitrypsin) therapy has been the
      standard treatment for people with insufficient α1PI blood levels. This disorder, also known
      as α1antitrypsin deficiency, was previously thought to be caused only as an inherited trait
      due to the gene PIzz. Recent evidence shows that it can also be an acquired disease.
      Specifically, individuals with HIV-1 disease have been found to have severely low α1PI blood
      levels (Bristow et al., 2001; Bristow et al., 2010; Bristow et al., 2012). Many people with
      the inherited version of α1PI deficiency eventually develop emphysema, and among individuals
      with HIV-1 disease, 90% have acquired α1PI deficiency. Whether they go on to develop
      emphysema is still unresolved.

      HIV-1 infected individuals are the first patient population identified so far in which severe
      α1PI deficiency is acquired through infection rather than being inherited.

      It was found that a decrease in α1PI blood levels is directly correlated to a decrease in CD4
      lymphocytes (Bristow et al., 2001; Bristow et al., 2012): In a pilot study to determine
      whether α1PI therapy might benefit the CD4 counts in HIV-1 infected patients
      (Clinicaltrials.gov NCT01370018), HIV-1 patients with infection-related α1PI deficiency
      received weekly α1PI therapy (120mg/kg) for a period of 8 weeks and results were compared
      with those of patients having the inherited version of α1PI deficiency who were
      simultaneously receiving weekly α1PI therapy (60mg/kg). None of the patients in the study had
      ever previously received α1PI therapy. It was found that CD4 cells rose to normal levels
      following 2 weeks of intravenous α1PI therapy with no adverse effects observed in the HIV-1
      patients (n=3) or the control group of HIV-1 uninfected, α1PI deficiency patients (n=2). The
      new crop of CD4 cells were functional, capable of fighting infection, and appeared to be
      generated from bone marrow-derived stem cells (Bristow et al., 2010). As a bonus, it was
      found in the HIV-1 patients that LDL levels (bad cholesterol) decreased and HDL levels (good
      cholesterol) increased {Bristow et al., in review).

      The information gained from the initial pilot study will be incorporated into this study
      design to further characterize the mechanism of lymphocyte renewal and to increase the number
      of patients observed. Only minor modifications to the pilot protocol are proposed including
      the sample size, addition of volunteers not receiving therapy, and a double-blind design: Ten
      (10) HIV-1 infected patients will be dosed with PROLASTIN®-C (Grifols Therapeutics Inc.),
      five (5) will be dosed with placebo, and five (5) uninfected volunteers not receiving therapy
      will be monitored.

      It has been observed that CD4 counts and cholesterol levels are correlated and that there is
      cyclic variation in individuals with and without HIV. To examine whether there are
      differences due to HIV infection in cyclic variation of CD4 counts, cholesterol levels, and
      other values monitored during this study, five (5) volunteers, who do not have HIV, will be
      included in the study for blood collection only.

      In a previous study, we determined that in individuals with abnormally low active α1PI
      levels, CD4 counts exhibit sinusoidal cycling with 23 day periodicity. Wave form appearance
      of CD4 cells with a peak every 23 days is a pattern that is indicative of adult thymopoiesis.
      We showed that in response to α1PI therapy, HIV infected and uninfected individuals exhibited
      an increased CD4 counts axis of oscillation, but no change in periodicity. In contrast, one
      uninfected individual who was not receiving therapy, exhibited no change in the axis of
      oscillation, but periodicity was 27 days. Human adult thymopoiesis is not well characterized,
      and based on these results, we have two hypotheses.

      One hypothesis is that in response to α1PI therapy, thymopoiesis will increase, manifested by
      an increased axis of oscillation and increased numbers of recent thymic emigrants. In the
      proposed study, we will perform weekly TREC analysis which measures recent thymic emigrants
      and is definitive for thymopoiesis. We will test whether the changes in TREC numbers
      corresponds with changes in the CD4 counts axis of oscillation in HIV infected individuals
      receiving α1PI therapy as compared with HIV infected individuals with abnormally low active
      α1PI levels not on α1PI therapy, and HIV uninfected individuals with normal active α1PI
      levels not on α1PI therapy.

      The second hypothesis is that in individuals with abnormally low active α1PI levels, the
      periodicity of CD4 counts is shorter than in individuals with normal active α1PI levels.
      Although we will measure periodicity in only 5 individuals with normal active α1PI levels and
      15 with abnormal active α1PI levels, this will allow us to determine whether active α1PI is a
      linear determinate of periodicity or whether there are other variables that regulate
      periodicity. In an 8-week study, only 2 periods can be observed. Thus, following an 8-week
      regimen of therapy, one study subject may be asked to continue for a second 8-week regimen of
      therapy to allow the observation of 5 periods.

      In addition to these two primary hypotheses regarding CD4 counts, we have found that HDL and
      LDL levels are linearly dependent on the balance of active and inactive α1PI levels
      (manuscript in review). This phenomenon is due the transport of HDL and LDL by CD4 cells. We
      found that in HIV infected individuals with abnormally low active α1PI and abnormally high
      inactive α1PI, HDL and LDL increased or decreased differently from individuals with normal
      active α1PI. Based on these results, our hypothesis is that in HIV infected individuals with
      abnormally low active α1PI receiving α1PI therapy, LDL levels will decrease and HDL levels
      will increase as active α1PI levels increase in contrast to HIV uninfected individuals with
      normal active α1PI levels not on therapy and in contrast to HIV infected individuals with
      abnormally low active α1PI levels not on therapy.

      Prolastin-C treatment will be given weekly for eight (8) to sixteen (16) weeks by intravenous
      infusion. Blood will be collected immediately prior to each infusion. As in the previous
      study, complete blood count, lymphocyte phenotype, extended lymphocyte phenotype, lymphocyte
      function; HIV-1 viral load, lipid levels, blood chemistry, and markers of inflammation will
      be measured. The present study will also include measurements for HIV-1 tropism and markers
      for recent thymic emigrants.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Basic Science
masking: Triple (Participant, Investigator, Outcomes Assessor)
measure: CD4 Counts
time frame: 9 weeks after initiation of treatment
description: It has been observed that CD4 counts and cholesterol levels are correlated and that there is cyclic variation in individuals with and without HIV.
measure: CD8
time frame: 9 weeks after initiation of treatment
description: It has been observed that CD4 counts and cholesterol levels are correlated and that there is cyclic variation in individuals with and without HIV.
measure: CD4/CD8 Ratio
time frame: 9 weeks after initiation of treatment
description: It has been observed that CD4 counts and cholesterol levels are correlated and that there is cyclic variation in individuals with and without HIV.
measure: Alpha-1 Proteinase Inhibitor
time frame: weekly for 8 weeks
measure: sj/betaTrec Ratio
time frame: weekly for 8 weeks
measure: High Density Lipoprotein (HDL)
time frame: weekly for 8 weeks
measure: Low Density Lipoprotein (LDL)
time frame: weekly for 8 weeks
arm group label: α1 Proteinase Inhibitor in HIV disease
arm group type: Experimental
description: α1Proteinase Inhibitor (120mg/kg Prolastin-C) weekly for 8 weeks
arm group label: Placebo in HIV disease
arm group type: Placebo Comparator
description: Placebos weekly for 8 weeks
arm group label: Uninfected controls
arm group type: No Intervention
description: Blood collection only for 8 weeks
intervention type: Biological
intervention name: α1 Proteinase Inhibitor
description: Prolastin-C treatment in HIV disease will be compared with placebo treatment in HIV disease and no treatment in uninfected volunteers.
arm group label: α1 Proteinase Inhibitor in HIV disease
other name: Prolastin
other name: Prolastin-C
other name: Zemaira
other name: Glassia
intervention type: Drug
intervention name: Placebos
description: Placebo treatment in HIV disease will be compared with Prolastin-C treatment in HIV disease and no treatment in uninfected volunteers.
arm group label: Placebo in HIV disease
other name: Saline
criteria: 
gender: All
minimum age: 18 Years
maximum age: 65 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Cynthia Bristow, PhD
role: Principal Investigator
affiliation: Institute for Human Genetics and Biochemistry
facility: 
country: United States
citation: Bristow CL, Babayeva MA, LaBrunda M, Mullen MP, Winston R. alpha1Proteinase inhibitor regulates CD4+ lymphocyte levels and is rate limiting in HIV-1 disease. PLoS One. 2012;7(2):e31383. doi: 10.1371/journal.pone.0031383. Epub 2012 Feb 17.
PMID: 22363634
citation: Bristow CL, Patel H, Arnold RR. Self antigen prognostic for human immunodeficiency virus disease progression. Clin Diagn Lab Immunol. 2001 Sep;8(5):937-42. doi: 10.1128/CDLI.8.5.937-942.2001.
PMID: 11527807
citation: Bristow CL, Ferrando-Martinez S, Ruiz-Mateos E, Leal M, Winston R. Development of Immature CD4+CD8+T Cells Into Mature CD4+ T Cells Requires Alpha-1 Antitrypsin as Observed by Treatment in HIV-1 Infected and Uninfected Controls. Front Cell Dev Biol. 2019 Nov 21;7:278. doi: 10.3389/fcell.2019.00278. eCollection 2019.
PMID: 31824943
responsible party type: Principal Investigator
investigator affiliation: Institute for Human Genetics and Biochemistry
investigator full name: Cynthia L Bristow, PhD
investigator title: Principal Investigator
mesh term: Acquired Immunodeficiency Syndrome
mesh term: HIV Infections
mesh term: Protease Inhibitors
mesh term: Alpha 1-Antitrypsin
sharing ipd: No
ipd description: Incomplete data was made available to the PI.
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
limitations and caveats: Early termination leading to small numbers of subjects analyzed; Technical problems with measurement leading to unreliable or uninterpretable data.
point of contact: 