<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/NCT03244059</url>
  </required_header>
  <id_info>
    <org_study_id>IRB-300000119</org_study_id>
    <nct_id>NCT03244059</nct_id>
  </id_info>
  <brief_title>Belimumab Treatment of Emphysema Patients With Anti-GRP78 Autoantibodies</brief_title>
  <acronym>BOTEGA</acronym>
  <official_title>Proof-of-concept Randomized, Double-blind, Phase IIa Study to Show Feasibility, Validate Assays and Approaches, and Explore Dosing and Safety of Belimumab in Pulmonary Emphysema Patients</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Alabama at Birmingham</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>GlaxoSmithKline</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>University of Alabama at Birmingham</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>Yes</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      This is intended to be an initial &quot;proof-of-concept&quot; study to show feasibility, validate&#xD;
      assays and approaches, and explore dosing and safety of belimumab in pulmonary emphysema&#xD;
      patients who have clinically relevant (and quantifiable) autoimmune responses. The primary&#xD;
      goal is to determine effects of belimumab on levels of autoantibodies against glucose&#xD;
      regulated protein 78 (GRP78) among patients with pulmonary emphysema attributable to&#xD;
      cigarette smoking. The investigators hypothesize that belimumab treatment will safely reduce&#xD;
      circulating levels of autoantibodies that are associated with emphysema, and comorbidities of&#xD;
      this lung disease, including atherosclerosis.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Specific Aim 1: To conduct a double-blind, Phase IIa trial, in which 18 former smokers with&#xD;
      pulmonary emphysema (per chest CT scans), and circulating anti-GRP78 autoantibody levels&#xD;
      &gt;mean normal values (by ELISA), will be randomized 2:1 to belimumab vs. placebo. Subjects&#xD;
      will receive 8 infusions of either belimumab or placebo over a 6 month interval. Plasma&#xD;
      anti-GRP78 will be measured pre-treatment, and at 1, 3, 5, and 7 months. The investigators&#xD;
      hypothesize belimumab therapy will more effectively reduce anti-GRP78 IgG autoantibodies, the&#xD;
      primary endpoint of this trial, compared to placebo.&#xD;
&#xD;
      Specific Aim 2: To determine effects of the belimumab therapy on secondary endpoints (at the&#xD;
      times detailed for Aim 1) that include levels of pneumococcal-binding antibodies (by ELISA),&#xD;
      circulating B-cell numbers and phenotypes (by flow cytometry), and the rate and severity of&#xD;
      adverse events (AE) at any time during treatment. The investigators hypothesize belimumab&#xD;
      will have dose-related effects on B-cell numbers and their differentiation, while minimally&#xD;
      reducing host defense antibodies, and will also have an acceptable AE profile.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">August 9, 2018</start_date>
  <completion_date type="Actual">April 1, 2022</completion_date>
  <primary_completion_date type="Actual">April 1, 2022</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <intervention_model_description>Patients will be randomly assigned to receive active:placebo in a ratio of 2:1.</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
    <masking_description>Double-blinded placebo controlled randomized clinical trial</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>Percent Change of Circulating Anti-GRP78 IgG Levels</measure>
    <time_frame>Plasma concentrations of the anti-GRP78 autoantibodies will be measured pre-treatment and at end of treatment at 210 days (or when subject withdraws)</time_frame>
    <description>Anti-GRP78 IgG is a clinically relevant surrogate biomarker of autoimmunity in pulmonary emphysema patients who have clinically relevant (and quantifiable) autoimmune responses</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Percent Change of Pneumococcal Polysaccharide-binding Antibodies</measure>
    <time_frame>Prior to treatment and at end of treatment on day 210 (or the conclusion of treatment if subject withdraws)</time_frame>
    <description>Treatment effects on concentrations of pneumococcal polysaccharide-binding antibodies by ELISA</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Percent Change of Circulating B-cells</measure>
    <time_frame>Prior to treatment, and at treatment end on day 210 or when subject participation is terminated</time_frame>
    <description>Treatment effect on relative percentages of circulating B-cells (CD20+) by flow cytometry</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Adverse Events</measure>
    <time_frame>Study start to completion (7 months)</time_frame>
    <description>Adverse events will be evaluated according to criteria outlined in the National Cancer Institure (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 4.0.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">17</enrollment>
  <condition>Chronic Obstructive Pulmonary Disease</condition>
  <condition>Emphysema</condition>
  <arm_group>
    <arm_group_label>Belimumab</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Subjects randomized to the experimental treatment arm will receive i.v. administrations of belimumab (10 mg/kg), consisting of three &quot;loading&quot; doses, two weeks apart, followed by five (5) more monthly infusions. The final assessment will be performed at month 8.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>These subjects will be treated with identically appearing placebo i.v. on the same schedule as the experimental arm subjects (i.e., three &quot;loading&quot; doses, two weeks apart, followed by five more monthly infusions. Again, the final assessment will be performed at month 7 (210+10 days after treatment start).</description>
  </arm_group>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>Belimumab</intervention_name>
    <description>Belimumab is an anti-BLyS (B-lymphocyte stimulating factor) agent administered by infusion.</description>
    <arm_group_label>Belimumab</arm_group_label>
    <other_name>Benlysta</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>An identically appearing placebo infusion.</description>
    <arm_group_label>Placebo</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. A history of past tobacco smoking (&gt;10 pack years), but quit for &gt;6 months at the time&#xD;
             of enrollment. Smoking cessation will be confirmed by serum cotinine assays.&#xD;
&#xD;
          2. Pulmonary emphysema per chest CT scans (F950&gt;5%). About 60% of COPD patients followed&#xD;
             in the LHC registry meet these criteria.6 Chest CTs are routine, standard of practice&#xD;
             evaluations for patients with COPD, so no new radiographic studies will be necessary&#xD;
             for this project.&#xD;
&#xD;
          3. Ability and willingness to give informed consent.&#xD;
&#xD;
          4. Plasma anti-GRP78 binding IgG &gt;mean values in former smokers with no lung disease&#xD;
             (standardized OD &gt;0.390) (hence this is a &quot;personalized medicine&quot; approach). Of the&#xD;
             330 emphysema subjects assayed for anti-GRP78 to date, 111 (67%) met this criterion.&#xD;
&#xD;
          5. Age 40-75 y.o. COPD is a disease of older individuals.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. History of prior acute COPD exacerbations or no more than one moderate exacerbation in&#xD;
             the last year and no exacerbations four months prior to enrollment. A past history of&#xD;
             an acute exacerbation is the single biggest risk for recurrence.36 Exclusion of these&#xD;
             higher-risk subjects will minimize drop-outs.&#xD;
&#xD;
          2. Oral steroids or cellular immunosuppressant use (e.g., cyclophosphamide) within 6&#xD;
             months.&#xD;
&#xD;
          3. History or clinical or laboratory evidence of other autoimmune syndromes.&#xD;
&#xD;
          4. Inability or unwillingness to complete the treatment and surveillance protocols.&#xD;
&#xD;
          5. Eligible for lung transplant at time of enrollment. This exclusion will mitigate any&#xD;
             potential, however slight, that a patient could be rejected for transplantation due to&#xD;
             surgeon concerns about this novel therapy (and will also obviate early drop-outs due&#xD;
             to transplantation).&#xD;
&#xD;
          6. History of malignant neoplasm within the last 5 years.&#xD;
&#xD;
          7. Evidence of serious suicide risk including any history of suicidal behavior in the&#xD;
             last 6 months and/or any suicidal ideation in the last 2 months or those, in the&#xD;
             investigator's judgment, pose a significant suicide risk.&#xD;
&#xD;
          8. History of a primary immunodeficiency.&#xD;
&#xD;
          9. Significant IgG deficiency (IgG level &lt; 400 mg/dL).&#xD;
&#xD;
         10. Have an IgA deficiency (IgA level &lt; 10 mg/dL).&#xD;
&#xD;
         11. Currently on any suppressive therapy for a chronic infection (such as tuberculosis,&#xD;
             pneumocystis, cytomegalovirus, herpes simplex virus, herpes zoster or atypical&#xD;
             mycobacteria).&#xD;
&#xD;
         12. Hospitalization for treatment of infection within 60 days of Day 0.&#xD;
&#xD;
         13. Use of parenteral (IV or IM) antibiotics (antibacterials, antivirals, anti-fungals, or&#xD;
             anti parasitic agents) within 60 days of Day 0.&#xD;
&#xD;
         14. Current drug or alcohol abuse or dependence, or a history of drug or alcohol abuse or&#xD;
             dependence within 365 days prior to Day 0.&#xD;
&#xD;
         15. History of a positive HIV test or positive screening test for HIV.&#xD;
&#xD;
         16. Serologic evidence of current or past Hepatitis B (HB) or Hepatitis C (HC) infection&#xD;
             based on positive tests for HBsAg or HBcAb, or HCAb.&#xD;
&#xD;
         17. History of an anaphylactic reaction to parenteral administration of contrast agents,&#xD;
             human or murine proteins or monoclonal antibodies.&#xD;
&#xD;
         18. Any other clinically significant abnormal laboratory value in the opinion of the&#xD;
             investigator.&#xD;
&#xD;
         19. Any intercurrent significant medical or psychiatric illness that the investigator&#xD;
             considers would make the candidate unsuitable for the study.&#xD;
&#xD;
         20. Women of Child Bearing Potential (WCBP) must have a negative serum pregnancy test&#xD;
             (either blood or urine) at screening, and agree to 1 of the following:&#xD;
&#xD;
             Complete abstinence from intercourse from 2 weeks prior to administration of the 1st&#xD;
             dose of study agent until 16 weeks after the last dose of study agent (Sexual&#xD;
             inactivity by abstinence must be consistent with the preferred and usual lifestyle of&#xD;
             the subject. Periodic abstinence (e.g. calendar, ovulation, symptothermal,&#xD;
             post-ovulation methods) and withdrawal are not acceptable methods of contraception)&#xD;
&#xD;
             OR&#xD;
&#xD;
             Consistent and correct use of 1 of the following acceptable methods of birth control&#xD;
             for 1 month prior to the start of the study agent, during the study, and 16 weeks&#xD;
             after the last dose of study agent:&#xD;
&#xD;
               -  Oral contraceptive, either combined or progestogen alone&#xD;
&#xD;
               -  Injectable progestogen&#xD;
&#xD;
               -  Implants of levonorgestrel or etonogestrel&#xD;
&#xD;
               -  Estrogenic vaginal ring&#xD;
&#xD;
               -  Percutaneous contraceptive patches&#xD;
&#xD;
               -  Intrauterine device (IUD) or intrauterine system (IUS) with &lt;1% failure rate as&#xD;
                  stated in the product label&#xD;
&#xD;
               -  Male partner sterilization (vasectomy with documentation of azoospermia) prior to&#xD;
                  the female subject's entry into the study, and this male is the sole partner for&#xD;
                  that subject. For this definition, &quot;documented&quot; refers to the outcome of the&#xD;
                  investigator's/designee's medical examination of the subject or review of the&#xD;
                  subject's medical history for study eligibility, as obtained via a verbal&#xD;
                  interview with the subject or from the subject's medical records&#xD;
&#xD;
               -  Double barrier method: condom and occlusive cap (diaphragm or cervical/vault&#xD;
                  caps) plus spermicidal agent (foam/gel/film/cream/suppository)&#xD;
&#xD;
         21. Use of Excluded Medications:&#xD;
&#xD;
               -  Anti-B-cell therapy:&#xD;
&#xD;
                    -  Wash out of 5 therapeutic half lives after prior B-cell therapy, or until&#xD;
                       pharmacodynamic effect would be minimal (e.g., 1 year following rituximab)&#xD;
&#xD;
               -  365 days Prior to Belimumab:&#xD;
&#xD;
                    -  Any biologic investigational agent (e.g., abetimus sodium, anti CD40L&#xD;
                       antibody, BG9588/ IDEC 131)&#xD;
&#xD;
               -  Investigational agent applies to any drug not approved for sale in the country in&#xD;
                  which it is being used&#xD;
&#xD;
               -  30 Days Prior to Belimumab (or 5 half lives, whichever is greater)&#xD;
&#xD;
                    -  Any non-biologic investigational agent&#xD;
&#xD;
               -  Investigational agent applies to any drug not approved for sale in the country in&#xD;
                  which it is being use&#xD;
&#xD;
               -  Live vaccines within 30 days prior to baseline or concurrently with belimumab&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>40 Years</minimum_age>
    <maximum_age>75 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <location>
    <facility>
      <name>UAB Lung Health Center</name>
      <address>
        <city>Birmingham</city>
        <state>Alabama</state>
        <zip>35205</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>June 2023</verification_date>
  <study_first_submitted>August 3, 2017</study_first_submitted>
  <study_first_submitted_qc>August 7, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">August 9, 2017</study_first_posted>
  <results_first_submitted>April 20, 2023</results_first_submitted>
  <results_first_submitted_qc>June 26, 2023</results_first_submitted_qc>
  <results_first_posted type="Actual">July 18, 2023</results_first_posted>
  <last_update_submitted>June 26, 2023</last_update_submitted>
  <last_update_submitted_qc>June 26, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">July 18, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>University of Alabama at Birmingham</investigator_affiliation>
    <investigator_full_name>Mark Dransfield, MD</investigator_full_name>
    <investigator_title>Principal Investigator</investigator_title>
  </responsible_party>
  <keyword>COPD</keyword>
  <keyword>belimumab</keyword>
  <keyword>biologic agent</keyword>
  <keyword>GRP78</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Lung Diseases, Obstructive</mesh_term>
    <mesh_term>Pulmonary Disease, Chronic Obstructive</mesh_term>
    <mesh_term>Pulmonary Emphysema</mesh_term>
    <mesh_term>Emphysema</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Belimumab</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <provided_document_section>
    <provided_document>
      <document_type>Study Protocol and Statistical Analysis Plan</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>June 19, 2020</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/59/NCT03244059/Prot_SAP_000.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <group_list>
        <group group_id="P1">
          <title>Belimumab</title>
          <description>Subjects randomized to the experimental treatment arm will receive i.v. administrations of belimumab (10 mg/kg), consisting of three &quot;loading&quot; doses, two weeks apart, followed by five (5) more monthly infusions. The final assessment will be performed at month 8.&#xD;
Belimumab: Belimumab is an anti-BLyS (B-lymphocyte stimulating factor) agent administered by infusion.</description>
        </group>
        <group group_id="P2">
          <title>Placebo</title>
          <description>These subjects will be treated with identically appearing placebo i.v. on the same schedule as the experimental arm subjects (i.e., three &quot;loading&quot; doses, two weeks apart, followed by five more monthly infusions. Again, the final assessment will be performed at month 7 (210+10 days after treatment start).&#xD;
Placebo: An identically appearing placebo infusion.</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Specific Aim 1</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="11"/>
                <participants group_id="P2" count="6"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="10"/>
                <participants group_id="P2" count="6"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Physician Decision</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
        <period>
          <title>Specific Aim 2</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="11"/>
                <participants group_id="P2" count="6"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="10"/>
                <participants group_id="P2" count="6"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Physician Decision</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>Belimumab</title>
          <description>Subjects randomized to the experimental treatment arm will receive i.v. administrations of belimumab (10 mg/kg), consisting of three &quot;loading&quot; doses, two weeks apart, followed by five (5) more monthly infusions. The final assessment will be performed at month 8.&#xD;
Belimumab: Belimumab is an anti-BLyS (B-lymphocyte stimulating factor) agent administered by infusion.</description>
        </group>
        <group group_id="B2">
          <title>Placebo</title>
          <description>These subjects will be treated with identically appearing placebo i.v. on the same schedule as the experimental arm subjects (i.e., three &quot;loading&quot; doses, two weeks apart, followed by five more monthly infusions. Again, the final assessment will be performed at month 7 (210+10 days after treatment start).&#xD;
Placebo: An identically appearing placebo infusion.</description>
        </group>
        <group group_id="B3">
          <title>Total</title>
          <description>Total of all reporting groups</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="11"/>
            <count group_id="B2" value="6"/>
            <count group_id="B3" value="17"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <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="69" spread="6"/>
                    <measurement group_id="B2" value="69" spread="6"/>
                    <measurement group_id="B3" value="69" spread="6"/>
                  </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="2"/>
                    <measurement group_id="B2" value="2"/>
                    <measurement group_id="B3" value="4"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="9"/>
                    <measurement group_id="B2" value="4"/>
                    <measurement group_id="B3" value="13"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Race (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>American Indian or Alaska Native</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Asian</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Native Hawaiian or Other Pacific Islander</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Black or African American</title>
                  <measurement_list>
                    <measurement group_id="B1" value="5"/>
                    <measurement group_id="B2" value="2"/>
                    <measurement group_id="B3" value="7"/>
                  </measurement_list>
                </category>
                <category>
                  <title>White</title>
                  <measurement_list>
                    <measurement group_id="B1" value="6"/>
                    <measurement group_id="B2" value="4"/>
                    <measurement group_id="B3" value="10"/>
                  </measurement_list>
                </category>
                <category>
                  <title>More than one race</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>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="11"/>
                    <measurement group_id="B2" value="6"/>
                    <measurement group_id="B3" value="17"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Percent Change of Circulating Anti-GRP78 IgG Levels</title>
        <description>Anti-GRP78 IgG is a clinically relevant surrogate biomarker of autoimmunity in pulmonary emphysema patients who have clinically relevant (and quantifiable) autoimmune responses</description>
        <time_frame>Plasma concentrations of the anti-GRP78 autoantibodies will be measured pre-treatment and at end of treatment at 210 days (or when subject withdraws)</time_frame>
        <population>Measured as Optical Density (OD) at 405 nM of ELISA. OD values are proportional to autoantibody concentration.</population>
        <group_list>
          <group group_id="O1">
            <title>Belimumab</title>
            <description>Subjects randomized to the experimental treatment arm will receive i.v. administrations of belimumab (10 mg/kg), consisting of three &quot;loading&quot; doses, two weeks apart, followed by five (5) more monthly infusions. The final assessment will be performed at month 8.&#xD;
Belimumab: Belimumab is an anti-BLyS (B-lymphocyte stimulating factor) agent administered by infusion.</description>
          </group>
          <group group_id="O2">
            <title>Placebo</title>
            <description>These subjects will be treated with identically appearing placebo i.v. on the same schedule as the experimental arm subjects (i.e., three &quot;loading&quot; doses, two weeks apart, followed by five more monthly infusions. Again, the final assessment will be performed at month 7 (210+10 days after treatment start).&#xD;
Placebo: An identically appearing placebo infusion.</description>
          </group>
        </group_list>
        <measure>
          <title>Percent Change of Circulating Anti-GRP78 IgG Levels</title>
          <description>Anti-GRP78 IgG is a clinically relevant surrogate biomarker of autoimmunity in pulmonary emphysema patients who have clinically relevant (and quantifiable) autoimmune responses</description>
          <population>Measured as Optical Density (OD) at 405 nM of ELISA. OD values are proportional to autoantibody concentration.</population>
          <units>% change</units>
          <param>Mean</param>
          <dispersion>Standard Error</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="10"/>
                <count group_id="O2" value="6"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-17.0" spread="5.4"/>
                    <measurement group_id="O2" value="-2.6" spread="5.1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Percent Change of Pneumococcal Polysaccharide-binding Antibodies</title>
        <description>Treatment effects on concentrations of pneumococcal polysaccharide-binding antibodies by ELISA</description>
        <time_frame>Prior to treatment and at end of treatment on day 210 (or the conclusion of treatment if subject withdraws)</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Belimumab</title>
            <description>Subjects randomized to the experimental treatment arm will receive i.v. administrations of belimumab (10 mg/kg), consisting of three &quot;loading&quot; doses, two weeks apart, followed by five (5) more monthly infusions. The final assessment will be performed at month 8.&#xD;
Belimumab: Belimumab is an anti-BLyS (B-lymphocyte stimulating factor) agent administered by infusion.</description>
          </group>
          <group group_id="O2">
            <title>Placebo</title>
            <description>These subjects will be treated with identically appearing placebo i.v. on the same schedule as the experimental arm subjects (i.e., three &quot;loading&quot; doses, two weeks apart, followed by five more monthly infusions. Again, the final assessment will be performed at month 7 (210+10 days after treatment start).&#xD;
Placebo: An identically appearing placebo infusion.</description>
          </group>
        </group_list>
        <measure>
          <title>Percent Change of Pneumococcal Polysaccharide-binding Antibodies</title>
          <description>Treatment effects on concentrations of pneumococcal polysaccharide-binding antibodies by ELISA</description>
          <units>Percent change</units>
          <param>Mean</param>
          <dispersion>Standard Error</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="10"/>
                <count group_id="O2" value="6"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-14.1" spread="9.1"/>
                    <measurement group_id="O2" value="-5.0" spread="6.5"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Percent Change of Circulating B-cells</title>
        <description>Treatment effect on relative percentages of circulating B-cells (CD20+) by flow cytometry</description>
        <time_frame>Prior to treatment, and at treatment end on day 210 or when subject participation is terminated</time_frame>
        <population>analyzed as % of CD20+ cells among peripheral blood mononuclear cells</population>
        <group_list>
          <group group_id="O1">
            <title>Belimumab</title>
            <description>Subjects randomized to the experimental treatment arm will receive i.v. administrations of belimumab (10 mg/kg), consisting of three &quot;loading&quot; doses, two weeks apart, followed by five (5) more monthly infusions. The final assessment will be performed at month 8.&#xD;
Belimumab: Belimumab is an anti-BLyS (B-lymphocyte stimulating factor) agent administered by infusion.</description>
          </group>
          <group group_id="O2">
            <title>Placebo</title>
            <description>These subjects will be treated with identically appearing placebo i.v. on the same schedule as the experimental arm subjects (i.e., three &quot;loading&quot; doses, two weeks apart, followed by five more monthly infusions. Again, the final assessment will be performed at month 7 (210+10 days after treatment start).&#xD;
Placebo: An identically appearing placebo infusion.</description>
          </group>
        </group_list>
        <measure>
          <title>Percent Change of Circulating B-cells</title>
          <description>Treatment effect on relative percentages of circulating B-cells (CD20+) by flow cytometry</description>
          <population>analyzed as % of CD20+ cells among peripheral blood mononuclear cells</population>
          <units>Percent change</units>
          <param>Mean</param>
          <dispersion>Standard Error</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="10"/>
                <count group_id="O2" value="6"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-12.2" spread="4.9"/>
                    <measurement group_id="O2" value="-5.0" spread="6.5"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Adverse Events</title>
        <description>Adverse events will be evaluated according to criteria outlined in the National Cancer Institure (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 4.0.</description>
        <time_frame>Study start to completion (7 months)</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Belimumab</title>
            <description>Subjects randomized to the experimental treatment arm will receive i.v. administrations of belimumab (10 mg/kg), consisting of three &quot;loading&quot; doses, two weeks apart, followed by five (5) more monthly infusions. The final assessment will be performed at month 8.&#xD;
Belimumab: Belimumab is an anti-BLyS (B-lymphocyte stimulating factor) agent administered by infusion.</description>
          </group>
          <group group_id="O2">
            <title>Placebo</title>
            <description>These subjects will be treated with identically appearing placebo i.v. on the same schedule as the experimental arm subjects (i.e., three &quot;loading&quot; doses, two weeks apart, followed by five more monthly infusions. Again, the final assessment will be performed at month 7 (210+10 days after treatment start).&#xD;
Placebo: An identically appearing placebo infusion.</description>
          </group>
        </group_list>
        <measure>
          <title>Adverse Events</title>
          <description>Adverse events will be evaluated according to criteria outlined in the National Cancer Institure (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 4.0.</description>
          <units>Adverse events</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="10"/>
                <count group_id="O2" value="6"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="10"/>
                    <measurement group_id="O2" value="4"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>210 days or the end of treatment if withdrawn prior to 7 month completion</time_frame>
      <desc>Adverse event tabulated and classified based on severity.</desc>
      <group_list>
        <group group_id="E1">
          <title>Belimumab</title>
          <description>Subjects randomized to the experimental treatment arm will receive i.v. administrations of belimumab (10 mg/kg), consisting of three &quot;loading&quot; doses, two weeks apart, followed by five (5) more monthly infusions. The final assessment will be performed at month 8.&#xD;
Belimumab: Belimumab is an anti-BLyS (B-lymphocyte stimulating factor) agent administered by infusion.</description>
        </group>
        <group group_id="E2">
          <title>Placebo</title>
          <description>These subjects will be treated with identically appearing placebo i.v. on the same schedule as the experimental arm subjects (i.e., three &quot;loading&quot; doses, two weeks apart, followed by five more monthly infusions. Again, the final assessment will be performed at month 7 (210+10 days after treatment start).&#xD;
Placebo: An identically appearing placebo infusion.</description>
        </group>
      </group_list>
      <serious_events>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, all-cause mortality</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Cardiac disorders</title>
            <event_list>
              <event>
                <sub_title>SAE</sub_title>
                <description>Two patients soon after beginning treatment had cardiac catheterizations</description>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="10"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Neoplasms benign, malignant and unspecified (incl cysts and polyps)</title>
            <event_list>
              <event>
                <sub_title>SAE</sub_title>
                <description>Gastric carcinoma diagnosed soon after start of treatment. Adjudicated as not related to intervention.</description>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>SAE</sub_title>
                <description>Acute exacerbation of COPD.</description>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="6"/>
              </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="4" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="4" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Blood and lymphatic system disorders</title>
            <event_list>
              <event>
                <sub_title>minor adverse event</sub_title>
                <description>Anemia</description>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>minor adverse event</sub_title>
                <description>constipation</description>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>minor adverse event</sub_title>
                <description>nausea</description>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="10"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>minor adverse event</sub_title>
                <description>Diarrhea</description>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Hepatobiliary disorders</title>
            <event_list>
              <event>
                <sub_title>minor adverse event</sub_title>
                <description>minor elevation of aspartate aminotransferase</description>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Metabolism and nutrition disorders</title>
            <event_list>
              <event>
                <sub_title>minor adverse event</sub_title>
                <description>Hyperglycemia</description>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Minor self limited</sub_title>
                <description>Head aches</description>
                <counts group_id="E1" events="4" subjects_affected="3" subjects_at_risk="10"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Minor self limited</sub_title>
                <description>blurred vision</description>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>minor adverse event</sub_title>
                <description>fatigue, restless, depressed</description>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Skin and subcutaneous tissue disorders</title>
            <event_list>
              <event>
                <sub_title>minor adverse event</sub_title>
                <description>rash (on foot)</description>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>Principal Investigators are NOT employed by the organization sponsoring the study.</pi_employee>
      <restrictive_agreement>There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed. </restrictive_agreement>
    </certain_agreements>
    <point_of_contact>
      <name_or_title>Mark Dransfield MD</name_or_title>
      <organization>University of Alabama at Birmingham</organization>
      <phone>205-934-5425</phone>
      <email>mdransfield@uabmc.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/NCT03244059
org study id: IRB-300000119
nct id: NCT03244059
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
is us export: Yes
This is intended to be an initial "proof-of-concept" study to show feasibility, validate
      assays and approaches, and explore dosing and safety of belimumab in pulmonary emphysema
      patients who have clinically relevant (and quantifiable) autoimmune responses. The primary
      goal is to determine effects of belimumab on levels of autoantibodies against glucose
      regulated protein 78 (GRP78) among patients with pulmonary emphysema attributable to
      cigarette smoking. The investigators hypothesize that belimumab treatment will safely reduce
      circulating levels of autoantibodies that are associated with emphysema, and comorbidities of
      this lung disease, including atherosclerosis.
Specific Aim 1: To conduct a double-blind, Phase IIa trial, in which 18 former smokers with
      pulmonary emphysema (per chest CT scans), and circulating anti-GRP78 autoantibody levels
      >mean normal values (by ELISA), will be randomized 2:1 to belimumab vs. placebo. Subjects
      will receive 8 infusions of either belimumab or placebo over a 6 month interval. Plasma
      anti-GRP78 will be measured pre-treatment, and at 1, 3, 5, and 7 months. The investigators
      hypothesize belimumab therapy will more effectively reduce anti-GRP78 IgG autoantibodies, the
      primary endpoint of this trial, compared to placebo.

      Specific Aim 2: To determine effects of the belimumab therapy on secondary endpoints (at the
      times detailed for Aim 1) that include levels of pneumococcal-binding antibodies (by ELISA),
      circulating B-cell numbers and phenotypes (by flow cytometry), and the rate and severity of
      adverse events (AE) at any time during treatment. The investigators hypothesize belimumab
      will have dose-related effects on B-cell numbers and their differentiation, while minimally
      reducing host defense antibodies, and will also have an acceptable AE profile.
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: Patients will be randomly assigned to receive active:placebo in a ratio of 2:1.
primary purpose: Treatment
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
masking description: Double-blinded placebo controlled randomized clinical trial
measure: Percent Change of Circulating Anti-GRP78 IgG Levels
time frame: Plasma concentrations of the anti-GRP78 autoantibodies will be measured pre-treatment and at end of treatment at 210 days (or when subject withdraws)
description: Anti-GRP78 IgG is a clinically relevant surrogate biomarker of autoimmunity in pulmonary emphysema patients who have clinically relevant (and quantifiable) autoimmune responses
measure: Percent Change of Pneumococcal Polysaccharide-binding Antibodies
time frame: Prior to treatment and at end of treatment on day 210 (or the conclusion of treatment if subject withdraws)
description: Treatment effects on concentrations of pneumococcal polysaccharide-binding antibodies by ELISA
measure: Percent Change of Circulating B-cells
time frame: Prior to treatment, and at treatment end on day 210 or when subject participation is terminated
description: Treatment effect on relative percentages of circulating B-cells (CD20+) by flow cytometry
measure: Adverse Events
time frame: Study start to completion (7 months)
description: Adverse events will be evaluated according to criteria outlined in the National Cancer Institure (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 4.0.
arm group label: Belimumab
arm group type: Experimental
description: Subjects randomized to the experimental treatment arm will receive i.v. administrations of belimumab (10 mg/kg), consisting of three "loading" doses, two weeks apart, followed by five (5) more monthly infusions. The final assessment will be performed at month 8.
arm group label: Placebo
arm group type: Placebo Comparator
description: These subjects will be treated with identically appearing placebo i.v. on the same schedule as the experimental arm subjects (i.e., three "loading" doses, two weeks apart, followed by five more monthly infusions. Again, the final assessment will be performed at month 7 (210+10 days after treatment start).
intervention type: Biological
intervention name: Belimumab
description: Belimumab is an anti-BLyS (B-lymphocyte stimulating factor) agent administered by infusion.
arm group label: Belimumab
other name: Benlysta
intervention type: Drug
intervention name: Placebo
description: An identically appearing placebo infusion.
arm group label: Placebo
criteria: 
gender: All
minimum age: 40 Years
maximum age: 75 Years
healthy volunteers: No
facility: 
country: United States
responsible party type: Principal Investigator
investigator affiliation: University of Alabama at Birmingham
investigator full name: Mark Dransfield, MD
investigator title: Principal Investigator
mesh term: Lung Diseases, Obstructive
mesh term: Pulmonary Disease, Chronic Obstructive
mesh term: Pulmonary Emphysema
mesh term: Emphysema
mesh term: Belimumab
sharing ipd: No
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 