<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/NCT01677286</url>
  </required_header>
  <id_info>
    <org_study_id>H-31546</org_study_id>
    <nct_id>NCT01677286</nct_id>
  </id_info>
  <brief_title>Safety and Effect of Doxycycline in Patients With Amyloidosis</brief_title>
  <official_title>A Phase II Study of Doxycycline in Patients With Amyloidosis</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Boston University</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Boston University</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>Yes</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      The tetracycline antibiotic doxycycline disrupts A beta amyloid fibrils (AB) in Alzheimer's&#xD;
      disease, transthyretin (ATTR) amyloid fibrils in familial amyloidotic polyneuropathy, and&#xD;
      immunoglobulin light chain (AL) amyloid fibrils in transgenic mouse models of disease. If&#xD;
      untreated, amyloid deposits impair organ function, affecting the morbidity and mortality of&#xD;
      patients.&#xD;
&#xD;
      This single-center, twelve-month, open-label, prospective, pilot phase II study aims to&#xD;
      determine whether doxycycline reduces amyloid deposits and improves organ function in&#xD;
      patients with systemic or localized amyloidosis.&#xD;
&#xD;
      The investigators plan to enroll patients with measurable amyloid disease according to&#xD;
      internationally-accepted diagnostic criteria. Patients must have stable organ function at&#xD;
      enrollment. Eligible subjects not receiving active treatments for amyloidosis affecting their&#xD;
      kidneys, heart, aerodigestive tracts, peripheral or autonomic nervous system(s), lungs, eyes,&#xD;
      skin, bladder, or breasts will undergo evaluations at baseline, 6 months, and 12 months - or&#xD;
      more frequently as clinically indicated.&#xD;
&#xD;
      Over 45 years experience indicates doxycycline is a safe, well tolerated antibiotic. The&#xD;
      investigators will use standard grading systems to assess doxycycline response following&#xD;
      twelve months of treatment.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      In transgenic animal models of disease, the tetracycline antibiotic doxycycline disrupts A&#xD;
      beta amyloid fibrils (AB) in Alzheimer's disease, transthyretin (ATTR) amyloid fibrils in&#xD;
      familial amyloidotic polyneuropathy, and immunoglobulin light chain (AL) amyloid fibrils.&#xD;
&#xD;
      The aim of this single-center, 12-month open label, prospective phase II study was to&#xD;
      determine a) the safety and tolerability of prolonged full dose doxycycline in patients with&#xD;
      amyloidosis, and b) the effect of doxycycline treatment on amyloid-induced organ dysfunction.&#xD;
&#xD;
      We enrolled 25 patients with measurable organ dysfunction caused by amyloid deposition who&#xD;
      were not receiving active treatment to control their amyloid production. All 25 subjects&#xD;
      received doxycycline 100 mg by both twice daily for up to 12 months depending on their&#xD;
      tolerance of the antibiotic. The primary endpoint, defined by the organ most affected by&#xD;
      amyloid, was measured at baseline, 6 and 12 months along with safety laboratory values.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">July 2012</start_date>
  <completion_date type="Actual">December 15, 2015</completion_date>
  <primary_completion_date type="Actual">May 22, 2015</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>Amyloid Cardiomyopathy: BNP</measure>
    <time_frame>12 months</time_frame>
    <description>Cardiac biomarkers (BNP, Troponin I) were assessed at baseline, 6 and 12 months, with change at end of study reported</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Amyloid Cardiomyopathy: Troponin I</measure>
    <time_frame>12 months</time_frame>
    <description>Cardiac biomarkers (BNP, Troponin I) were assessed at baseline, 6 and 12 months, with change at change at end of study reported</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Amyloid Nephropathy: Creatinine Clearance</measure>
    <time_frame>12 months</time_frame>
    <description>Creatinine clearance (ml/min) and proteinuria (g/day) were assessed at baseline, 6 and 12 months, with change at change at end of study reported</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Amyloid Nephropathy: Proteinuria</measure>
    <time_frame>Data were assessed at baseline, 6 and 12 months, with change at end of study reported</time_frame>
    <description>Patients with predominant amyloid kidney involvement at enrollment.</description>
  </primary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">25</enrollment>
  <condition>Amyloidosis</condition>
  <arm_group>
    <arm_group_label>doxycycline 100 mg po bid x 12 months</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Open-label doxycycline 100 mg twice daily by mouth will be administered to subjects for 12 months.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Doxycycline 100 mg po bid x 12 months</intervention_name>
    <description>100mg by mouth twice daily for 1 year.</description>
    <arm_group_label>doxycycline 100 mg po bid x 12 months</arm_group_label>
    <other_name>CAS: 564-25-0; ATC code: J01AA02 A01AB22; PubChem: CID 11256</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Age 18 or older&#xD;
&#xD;
          -  Biopsy-proven amyloidosis&#xD;
&#xD;
          -  Biochemical or clinical evidence of amyloid induced end-organ dysfunction&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Concurrent use of other tetracyclines&#xD;
&#xD;
          -  Ongoing active treatment for amyloidosis&#xD;
&#xD;
          -  Pregnancy or unwillingness to use contraception by women of childbearing age&#xD;
&#xD;
          -  Doxycycline drug allergy/hypersensitivity&#xD;
&#xD;
          -  ECOG performance status &gt; 3&#xD;
&#xD;
          -  NYHA class &gt; 3&#xD;
&#xD;
          -  Renal insufficiency (estimated creatinine clearance &lt; 25 ml/min)&#xD;
&#xD;
          -  Transaminitis (AST or ALT &gt; 5 times upper limit of normal)&#xD;
&#xD;
          -  Diabetes mellitus or hemoglobin A1C &gt; 6.2%&#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>John L Berk, M.D.</last_name>
    <role>Principal Investigator</role>
    <affiliation>Boston University</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Boston University</name>
      <address>
        <city>Boston</city>
        <state>Massachusetts</state>
        <zip>02118</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <reference>
    <citation>Cardoso I, Merlini G, Saraiva MJ. 4'-iodo-4'-deoxydoxorubicin and tetracyclines disrupt transthyretin amyloid fibrils in vitro producing noncytotoxic species: screening for TTR fibril disrupters. FASEB J. 2003 May;17(8):803-9. doi: 10.1096/fj.02-0764com.</citation>
    <PMID>12724338</PMID>
  </reference>
  <reference>
    <citation>Cardoso I, Saraiva MJ. Doxycycline disrupts transthyretin amyloid: evidence from studies in a FAP transgenic mice model. FASEB J. 2006 Feb;20(2):234-9. doi: 10.1096/fj.05-4509com.</citation>
    <PMID>16449795</PMID>
  </reference>
  <reference>
    <citation>Forloni G, Colombo L, Girola L, Tagliavini F, Salmona M. Anti-amyloidogenic activity of tetracyclines: studies in vitro. FEBS Lett. 2001 Jan 5;487(3):404-7. doi: 10.1016/s0014-5793(00)02380-2.</citation>
    <PMID>11163366</PMID>
  </reference>
  <reference>
    <citation>Ward JE, Ren R, Toraldo G, Soohoo P, Guan J, O'Hara C, Jasuja R, Trinkaus-Randall V, Liao R, Connors LH, Seldin DC. Doxycycline reduces fibril formation in a transgenic mouse model of AL amyloidosis. Blood. 2011 Dec 15;118(25):6610-7. doi: 10.1182/blood-2011-04-351643. Epub 2011 Oct 12.</citation>
    <PMID>21998211</PMID>
  </reference>
  <reference>
    <citation>Obici L, Cortese A, Lozza A, Lucchetti J, Gobbi M, Palladini G, Perlini S, Saraiva MJ, Merlini G. Doxycycline plus tauroursodeoxycholic acid for transthyretin amyloidosis: a phase II study. Amyloid. 2012 Jun;19 Suppl 1:34-6. doi: 10.3109/13506129.2012.678508. Epub 2012 May 2.</citation>
    <PMID>22551192</PMID>
  </reference>
  <reference>
    <citation>Giorgetti S, Raimondi S, Pagano K, Relini A, Bucciantini M, Corazza A, Fogolari F, Codutti L, Salmona M, Mangione P, Colombo L, De Luigi A, Porcari R, Gliozzi A, Stefani M, Esposito G, Bellotti V, Stoppini M. Effect of tetracyclines on the dynamics of formation and destructuration of beta2-microglobulin amyloid fibrils. J Biol Chem. 2011 Jan 21;286(3):2121-31. doi: 10.1074/jbc.M110.178376. Epub 2010 Nov 10.</citation>
    <PMID>21068391</PMID>
  </reference>
  <reference>
    <citation>Cardoso I, Martins D, Ribeiro T, Merlini G, Saraiva MJ. Synergy of combined doxycycline/TUDCA treatment in lowering Transthyretin deposition and associated biomarkers: studies in FAP mouse models. J Transl Med. 2010 Jul 30;8:74. doi: 10.1186/1479-5876-8-74.</citation>
    <PMID>20673327</PMID>
  </reference>
  <verification_date>July 2017</verification_date>
  <study_first_submitted>August 21, 2012</study_first_submitted>
  <study_first_submitted_qc>August 31, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">September 3, 2012</study_first_posted>
  <results_first_submitted>March 19, 2017</results_first_submitted>
  <results_first_submitted_qc>May 10, 2017</results_first_submitted_qc>
  <results_first_posted type="Actual">June 6, 2017</results_first_posted>
  <last_update_submitted>July 4, 2017</last_update_submitted>
  <last_update_submitted_qc>July 4, 2017</last_update_submitted_qc>
  <last_update_posted type="Actual">August 1, 2017</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Boston University</investigator_affiliation>
    <investigator_full_name>John L. Berk</investigator_full_name>
    <investigator_title>Assistant Director, Amyloidosis Center</investigator_title>
  </responsible_party>
  <keyword>AL Amyloidosis</keyword>
  <keyword>Primary Amyloidosis</keyword>
  <keyword>Hereditary Amyloidosis</keyword>
  <keyword>Familial Amyloidosis</keyword>
  <keyword>SSA Amyloidosis</keyword>
  <keyword>Senile Systemic Amyloidosis</keyword>
  <keyword>AA Amyloidosis</keyword>
  <keyword>Secondary Amyloidosis</keyword>
  <keyword>Localized Amyloidosis</keyword>
  <keyword>Systemic Amyloidosis</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <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>Undecided</sharing_ipd>
    <ipd_description>Primary manuscript reporting outcomes is in preparation. Once completed, we will consider IPD sharing plan.</ipd_description>
  </patient_data>

  <clinical_results>

    <participant_flow>
      <recruitment_details>Patients referred to an amyloidosis center and no longer requiring active treatment to control progressive disease were recruited to the study.</recruitment_details>
      <group_list>
        <group group_id="P1">
          <title>Doxycycline 100 mg po Bid x 12 Months</title>
          <description>Open-label doxycycline 100 mg twice daily by mouth will be administered to subjects for 12 months.</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="25"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="14"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="11"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>Doxycycline 100 mg po Bid x 12 Months</title>
          <description>Open-label doxycycline 100 mg twice daily by mouth will be administered to subjects for 12 months.</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="25"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>Years</units>
          <param>Median</param>
          <dispersion>Full Range</dispersion>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="25"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="65" lower_limit="36" upper_limit="82"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Sex: Female, Male</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="25"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <title>Female</title>
                  <measurement_list>
                    <measurement group_id="B1" value="6"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="19"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Race/Ethnicity, Customized</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <title>White</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="25"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="24"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Multiple</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="25"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Not hispanic or latino</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="25"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="24"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Unknown/not reported</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="25"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Region of Enrollment</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <title>United States</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="25"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="25"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Brain Natriuretic Peptide (BNP)</title>
          <description>Study participants with predominant cardiac amyloid involvement.</description>
          <population>Patients with predominant amyloid cardiomyopathy constituted the &quot;cardiac group&quot; (n=12). Serial cardiac biomarkers (BNP, Troponin I) determinations were used to assess the effect of doxycycline on cardiac amyloid disease progression.</population>
          <units>pg/mL</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="12"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="385" spread="294"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Troponin I</title>
          <description>Study participants with predominant cardiac amyloid involvement.</description>
          <population>Patients with predominant amyloid cardiomyopathy constituted the &quot;cardiac group&quot; (n=12). Serial cardiac biomarkers (BNP, Troponin I) determinations were used to assess the effect of doxycycline on cardiac amyloid disease progression.</population>
          <units>ng/mL</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="12"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="0.11" spread="0.07"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Creatinine Clearance (mL/min)</title>
          <description>Study participants with predominant renal amyloid involvement.</description>
          <population>Patients with predominant amyloid nephropathy constituted the &quot;renal group&quot; (n=10). Serial creatinine clearance and proteinuria were used to assess the effect of doxycycline on renal amyloid disease progression.</population>
          <units>mL/min</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="10"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="83.3" spread="36.5"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Proteinuria (g/day)</title>
          <description>Study participants with predominant renal amyloid involvement.</description>
          <population>Patients with predominant amyloid nephropathy constituted the &quot;renal group&quot; (n=10). Serial creatinine clearance and proteinuria were used to assess the effect of doxycycline on renal amyloid disease progression.</population>
          <units>g/day</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="10"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="5.99" spread="3.15"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Amyloid Cardiomyopathy: BNP</title>
        <description>Cardiac biomarkers (BNP, Troponin I) were assessed at baseline, 6 and 12 months, with change at end of study reported</description>
        <time_frame>12 months</time_frame>
        <population>Analysis is limited to the patients with predominant amyloid heart involvement at enrollment. Mixed models analyses of change from baseline levels of cardiac biomarkers (BNP, Troponin I) were performed to include all collected data.</population>
        <group_list>
          <group group_id="O1">
            <title>Cardiomyopathy</title>
            <description>Patients with predominant amyloid involvement of the heart.</description>
          </group>
        </group_list>
        <measure>
          <title>Amyloid Cardiomyopathy: BNP</title>
          <description>Cardiac biomarkers (BNP, Troponin I) were assessed at baseline, 6 and 12 months, with change at end of study reported</description>
          <population>Analysis is limited to the patients with predominant amyloid heart involvement at enrollment. Mixed models analyses of change from baseline levels of cardiac biomarkers (BNP, Troponin I) were performed to include all collected data.</population>
          <units>pg/mL</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="12"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="883" spread="703"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
            </group_id_list>
            <groups_desc>BNP pg/mL, baseline versus end study values</groups_desc>
            <non_inferiority_type>Other</non_inferiority_type>
            <non_inferiority_desc>P-values and confidence intervals are not adjusted for multiple testing</non_inferiority_desc>
            <p_value>0.035</p_value>
            <method>Mixed Models Analysis</method>
            <method_desc>degrees of freedom = 12</method_desc>
            <param_type>Mean outcome change</param_type>
            <param_value>171</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>14.1</ci_lower_limit>
            <ci_upper_limit>328</ci_upper_limit>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Amyloid Cardiomyopathy: Troponin I</title>
        <description>Cardiac biomarkers (BNP, Troponin I) were assessed at baseline, 6 and 12 months, with change at change at end of study reported</description>
        <time_frame>12 months</time_frame>
        <population>Patients with predominant amyloid involvement of the heart.</population>
        <group_list>
          <group group_id="O1">
            <title>Cardiomyopathy</title>
            <description>Patients with predominant amyloid involvement of the heart.</description>
          </group>
        </group_list>
        <measure>
          <title>Amyloid Cardiomyopathy: Troponin I</title>
          <description>Cardiac biomarkers (BNP, Troponin I) were assessed at baseline, 6 and 12 months, with change at change at end of study reported</description>
          <population>Patients with predominant amyloid involvement of the heart.</population>
          <units>ng/mL</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="12"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.15" spread="0.07"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
            </group_id_list>
            <groups_desc>Troponin I ng/mL, baseline versus end study levels.</groups_desc>
            <non_inferiority_type>Other</non_inferiority_type>
            <non_inferiority_desc>P-values and confidence intervals are not adjusted for multiple testing</non_inferiority_desc>
            <p_value>0.340</p_value>
            <method>Mixed Models Analysis</method>
            <method_desc>degrees of freedom = 12</method_desc>
            <param_type>Mean outcome change</param_type>
            <param_value>0.0072</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-0.009</ci_lower_limit>
            <ci_upper_limit>0.0234</ci_upper_limit>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Amyloid Nephropathy: Creatinine Clearance</title>
        <description>Creatinine clearance (ml/min) and proteinuria (g/day) were assessed at baseline, 6 and 12 months, with change at change at end of study reported</description>
        <time_frame>12 months</time_frame>
        <population>Analysis is limited to the patients with predominant amyloid kidney involvement at enrollment. Mixed models analyses of change from baseline levels of creatinine clearance (ml/min) and proteinuria (g/day) were performed to include all collected data.</population>
        <group_list>
          <group group_id="O1">
            <title>Amyloid Nephropathy</title>
            <description>Patients with predominant amyloid kidney involvement at enrollment.</description>
          </group>
        </group_list>
        <measure>
          <title>Amyloid Nephropathy: Creatinine Clearance</title>
          <description>Creatinine clearance (ml/min) and proteinuria (g/day) were assessed at baseline, 6 and 12 months, with change at change at end of study reported</description>
          <population>Analysis is limited to the patients with predominant amyloid kidney involvement at enrollment. Mixed models analyses of change from baseline levels of creatinine clearance (ml/min) and proteinuria (g/day) were performed to include all collected data.</population>
          <units>ml/min</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="10"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="82.4" spread="48.0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
            </group_id_list>
            <groups_desc>Creatinine clearance, baseline versus end study levels.</groups_desc>
            <non_inferiority_type>Other</non_inferiority_type>
            <non_inferiority_desc>P-values and confidence intervals are not adjusted for multiple testing</non_inferiority_desc>
            <p_value>0.017</p_value>
            <method>Mixed Models Analysis</method>
            <method_desc>degrees of freedom = 10</method_desc>
            <param_type>Change in outcome measure</param_type>
            <param_value>-7.39</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-13.12</ci_lower_limit>
            <ci_upper_limit>-1.67</ci_upper_limit>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Amyloid Nephropathy: Proteinuria</title>
        <description>Patients with predominant amyloid kidney involvement at enrollment.</description>
        <time_frame>Data were assessed at baseline, 6 and 12 months, with change at end of study reported</time_frame>
        <population>Analysis is limited to the patients with predominant amyloid kidney involvement at enrollment. Mixed models analyses of change from baseline levels of creatinine clearance (ml/min) and proteinuria (g/day) were performed to include all data collected at baseline, 6 and 12 months.</population>
        <group_list>
          <group group_id="O1">
            <title>Amyloid Nephropathy: Proteinuria (g/Day)</title>
            <description>Patients with predominant amyloid kidney involvement at enrollment.</description>
          </group>
        </group_list>
        <measure>
          <title>Amyloid Nephropathy: Proteinuria</title>
          <description>Patients with predominant amyloid kidney involvement at enrollment.</description>
          <population>Analysis is limited to the patients with predominant amyloid kidney involvement at enrollment. Mixed models analyses of change from baseline levels of creatinine clearance (ml/min) and proteinuria (g/day) were performed to include all data collected at baseline, 6 and 12 months.</population>
          <units>g/day</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="10"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="5.91" spread="3.85"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
            </group_id_list>
            <groups_desc>Proteinuria (g/24 hours), baseline versus end study levels.</groups_desc>
            <non_inferiority_type>Other</non_inferiority_type>
            <non_inferiority_desc>P-values and confidence intervals are not adjusted for multiple testing</non_inferiority_desc>
            <p_value>0.603</p_value>
            <method>Mixed Models Analysis</method>
            <method_desc>degrees of freedom = 10</method_desc>
            <param_type>Change in outcome measure</param_type>
            <param_value>0.091</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-0.285</ci_lower_limit>
            <ci_upper_limit>0.466</ci_upper_limit>
          </analysis>
        </analysis_list>
      </outcome>
    </outcome_list>

    <reported_events>
      <group_list>
        <group group_id="E1">
          <title>Doxycycline 100 mg po Bid x 12 Months</title>
          <description>Open-label doxycycline 100 mg twice daily by mouth was administered to subjects for 12 months, if tolerated.</description>
        </group>
      </group_list>
      <serious_events>
        <default_assessment>Non-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="25"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="12" subjects_at_risk="25"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Blood and lymphatic system disorders</title>
            <event_list>
              <event>
                <sub_title>osteonecrosis</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Deep vein thrombosis</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="25"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Cardiac disorders</title>
            <event_list>
              <event>
                <sub_title>Fluid overload</sub_title>
                <assessment>Systematic Assessment</assessment>
                <description>SOB, edema</description>
                <counts group_id="E1" events="4" subjects_affected="3" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Arrhythmia</sub_title>
                <description>Ventricular trachycardia</description>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="25"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Bloating</sub_title>
                <assessment>Systematic Assessment</assessment>
                <description>Abdominal distension</description>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Hernia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="25"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Cytomegalovirus infection</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="25"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Hip disease</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="25"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Renal and urinary disorders</title>
            <event_list>
              <event>
                <sub_title>Urinary retention</sub_title>
                <assessment>Systematic Assessment</assessment>
                <counts group_id="E1" 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>Sun hypersensitivity</sub_title>
                <assessment>Systematic Assessment</assessment>
                <description>Burns/desquamation induced by sun hypersensitivity</description>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Skin cancer</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="25"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Surgical and medical procedures</title>
            <event_list>
              <event>
                <sub_title>Orthopedic issues</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="25"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>5</frequency_threshold>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="21" subjects_at_risk="25"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>GI disorder</sub_title>
                <counts group_id="E1" events="18" subjects_affected="9" subjects_at_risk="25"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Infection</sub_title>
                <assessment>Non-systematic Assessment</assessment>
                <counts group_id="E1" events="8" subjects_affected="5" subjects_at_risk="25"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Skin and subcutaneous tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Skin disruption</sub_title>
                <counts group_id="E1" events="21" subjects_affected="15" subjects_at_risk="25"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>Principal Investigators are NOT employed by the organization sponsoring the study.</pi_employee>
      <restrictive_agreement>There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed. </restrictive_agreement>
    </certain_agreements>
    <point_of_contact>
      <name_or_title>John Berk, MD</name_or_title>
      <organization>Boston Medical Center</organization>
      <phone>617-638-4494</phone>
      <email>jberk@bu.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/NCT01677286
org study id: H-31546
nct id: NCT01677286
lead sponsor: 
has dmc: No
is fda regulated drug: Yes
is fda regulated device: No
is us export: Yes
The tetracycline antibiotic doxycycline disrupts A beta amyloid fibrils (AB) in Alzheimer's
      disease, transthyretin (ATTR) amyloid fibrils in familial amyloidotic polyneuropathy, and
      immunoglobulin light chain (AL) amyloid fibrils in transgenic mouse models of disease. If
      untreated, amyloid deposits impair organ function, affecting the morbidity and mortality of
      patients.

      This single-center, twelve-month, open-label, prospective, pilot phase II study aims to
      determine whether doxycycline reduces amyloid deposits and improves organ function in
      patients with systemic or localized amyloidosis.

      The investigators plan to enroll patients with measurable amyloid disease according to
      internationally-accepted diagnostic criteria. Patients must have stable organ function at
      enrollment. Eligible subjects not receiving active treatments for amyloidosis affecting their
      kidneys, heart, aerodigestive tracts, peripheral or autonomic nervous system(s), lungs, eyes,
      skin, bladder, or breasts will undergo evaluations at baseline, 6 months, and 12 months - or
      more frequently as clinically indicated.

      Over 45 years experience indicates doxycycline is a safe, well tolerated antibiotic. The
      investigators will use standard grading systems to assess doxycycline response following
      twelve months of treatment.
In transgenic animal models of disease, the tetracycline antibiotic doxycycline disrupts A
      beta amyloid fibrils (AB) in Alzheimer's disease, transthyretin (ATTR) amyloid fibrils in
      familial amyloidotic polyneuropathy, and immunoglobulin light chain (AL) amyloid fibrils.

      The aim of this single-center, 12-month open label, prospective phase II study was to
      determine a) the safety and tolerability of prolonged full dose doxycycline in patients with
      amyloidosis, and b) the effect of doxycycline treatment on amyloid-induced organ dysfunction.

      We enrolled 25 patients with measurable organ dysfunction caused by amyloid deposition who
      were not receiving active treatment to control their amyloid production. All 25 subjects
      received doxycycline 100 mg by both twice daily for up to 12 months depending on their
      tolerance of the antibiotic. The primary endpoint, defined by the organ most affected by
      amyloid, was measured at baseline, 6 and 12 months along with safety laboratory values.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Amyloid Cardiomyopathy: BNP
time frame: 12 months
description: Cardiac biomarkers (BNP, Troponin I) were assessed at baseline, 6 and 12 months, with change at end of study reported
measure: Amyloid Cardiomyopathy: Troponin I
time frame: 12 months
description: Cardiac biomarkers (BNP, Troponin I) were assessed at baseline, 6 and 12 months, with change at change at end of study reported
measure: Amyloid Nephropathy: Creatinine Clearance
time frame: 12 months
description: Creatinine clearance (ml/min) and proteinuria (g/day) were assessed at baseline, 6 and 12 months, with change at change at end of study reported
measure: Amyloid Nephropathy: Proteinuria
time frame: Data were assessed at baseline, 6 and 12 months, with change at end of study reported
description: Patients with predominant amyloid kidney involvement at enrollment.
arm group label: doxycycline 100 mg po bid x 12 months
arm group type: Experimental
description: Open-label doxycycline 100 mg twice daily by mouth will be administered to subjects for 12 months.
intervention type: Drug
intervention name: Doxycycline 100 mg po bid x 12 months
description: 100mg by mouth twice daily for 1 year.
arm group label: doxycycline 100 mg po bid x 12 months
other name: CAS: 564-25-0; ATC code: J01AA02 A01AB22; PubChem: CID 11256
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: John L Berk, M.D.
role: Principal Investigator
affiliation: Boston University
facility: 
country: United States
citation: Cardoso I, Merlini G, Saraiva MJ. 4'-iodo-4'-deoxydoxorubicin and tetracyclines disrupt transthyretin amyloid fibrils in vitro producing noncytotoxic species: screening for TTR fibril disrupters. FASEB J. 2003 May;17(8):803-9. doi: 10.1096/fj.02-0764com.
PMID: 12724338
citation: Cardoso I, Saraiva MJ. Doxycycline disrupts transthyretin amyloid: evidence from studies in a FAP transgenic mice model. FASEB J. 2006 Feb;20(2):234-9. doi: 10.1096/fj.05-4509com.
PMID: 16449795
citation: Forloni G, Colombo L, Girola L, Tagliavini F, Salmona M. Anti-amyloidogenic activity of tetracyclines: studies in vitro. FEBS Lett. 2001 Jan 5;487(3):404-7. doi: 10.1016/s0014-5793(00)02380-2.
PMID: 11163366
citation: Ward JE, Ren R, Toraldo G, Soohoo P, Guan J, O'Hara C, Jasuja R, Trinkaus-Randall V, Liao R, Connors LH, Seldin DC. Doxycycline reduces fibril formation in a transgenic mouse model of AL amyloidosis. Blood. 2011 Dec 15;118(25):6610-7. doi: 10.1182/blood-2011-04-351643. Epub 2011 Oct 12.
PMID: 21998211
citation: Obici L, Cortese A, Lozza A, Lucchetti J, Gobbi M, Palladini G, Perlini S, Saraiva MJ, Merlini G. Doxycycline plus tauroursodeoxycholic acid for transthyretin amyloidosis: a phase II study. Amyloid. 2012 Jun;19 Suppl 1:34-6. doi: 10.3109/13506129.2012.678508. Epub 2012 May 2.
PMID: 22551192
citation: Giorgetti S, Raimondi S, Pagano K, Relini A, Bucciantini M, Corazza A, Fogolari F, Codutti L, Salmona M, Mangione P, Colombo L, De Luigi A, Porcari R, Gliozzi A, Stefani M, Esposito G, Bellotti V, Stoppini M. Effect of tetracyclines on the dynamics of formation and destructuration of beta2-microglobulin amyloid fibrils. J Biol Chem. 2011 Jan 21;286(3):2121-31. doi: 10.1074/jbc.M110.178376. Epub 2010 Nov 10.
PMID: 21068391
citation: Cardoso I, Martins D, Ribeiro T, Merlini G, Saraiva MJ. Synergy of combined doxycycline/TUDCA treatment in lowering Transthyretin deposition and associated biomarkers: studies in FAP mouse models. J Transl Med. 2010 Jul 30;8:74. doi: 10.1186/1479-5876-8-74.
PMID: 20673327
responsible party type: Principal Investigator
investigator affiliation: Boston University
investigator full name: John L. Berk
investigator title: Assistant Director, Amyloidosis Center
mesh term: Amyloidosis
mesh term: Doxycycline
sharing ipd: Undecided
ipd description: Primary manuscript reporting outcomes is in preparation. Once completed, we will consider IPD sharing plan.
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 