<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/NCT03253913</url>
  </required_header>
  <id_info>
    <org_study_id>2016-4904</org_study_id>
    <secondary_id>1R34HL138235-01</secondary_id>
    <nct_id>NCT03253913</nct_id>
  </id_info>
  <brief_title>Resveratrol and Sirolimus in Lymphangioleiomyomatosis Trial</brief_title>
  <acronym>RESULT</acronym>
  <official_title>Resveratrol and Sirolimus in Lymphangioleiomyomatosis Trial (RESULT)</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Cincinnati</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>University of Cincinnati</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      RESULT is a phase II dose-escalating, open-label, safety and efficacy study to determine if&#xD;
      there is a potential benefit of resveratrol in combination with sirolimus in patients with&#xD;
      lymphangioleiomyomatosis (LAM). The primary study objective is to assess the change in serum&#xD;
      vascular endothelial growth factor-D (VEGF-D) level after 24 weeks of treatment with a&#xD;
      combination of resveratrol and sirolimus as compared to the VEGF-D level in patients on a&#xD;
      stable dose of sirolimus alone. The secondary objectives of this study include an assessment&#xD;
      of the safety and adverse effect profile of combined resveratrol and sirolimus in adult&#xD;
      patients with LAM, and to determine the effect of treatment with a combination of resveratrol&#xD;
      and sirolimus on changes in lung function and quality of life.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Study Design RESULT was an open label, dose-escalation, phase 2 study with longitudinal&#xD;
      repeated measures. In order to be eligible for trial inclusion, patients had to satisfy all&#xD;
      of the following criteria: 1) confirmed diagnosis of LAM per the American Thoracic&#xD;
      Society/Japanese Respiratory Society Clinical Practice Guidelines14, 2) age ≥18 years with&#xD;
      signed informed consent, 3) on sirolimus for at least 20 weeks, and 4) VEGF-D stabilization&#xD;
      as demonstrated by two stable values post initiation of sirolimus and drawn at least 12 weeks&#xD;
      apart from each other. Key exclusion criteria included inability to provide consent, active&#xD;
      listing for lung transplantation, enrolled in another interventional clinical trial, known&#xD;
      allergy or hypersensitivity to resveratrol, and current or planned pregnancy in the next six&#xD;
      months.&#xD;
&#xD;
      RESULT was a single site study conducted at the University of Cincinnati (UC). Study&#xD;
      enrollment was open to LAM patients throughout the United States with travel reimbursement&#xD;
      provided through the study. The study was reviewed and approved by UC's Institutional Review&#xD;
      Board (IRB 2016-4904). An independent Data and Safety Monitoring Board (DSMB) was convened&#xD;
      and met every six months to ensure the safety of study participants. All subjects provided&#xD;
      written informed consent prior to the conduct of any study related activity.&#xD;
&#xD;
      Outcome Measures The primary objective of this study was to assess the change in serum VEGF-D&#xD;
      value after 24 weeks of treatment with a combination of resveratrol and sirolimus, as&#xD;
      compared to the historical VEGF-D values of patients prior to the study on sirolimus alone.&#xD;
      Serial assessments of serum VEGF-D, pulmonary function tests (PFTs), treatment related&#xD;
      adverse effects (AEs), complete blood count, liver and renal function tests, and HRQOL were&#xD;
      performed at baseline and at 8, 16, and 24 weeks. In addition, sirolimus trough levels,&#xD;
      measured 24 +/- 4 hours following the last dose, were assessed at baseline and at weeks 2, 4,&#xD;
      8, 12, 16, 18, 20 and 24. VEGF-D quantification was performed at the Translational Trial&#xD;
      Development and Support Laboratory based at Cincinnati Children's Hospital Medical Center in&#xD;
      a College of American Pathologists (CAP)/Clinical Laboratory Improvement Amendments (CLIA)&#xD;
      approved manner. All other laboratory assessments were performed via Quest Diagnostics. HRQOL&#xD;
      was measured by using four validated scales: St. George's Respiratory Questionnaire (SGRQ),&#xD;
      University of California San Diego Shortness of Breath score (SDSOB), EuroQol visual analogue&#xD;
      scale (EQVAS), and A Tool to Assess Quality of Life in LAM (ATAQ-LAM).&#xD;
&#xD;
      Study Drug Resveratrol used in this study was obtained from Evolva and manufactured by&#xD;
      fermentation using genetically modified yeast in a process that results in trans-resveratrol&#xD;
      with a purity of at least 98%, and packaged into capsules with each capsule containing 125mg&#xD;
      resveratrol. The capsules were independently verified for content by mass spectrometry&#xD;
      performed at UC and for sterility by microbial testing at Q Laboratories Inc., Cincinnati.&#xD;
      Investigational new drug (IND) designation for studying Resveratrol in this trial was&#xD;
      obtained from the United States Food and Drug Administration (FDA): IND 131722; IND Sponsor:&#xD;
      N. Gupta.&#xD;
&#xD;
      Resveratrol was administered in a stepwise dose escalating fashion at 8-week intervals with&#xD;
      assessment of VEGF-D, PFTs, AEs, and HRQOL prior to each dose escalation. The starting dose&#xD;
      of resveratrol was 250mg once daily for the first 8 weeks, followed by 500mg daily from Weeks&#xD;
      8 - 16, and 500mg twice daily for the last 8 weeks (Weeks 16 - 24), with provisions for dose&#xD;
      reduction if necessitated by AEs. Treatment related AEs were tabulated using the National&#xD;
      Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE) version 4.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">March 31, 2018</start_date>
  <completion_date type="Actual">October 15, 2022</completion_date>
  <primary_completion_date type="Actual">October 15, 2022</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>Serum Vascular Endothelial Growth Factor-D (VEGF-D) Levels After Treatment With a Combination of Resveratrol and Sirolimus as Compared to Baseline Serum VEGF-D Levels on Sirolimus Alone</measure>
    <time_frame>Baseline, Week 8, Week 16, Week 24</time_frame>
    <description>Change in serum VEGF-D level in pg/ml after treatment with a combination of resveratrol and sirolimus as compared to the historical VEGF-D level in patients on a stable dose of sirolimus alone. Baseline VEGF-D values represent serum VEGF-D levels on stable dose of sirolimus alone prior to starting study drug.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Number of Treatment-Emergent Adverse Events</measure>
    <time_frame>Baseline, Week 8, Week 16, Week 24</time_frame>
    <description>Safety and adverse effect profile of combined resveratrol and sirolimus in adult patients with LAM</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in Forced Expiratory Volume in One-second (FEV1) After 24 Weeks of Combined Treatment With Resveratrol and Sirolimus</measure>
    <time_frame>Baseline, Week 8, Week 16, Week 24</time_frame>
    <description>Difference in the absolute Forced expiratory volume in one-second (FEV1) after 24 weeks of treatment. FEV1 values reported are in liters. There are no definite minimum and maximum values of FEV1 as it is a physiological measure of lung function and varies from individual to individual. Higher FEV1 scores indicate better lung function.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>St. George's Respiratory Questionnaire (SGRQ) Quality of Life Assessment Scores After Treatment With Combined Resveratrol and Sirolimus</measure>
    <time_frame>Baseline, Week 8, Week 16, Week 24.</time_frame>
    <description>Quality of life scores will be calculated by using SGRQ to determine if the combination of resveratrol and sirolimus can improve the quality of life in patients with LAM. This 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 worse quality of life.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Scores on &quot;A Tool to Assess Quality of Life in LAM (ATAQ-LAM) Quality of Life Assessment&quot; Scale After Treatment With 24 Weeks of Resveratrol and Sirolimus</measure>
    <time_frame>Baseline, Week 8, Week 16, Week 24</time_frame>
    <description>Quality of life scores will be calculated by using ATAQ-LAM to determine if the combination of resveratrol and sirolimus can improve the quality of life in patients with LAM. A Tool to Assess Quality of Life in LAM (ATAQ-LAM) is a disease-specific instrument designed to assess HRQOL in patients with LAM, and consists of 32 items divided into 4 domains: exertional dyspnea, cough, fatigue, and emotional well-being. The total scores on this scale can range between 32 - 192, with higher scores indicating worse quality of life.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>San Diego Shortness of Breath Score (SD-SOB) Quality of Life Assessment Scores After Treatment With 24 Weeks of Resveratrol and Sirolimus</measure>
    <time_frame>Baseline, Week 8, Week 16, Week 24</time_frame>
    <description>The San Diego shortness of breath questionnaire measures the quality-of-life impairment secondary to dyspnea resulting from pulmonary disorders. It is a 24-item measure that assesses self-reported shortness of breath while performing a variety of activities of daily living, with higher scores indicating worse quality of life.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>EuroQOL Visual Analogue Scale (EQ-5D) Scores After Treatment With 24 Weeks of Sirolimus and Resveratrol.</measure>
    <time_frame>Baseline, Week 8, Week 16, Week 24</time_frame>
    <description>The EuroQOL visual-analogue scale (EQVAS) measures self-reported ratings of health status. Scores range from 0 to100, with lower scores indicating worse functioning.</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">25</enrollment>
  <condition>Lymphangioleiomyomatosis</condition>
  <arm_group>
    <arm_group_label>Treatment Arm</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Resveratrol 250mg daily for the first 8 weeks, followed by 250mg twice daily for the next 8 weeks, and then 500mg twice daily for the last 8 weeks.&#xD;
Patients will be on a stable background therapy of sirolimus prior to enrolling and will continue on that regimen throughout the study.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Sirolimus</intervention_name>
    <description>Patients will have been on a stable dose of sirolimus prior to enrolling and will continue that throughout the study.</description>
    <arm_group_label>Treatment Arm</arm_group_label>
    <other_name>Rapamycin</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Resveratrol</intervention_name>
    <description>Escalating doses of resveratrol will be given throughout the study. Patients will start at 250mg daily for 8 weeks, followed by 500mg daily for 8 weeks, and 500mg BID for the last 8 weeks.</description>
    <arm_group_label>Treatment Arm</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
        Subjects enrolled in the trial must meet all of the following criteria.&#xD;
&#xD;
          1. Definitive diagnosis LAM based on the presence of characteristic cystic change on&#xD;
             high-resolution computed tomography (HRCT) of the chest. The diagnosis must be&#xD;
             confirmed by one of the following:&#xD;
&#xD;
             A) Histopathological confirmation by biopsy (lung, abdominal mass, lymph node or&#xD;
             kidney or cytology from thoracic or abdominal sources revealing human melanoma&#xD;
             black-45 (HMB45)+ staining of spindled/epithelioid cells) B) Compatible chest CT scan&#xD;
             findings in the setting of tuberous sclerosis, angiomyolipomas (diagnosed by CT,&#xD;
             magnetic resonance imaging (MRI) by the site radiologist or biopsy) or chylous pleural&#xD;
             effusion (verified by tap) C) Chest CT scan findings compatible with LAM and a VEGF-D&#xD;
             level ≥ 800pg/ml.&#xD;
&#xD;
          2. Age 18 years or greater.&#xD;
&#xD;
          3. Signed and dated informed consent&#xD;
&#xD;
          4. Currently on sirolimus for treatment of LAM for at least 20 weeks&#xD;
&#xD;
          5. Evidence of disease stabilization on sirolimus as demonstrated by two stable values of&#xD;
             serum VEGF-D post initiation of sirolimus drawn at least 12 weeks apart from each&#xD;
             other. For the purpose of this study, a variation in serum VEGF-D of less than or&#xD;
             equal to 15% is considered stable.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Subjects who meet any of the following criteria are not eligible for enrollment as&#xD;
             study participants:&#xD;
&#xD;
               1. Known allergy or hypersensitivity to Resveratrol&#xD;
&#xD;
               2. Inability to provide informed consent&#xD;
&#xD;
               3. Active enrollment in other clinical drug trials for LAM&#xD;
&#xD;
               4. Pregnant or plan to become pregnant in the next 6 months&#xD;
&#xD;
               5. Breast feeding&#xD;
&#xD;
               6. Inability to comply with pulmonary function tests or follow up visits&#xD;
&#xD;
               7. Inadequate contraception&#xD;
&#xD;
               8. Use of estrogen containing medications within the 30 days prior to randomization&#xD;
&#xD;
               9. History of organ transplant&#xD;
&#xD;
              10. Actively listed for lung transplantation&#xD;
&#xD;
              11. Inability to comply with study procedures or attend scheduled study visits&#xD;
&#xD;
              12. Any clinically significant medical disease (other than LAM) that is associated&#xD;
                  with an expected survival of less than 2 years, or likely to impact the ability&#xD;
                  of the patient to participate in the study in the opinion of the investigator, or&#xD;
                  impact the study efficacy or safety assessments.&#xD;
      </textblock>
    </criteria>
    <gender>Female</gender>
    <gender_based>Yes</gender_based>
    <gender_description>LAM is a disease that almost exclusively involves females. Thus trial participants will be females only.</gender_description>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Nishant Gupta, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Cincinnati</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>University of Cincinnati</name>
      <address>
        <city>Cincinnati</city>
        <state>Ohio</state>
        <zip>45267</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>January 2023</verification_date>
  <study_first_submitted>August 10, 2017</study_first_submitted>
  <study_first_submitted_qc>August 17, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">August 18, 2017</study_first_posted>
  <results_first_submitted>October 26, 2022</results_first_submitted>
  <results_first_submitted_qc>January 14, 2023</results_first_submitted_qc>
  <results_first_posted type="Actual">February 1, 2023</results_first_posted>
  <last_update_submitted>January 14, 2023</last_update_submitted>
  <last_update_submitted_qc>January 14, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">February 1, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>University of Cincinnati</investigator_affiliation>
    <investigator_full_name>Nishant Gupta, MD, MS</investigator_full_name>
    <investigator_title>Adjunct Assistant Professor</investigator_title>
  </responsible_party>
  <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>Resveratrol</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <provided_document_section>
    <provided_document>
      <document_type>Study Protocol and Statistical Analysis Plan</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>July 31, 2018</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/13/NCT03253913/Prot_SAP_001.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <group_list>
        <group group_id="P1">
          <title>Treatment Arm</title>
          <description>Resveratrol 250mg daily for the first 8 weeks, followed by 250mg twice daily for the next 8 weeks, and then 500mg twice daily for the last 8 weeks.&#xD;
Patients will be on a stable background therapy of sirolimus prior to enrolling and will continue on that regimen throughout the study.&#xD;
Sirolimus: Patients will be on a stable dose of sirolimus prior to enrolling and will continue that throughout the study.&#xD;
Resveratrol: Escalating doses of resveratrol will be given throughout the study. Patients will start at 250mg daily for 8 weeks, followed by 500mg daily for 8 weeks, and 500mg BID for the last 8 weeks.</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>First 8 Weeks (250mg Daily Resveratrol)</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="25"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
        <period>
          <title>Weeks 8 - 16 (Resveratrol 500mg Daily)</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="25"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
        <period>
          <title>Weeks 16-24 (Resveratrol 1,000mg Daily)</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="25"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>Treatment Arm</title>
          <description>Resveratrol 250mg daily for the first 8 weeks, followed by 250mg twice daily for the next 8 weeks, and then 500mg twice daily for the last 8 weeks.&#xD;
Patients will be on a stable background therapy of sirolimus prior to enrolling and will continue on that regimen throughout the study.&#xD;
Sirolimus: Patients will be on a stable dose of sirolimus prior to enrolling and will continue that throughout the study.&#xD;
Resveratrol: Escalating doses of resveratrol will be given throughout the study. Patients will start at 250mg daily for 8 weeks, followed by 500mg daily for 8 weeks, and 500mg BID for the last 8 weeks.</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>Inter-Quartile Range</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="51" lower_limit="47" upper_limit="58"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Sex: Female, Male</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Female</title>
                  <measurement_list>
                    <measurement group_id="B1" value="25"/>
                  </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>Ethnicity (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Not Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="25"/>
                  </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>Race (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>American Indian or Alaska Native</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Asian</title>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                  </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="23"/>
                  </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>
          <units>participants</units>
          <param>Number</param>
          <class_list>
            <class>
              <title>United States</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="25"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Serum Vascular Endothelial Growth Factor-D (VEGF-D) Levels After Treatment With a Combination of Resveratrol and Sirolimus as Compared to Baseline Serum VEGF-D Levels on Sirolimus Alone</title>
        <description>Change in serum VEGF-D level in pg/ml after treatment with a combination of resveratrol and sirolimus as compared to the historical VEGF-D level in patients on a stable dose of sirolimus alone. Baseline VEGF-D values represent serum VEGF-D levels on stable dose of sirolimus alone prior to starting study drug.</description>
        <time_frame>Baseline, Week 8, Week 16, Week 24</time_frame>
        <population>Longitudinal slope of serum VEGF-D levels</population>
        <group_list>
          <group group_id="O1">
            <title>Treatment Arm</title>
            <description>Resveratrol 250mg daily for the first 8 weeks, followed by 250mg twice daily for the next 8 weeks, and then 500mg twice daily for the last 8 weeks.&#xD;
Patients will be on a stable background therapy of sirolimus prior to enrolling and will continue on that regimen throughout the study.&#xD;
Sirolimus: Patients will be on a stable dose of sirolimus prior to enrolling and will continue that throughout the study.&#xD;
Resveratrol: Escalating doses of resveratrol will be given throughout the study. Patients will start at 250mg daily for 8 weeks, followed by 500mg daily for 8 weeks, and 500mg BID for the last 8 weeks.</description>
          </group>
        </group_list>
        <measure>
          <title>Serum Vascular Endothelial Growth Factor-D (VEGF-D) Levels After Treatment With a Combination of Resveratrol and Sirolimus as Compared to Baseline Serum VEGF-D Levels on Sirolimus Alone</title>
          <description>Change in serum VEGF-D level in pg/ml after treatment with a combination of resveratrol and sirolimus as compared to the historical VEGF-D level in patients on a stable dose of sirolimus alone. Baseline VEGF-D values represent serum VEGF-D levels on stable dose of sirolimus alone prior to starting study drug.</description>
          <population>Longitudinal slope of serum VEGF-D levels</population>
          <units>pg/ml</units>
          <param>Median</param>
          <dispersion>Inter-Quartile Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="25"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Baseline VEGF-D level in patients on a stable dose of sirolimus alone</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="617" lower_limit="489" upper_limit="677"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Week 8</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="543" lower_limit="455" upper_limit="704"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Week 16</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="581" lower_limit="485" upper_limit="724"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Week 24</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="575" lower_limit="448" upper_limit="673"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Number of Treatment-Emergent Adverse Events</title>
        <description>Safety and adverse effect profile of combined resveratrol and sirolimus in adult patients with LAM</description>
        <time_frame>Baseline, Week 8, Week 16, Week 24</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Treatment Arm</title>
            <description>Resveratrol 250mg daily for the first 8 weeks, followed by 250mg twice daily for the next 8 weeks, and then 500mg twice daily for the last 8 weeks.&#xD;
Patients will be on a stable background therapy of sirolimus prior to enrolling and will continue on that regimen throughout the study.&#xD;
Sirolimus: Patients will be on a stable dose of sirolimus prior to enrolling and will continue that throughout the study.&#xD;
Resveratrol: Escalating doses of resveratrol will be given throughout the study. Patients will start at 250mg daily for 8 weeks, followed by 500mg daily for 8 weeks, and 500mg BID for the last 8 weeks.</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Treatment-Emergent Adverse Events</title>
          <description>Safety and adverse effect profile of combined resveratrol and sirolimus in adult patients with LAM</description>
          <units>Adverse effects</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="25"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>250 mg daily</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="42"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>500mg daily</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="25"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>1000mg daily</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="25"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change in Forced Expiratory Volume in One-second (FEV1) After 24 Weeks of Combined Treatment With Resveratrol and Sirolimus</title>
        <description>Difference in the absolute Forced expiratory volume in one-second (FEV1) after 24 weeks of treatment. FEV1 values reported are in liters. There are no definite minimum and maximum values of FEV1 as it is a physiological measure of lung function and varies from individual to individual. Higher FEV1 scores indicate better lung function.</description>
        <time_frame>Baseline, Week 8, Week 16, Week 24</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Treatment Arm</title>
            <description>Resveratrol 250mg daily for the first 8 weeks, followed by 250mg twice daily for the next 8 weeks, and then 500mg twice daily for the last 8 weeks.&#xD;
Patients will be on a stable background therapy of sirolimus prior to enrolling and will continue on that regimen throughout the study.&#xD;
Sirolimus: Patients will be on a stable dose of sirolimus prior to enrolling and will continue that throughout the study.&#xD;
Resveratrol: Escalating doses of resveratrol will be given throughout the study. Patients will start at 250mg daily for 8 weeks, followed by 500mg daily for 8 weeks, and 500mg BID for the last 8 weeks.</description>
          </group>
        </group_list>
        <measure>
          <title>Change in Forced Expiratory Volume in One-second (FEV1) After 24 Weeks of Combined Treatment With Resveratrol and Sirolimus</title>
          <description>Difference in the absolute Forced expiratory volume in one-second (FEV1) after 24 weeks of treatment. FEV1 values reported are in liters. There are no definite minimum and maximum values of FEV1 as it is a physiological measure of lung function and varies from individual to individual. Higher FEV1 scores indicate better lung function.</description>
          <units>Absolute FEV1 in liters</units>
          <param>Median</param>
          <dispersion>Inter-Quartile Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="25"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Baseline</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1.74" lower_limit="1.46" upper_limit="2.3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Week 8</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1.98" lower_limit="1.4" upper_limit="2.36"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Week 16</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2.01" lower_limit="1.18" upper_limit="2.57"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Week 24</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1.94" lower_limit="1.2" upper_limit="2.59"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>St. George's Respiratory Questionnaire (SGRQ) Quality of Life Assessment Scores After Treatment With Combined Resveratrol and Sirolimus</title>
        <description>Quality of life scores will be calculated by using SGRQ to determine if the combination of resveratrol and sirolimus can improve the quality of life in patients with LAM. This 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 worse quality of life.</description>
        <time_frame>Baseline, Week 8, Week 16, Week 24.</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Treatment Arm</title>
            <description>Resveratrol 250mg daily for the first 8 weeks, followed by 250mg twice daily for the next 8 weeks, and then 500mg twice daily for the last 8 weeks.&#xD;
Patients will be on a stable background therapy of sirolimus prior to enrolling and will continue on that regimen throughout the study.&#xD;
Sirolimus: Patients will be on a stable dose of sirolimus prior to enrolling and will continue that throughout the study.&#xD;
Resveratrol: Escalating doses of resveratrol will be given throughout the study. Patients will start at 250mg daily for 8 weeks, followed by 500mg daily for 8 weeks, and 500mg BID for the last 8 weeks.</description>
          </group>
        </group_list>
        <measure>
          <title>St. George's Respiratory Questionnaire (SGRQ) Quality of Life Assessment Scores After Treatment With Combined Resveratrol and Sirolimus</title>
          <description>Quality of life scores will be calculated by using SGRQ to determine if the combination of resveratrol and sirolimus can improve the quality of life in patients with LAM. This 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 worse quality of life.</description>
          <units>score on a scale</units>
          <param>Median</param>
          <dispersion>Inter-Quartile Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="25"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Baseline</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="42" lower_limit="39" upper_limit="46"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Week 8</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="43.5" lower_limit="38" upper_limit="49"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Week 16</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="43" lower_limit="40" upper_limit="49"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Week 24</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="42" lower_limit="39" upper_limit="47"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Scores on &quot;A Tool to Assess Quality of Life in LAM (ATAQ-LAM) Quality of Life Assessment&quot; Scale After Treatment With 24 Weeks of Resveratrol and Sirolimus</title>
        <description>Quality of life scores will be calculated by using ATAQ-LAM to determine if the combination of resveratrol and sirolimus can improve the quality of life in patients with LAM. A Tool to Assess Quality of Life in LAM (ATAQ-LAM) is a disease-specific instrument designed to assess HRQOL in patients with LAM, and consists of 32 items divided into 4 domains: exertional dyspnea, cough, fatigue, and emotional well-being. The total scores on this scale can range between 32 - 192, with higher scores indicating worse quality of life.</description>
        <time_frame>Baseline, Week 8, Week 16, Week 24</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Treatment Arm</title>
            <description>Resveratrol 250mg daily for the first 8 weeks, followed by 250mg twice daily for the next 8 weeks, and then 500mg twice daily for the last 8 weeks.&#xD;
Patients will be on a stable background therapy of sirolimus prior to enrolling and will continue on that regimen throughout the study.&#xD;
Sirolimus: Patients will be on a stable dose of sirolimus prior to enrolling and will continue that throughout the study.&#xD;
Resveratrol: Escalating doses of resveratrol will be given throughout the study. Patients will start at 250mg daily for 8 weeks, followed by 500mg daily for 8 weeks, and 500mg BID for the last 8 weeks.</description>
          </group>
        </group_list>
        <measure>
          <title>Scores on &quot;A Tool to Assess Quality of Life in LAM (ATAQ-LAM) Quality of Life Assessment&quot; Scale After Treatment With 24 Weeks of Resveratrol and Sirolimus</title>
          <description>Quality of life scores will be calculated by using ATAQ-LAM to determine if the combination of resveratrol and sirolimus can improve the quality of life in patients with LAM. A Tool to Assess Quality of Life in LAM (ATAQ-LAM) is a disease-specific instrument designed to assess HRQOL in patients with LAM, and consists of 32 items divided into 4 domains: exertional dyspnea, cough, fatigue, and emotional well-being. The total scores on this scale can range between 32 - 192, with higher scores indicating worse quality of life.</description>
          <units>score on a scale</units>
          <param>Median</param>
          <dispersion>Inter-Quartile Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="25"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Baseline</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="72" lower_limit="54" upper_limit="88"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Week 8</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="70" lower_limit="49" upper_limit="101"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Week 16</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="60" lower_limit="44" upper_limit="82"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Week 24</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="57" lower_limit="47" upper_limit="87"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>San Diego Shortness of Breath Score (SD-SOB) Quality of Life Assessment Scores After Treatment With 24 Weeks of Resveratrol and Sirolimus</title>
        <description>The San Diego shortness of breath questionnaire measures the quality-of-life impairment secondary to dyspnea resulting from pulmonary disorders. It is a 24-item measure that assesses self-reported shortness of breath while performing a variety of activities of daily living, with higher scores indicating worse quality of life.</description>
        <time_frame>Baseline, Week 8, Week 16, Week 24</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Treatment Arm</title>
            <description>Resveratrol 250mg daily for the first 8 weeks, followed by 250mg twice daily for the next 8 weeks, and then 500mg twice daily for the last 8 weeks.&#xD;
Patients will be on a stable background therapy of sirolimus prior to enrolling and will continue on that regimen throughout the study.&#xD;
Sirolimus: Patients will be on a stable dose of sirolimus prior to enrolling and will continue that throughout the study.&#xD;
Resveratrol: Escalating doses of resveratrol will be given throughout the study. Patients will start at 250mg daily for 8 weeks, followed by 500mg daily for 8 weeks, and 500mg BID for the last 8 weeks.</description>
          </group>
        </group_list>
        <measure>
          <title>San Diego Shortness of Breath Score (SD-SOB) Quality of Life Assessment Scores After Treatment With 24 Weeks of Resveratrol and Sirolimus</title>
          <description>The San Diego shortness of breath questionnaire measures the quality-of-life impairment secondary to dyspnea resulting from pulmonary disorders. It is a 24-item measure that assesses self-reported shortness of breath while performing a variety of activities of daily living, with higher scores indicating worse quality of life.</description>
          <units>score on a scale</units>
          <param>Median</param>
          <dispersion>Inter-Quartile Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="25"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Baseline</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="29" lower_limit="21" upper_limit="35"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Week 8</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="31" lower_limit="16" upper_limit="44"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Week 16</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="23" lower_limit="15" upper_limit="42"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Week 24</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="22" lower_limit="12" upper_limit="40"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>EuroQOL Visual Analogue Scale (EQ-5D) Scores After Treatment With 24 Weeks of Sirolimus and Resveratrol.</title>
        <description>The EuroQOL visual-analogue scale (EQVAS) measures self-reported ratings of health status. Scores range from 0 to100, with lower scores indicating worse functioning.</description>
        <time_frame>Baseline, Week 8, Week 16, Week 24</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Treatment Arm</title>
            <description>Resveratrol 250mg daily for the first 8 weeks, followed by 250mg twice daily for the next 8 weeks, and then 500mg twice daily for the last 8 weeks.&#xD;
Patients will be on a stable background therapy of sirolimus prior to enrolling and will continue on that regimen throughout the study.&#xD;
Sirolimus: Patients will be on a stable dose of sirolimus prior to enrolling and will continue that throughout the study.&#xD;
Resveratrol: Escalating doses of resveratrol will be given throughout the study. Patients will start at 250mg daily for 8 weeks, followed by 500mg daily for 8 weeks, and 500mg BID for the last 8 weeks.</description>
          </group>
        </group_list>
        <measure>
          <title>EuroQOL Visual Analogue Scale (EQ-5D) Scores After Treatment With 24 Weeks of Sirolimus and Resveratrol.</title>
          <description>The EuroQOL visual-analogue scale (EQVAS) measures self-reported ratings of health status. Scores range from 0 to100, with lower scores indicating worse functioning.</description>
          <units>score on a scale</units>
          <param>Median</param>
          <dispersion>Inter-Quartile Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="25"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Baseline</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="80" lower_limit="65" upper_limit="85"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Week 8</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="85" lower_limit="75" upper_limit="90"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Week 16</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="90" lower_limit="75" upper_limit="95"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Week 24</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="90" lower_limit="80" upper_limit="90"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>24 weeks</time_frame>
      <desc>Adverse effects were tabulated using the National Cancer Institute's Common Terminology Criteria for Adverse Events version 4.</desc>
      <group_list>
        <group group_id="E1">
          <title>250mg Resveratrol Daily (First 8 Weeks)</title>
          <description>250mg resveratrol added to pre-existing sirolimus</description>
        </group>
        <group group_id="E2">
          <title>500mg Daily Resveratrol (Weeks 8 - 16)</title>
          <description>500mg resveratrol added to pre-existing sirolimus</description>
        </group>
        <group group_id="E3">
          <title>1,000mg Daily Resveratrol</title>
          <description>1,000mg resveratrol added to pre-existing sirolimus</description>
        </group>
      </group_list>
      <serious_events>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, all-cause mortality</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="25"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="25"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="25"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="25"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="25"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>5</frequency_threshold>
        <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="14" subjects_at_risk="25"/>
                <counts group_id="E2" subjects_affected="5" subjects_at_risk="25"/>
                <counts group_id="E3" subjects_affected="6" subjects_at_risk="25"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>nausea</sub_title>
                <counts group_id="E1" events="4" subjects_affected="3" subjects_at_risk="25"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="25"/>
                <counts group_id="E3" events="3" subjects_affected="2" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>diarrhea</sub_title>
                <counts group_id="E1" events="4" subjects_affected="4" subjects_at_risk="25"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="25"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>gastrointestinal discomfort</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="25"/>
                <counts group_id="E2" events="2" subjects_affected="1" subjects_at_risk="25"/>
                <counts group_id="E3" events="4" subjects_affected="3" subjects_at_risk="25"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Infection</sub_title>
                <counts group_id="E1" events="7" subjects_affected="6" subjects_at_risk="25"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="25"/>
                <counts group_id="E3" events="2" subjects_affected="2" 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>Nishant Gupta, MD</name_or_title>
      <organization>University of Cincinnati</organization>
      <phone>5135584831</phone>
      <email>nishant.gupta@uc.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/NCT03253913
org study id: 2016-4904
secondary id: 1R34HL138235-01
nct id: NCT03253913
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
RESULT is a phase II dose-escalating, open-label, safety and efficacy study to determine if
      there is a potential benefit of resveratrol in combination with sirolimus in patients with
      lymphangioleiomyomatosis (LAM). The primary study objective is to assess the change in serum
      vascular endothelial growth factor-D (VEGF-D) level after 24 weeks of treatment with a
      combination of resveratrol and sirolimus as compared to the VEGF-D level in patients on a
      stable dose of sirolimus alone. The secondary objectives of this study include an assessment
      of the safety and adverse effect profile of combined resveratrol and sirolimus in adult
      patients with LAM, and to determine the effect of treatment with a combination of resveratrol
      and sirolimus on changes in lung function and quality of life.
Study Design RESULT was an open label, dose-escalation, phase 2 study with longitudinal
      repeated measures. In order to be eligible for trial inclusion, patients had to satisfy all
      of the following criteria: 1) confirmed diagnosis of LAM per the American Thoracic
      Society/Japanese Respiratory Society Clinical Practice Guidelines14, 2) age ≥18 years with
      signed informed consent, 3) on sirolimus for at least 20 weeks, and 4) VEGF-D stabilization
      as demonstrated by two stable values post initiation of sirolimus and drawn at least 12 weeks
      apart from each other. Key exclusion criteria included inability to provide consent, active
      listing for lung transplantation, enrolled in another interventional clinical trial, known
      allergy or hypersensitivity to resveratrol, and current or planned pregnancy in the next six
      months.

      RESULT was a single site study conducted at the University of Cincinnati (UC). Study
      enrollment was open to LAM patients throughout the United States with travel reimbursement
      provided through the study. The study was reviewed and approved by UC's Institutional Review
      Board (IRB 2016-4904). An independent Data and Safety Monitoring Board (DSMB) was convened
      and met every six months to ensure the safety of study participants. All subjects provided
      written informed consent prior to the conduct of any study related activity.

      Outcome Measures The primary objective of this study was to assess the change in serum VEGF-D
      value after 24 weeks of treatment with a combination of resveratrol and sirolimus, as
      compared to the historical VEGF-D values of patients prior to the study on sirolimus alone.
      Serial assessments of serum VEGF-D, pulmonary function tests (PFTs), treatment related
      adverse effects (AEs), complete blood count, liver and renal function tests, and HRQOL were
      performed at baseline and at 8, 16, and 24 weeks. In addition, sirolimus trough levels,
      measured 24 +/- 4 hours following the last dose, were assessed at baseline and at weeks 2, 4,
      8, 12, 16, 18, 20 and 24. VEGF-D quantification was performed at the Translational Trial
      Development and Support Laboratory based at Cincinnati Children's Hospital Medical Center in
      a College of American Pathologists (CAP)/Clinical Laboratory Improvement Amendments (CLIA)
      approved manner. All other laboratory assessments were performed via Quest Diagnostics. HRQOL
      was measured by using four validated scales: St. George's Respiratory Questionnaire (SGRQ),
      University of California San Diego Shortness of Breath score (SDSOB), EuroQol visual analogue
      scale (EQVAS), and A Tool to Assess Quality of Life in LAM (ATAQ-LAM).

      Study Drug Resveratrol used in this study was obtained from Evolva and manufactured by
      fermentation using genetically modified yeast in a process that results in trans-resveratrol
      with a purity of at least 98%, and packaged into capsules with each capsule containing 125mg
      resveratrol. The capsules were independently verified for content by mass spectrometry
      performed at UC and for sterility by microbial testing at Q Laboratories Inc., Cincinnati.
      Investigational new drug (IND) designation for studying Resveratrol in this trial was
      obtained from the United States Food and Drug Administration (FDA): IND 131722; IND Sponsor:
      N. Gupta.

      Resveratrol was administered in a stepwise dose escalating fashion at 8-week intervals with
      assessment of VEGF-D, PFTs, AEs, and HRQOL prior to each dose escalation. The starting dose
      of resveratrol was 250mg once daily for the first 8 weeks, followed by 500mg daily from Weeks
      8 - 16, and 500mg twice daily for the last 8 weeks (Weeks 16 - 24), with provisions for dose
      reduction if necessitated by AEs. Treatment related AEs were tabulated using the National
      Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE) version 4.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Serum Vascular Endothelial Growth Factor-D (VEGF-D) Levels After Treatment With a Combination of Resveratrol and Sirolimus as Compared to Baseline Serum VEGF-D Levels on Sirolimus Alone
time frame: Baseline, Week 8, Week 16, Week 24
description: Change in serum VEGF-D level in pg/ml after treatment with a combination of resveratrol and sirolimus as compared to the historical VEGF-D level in patients on a stable dose of sirolimus alone. Baseline VEGF-D values represent serum VEGF-D levels on stable dose of sirolimus alone prior to starting study drug.
measure: Number of Treatment-Emergent Adverse Events
time frame: Baseline, Week 8, Week 16, Week 24
description: Safety and adverse effect profile of combined resveratrol and sirolimus in adult patients with LAM
measure: Change in Forced Expiratory Volume in One-second (FEV1) After 24 Weeks of Combined Treatment With Resveratrol and Sirolimus
time frame: Baseline, Week 8, Week 16, Week 24
description: Difference in the absolute Forced expiratory volume in one-second (FEV1) after 24 weeks of treatment. FEV1 values reported are in liters. There are no definite minimum and maximum values of FEV1 as it is a physiological measure of lung function and varies from individual to individual. Higher FEV1 scores indicate better lung function.
measure: St. George's Respiratory Questionnaire (SGRQ) Quality of Life Assessment Scores After Treatment With Combined Resveratrol and Sirolimus
time frame: Baseline, Week 8, Week 16, Week 24.
description: Quality of life scores will be calculated by using SGRQ to determine if the combination of resveratrol and sirolimus can improve the quality of life in patients with LAM. This 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 worse quality of life.
measure: Scores on "A Tool to Assess Quality of Life in LAM (ATAQ-LAM) Quality of Life Assessment" Scale After Treatment With 24 Weeks of Resveratrol and Sirolimus
time frame: Baseline, Week 8, Week 16, Week 24
description: Quality of life scores will be calculated by using ATAQ-LAM to determine if the combination of resveratrol and sirolimus can improve the quality of life in patients with LAM. A Tool to Assess Quality of Life in LAM (ATAQ-LAM) is a disease-specific instrument designed to assess HRQOL in patients with LAM, and consists of 32 items divided into 4 domains: exertional dyspnea, cough, fatigue, and emotional well-being. The total scores on this scale can range between 32 - 192, with higher scores indicating worse quality of life.
measure: San Diego Shortness of Breath Score (SD-SOB) Quality of Life Assessment Scores After Treatment With 24 Weeks of Resveratrol and Sirolimus
time frame: Baseline, Week 8, Week 16, Week 24
description: The San Diego shortness of breath questionnaire measures the quality-of-life impairment secondary to dyspnea resulting from pulmonary disorders. It is a 24-item measure that assesses self-reported shortness of breath while performing a variety of activities of daily living, with higher scores indicating worse quality of life.
measure: EuroQOL Visual Analogue Scale (EQ-5D) Scores After Treatment With 24 Weeks of Sirolimus and Resveratrol.
time frame: Baseline, Week 8, Week 16, Week 24
description: The EuroQOL visual-analogue scale (EQVAS) measures self-reported ratings of health status. Scores range from 0 to100, with lower scores indicating worse functioning.
arm group label: Treatment Arm
arm group type: Experimental
description: Resveratrol 250mg daily for the first 8 weeks, followed by 250mg twice daily for the next 8 weeks, and then 500mg twice daily for the last 8 weeks.
Patients will be on a stable background therapy of sirolimus prior to enrolling and will continue on that regimen throughout the study.
intervention type: Drug
intervention name: Sirolimus
description: Patients will have been on a stable dose of sirolimus prior to enrolling and will continue that throughout the study.
arm group label: Treatment Arm
other name: Rapamycin
intervention type: Drug
intervention name: Resveratrol
description: Escalating doses of resveratrol will be given throughout the study. Patients will start at 250mg daily for 8 weeks, followed by 500mg daily for 8 weeks, and 500mg BID for the last 8 weeks.
arm group label: Treatment Arm
criteria: 
gender: Female
gender based: Yes
gender description: LAM is a disease that almost exclusively involves females. Thus trial participants will be females only.
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Nishant Gupta, MD
role: Principal Investigator
affiliation: University of Cincinnati
facility: 
country: United States
responsible party type: Principal Investigator
investigator affiliation: University of Cincinnati
investigator full name: Nishant Gupta, MD, MS
investigator title: Adjunct Assistant Professor
mesh term: Lymphangioleiomyomatosis
mesh term: Sirolimus
mesh term: Resveratrol
sharing ipd: No
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 