<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/NCT02207556</url>
  </required_header>
  <id_info>
    <org_study_id>22850</org_study_id>
    <secondary_id>KL2TR001438</secondary_id>
    <secondary_id>K23HL141445</secondary_id>
    <secondary_id>86-004-26</secondary_id>
    <nct_id>NCT02207556</nct_id>
  </id_info>
  <brief_title>Doxycycline to Upgrade Organ Response in Light Chain (AL) Amyloidosis Trial</brief_title>
  <acronym>DUAL</acronym>
  <official_title>Doxycycline to Upgrade Organ Response in Light Chain (AL) Amyloidosis (DUAL) Trial: A Phase II Open Label Study of Oral Doxycycline Administered as an Adjunct to Plasma Cell Directed Therapy in Light Chain (AL) Amyloidosis</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Medical College of Wisconsin</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>National Heart, Lung, and Blood Institute (NHLBI)</agency>
      <agency_class>NIH</agency_class>
    </collaborator>
  </sponsors>
  <source>Medical College of Wisconsin</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>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      In this study the investigators want to find out more about the addition of the antibiotic,&#xD;
      doxycycline, to standard anti-amyloid therapy in people with amyloidosis. The investigators&#xD;
      want to find out whether doxycycline improves the response to standard anti-amyloid therapy&#xD;
      and whether it causes any problems (side effects).&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Organ response to anti-plasma cell therapy in AL amyloidosis tends to lags behind hematologic&#xD;
      response as chemotherapy may not clear pre-formed organ amyloid. Doxycycline has been shown&#xD;
      to have inhibitory effects on amyloid fibril formation as well as de-fibrillogenic effects&#xD;
      and shown to be beneficial in in vitro, murine models and other preclinical studies. The&#xD;
      investigators will prospectively evaluate the safety and efficacy of doxycycline in AL&#xD;
      amyloidosis patients when used in conjunction with anti-plasma cell chemotherapy.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">October 1, 2014</start_date>
  <completion_date type="Actual">May 19, 2020</completion_date>
  <primary_completion_date type="Actual">July 31, 2017</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Hematologic Response</measure>
    <time_frame>1 year</time_frame>
    <description>This measure will record the number of subjects for each grade of response to therapy for subjects with Systematic Disease (hematologic) only. Hematologic response will be determined as follows.&#xD;
Complete response (CR) - Negative serum/urine immunofixation with normal Free Light Chain (FLC) ratio&#xD;
Very Good Partial Response (VGPR)- Difference between involved and uninvolved FLCs (dFLC) &lt; 40 mg/L&#xD;
Partial Response (PR)- dFLC decrease &gt; 50%&#xD;
No Response (NR)- less then PR.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Amyloid Organ Response</measure>
    <time_frame>6 months and 1 year</time_frame>
    <description>This measure is the number of subjects (systemic disease only) for each grade of response. Efficacy will be measured in heart, liver, or kidney.&#xD;
Heart N-terminal (NT)-proBNP response &gt;30% and &gt; 300 ng/L decrease in patients with baseline NT-proBNP ≥650 ng/L (Patients with progressively worsening renal function cannot be scored for NT-proBNP progression).&#xD;
Improvement by 2 New York Heart Association (NYHA) classes without an increase in diuretic use or in echocardiographic wall thickness ≥ 2 mm reduction in the interventricular septal thickness by echocardiogram or improvement of ejection fraction by ≥20%.&#xD;
Liver&#xD;
≥50% decrease in an initially elevated alkaline phosphatase level, or Decrease in liver size by at least 2 cm by ultrasound.&#xD;
Kidney 50% reduction in 24-hour urine protein excretion (at least 0.5 g/day) without worsening of creatinine or creatinine clearance by 25% over baseline.&#xD;
Soft Tissue RECIST criteria will be used.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Mortality</measure>
    <time_frame>Baseline, 3 months, 6 months, 1 year</time_frame>
    <description>The number of living subjects will be determined at Baseline, 3 months, 6 months and 1 year</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Patient-reported Health Quality of Life</measure>
    <time_frame>Baseline, 3, 6, 9 and 12 months</time_frame>
    <description>Subjects will complete the Patient Reported Outcomes Measurement Information System Global Health instrument, a 10-item standardized patient-reported outcome measure that provides global ratings of physical function, fatigue, pain, emotional distress to report on common domains of health-related quality of life. The survey comprises a series of 5-response Likert-style questions. For each question, a low score indicates lesser or absent symptom or condition and higher indicates more severe symptom or condition (e.g., 1= None to 5=Very severe). Automated scoring produces a T-score for each domain. This measure reports the physical health score. T-scores for this domain range from 16.2 to 67.7. Higher scores indicate poorer physical health.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Patient-reported Mental Quality of Life</measure>
    <time_frame>Baseline, 3, 6, 9 and 12 months</time_frame>
    <description>Subjects will complete the Patient Reported Outcomes Measurement Information System Global Health instrument, a 10-item standardized patient-reported outcome measure that provides global ratings of physical function, fatigue, pain, emotional distress to report on common domains of health-related quality of life. The survey comprises a series of 5-response Likert-style questions. For each question, a low score indicates lesser or absent symptom or condition and higher indicates more severe symptom or condition (e.g., 1= None to 5=Very severe). Automated scoring produces a T-score for each domain. This measure reports the mental health score. T-scores for this domain range from 21.2 to 67.6. Higher scores indicate poorer mental health.</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">32</enrollment>
  <condition>Primary Systemic Amyloidosis</condition>
  <arm_group>
    <arm_group_label>Doxycycline</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Doxycycline will be administered at dose of 100mg orally twice daily for 1 year.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Doxycycline</intervention_name>
    <description>Doxycycline will be continued until one of the following criteria is met:&#xD;
Patient has completed 1 year of doxycycline therapy&#xD;
Patient develops any grade 3-4 toxicity related to doxycycline use.</description>
    <arm_group_label>Doxycycline</arm_group_label>
    <other_name>Doxycycline monohydrate</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Patients with biopsy proven AL amyloidosis.&#xD;
&#xD;
          2. Patients ≥ 18 years of age are eligible.&#xD;
&#xD;
          3. Patient must provide informed consent.&#xD;
&#xD;
          4. All patients must have measurable amyloid organ involvement of a vital organ (eg.&#xD;
             heart, liver, kidneys). Localized amyloidosis will also be eligible as long as the&#xD;
             amyloid involvement is radiologically measurable.&#xD;
&#xD;
          5. A negative pregnancy test will be required for all women of child bearing potential.&#xD;
             Breast feeding is not permitted.&#xD;
&#xD;
          6. Patients who have previously been taking doxycycline will be eligible as long as there&#xD;
             is no contraindication to stay on doxycycline 100 mg twice daily (BID) for 1 year in&#xD;
             the opinion of the treating physician.&#xD;
&#xD;
          7. Creatinine clearance of &gt;25 ml/min.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Patients with severe malabsorption syndrome precluding absorption of oral agents will&#xD;
             be excluded.&#xD;
&#xD;
          2. Known intolerance or allergic reactions with doxycycline.&#xD;
&#xD;
          3. Previous chemotherapy for AL amyloidosis.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Anita D'Souza, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Medical College of Wisconsin</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Froedtert &amp; Medical College of Wisconsin</name>
      <address>
        <city>Milwaukee</city>
        <state>Wisconsin</state>
        <zip>53226</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>June 2021</verification_date>
  <study_first_submitted>July 23, 2014</study_first_submitted>
  <study_first_submitted_qc>July 31, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">August 4, 2014</study_first_posted>
  <results_first_submitted>December 18, 2019</results_first_submitted>
  <results_first_submitted_qc>December 18, 2019</results_first_submitted_qc>
  <results_first_posted type="Actual">January 7, 2020</results_first_posted>
  <last_update_submitted>June 18, 2021</last_update_submitted>
  <last_update_submitted_qc>June 18, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">July 9, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Medical College of Wisconsin</investigator_affiliation>
    <investigator_full_name>Anita D'Souza</investigator_full_name>
    <investigator_title>Assistant Professor</investigator_title>
  </responsible_party>
  <keyword>AL amyloidosis</keyword>
  <keyword>amyloidosis</keyword>
  <keyword>light chain amyloidosis</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Immunoglobulin Light-chain Amyloidosis</mesh_term>
    <mesh_term>Amyloidosis</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Doxycycline</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>August 19, 2016</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/56/NCT02207556/Prot_SAP_000.pdf</document_url>
    </provided_document>
    <provided_document>
      <document_type>Informed Consent Form</document_type>
      <document_has_protocol>No</document_has_protocol>
      <document_has_icf>Yes</document_has_icf>
      <document_has_sap>No</document_has_sap>
      <document_date>September 14, 2016</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/56/NCT02207556/ICF_001.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <recruitment_details>Subjects were stratified by the type of amyloidosis. Subjects with primarily organ-based disease were classified as Localized Disease), whereas subjects with hematologic disease were classified as Systematic Disease. Each population received the same intervention but assessment of the clinical outcomes used different classification categories.</recruitment_details>
      <group_list>
        <group group_id="P1">
          <title>Doxycycline (Localized Disease)</title>
          <description>Doxycycline will be administered at dose of 100mg orally twice daily for 1 year.&#xD;
Doxycycline: Doxycycline will be continued until one of the following criteria is met:&#xD;
Patient has completed 1 year of doxycycline therapy&#xD;
Patient develops any grade 3-4 toxicity related to doxycycline use.</description>
        </group>
        <group group_id="P2">
          <title>Doxacycline (Systemic Disease)</title>
          <description>Doxycycline will be administered at dose of 100mg orally twice daily for 1 year.&#xD;
Doxycycline: Doxycycline will be continued until one of the following criteria is met:&#xD;
Patient has completed 1 year of doxycycline therapy&#xD;
Patient develops any grade 3-4 toxicity related to doxycycline use.</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="7"/>
                <participants group_id="P2" count="25"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="5"/>
                <participants group_id="P2" count="20"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="2"/>
                <participants group_id="P2" count="5"/>
              </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>
              <title>Withdrawal by Subject</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Death</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="5"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <population>Two subjects in the Localized Disease arm signed consent, but did not proceed to the treatment phase of the study. One subject withdrew consent and one subject was determined to be ineligible and was withdrawn by the investigator. Baseline demographic data were collected for these subjects.</population>
      <group_list>
        <group group_id="B1">
          <title>Doxycycline (Localized Disease)</title>
          <description>Doxycycline will be administered at dose of 100mg orally twice daily for 1 year.&#xD;
Doxycycline: Doxycycline will be continued until one of the following criteria is met:&#xD;
Patient has completed 1 year of doxycycline therapy&#xD;
Patient develops any grade 3-4 toxicity related to doxycycline use.</description>
        </group>
        <group group_id="B2">
          <title>Doxycycline (Systemic Disease)</title>
          <description>Doxycycline will be administered at dose of 100mg orally twice daily for 1 year.&#xD;
Doxycycline: Doxycycline will be continued until one of the following criteria is met:&#xD;
Patient has completed 1 year of doxycycline therapy&#xD;
Patient develops any grade 3-4 toxicity related to doxycycline use.</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="7"/>
            <count group_id="B2" value="25"/>
            <count group_id="B3" value="32"/>
          </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_list>
                </category>
                <category>
                  <title>Between 18 and 65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="3"/>
                    <measurement group_id="B2" value="16"/>
                    <measurement group_id="B3" value="19"/>
                  </measurement_list>
                </category>
                <category>
                  <title>&gt;=65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="4"/>
                    <measurement group_id="B2" value="9"/>
                    <measurement group_id="B3" value="13"/>
                  </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="61.3" spread="10.6"/>
                    <measurement group_id="B2" value="65.5" spread="11.4"/>
                    <measurement group_id="B3" value="62.5" spread="10.5"/>
                  </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="5"/>
                    <measurement group_id="B2" value="9"/>
                    <measurement group_id="B3" value="14"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                    <measurement group_id="B2" value="16"/>
                    <measurement group_id="B3" value="18"/>
                  </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="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Not Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="7"/>
                    <measurement group_id="B2" value="25"/>
                    <measurement group_id="B3" value="32"/>
                  </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>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="0"/>
                    <measurement group_id="B2" value="4"/>
                    <measurement group_id="B3" value="4"/>
                  </measurement_list>
                </category>
                <category>
                  <title>White</title>
                  <measurement_list>
                    <measurement group_id="B1" value="7"/>
                    <measurement group_id="B2" value="21"/>
                    <measurement group_id="B3" value="28"/>
                  </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="7"/>
                    <measurement group_id="B2" value="25"/>
                    <measurement group_id="B3" value="32"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Hematologic Response</title>
        <description>This measure will record the number of subjects for each grade of response to therapy for subjects with Systematic Disease (hematologic) only. Hematologic response will be determined as follows.&#xD;
Complete response (CR) - Negative serum/urine immunofixation with normal Free Light Chain (FLC) ratio&#xD;
Very Good Partial Response (VGPR)- Difference between involved and uninvolved FLCs (dFLC) &lt; 40 mg/L&#xD;
Partial Response (PR)- dFLC decrease &gt; 50%&#xD;
No Response (NR)- less then PR.</description>
        <time_frame>1 year</time_frame>
        <population>Hematologic response is not relevant to subjects with localized disease. Subjects with localized disease were not included in this analysis. Five participants had expired by the 1 year time point</population>
        <group_list>
          <group group_id="O1">
            <title>Doxycycline (Systemic Disease)</title>
            <description>Doxycycline will be administered at dose of 100mg orally twice daily for 1 year.&#xD;
Doxycycline: Doxycycline will be continued until one of the following criteria is met:&#xD;
Patient has completed 1 year of doxycycline therapy&#xD;
Patient develops any grade 3-4 toxicity related to doxycycline use.</description>
          </group>
        </group_list>
        <measure>
          <title>Hematologic Response</title>
          <description>This measure will record the number of subjects for each grade of response to therapy for subjects with Systematic Disease (hematologic) only. Hematologic response will be determined as follows.&#xD;
Complete response (CR) - Negative serum/urine immunofixation with normal Free Light Chain (FLC) ratio&#xD;
Very Good Partial Response (VGPR)- Difference between involved and uninvolved FLCs (dFLC) &lt; 40 mg/L&#xD;
Partial Response (PR)- dFLC decrease &gt; 50%&#xD;
No Response (NR)- less then PR.</description>
          <population>Hematologic response is not relevant to subjects with localized disease. Subjects with localized disease were not included in this analysis. Five participants had expired by the 1 year time point</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="25"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Complete Response (CR)</title>
                  <measurement_list>
                    <measurement group_id="O1" value="6"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Partial Response (PR)</title>
                  <measurement_list>
                    <measurement group_id="O1" value="3"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Very Good Partial Response (VGPR)</title>
                  <measurement_list>
                    <measurement group_id="O1" value="11"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Expired at 1 year</title>
                  <measurement_list>
                    <measurement group_id="O1" value="5"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Amyloid Organ Response</title>
        <description>This measure is the number of subjects (systemic disease only) for each grade of response. Efficacy will be measured in heart, liver, or kidney.&#xD;
Heart N-terminal (NT)-proBNP response &gt;30% and &gt; 300 ng/L decrease in patients with baseline NT-proBNP ≥650 ng/L (Patients with progressively worsening renal function cannot be scored for NT-proBNP progression).&#xD;
Improvement by 2 New York Heart Association (NYHA) classes without an increase in diuretic use or in echocardiographic wall thickness ≥ 2 mm reduction in the interventricular septal thickness by echocardiogram or improvement of ejection fraction by ≥20%.&#xD;
Liver&#xD;
≥50% decrease in an initially elevated alkaline phosphatase level, or Decrease in liver size by at least 2 cm by ultrasound.&#xD;
Kidney 50% reduction in 24-hour urine protein excretion (at least 0.5 g/day) without worsening of creatinine or creatinine clearance by 25% over baseline.&#xD;
Soft Tissue RECIST criteria will be used.</description>
        <time_frame>6 months and 1 year</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Doxycycline (6 Months)</title>
            <description>Doxycycline will be administered at dose of 100mg orally twice daily for 1 year.&#xD;
Doxycycline: Doxycycline will be continued until one of the following criteria is met:&#xD;
Patient has completed 1 year of doxycycline therapy&#xD;
Patient develops any grade 3-4 toxicity related to doxycycline use.</description>
          </group>
          <group group_id="O2">
            <title>Doxycycline (1 Year)</title>
            <description>Doxycycline will be administered at dose of 100mg orally twice daily for 1 year.&#xD;
Doxycycline: Doxycycline will be continued until one of the following criteria is met:&#xD;
Patient has completed 1 year of doxycycline therapy&#xD;
Patient develops any grade 3-4 toxicity related to doxycycline use.</description>
          </group>
        </group_list>
        <measure>
          <title>Amyloid Organ Response</title>
          <description>This measure is the number of subjects (systemic disease only) for each grade of response. Efficacy will be measured in heart, liver, or kidney.&#xD;
Heart N-terminal (NT)-proBNP response &gt;30% and &gt; 300 ng/L decrease in patients with baseline NT-proBNP ≥650 ng/L (Patients with progressively worsening renal function cannot be scored for NT-proBNP progression).&#xD;
Improvement by 2 New York Heart Association (NYHA) classes without an increase in diuretic use or in echocardiographic wall thickness ≥ 2 mm reduction in the interventricular septal thickness by echocardiogram or improvement of ejection fraction by ≥20%.&#xD;
Liver&#xD;
≥50% decrease in an initially elevated alkaline phosphatase level, or Decrease in liver size by at least 2 cm by ultrasound.&#xD;
Kidney 50% reduction in 24-hour urine protein excretion (at least 0.5 g/day) without worsening of creatinine or creatinine clearance by 25% over baseline.&#xD;
Soft Tissue RECIST criteria will be used.</description>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="25"/>
                <count group_id="O2" value="25"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Progressive Disease</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="8"/>
                    <measurement group_id="O2" value="3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Stable Disease</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="8"/>
                    <measurement group_id="O2" value="8"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Response</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="6"/>
                    <measurement group_id="O2" value="9"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Expired</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="3"/>
                    <measurement group_id="O2" value="5"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Mortality</title>
        <description>The number of living subjects will be determined at Baseline, 3 months, 6 months and 1 year</description>
        <time_frame>Baseline, 3 months, 6 months, 1 year</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Doxycycline (Localized Disease)</title>
            <description>Doxycycline will be administered at dose of 100mg orally twice daily for 1 year.&#xD;
Doxycycline: Doxycycline will be continued until one of the following criteria is met:&#xD;
Patient has completed 1 year of doxycycline therapy&#xD;
Patient develops any grade 3-4 toxicity related to doxycycline use.</description>
          </group>
          <group group_id="O2">
            <title>Doxacycline (Systemic Disease)</title>
            <description>Doxycycline will be administered at dose of 100mg orally twice daily for 1 year.&#xD;
Doxycycline: Doxycycline will be continued until one of the following criteria is met:&#xD;
Patient has completed 1 year of doxycycline therapy&#xD;
Patient develops any grade 3-4 toxicity related to doxycycline use.</description>
          </group>
        </group_list>
        <measure>
          <title>Mortality</title>
          <description>The number of living subjects will be determined at Baseline, 3 months, 6 months and 1 year</description>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="6"/>
                <count group_id="O2" value="25"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Baseline</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="6"/>
                    <measurement group_id="O2" value="25"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>3 Months</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="6"/>
                    <measurement group_id="O2" value="23"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>6 Months</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="6"/>
                    <measurement group_id="O2" value="22"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>1 Year</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="6"/>
                    <measurement group_id="O2" value="20"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Patient-reported Health Quality of Life</title>
        <description>Subjects will complete the Patient Reported Outcomes Measurement Information System Global Health instrument, a 10-item standardized patient-reported outcome measure that provides global ratings of physical function, fatigue, pain, emotional distress to report on common domains of health-related quality of life. The survey comprises a series of 5-response Likert-style questions. For each question, a low score indicates lesser or absent symptom or condition and higher indicates more severe symptom or condition (e.g., 1= None to 5=Very severe). Automated scoring produces a T-score for each domain. This measure reports the physical health score. T-scores for this domain range from 16.2 to 67.7. Higher scores indicate poorer physical health.</description>
        <time_frame>Baseline, 3, 6, 9 and 12 months</time_frame>
        <population>One subject in the Localized cohort withdrew consent prior to the 6-month visit. Five subjects in the Systemic Disease cohort expired during the course of the study; two subjects came off study; and one was lost to follow-up.</population>
        <group_list>
          <group group_id="O1">
            <title>Doxycycline (Localized Disease)</title>
            <description>Doxycycline will be administered at dose of 100mg orally twice daily for 1 year.&#xD;
Doxycycline: Doxycycline will be continued until one of the following criteria is met:&#xD;
Patient has completed 1 year of doxycycline therapy&#xD;
Patient develops any grade 3-4 toxicity related to doxycycline use.</description>
          </group>
          <group group_id="O2">
            <title>Doxacycline (Systemic Disease)</title>
            <description>Doxycycline will be administered at dose of 100mg orally twice daily for 1 year.&#xD;
Doxycycline: Doxycycline will be continued until one of the following criteria is met:&#xD;
Patient has completed 1 year of doxycycline therapy&#xD;
Patient develops any grade 3-4 toxicity related to doxycycline use.</description>
          </group>
        </group_list>
        <measure>
          <title>Patient-reported Health Quality of Life</title>
          <description>Subjects will complete the Patient Reported Outcomes Measurement Information System Global Health instrument, a 10-item standardized patient-reported outcome measure that provides global ratings of physical function, fatigue, pain, emotional distress to report on common domains of health-related quality of life. The survey comprises a series of 5-response Likert-style questions. For each question, a low score indicates lesser or absent symptom or condition and higher indicates more severe symptom or condition (e.g., 1= None to 5=Very severe). Automated scoring produces a T-score for each domain. This measure reports the physical health score. T-scores for this domain range from 16.2 to 67.7. Higher scores indicate poorer physical health.</description>
          <population>One subject in the Localized cohort withdrew consent prior to the 6-month visit. Five subjects in the Systemic Disease cohort expired during the course of the study; two subjects came off study; and one was lost to follow-up.</population>
          <units>score on a scale</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="6"/>
                <count group_id="O2" value="25"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Baseline</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="6"/>
                    <count group_id="O2" value="25"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="46.1" spread="9.4"/>
                    <measurement group_id="O2" value="40.9" spread="0.3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>3 Months</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="6"/>
                    <count group_id="O2" value="22"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="51.1" spread="8.8"/>
                    <measurement group_id="O2" value="40.2" spread="0.4"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>6 Months</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="5"/>
                    <count group_id="O2" value="20"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="48.3" spread="6.3"/>
                    <measurement group_id="O2" value="40.6" spread="0.4"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>9 Months</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="5"/>
                    <count group_id="O2" value="20"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="48.9" spread="8.0"/>
                    <measurement group_id="O2" value="41.7" spread="0.5"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>12 Months</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="5"/>
                    <count group_id="O2" value="17"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="49.4" spread="7.7"/>
                    <measurement group_id="O2" value="44.3" spread="0.4"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Patient-reported Mental Quality of Life</title>
        <description>Subjects will complete the Patient Reported Outcomes Measurement Information System Global Health instrument, a 10-item standardized patient-reported outcome measure that provides global ratings of physical function, fatigue, pain, emotional distress to report on common domains of health-related quality of life. The survey comprises a series of 5-response Likert-style questions. For each question, a low score indicates lesser or absent symptom or condition and higher indicates more severe symptom or condition (e.g., 1= None to 5=Very severe). Automated scoring produces a T-score for each domain. This measure reports the mental health score. T-scores for this domain range from 21.2 to 67.6. Higher scores indicate poorer mental health.</description>
        <time_frame>Baseline, 3, 6, 9 and 12 months</time_frame>
        <population>One subject in the Localized cohort withdrew consent prior to the 6-month visit. Five subjects in the Systemic Disease cohort expired during the course of the study; two subjects came off study; and one was lost to follow-up.</population>
        <group_list>
          <group group_id="O1">
            <title>Doxycycline (Localized Disease)</title>
            <description>Doxycycline will be administered at dose of 100mg orally twice daily for 1 year.&#xD;
Doxycycline: Doxycycline will be continued until one of the following criteria is met:&#xD;
Patient has completed 1 year of doxycycline therapy&#xD;
Patient develops any grade 3-4 toxicity related to doxycycline use.</description>
          </group>
          <group group_id="O2">
            <title>Doxacycline (Systemic Disease)</title>
            <description>Doxycycline will be administered at dose of 100mg orally twice daily for 1 year.&#xD;
Doxycycline: Doxycycline will be continued until one of the following criteria is met:&#xD;
Patient has completed 1 year of doxycycline therapy&#xD;
Patient develops any grade 3-4 toxicity related to doxycycline use.</description>
          </group>
        </group_list>
        <measure>
          <title>Patient-reported Mental Quality of Life</title>
          <description>Subjects will complete the Patient Reported Outcomes Measurement Information System Global Health instrument, a 10-item standardized patient-reported outcome measure that provides global ratings of physical function, fatigue, pain, emotional distress to report on common domains of health-related quality of life. The survey comprises a series of 5-response Likert-style questions. For each question, a low score indicates lesser or absent symptom or condition and higher indicates more severe symptom or condition (e.g., 1= None to 5=Very severe). Automated scoring produces a T-score for each domain. This measure reports the mental health score. T-scores for this domain range from 21.2 to 67.6. Higher scores indicate poorer mental health.</description>
          <population>One subject in the Localized cohort withdrew consent prior to the 6-month visit. Five subjects in the Systemic Disease cohort expired during the course of the study; two subjects came off study; and one was lost to follow-up.</population>
          <units>score on a scale</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="6"/>
                <count group_id="O2" value="25"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Baseline</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="6"/>
                    <count group_id="O2" value="25"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="52.1" spread="10.4"/>
                    <measurement group_id="O2" value="47.9" spread="0.6"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>3 Month</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="6"/>
                    <count group_id="O2" value="22"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="51.4" spread="10.0"/>
                    <measurement group_id="O2" value="46.0" spread="0.5"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>6 Months</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="5"/>
                    <count group_id="O2" value="20"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="51.2" spread="9.0"/>
                    <measurement group_id="O2" value="46.4" spread="0.5"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>9 Months</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="5"/>
                    <count group_id="O2" value="20"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="52.6" spread="11.9"/>
                    <measurement group_id="O2" value="46.7" spread="0.5"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>12 Months</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="5"/>
                    <count group_id="O2" value="17"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="50.7" spread="10.2"/>
                    <measurement group_id="O2" value="50.6" spread="0.6"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>1 year</time_frame>
      <desc>Grade was determined using the Common Terminology Criteria for Adverse Events (CTCAE) v 4.03. Events graded as 4 or 5 were considered serious regardless of the standard criteria.</desc>
      <group_list>
        <group group_id="E1">
          <title>Doxycycline (Localized Disease)</title>
          <description>Doxycycline will be administered at dose of 100mg orally twice daily for 1 year.&#xD;
Doxycycline: Doxycycline will be continued until one of the following criteria is met:&#xD;
Patient has completed 1 year of doxycycline therapy&#xD;
Patient develops any grade 3-4 toxicity related to doxycycline use.</description>
        </group>
        <group group_id="E2">
          <title>Doxycycline (Systemic Disease)</title>
          <description>Doxycycline will be administered at dose of 100mg orally twice daily for 1 year.&#xD;
Doxycycline: Doxycycline will be continued until one of the following criteria is met:&#xD;
Patient has completed 1 year of doxycycline therapy&#xD;
Patient develops any grade 3-4 toxicity related to doxycycline use.</description>
        </group>
      </group_list>
      <serious_events>
        <default_vocab>CTCAE v4.03</default_vocab>
        <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="5"/>
                <counts group_id="E2" subjects_affected="5" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="5"/>
                <counts group_id="E2" subjects_affected="13" subjects_at_risk="25"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Blood and lymphatic system disorders</title>
            <event_list>
              <event>
                <sub_title>Lymphocyte production decreased</sub_title>
                <description>CTCAE v4.03 Grade 4</description>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" events="7" subjects_affected="7" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Neutrophil Count Decreased</sub_title>
                <description>CTCAE v4.03 Grade 4</description>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" events="6" subjects_affected="6" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Platelet Count Decreased</sub_title>
                <description>CTCAE v4.03 Grade 4</description>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" events="10" subjects_affected="10" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>White Blood Cell Count Decreased</sub_title>
                <description>CTCAE v4.03 Grade 4</description>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" events="5" subjects_affected="5" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title vocab="SNOMED">Death in Hospice</sub_title>
                <description>CTCAE v4.03 Grade 5</description>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title vocab="SNOMED">Thrombosis of Vein of Lower Limb</sub_title>
                <description>CTCAE v4.03 Grade 4</description>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="25"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Cardiac disorders</title>
            <event_list>
              <event>
                <sub_title>Progressive cardiac amyloidosis</sub_title>
                <description>CTCAE v4.03 Grade 5</description>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title vocab="SNOMED">Natural Death</sub_title>
                <description>CTCAE v4.03 Grade 5</description>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="25"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Colitis</sub_title>
                <description>CTCA v4.03 Grade 5</description>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="25"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Hepatobiliary disorders</title>
            <event_list>
              <event>
                <sub_title>Aspartate Aminotransferase Increased</sub_title>
                <description>CTCAE v4.03 Grade 4</description>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Alanine Aminotransferase Increased</sub_title>
                <description>CTCAE v4.03 Grade 4</description>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="25"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Adenovirus Infection</sub_title>
                <description>CTCAE v4.03 Grade 4</description>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title vocab="SNOMED">Bacterial Sepsis</sub_title>
                <description>CTCAE v4.03 Grade 4</description>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="25"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Metabolism and nutrition disorders</title>
            <event_list>
              <event>
                <sub_title>Hyperuricemia</sub_title>
                <description>CTCAE v4.03 Grade 4</description>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="25"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Renal and urinary disorders</title>
            <event_list>
              <event>
                <sub_title>Chronic Kidney Disease</sub_title>
                <description>CTCAE v4.03 Grade 4</description>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="25"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Respiratory Failure</sub_title>
                <description>CTCAE v4.03 Grade 4</description>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="25"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Skin and subcutaneous tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Drug-Induced Lupus</sub_title>
                <description>CTCAE v4.03 Grade 3</description>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="5"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="25"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>5</frequency_threshold>
        <default_vocab>CTCAE v4.03</default_vocab>
        <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="5" subjects_at_risk="5"/>
                <counts group_id="E2" subjects_affected="24" subjects_at_risk="25"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Blood and lymphatic system disorders</title>
            <event_list>
              <event>
                <sub_title>Anemia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" events="15" subjects_affected="15" subjects_at_risk="25"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Cardiac disorders</title>
            <event_list>
              <event>
                <sub_title>Cardiac Tropinin T Increased</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="5"/>
                <counts group_id="E2" events="4" subjects_affected="4" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Tachycardia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" events="9" subjects_affected="9" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Sinus Tachycardia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" events="6" subjects_affected="6" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Left Atrium Enlarged</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" events="4" subjects_affected="4" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Palpitations</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" events="4" subjects_affected="4" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Chest Pain - Cardiac</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" events="3" subjects_affected="3" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Irregular Heartbeat</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" events="3" subjects_affected="3" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Right Atrium Enlarged</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" events="3" subjects_affected="3" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Bradycardia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Chest Tightness</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Murmur, Systolic II/IV</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Sinus Bradycardia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="25"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Ear and labyrinth disorders</title>
            <event_list>
              <event>
                <sub_title>Hearing Impaired</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="5"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Vertigo</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="25"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Eye disorders</title>
            <event_list>
              <event>
                <sub_title>Blurred Vison</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" events="3" subjects_affected="3" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Periorbital Edema/Puffiness</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" events="3" subjects_affected="3" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Cataract</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Dry Eye</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Eye Discharge</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Photophobia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Watering Eyes</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="25"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Nausea</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="5"/>
                <counts group_id="E2" events="14" subjects_affected="14" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Diarrhea</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="5"/>
                <counts group_id="E2" events="15" subjects_affected="15" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Constipation</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" events="11" subjects_affected="11" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Abdominal Pain</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" events="10" subjects_affected="10" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Bloating</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" events="7" subjects_affected="7" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Dry Mouth</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" events="7" subjects_affected="7" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Dysphagia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" events="6" subjects_affected="6" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Sore Throat</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" events="6" subjects_affected="6" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Vomiting</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" events="6" subjects_affected="6" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Hemorrhoids</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" events="4" subjects_affected="4" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Macroglossia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" events="3" subjects_affected="3" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Mucocitis, Oral</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" events="3" subjects_affected="3" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Flatulence</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="25"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Fatigue</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="5"/>
                <counts group_id="E2" events="15" subjects_affected="15" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Edema, Limb</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="5"/>
                <counts group_id="E2" events="15" subjects_affected="15" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Pain</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="5"/>
                <counts group_id="E2" events="8" subjects_affected="8" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Rib Pain</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="5"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Fever</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" events="8" subjects_affected="8" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Noncardiac Chest Pain</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" events="7" subjects_affected="7" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Chills</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" events="5" subjects_affected="5" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Gait Disturbance, Unsteady</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" events="3" subjects_affected="3" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Edema, Tongue</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="25"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Upper Respiratory Infection</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="5"/>
                <counts group_id="E2" events="6" subjects_affected="6" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Rhinitis Infective</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="5"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Streptococcal Test, Positive</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="5"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Upper Respiratory Infection</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" events="6" subjects_affected="6" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Urinary Tract Infection</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" events="3" subjects_affected="3" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Thrush</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="25"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Injury, poisoning and procedural complications</title>
            <event_list>
              <event>
                <sub_title>Bruising</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="5"/>
                <counts group_id="E2" events="8" subjects_affected="8" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Fall</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="5"/>
                <counts group_id="E2" events="9" subjects_affected="9" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Sunburn (Burn)</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="5"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Inguinal Hernia Repair</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Injury to Lip</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Skin Tear</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="25"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>Hypercalcemia</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="5"/>
                <counts group_id="E2" events="6" subjects_affected="6" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Hyperglycemia</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="5"/>
                <counts group_id="E2" events="17" subjects_affected="17" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Hyponatremia</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="5"/>
                <counts group_id="E2" events="16" subjects_affected="16" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Hyperkalemia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="5"/>
                <counts group_id="E2" events="7" subjects_affected="7" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Hypoalbuminemia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="5"/>
                <counts group_id="E2" events="15" subjects_affected="15" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Hypokalemia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="5"/>
                <counts group_id="E2" events="14" subjects_affected="14" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Weight Gain</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="5"/>
                <counts group_id="E2" events="6" subjects_affected="6" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Weight Loss</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="5"/>
                <counts group_id="E2" events="16" subjects_affected="16" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Platelet Count Decreased</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" events="8" subjects_affected="8" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Lymphocyte Count Decreased</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="5"/>
                <counts group_id="E2" events="12" subjects_affected="12" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>White Cell Count Decreased</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="5"/>
                <counts group_id="E2" events="10" subjects_affected="10" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Neutrophil Cound Decreased</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" events="6" subjects_affected="6" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>AST Increased</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="5"/>
                <counts group_id="E2" events="8" subjects_affected="8" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>ALT Increased</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="5"/>
                <counts group_id="E2" events="5" subjects_affected="5" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Creatinine Increased</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" events="10" subjects_affected="10" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Hypocalcemia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" events="10" subjects_affected="10" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Alkaline Phosphatase Increased</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" events="7" subjects_affected="7" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Hyopohosphatemia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" events="6" subjects_affected="6" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Hypomagnesemia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" events="5" subjects_affected="5" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Bilirubin Increased</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" events="4" subjects_affected="4" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Hypermagnesemia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" events="3" subjects_affected="3" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Hypernatremia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Hypoglycemia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="25"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Metabolism and nutrition disorders</title>
            <event_list>
              <event>
                <sub_title>Hyperuricemia</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="5"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Anorexia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="5"/>
                <counts group_id="E2" events="11" subjects_affected="11" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Low Vitamin D</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="5"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Hyperuricemia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" events="8" subjects_affected="8" subjects_at_risk="25"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Arthralgia</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="5"/>
                <counts group_id="E2" events="5" subjects_affected="5" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Pain in extremity</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="5"/>
                <counts group_id="E2" events="11" subjects_affected="11" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Generalized Muscle Weakness</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" events="10" subjects_affected="10" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Back Pain</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" events="8" subjects_affected="8" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Stiffness</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" events="8" subjects_affected="8" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Neck Pain</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" events="4" subjects_affected="4" subjects_at_risk="25"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Paresthesia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="5"/>
                <counts group_id="E2" events="6" subjects_affected="6" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Dizziness</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" events="15" subjects_affected="15" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Dysgeusia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" events="13" subjects_affected="13" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Peripheral Sensory Neuropathy</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" events="8" subjects_affected="8" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Headache</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" events="7" subjects_affected="7" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Akathisia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Hypersomnia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="25"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Psychiatric disorders</title>
            <event_list>
              <event>
                <sub_title>Anxiety</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="5"/>
                <counts group_id="E2" events="8" subjects_affected="8" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Depression</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="5"/>
                <counts group_id="E2" events="4" subjects_affected="4" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Insomnia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" events="13" subjects_affected="13" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Confusion</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" events="3" subjects_affected="3" subjects_at_risk="25"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Renal and urinary disorders</title>
            <event_list>
              <event>
                <sub_title>Nocturia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="5"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Urine Output Decreased</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="5"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Urinary Frequency</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" events="7" subjects_affected="7" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Proteinuria</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" events="5" subjects_affected="5" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Hematuria</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" events="4" subjects_affected="4" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Acute Kidney Injury</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" events="3" subjects_affected="3" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Urinary Incontinence</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Urinary Retention</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Urinary Tract Pain</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Urinary Urgency</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="25"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Reproductive system and breast disorders</title>
            <event_list>
              <event>
                <sub_title>Night Sweats</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="25"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Dyspnea</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="5"/>
                <counts group_id="E2" events="12" subjects_affected="12" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Tachypnea</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="5"/>
                <counts group_id="E2" events="6" subjects_affected="6" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Cough</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="5"/>
                <counts group_id="E2" events="12" subjects_affected="12" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Laryngeal Hemorrhage</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="5"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Lung Crackles</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="5"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Hypoxia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" events="7" subjects_affected="7" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Nasal Congestion</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" events="7" subjects_affected="7" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Epistaxis</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" events="6" subjects_affected="6" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Wheezing</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" events="4" subjects_affected="4" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Hiccups</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" events="3" subjects_affected="3" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Pleural Effusion</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Rales</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="25"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Skin and subcutaneous tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Bullous Dermatitis</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="5"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Contact Dermatitis</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="5"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Dry Skin</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="5"/>
                <counts group_id="E2" events="7" subjects_affected="7" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Erythema</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" events="5" subjects_affected="5" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Purpura</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" events="4" subjects_affected="4" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Photosensitivity</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" events="3" subjects_affected="3" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Rash</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" events="3" subjects_affected="3" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Erythematous Rash</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Petichial Rash</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Ulceration, Skin</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="25"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Vascular disorders</title>
            <event_list>
              <event>
                <sub_title>Hypertension</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="5"/>
                <counts group_id="E2" events="6" subjects_affected="6" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Hypotension</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" events="11" subjects_affected="11" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Jugular Vein Distention</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" events="3" subjects_affected="3" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Cyanosis</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Flushiing</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="25"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>All Principal Investigators ARE employed by the organization sponsoring the study.</pi_employee>
      <restrictive_agreement>There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed. </restrictive_agreement>
    </certain_agreements>
    <point_of_contact>
      <name_or_title>Dr. Anita D'Souza</name_or_title>
      <organization>Medical College of Wisconsin</organization>
      <phone>414-805-0637</phone>
      <email>dsouza@mcw.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/NCT02207556
org study id: 22850
secondary id: KL2TR001438
secondary id: K23HL141445
secondary id: 86-004-26
nct id: NCT02207556
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
is us export: No
In this study the investigators want to find out more about the addition of the antibiotic,
      doxycycline, to standard anti-amyloid therapy in people with amyloidosis. The investigators
      want to find out whether doxycycline improves the response to standard anti-amyloid therapy
      and whether it causes any problems (side effects).
Organ response to anti-plasma cell therapy in AL amyloidosis tends to lags behind hematologic
      response as chemotherapy may not clear pre-formed organ amyloid. Doxycycline has been shown
      to have inhibitory effects on amyloid fibril formation as well as de-fibrillogenic effects
      and shown to be beneficial in in vitro, murine models and other preclinical studies. The
      investigators will prospectively evaluate the safety and efficacy of doxycycline in AL
      amyloidosis patients when used in conjunction with anti-plasma cell chemotherapy.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Hematologic Response
time frame: 1 year
description: This measure will record the number of subjects for each grade of response to therapy for subjects with Systematic Disease (hematologic) only. Hematologic response will be determined as follows.
Complete response (CR) - Negative serum/urine immunofixation with normal Free Light Chain (FLC) ratio
Very Good Partial Response (VGPR)- Difference between involved and uninvolved FLCs (dFLC) < 40 mg/L
Partial Response (PR)- dFLC decrease > 50%
No Response (NR)- less then PR.
measure: Amyloid Organ Response
time frame: 6 months and 1 year
description: This measure is the number of subjects (systemic disease only) for each grade of response. Efficacy will be measured in heart, liver, or kidney.
Heart N-terminal (NT)-proBNP response >30% and > 300 ng/L decrease in patients with baseline NT-proBNP ≥650 ng/L (Patients with progressively worsening renal function cannot be scored for NT-proBNP progression).
Improvement by 2 New York Heart Association (NYHA) classes without an increase in diuretic use or in echocardiographic wall thickness ≥ 2 mm reduction in the interventricular septal thickness by echocardiogram or improvement of ejection fraction by ≥20%.
Liver
≥50% decrease in an initially elevated alkaline phosphatase level, or Decrease in liver size by at least 2 cm by ultrasound.
Kidney 50% reduction in 24-hour urine protein excretion (at least 0.5 g/day) without worsening of creatinine or creatinine clearance by 25% over baseline.
Soft Tissue RECIST criteria will be used.
measure: Mortality
time frame: Baseline, 3 months, 6 months, 1 year
description: The number of living subjects will be determined at Baseline, 3 months, 6 months and 1 year
measure: Patient-reported Health Quality of Life
time frame: Baseline, 3, 6, 9 and 12 months
description: Subjects will complete the Patient Reported Outcomes Measurement Information System Global Health instrument, a 10-item standardized patient-reported outcome measure that provides global ratings of physical function, fatigue, pain, emotional distress to report on common domains of health-related quality of life. The survey comprises a series of 5-response Likert-style questions. For each question, a low score indicates lesser or absent symptom or condition and higher indicates more severe symptom or condition (e.g., 1= None to 5=Very severe). Automated scoring produces a T-score for each domain. This measure reports the physical health score. T-scores for this domain range from 16.2 to 67.7. Higher scores indicate poorer physical health.
measure: Patient-reported Mental Quality of Life
time frame: Baseline, 3, 6, 9 and 12 months
description: Subjects will complete the Patient Reported Outcomes Measurement Information System Global Health instrument, a 10-item standardized patient-reported outcome measure that provides global ratings of physical function, fatigue, pain, emotional distress to report on common domains of health-related quality of life. The survey comprises a series of 5-response Likert-style questions. For each question, a low score indicates lesser or absent symptom or condition and higher indicates more severe symptom or condition (e.g., 1= None to 5=Very severe). Automated scoring produces a T-score for each domain. This measure reports the mental health score. T-scores for this domain range from 21.2 to 67.6. Higher scores indicate poorer mental health.
arm group label: Doxycycline
arm group type: Experimental
description: Doxycycline will be administered at dose of 100mg orally twice daily for 1 year.
intervention type: Drug
intervention name: Doxycycline
description: Doxycycline will be continued until one of the following criteria is met:
Patient has completed 1 year of doxycycline therapy
Patient develops any grade 3-4 toxicity related to doxycycline use.
arm group label: Doxycycline
other name: Doxycycline monohydrate
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Anita D'Souza, MD
role: Principal Investigator
affiliation: Medical College of Wisconsin
facility: 
country: United States
responsible party type: Principal Investigator
investigator affiliation: Medical College of Wisconsin
investigator full name: Anita D'Souza
investigator title: Assistant Professor
mesh term: Immunoglobulin Light-chain Amyloidosis
mesh term: Amyloidosis
mesh term: Doxycycline
sharing ipd: No
provided document: 
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 