<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/NCT01687179</url>
  </required_header>
  <id_info>
    <org_study_id>SAIL-1100</org_study_id>
    <secondary_id>1ZIAHL002541-21</secondary_id>
    <nct_id>NCT01687179</nct_id>
  </id_info>
  <brief_title>Safety Study of Sirolimus and Hydroxychloroquine in Women With Lymphangioleiomyomatosis</brief_title>
  <acronym>SAIL</acronym>
  <official_title>Targeting Autophagy for the Treatment of TSC and LAM: a Phase I Trial of Hydroxychloroquine and Sirolimus</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Brigham and Women's Hospital</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>Brigham and Women's Hospital</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Specific Aim 1: To investigate whether, in Lymphangioleiomyomatosis (LAM) patients, the&#xD;
      combination of sirolimus and hydroxychloroquine is safe and well tolerated&#xD;
&#xD;
      Specific Aim 2: To investigate whether, in LAM patients, 6 months of combination therapy with&#xD;
      sirolimus and hydroxychloroquine results in improvement of indicators of disease, and whether&#xD;
      the gains are sustained after stopping therapy.&#xD;
&#xD;
      Specific Aim 3: To investigate the potential role of a LAM-specific peripheral blood&#xD;
      signature to predict rates of disease progression and determine responsiveness to combination&#xD;
      therapy.&#xD;
&#xD;
      This will be a phase I dose escalation study of the combination of sirolimus (2 mg adjusted&#xD;
      to keep trough levels between 5-15 ng/ml) and hydroxychloroquine (200 mg or 400 mg) taken&#xD;
      orally daily. Up to 18 adult women with LAM will be enrolled.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This will be a phase I dose escalation study of the combination of sirolimus (2 mg adjusted&#xD;
      to keep trough levels between 5-15 ng/ml) and hydroxychloroquine (200 mg or 400 mg) taken&#xD;
      orally daily for 6 months. The study is to be conducted at 2 sites. Up to 18 adult women with&#xD;
      LAM will be enrolled, and each recruiting site will recruit between 8-12 subjects. The&#xD;
      protocol will use the following eligibility criteria.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date>September 2012</start_date>
  <completion_date type="Actual">August 2015</completion_date>
  <primary_completion_date type="Actual">August 2015</primary_completion_date>
  <phase>Phase 1</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <intervention_model>Sequential Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Safety of Combination Therapy With Sirolimus and Hydroxychloroquine in LAM Patients</measure>
    <time_frame>48 weeks</time_frame>
    <description>The Primary endpoint of this study was safety. Safety was assessed based on the adverse events and serious adverse events that occurred in these patients when they were on this combination therapy. Percentage of adverse events in each system at a dose was calculated from the total adverse events at that dose. Subjects were closely monitored and adverse events were classified and graded according to the &quot;Common Terminology Criteria for Adverse Events, (CTCAE) Version 4.0&quot;.</description>
  </primary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">14</enrollment>
  <condition>Lymphangioleiomyomatosis</condition>
  <arm_group>
    <arm_group_label>&quot;Sirolimus&quot; and &quot;Hydroxychloroquine&quot;</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Subjects will take Sirolimus at an initial dose of 2mg followed by dose adjustment to keep Sirolimus trough levels between 5-15ng/ml consistent with the effective dose in the MILES trial. In addition to Sirolimus subjects will receive Hydroxychloroquine at 200 mg daily for 6 months. Once safety is established at the lower dose (&quot;Sirolimus&quot; and &quot;Hydroxychloroquine&quot; 200 mg), subjects enrolled henceforth will receive Sirolimus and Hydroxychloroquine 400 mg (200 mg twice a day) for 6 months.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>&quot;Sirolimus&quot; and &quot;Hydroxychloroquine&quot; 200 mg</intervention_name>
    <description>This will be a phase I dose escalation study of the combination of &quot;Sirolimus&quot; (2 mg adjusted to keep trough levels between 5-15 ng/ml) and &quot;Hydroxychloroquine&quot; 200 mg taken orally daily.</description>
    <arm_group_label>&quot;Sirolimus&quot; and &quot;Hydroxychloroquine&quot;</arm_group_label>
    <other_name>sirolimus(rapamune), hydroxychloroquine (plaquenil)</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>&quot;Sirolimus&quot; and &quot;Hydroxychloroquine&quot; 400 mg</intervention_name>
    <description>Once safety is established with the lower dose, (Sirolimus and Hydroxychloroquine 200 mg), subjects will receive Sirolimus 2 mg (adjusted to keep trough levels between 5 to 15 ng/ml) and hydroxychloroquine 200 mg twice a day.</description>
    <arm_group_label>&quot;Sirolimus&quot; and &quot;Hydroxychloroquine&quot;</arm_group_label>
    <other_name>Sirolimus (Rapamune), Hydroxychloroquine (plaquenil)</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Female age 18 or older&#xD;
&#xD;
          -  Ability to give informed consent&#xD;
&#xD;
          -  Diagnosis of LAM as defined as typical cystic change on CT plus:&#xD;
&#xD;
               -  biopsy or cytology of any tissue demonstrating LAM&#xD;
&#xD;
               -  angiomyolipoma, chylothorax, lymphangioleiomyoma, or tuberous sclerosis&#xD;
&#xD;
               -  serum VEGFD greater or equal to 800pg/ml&#xD;
&#xD;
          -  Post-bronchodilator FEV1 equal or less than 80% of predicted or DLCO equal equal or&#xD;
             less than 70% of predicted, or RV &gt; 120% of predicted at baseline&#xD;
&#xD;
          -  Women of childbearing potential must agree to use 2 forms of barrier contraception&#xD;
             during and for 8 weeks after the last dose of medication.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  History of intolerance of mTOR inhibitors&#xD;
&#xD;
          -  History of intolerance to hydroxychloroquine&#xD;
&#xD;
          -  History of severe psoriasis&#xD;
&#xD;
          -  History of porphyria cutanea tarda&#xD;
&#xD;
          -  Uncontrolled intercurrent illness&#xD;
&#xD;
          -  Pregnant, breast feeding, or plan to become pregnant in the next year&#xD;
&#xD;
          -  Inadequate contraception&#xD;
&#xD;
          -  Significant hematological or hepatic abnormalities&#xD;
&#xD;
          -  Use of an investigational drug within 30 days of study start&#xD;
&#xD;
          -  Inability to attend scheduled clinic visits&#xD;
&#xD;
          -  Inability to perform PFTs&#xD;
&#xD;
          -  Creatinine &gt; 2.5mg/dL&#xD;
&#xD;
          -  Recent pneumothorax within 8 weeks of screening&#xD;
&#xD;
          -  History of malignancy in the last 2 years other than basal cell skin cancer&#xD;
&#xD;
          -  Use of estrogen containing medication within 30 days of screening&#xD;
&#xD;
          -  Abnormal G6PD levels at baseline&#xD;
&#xD;
          -  Preexisting maculopathy or retinopathy&#xD;
&#xD;
          -  Preexisting myopathy&#xD;
&#xD;
          -  Currently taking doxycycline, metformin, lupron, simvastatin&#xD;
&#xD;
          -  Unable to undergo CT or MRI&#xD;
&#xD;
          -  History of seizure within last year&#xD;
&#xD;
          -  Hepatitis B, C, HIV positive serology&#xD;
&#xD;
          -  Use of alternative medical therapies for LAM for at least 6 weeks prior to study&#xD;
             participation&#xD;
&#xD;
          -  History of myocardial infarct, angina, or stroke related to atherosclerosis&#xD;
&#xD;
          -  History of cardiomyopathy&#xD;
&#xD;
          -  Previous lung transplant&#xD;
&#xD;
          -  Surgery (involving entry into a body cavity or requiring 3 or more stitches) within 2&#xD;
             months of initiation of study drug&#xD;
&#xD;
          -  Uncontrolled cholesterol &gt; 350mg/dL, triglycerides &gt; 400mg/dL&#xD;
      </textblock>
    </criteria>
    <gender>Female</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>85 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Elizabeth P Henske, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Brigham and Women's Hospital</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Joel Moss, MD, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>National Heart, Lung, and Blood Institute (NHLBI)</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Brigham and Women's Hospital</name>
      <address>
        <city>Boston</city>
        <state>Massachusetts</state>
        <zip>02120</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>September 2018</verification_date>
  <study_first_submitted>August 2, 2012</study_first_submitted>
  <study_first_submitted_qc>September 13, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">September 18, 2012</study_first_posted>
  <results_first_submitted>March 30, 2017</results_first_submitted>
  <results_first_submitted_qc>September 13, 2018</results_first_submitted_qc>
  <results_first_posted type="Actual">October 11, 2018</results_first_posted>
  <last_update_submitted>September 13, 2018</last_update_submitted>
  <last_update_submitted_qc>September 13, 2018</last_update_submitted_qc>
  <last_update_posted type="Actual">October 11, 2018</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Brigham and Women's Hospital</investigator_affiliation>
    <investigator_full_name>Elizabeth Henske</investigator_full_name>
    <investigator_title>Overall Principal Investigator</investigator_title>
  </responsible_party>
  <keyword>LAM</keyword>
  <keyword>TSC</keyword>
  <keyword>lymphangioleiomyomatosis</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Lymphangioleiomyomatosis</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Sirolimus</mesh_term>
    <mesh_term>Hydroxychloroquine</mesh_term>
    <mesh_term>Temsirolimus</mesh_term>
    <mesh_term>MTOR Inhibitors</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>

  <clinical_results>

    <participant_flow>
      <group_list>
        <group group_id="P1">
          <title>Sirolimus and Hydroxychloroquine 200 mg</title>
          <description>This will be a phase I dose escalation study of the combination of sirolimus (2 mg adjusted to keep trough levels between 5-15 ng/ml) and hydroxychloroquine 200 mg taken orally daily.</description>
        </group>
        <group group_id="P2">
          <title>Sirolimus and HydroxyChloroquine 400 mg</title>
          <description>Once safety is established with the lower dose, (Sirolimus and Hydroxychloroquine 200 mg), subjects will receive Sirolimus 2 mg (adjusted to keep trough levels between 5 to 15 ng/ml) and hydroxychloroquine 200 mg twice a day.</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="3"/>
                <participants group_id="P2" count="10"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="2"/>
                <participants group_id="P2" count="6"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="4"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <population>1 subject failed to qualify for the study at the screening visit. Since the subject had signed consent, we considered the participant to be enrolled on the study.</population>
      <group_list>
        <group group_id="B1">
          <title>Sirolimus and Hydroxychloroquine</title>
          <description>Subjects will take sirolimus at an initial dose of 2mg followed by dose adjustment to keep sirolimus trough levels between 5-15ng/ml consistent with the effective dose in the MILES trial. In addition to sirolimus subjects will receive hydroxychloroquine at 200 mg daily or twice a day for 6 months, depending on time of enrollment into the study, following a standard phase I dose escalation.&#xD;
sirolimus and hydroxychloroquine: This will be a phase I dose escalation study of the combination of sirolimus (2 mg adjusted to keep trough levels between 5-15 ng/ml) and hydroxychloroquine (200 mg or 400 mg) taken orally daily.</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="14"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <population>1 subject screen failed.</population>
          <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="13"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="49" lower_limit="40" upper_limit="65"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Sex: Female, Male</title>
          <population>1 subject screen failed.</population>
          <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="13"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <title>Female</title>
                  <measurement_list>
                    <measurement group_id="B1" value="13"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Race (NIH/OMB)</title>
          <population>1 subject screen failed.</population>
          <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="13"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <title>American Indian or Alaska Native</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Asian</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Native Hawaiian or Other Pacific Islander</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Black or African American</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>White</title>
                  <measurement_list>
                    <measurement group_id="B1" value="12"/>
                  </measurement_list>
                </category>
                <category>
                  <title>More than one race</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Region of Enrollment</title>
          <population>1 subject screen failed.</population>
          <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="13"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="13"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Post-Menopause</title>
          <population>1 subject screen failed.</population>
          <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="13"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="6"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Pneumothorax</title>
          <population>1 subject screen failed.</population>
          <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="13"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="9"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Angiomyolipoma</title>
          <population>1 subject screen failed.</population>
          <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="13"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Tuberous Sclerois (TSC)- Lymphangioleiomyomatosis (LAM)</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="14"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Lung Biopsy</title>
          <population>1 subject screen failed.</population>
          <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="13"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="8"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Chylothorax</title>
          <population>1 subject screen failed</population>
          <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="13"/>
                  </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>6 minute walk distance (6MWD) (m)</title>
          <population>1 subject screen failed.</population>
          <units>m</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="13"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="442" spread="103"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>St. George's Respiratory Questionnaire (SGRQ)</title>
          <description>The Saint George's Respiratory Questionnaire (SGRQ) is a disease-specific instrument designed to measure impact on overall health, daily life, and perceived well-being in patients with obstructive airways disease. Scores range from 0 to 100, with higher scores indicating more limitations.</description>
          <population>1 subject screen failed.</population>
          <units>units on a scale</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="13"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="43.8" spread="19.2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Log VEGF-D (Veascular Endothelial Growth factor)</title>
          <population>1 subject screen failed.</population>
          <units>log(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="13"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="3.11" spread="0.33"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>FEV1</title>
          <population>1 Subject Screen failed.</population>
          <units>Litres</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="13"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="1.6" spread="0.7"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>FEV1 (%)</title>
          <units>Percent predicted</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="14"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="59" spread="21"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>FVC (L)</title>
          <population>1 subject screen failed.</population>
          <units>Litres</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="13"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="2.8" spread="0.7"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>FVC (%)</title>
          <population>1 Subject Screen failed.</population>
          <units>Percent predicted</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="13"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="81" spread="16"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>DLCO (ml/min/mmhg)</title>
          <population>1 Subject screen failed.</population>
          <units>ml/min/mmhg</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="13"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="9.8" spread="3.1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>DLCO (%)</title>
          <population>1 Subject screen failed.</population>
          <units>percent predicted</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="13"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="43" spread="15"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Safety of Combination Therapy With Sirolimus and Hydroxychloroquine in LAM Patients</title>
        <description>The Primary endpoint of this study was safety. Safety was assessed based on the adverse events and serious adverse events that occurred in these patients when they were on this combination therapy. Percentage of adverse events in each system at a dose was calculated from the total adverse events at that dose. Subjects were closely monitored and adverse events were classified and graded according to the &quot;Common Terminology Criteria for Adverse Events, (CTCAE) Version 4.0&quot;.</description>
        <time_frame>48 weeks</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Sirolimus and Hydroxychloroquine 200 mg</title>
            <description>This will be a phase I dose escalation study of the combination of sirolimus (2 mg adjusted to keep trough levels between 5-15 ng/ml) and hydroxychloroquine 200 mg taken orally daily. Safety of the drug combination was assessed by the occurrence of adverse events in these 3 patients.</description>
          </group>
          <group group_id="O2">
            <title>Sirolimus and Hydroxychloroquine 400 mg</title>
            <description>Once safety is established with the lower dose, (Sirolimus and Hydroxychloroquine 200 mg), subjects will receive Sirolimus 2 mg (adjusted to keep trough levels between 5 to 15 ng/ml) and hydroxychloroquine 200 mg twice a day. Safety of this dose was assessed by the occurrence of adverse events in these 10 patients.</description>
          </group>
        </group_list>
        <measure>
          <title>Safety of Combination Therapy With Sirolimus and Hydroxychloroquine in LAM Patients</title>
          <description>The Primary endpoint of this study was safety. Safety was assessed based on the adverse events and serious adverse events that occurred in these patients when they were on this combination therapy. Percentage of adverse events in each system at a dose was calculated from the total adverse events at that dose. Subjects were closely monitored and adverse events were classified and graded according to the &quot;Common Terminology Criteria for Adverse Events, (CTCAE) Version 4.0&quot;.</description>
          <units>Percentage of adverse events</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="3"/>
                <count group_id="O2" value="10"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Cardiac Disorders</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2.27"/>
                    <measurement group_id="O2" value="1.11"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Eye Disorders</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="1.11"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>GI Disorders</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="18.18"/>
                    <measurement group_id="O2" value="22.22"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>General Disorders, Administration site condistions</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="18.18"/>
                    <measurement group_id="O2" value="6.67"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Immune System disorders</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="0.56"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Infections and infestations</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="15.91"/>
                    <measurement group_id="O2" value="8.33"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Injury, poisoning, procedural complications</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="0.56"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Investigations</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="6.82"/>
                    <measurement group_id="O2" value="20"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Metabolism and nutrition disorders</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="3.33"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Musculoskeletal, connective tissue disorders</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="4.44"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Nervous system disorders</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="4.55"/>
                    <measurement group_id="O2" value="5.00"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Psychiatric disorders</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="0.56"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Renal and urinary disorders</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="7.78"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Reproductive system and breast disorder</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="6.82"/>
                    <measurement group_id="O2" value="1.11"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Respiratory, thoracic, mediastinal disorders</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2.27"/>
                    <measurement group_id="O2" value="9.44"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Skin and Subcutaneous disorders</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="25.0"/>
                    <measurement group_id="O2" value="6.11"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Vascular disorders</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="1.67"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>48 weeks</time_frame>
      <group_list>
        <group group_id="E1">
          <title>Sirolimus and Hydroxychloroquine 200 mg</title>
          <description>This will be a phase I dose escalation study of the combination of sirolimus (2 mg adjusted to keep trough levels between 5-15 ng/ml) and hydroxychloroquine 200 mg taken orally daily.</description>
        </group>
        <group group_id="E2">
          <title>Sirolimus and Hydroxychloroquine 400 mg</title>
          <description>Once safety is established with the lower dose, (Sirolimus and Hydroxychloroquine 200 mg), subjects will receive Sirolimus 2 mg (adjusted to keep trough levels between 5 to 15 ng/ml) and hydroxychloroquine 200 mg twice a day.</description>
        </group>
      </group_list>
      <serious_events>
        <default_vocab>CTCAE (4.0)</default_vocab>
        <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="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="10"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>radiculitis</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>0</frequency_threshold>
        <default_vocab>CTCAE (4.0)</default_vocab>
        <default_assessment>Non-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="3" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="9" subjects_at_risk="10"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Diarrhea</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="6" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Oral Mucositis</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="6" subjects_at_risk="10"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>Abnormal Investigations</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="6" subjects_at_risk="10"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Skin and subcutaneous tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Rash/ Acne</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="5" subjects_at_risk="10"/>
              </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>Elizabeth P. Henske, MD</name_or_title>
      <organization>Brigham and Women's Hospital</organization>
      <phone>857-307-0782</phone>
      <email>ehenske@bwh.harvard.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/NCT01687179
org study id: SAIL-1100
secondary id: 1ZIAHL002541-21
nct id: NCT01687179
lead sponsor: 
collaborator: 
has dmc: Yes
Specific Aim 1: To investigate whether, in Lymphangioleiomyomatosis (LAM) patients, the
      combination of sirolimus and hydroxychloroquine is safe and well tolerated

      Specific Aim 2: To investigate whether, in LAM patients, 6 months of combination therapy with
      sirolimus and hydroxychloroquine results in improvement of indicators of disease, and whether
      the gains are sustained after stopping therapy.

      Specific Aim 3: To investigate the potential role of a LAM-specific peripheral blood
      signature to predict rates of disease progression and determine responsiveness to combination
      therapy.

      This will be a phase I dose escalation study of the combination of sirolimus (2 mg adjusted
      to keep trough levels between 5-15 ng/ml) and hydroxychloroquine (200 mg or 400 mg) taken
      orally daily. Up to 18 adult women with LAM will be enrolled.
This will be a phase I dose escalation study of the combination of sirolimus (2 mg adjusted
      to keep trough levels between 5-15 ng/ml) and hydroxychloroquine (200 mg or 400 mg) taken
      orally daily for 6 months. The study is to be conducted at 2 sites. Up to 18 adult women with
      LAM will be enrolled, and each recruiting site will recruit between 8-12 subjects. The
      protocol will use the following eligibility criteria.
intervention model: Sequential Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Safety of Combination Therapy With Sirolimus and Hydroxychloroquine in LAM Patients
time frame: 48 weeks
description: The Primary endpoint of this study was safety. Safety was assessed based on the adverse events and serious adverse events that occurred in these patients when they were on this combination therapy. Percentage of adverse events in each system at a dose was calculated from the total adverse events at that dose. Subjects were closely monitored and adverse events were classified and graded according to the "Common Terminology Criteria for Adverse Events, (CTCAE) Version 4.0".
arm group label: "Sirolimus" and "Hydroxychloroquine"
arm group type: Experimental
description: Subjects will take Sirolimus at an initial dose of 2mg followed by dose adjustment to keep Sirolimus trough levels between 5-15ng/ml consistent with the effective dose in the MILES trial. In addition to Sirolimus subjects will receive Hydroxychloroquine at 200 mg daily for 6 months. Once safety is established at the lower dose ("Sirolimus" and "Hydroxychloroquine" 200 mg), subjects enrolled henceforth will receive Sirolimus and Hydroxychloroquine 400 mg (200 mg twice a day) for 6 months.
intervention type: Drug
intervention name: "Sirolimus" and "Hydroxychloroquine" 200 mg
description: This will be a phase I dose escalation study of the combination of "Sirolimus" (2 mg adjusted to keep trough levels between 5-15 ng/ml) and "Hydroxychloroquine" 200 mg taken orally daily.
arm group label: "Sirolimus" and "Hydroxychloroquine"
other name: sirolimus(rapamune), hydroxychloroquine (plaquenil)
intervention type: Drug
intervention name: "Sirolimus" and "Hydroxychloroquine" 400 mg
description: Once safety is established with the lower dose, (Sirolimus and Hydroxychloroquine 200 mg), subjects will receive Sirolimus 2 mg (adjusted to keep trough levels between 5 to 15 ng/ml) and hydroxychloroquine 200 mg twice a day.
arm group label: "Sirolimus" and "Hydroxychloroquine"
other name: Sirolimus (Rapamune), Hydroxychloroquine (plaquenil)
criteria: 
gender: Female
minimum age: 18 Years
maximum age: 85 Years
healthy volunteers: No
last name: Elizabeth P Henske, MD
role: Principal Investigator
affiliation: Brigham and Women's Hospital
last name: Joel Moss, MD, PhD
role: Principal Investigator
affiliation: National Heart, Lung, and Blood Institute (NHLBI)
facility: 
country: United States
responsible party type: Principal Investigator
investigator affiliation: Brigham and Women's Hospital
investigator full name: Elizabeth Henske
investigator title: Overall Principal Investigator
mesh term: Lymphangioleiomyomatosis
mesh term: Sirolimus
mesh term: Hydroxychloroquine
mesh term: Temsirolimus
mesh term: MTOR Inhibitors
sharing ipd: No
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 