<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/NCT02257970</url>
  </required_header>
  <id_info>
    <org_study_id>7781</org_study_id>
    <nct_id>NCT02257970</nct_id>
  </id_info>
  <brief_title>Lymphedema Study for Arm or Leg Lymphedema</brief_title>
  <official_title>Placebo-controlled, Case-controlled, Open Label Therapeutic Trial for Unilateral or Bilateral Lymphedema of Arm or Leg.</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Stanford University</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Stanford University</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      This study compares the effectiveness of a study drug versus placebo in the treatment of&#xD;
      lymphedema.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Part 1 is feasibility, exploratory, open-label study of ketoprofen, to document effects.&#xD;
&#xD;
      Part 2, is open-label trial of ketoprofen to document histological response. Part 3 is&#xD;
      double-blind randomized trial of receive placebo or ketoprofen to evaluate safety and&#xD;
      efficacy.&#xD;
&#xD;
      We will try to determine how the study drug affects the body tissue by obtaining tissue&#xD;
      biopsies (small pieces of skin from the arm or leg) before treatment and after treatment.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date>March 2009</start_date>
  <completion_date type="Actual">March 2017</completion_date>
  <primary_completion_date type="Actual">December 2016</primary_completion_date>
  <phase>Phase 4</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Sequential Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Part 1: Count of Participants Able to Complete Ketoprofen Treatment</measure>
    <time_frame>Baseline to month 6</time_frame>
    <description>Participants who were able to complete ketoprofen treatment and experienced no treatment-related serious adverse events.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Part 2: Change From Baseline in Cutaneous Histological Architecture</measure>
    <time_frame>Baseline; Month 4</time_frame>
    <description>Quantitative assessment of paired histological specimens of lymphedema skin pre- and post-treatment with ketoprofen. The impact of treatment on cutaneous histopathology was evaluated through the use of an empirically-derived scoring system (comprised of dermal thickness, intercellular mucin content, deep dermal collagen content, and perivascular infiltrate); this quantitative assessment was developed and performed by a dermatopathologist. Each characteristic was weighted equally and each specimen was assigned a cumulative subscale score of 0-5. The scores were summed for a total score (range: 0-20) which is presented here. Higher scores indicate a higher degree of pathology. A quantitatively higher negative change indicates a more favorable therapeutic response in the histology.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Part 3: Measurement of Skin Thickness</measure>
    <time_frame>Baseline and 4 months</time_frame>
    <description>Caliper-measured skin thickness (mm) was serially assessed and pre-to-post paired analysis was performed for both arms (Placebo and Ketoprofen) of the study.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Part 2: Measurement of Skin Thickness</measure>
    <time_frame>Baseline and 4 months</time_frame>
    <description>Caliper measured skin thickness (mm) of lymphedema-affected limb was serially assessed and pre-to-post paired analysis was performed.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Part 3: Change From Baseline in Cutaneous Histological Architecture</measure>
    <time_frame>Baseline; 4 months</time_frame>
    <description>Quantitative assessment of paired histological specimens of lymphedema skin pre- and post-treatment with ketoprofen or placebo, respectively. The impact of treatment on cutaneous histopathology was evaluated through the use of an empirically-derived scoring system (comprised of dermal thickness, intercellular mucin content, deep dermal collagen content, and perivascular infiltrate); this quantitative assessment was developed and performed by a dermatopathologist. Each characteristic was weighted equally and each specimen was assigned a cumulative subscale score of 0-5. The scores were summed for a total score (range: 0-20) which is presented here. Higher scores indicate a higher degree of pathology. For the analysis, the 4-month post-minus-pre change in this score for ketoprofen- and placebo-recipients, respectively, was compared. A quantitatively higher negative change indicates a more favorable therapeutic response in the histology.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Part 2/Part 3: Change From Baseline in Bioimpedance Spectroscopy</measure>
    <time_frame>Baseline; 4 months</time_frame>
    <description>A four-electrode configuration was used to non-invasively assess the extracellular and intracellular fluid contents of the limb. Data were analyzed according to Cole theory, using the manufacturer's software (Impedimed Ltd.), to provide values for a bioimpedance ratio (Ro), the resistance of the extracellular fluid including lymph, R∞ the resistance of total tissue fluid and Ri, the resistance of the intracellular fluid. For the purposes of these investigations, in patients with unilateral lymphedema, the ratio of Ro in the affected:unaffected limbs was analyzed in each patient, as a measure of the bioimpedance attributable to the extracellular fluid content. An Ro level of 1.034 was considered normal; values ≥1.034 were considered abnormal.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Part 2/Part 3: Change in Limb Volume</measure>
    <time_frame>Baseline; 4 months</time_frame>
    <description>Quantitative assessment of limb volume (ml) of the affected limb at study end compared to pre-treatment values.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Part 3: Change in Systemic Inflammatory Mediator Granulocyte Colony Stimulating Factor (G-CSF)</measure>
    <time_frame>Baseline; 4 months</time_frame>
    <description>The systemic inflammatory response of G-CSF, in the two treatment groups, Ketoprofen and Placebo, will be assessed with Luminex-bead inflammasome analysis of pre- and post-treatment plasma samples. G-CSF, a glycoprotein, is an inflammatory cytokine produced by endothelium and immune cells. Ketoprofen is a unique NSAID possessing dual pathways of inflammatory inhibition, blocking cyclooxygenase (COX) and 5-LO. Measurement using median fluorescence intensity (MFI) was employed.</description>
  </secondary_outcome>
  <number_of_arms>4</number_of_arms>
  <enrollment type="Actual">117</enrollment>
  <condition>Lymphedema</condition>
  <arm_group>
    <arm_group_label>Part 1: Exploratory Group</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Ketoprofen 225-300 mgs daily, taken orally&#xD;
Ketoprofen-exploratory group: 225-300 mgs daily for four to six months</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Part 2: Open-label Group</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Ketoprofen 225 mg daily, taken orally&#xD;
Open-label group: 75 mgs, three times daily, for four months</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Part 3: Placebo Group</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Participants randomized to receive placebo: placebo, three times daily, taken orally&#xD;
Placebo: 1 capsule, three times daily, for four months</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Part 3: Ketoprofen Group</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Participants randomized to receive active medication: ketoprofen 75 mgs., three times daily, taken orally&#xD;
Ketoprofen: 1 capsule, three times daily, for four months</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Ketoprofen</intervention_name>
    <arm_group_label>Part 1: Exploratory Group</arm_group_label>
    <arm_group_label>Part 2: Open-label Group</arm_group_label>
    <arm_group_label>Part 3: Ketoprofen Group</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>Placebo to match ketoprofen.</description>
    <arm_group_label>Part 3: Placebo Group</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  a history of lymphedema of one or more limbs (unilateral or bilateral), with a&#xD;
             duration of &gt; 6 months.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Patients with active cancer, infection or bleeding tendency will be excluded.&#xD;
&#xD;
          -  We will also exclude patients with medical contraindications to NSAIDs, including&#xD;
             history of allergies, know gastrointestinal intolerance, or other serious systemic&#xD;
             illness (e.g., renal failure, hepatic dysfunction, congestive heart failure,&#xD;
             neurological or psychological impairment) that would impair the patients' ability to&#xD;
             participate.&#xD;
&#xD;
          -  Minors (&lt;18 years of age) *&gt;90 years of age&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>90 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Stanley G Rockson, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Stanford University</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Stanford University</name>
      <address>
        <city>Stanford</city>
        <state>California</state>
        <zip>94305</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <link>
    <url>http://stanfordhealthcare.org/medical-clinics/center-lymphatic-venous-disorders.html</url>
    <description>Stanford Health Care: Center for Lymphatic and Venous Disorders</description>
  </link>
  <verification_date>October 2022</verification_date>
  <study_first_submitted>August 25, 2014</study_first_submitted>
  <study_first_submitted_qc>October 6, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">October 7, 2014</study_first_posted>
  <results_first_submitted>July 19, 2018</results_first_submitted>
  <results_first_submitted_qc>August 15, 2018</results_first_submitted_qc>
  <results_first_posted type="Actual">September 14, 2018</results_first_posted>
  <last_update_submitted>October 25, 2022</last_update_submitted>
  <last_update_submitted_qc>October 25, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">October 27, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Stanford University</investigator_affiliation>
    <investigator_full_name>Stanley Rockson</investigator_full_name>
    <investigator_title>Allan and Tina Neill Professor of Lymphatic Research and Medicine; Professor of Cardiovascular Medicine</investigator_title>
  </responsible_party>
  <keyword>Lymphedema</keyword>
  <keyword>edema</keyword>
  <keyword>swelling</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Lymphedema</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Ketoprofen</mesh_term>
  </intervention_browse>

  <clinical_results>

    <participant_flow>
      <recruitment_details>Part 1 was feasibility, exploratory, open-label ketoprofen, to document effects. Part 2 was open-label trial of ketoprofen to document histological response. Part 3 was double-blind randomized to receive placebo or ketoprofen to evaluate safety and efficacy.</recruitment_details>
      <group_list>
        <group group_id="P1">
          <title>Part 1: Exploratory Group</title>
          <description>Ketoprofen 225-300 mgs daily, taken orally&#xD;
Ketoprofen-exploratory group: 225-300 mgs daily for four to six months</description>
        </group>
        <group group_id="P2">
          <title>Part 2: Open-label Group</title>
          <description>Ketoprofen 225 mg daily, taken orally&#xD;
Open-label group: 75 mgs, three times daily, for four months</description>
        </group>
        <group group_id="P3">
          <title>Part 3: Placebo Group</title>
          <description>Participants randomized to receive placebo: placebo, three times daily, taken orally&#xD;
Placebo: 1 capsule, three times daily, for four months</description>
        </group>
        <group group_id="P4">
          <title>Part 3: Ketoprofen Group</title>
          <description>Participants randomized to receive active medication: ketoprofen 75 mgs., three times daily, taken orally&#xD;
Ketoprofen: 1 capsule, three times daily, for four months</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Part 1</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="50"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="0"/>
                <participants group_id="P4" count="0"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="50"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="0"/>
                <participants group_id="P4" count="0"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="0"/>
                <participants group_id="P4" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
        <period>
          <title>Part 2</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="23"/>
                <participants group_id="P3" count="0"/>
                <participants group_id="P4" count="0"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="16"/>
                <participants group_id="P3" count="0"/>
                <participants group_id="P4" count="0"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="7"/>
                <participants group_id="P3" count="0"/>
                <participants group_id="P4" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
        <period>
          <title>Part 3</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="23"/>
                <participants group_id="P4" count="21"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="16"/>
                <participants group_id="P4" count="14"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="7"/>
                <participants group_id="P4" count="7"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <population>Participants that completed the protocol were included in Baseline Characteristics.</population>
      <group_list>
        <group group_id="B1">
          <title>Part 1: Exploratory Group</title>
          <description>Ketoprofen 225-300 mgs daily, taken orally&#xD;
Ketoprofen-exploratory group: 225-300 mgs daily for four to six months</description>
        </group>
        <group group_id="B2">
          <title>Part 2: Open-label Group</title>
          <description>Ketoprofen 225 mg daily&#xD;
Open-label group: 75 mgs, 1 capsule, taken orally, three times daily, for four months</description>
        </group>
        <group group_id="B3">
          <title>Part 3: Placebo Group</title>
          <description>Participants randomized to receive placebo:&#xD;
1 capsule, taken orally, three times daily, for four months</description>
        </group>
        <group group_id="B4">
          <title>Part 3: Ketoprofen Group</title>
          <description>Participants randomized to receive active medication, Ketoprofen 225 mg daily:&#xD;
Ketoprofen: 75 mgs, 1 capsule, three times daily, for four months</description>
        </group>
        <group group_id="B5">
          <title>Total</title>
          <description>Total of all reporting groups</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="50"/>
            <count group_id="B2" value="16"/>
            <count group_id="B3" value="16"/>
            <count group_id="B4" value="14"/>
            <count group_id="B5" value="96"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>&lt;=18 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="0"/>
                    <measurement group_id="B5" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Between 18 and 65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="39"/>
                    <measurement group_id="B2" value="12"/>
                    <measurement group_id="B3" value="14"/>
                    <measurement group_id="B4" value="10"/>
                    <measurement group_id="B5" value="75"/>
                  </measurement_list>
                </category>
                <category>
                  <title>&gt;=65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="11"/>
                    <measurement group_id="B2" value="4"/>
                    <measurement group_id="B3" value="2"/>
                    <measurement group_id="B4" value="4"/>
                    <measurement group_id="B5" value="21"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Age</title>
          <units>years</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="56.72" spread="13.46"/>
                    <measurement group_id="B2" value="56.43" spread="11.15"/>
                    <measurement group_id="B3" value="50.25" spread="15.12"/>
                    <measurement group_id="B4" value="53.92" spread="13.14"/>
                    <measurement group_id="B5" value="54.92" spread="13.07"/>
                  </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="41"/>
                    <measurement group_id="B2" value="13"/>
                    <measurement group_id="B3" value="14"/>
                    <measurement group_id="B4" value="14"/>
                    <measurement group_id="B5" value="82"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="9"/>
                    <measurement group_id="B2" value="3"/>
                    <measurement group_id="B3" value="2"/>
                    <measurement group_id="B4" value="0"/>
                    <measurement group_id="B5" value="14"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Lymphedema classification</title>
          <description>Primary lymphedema is defined as having been born with the condition, or developed the condition in the first year of life.&#xD;
Secondary lymphedema is defined as a condition that results due to some other event (e.g., trauma, cancer treatment, May-Turner Syndrome (MTS)).</description>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Primary</title>
                  <measurement_list>
                    <measurement group_id="B1" value="4"/>
                    <measurement group_id="B2" value="5"/>
                    <measurement group_id="B3" value="4"/>
                    <measurement group_id="B4" value="2"/>
                    <measurement group_id="B5" value="15"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Secondary</title>
                  <measurement_list>
                    <measurement group_id="B1" value="46"/>
                    <measurement group_id="B2" value="11"/>
                    <measurement group_id="B3" value="12"/>
                    <measurement group_id="B4" value="12"/>
                    <measurement group_id="B5" value="81"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Lymphedema location</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Upper extermity</title>
                  <measurement_list>
                    <measurement group_id="B1" value="18"/>
                    <measurement group_id="B2" value="4"/>
                    <measurement group_id="B3" value="5"/>
                    <measurement group_id="B4" value="2"/>
                    <measurement group_id="B5" value="29"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Lower extremity</title>
                  <measurement_list>
                    <measurement group_id="B1" value="32"/>
                    <measurement group_id="B2" value="12"/>
                    <measurement group_id="B3" value="11"/>
                    <measurement group_id="B4" value="12"/>
                    <measurement group_id="B5" value="67"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Part 1: Count of Participants Able to Complete Ketoprofen Treatment</title>
        <description>Participants who were able to complete ketoprofen treatment and experienced no treatment-related serious adverse events.</description>
        <time_frame>Baseline to month 6</time_frame>
        <population>This outcome was assessed in Part 1 participants only.</population>
        <group_list>
          <group group_id="O1">
            <title>Part 1: Exploratory Group</title>
            <description>Ketoprofen 225-300 mgs daily, taken orally&#xD;
Ketoprofen-exploratory group: 225-300 mgs daily for four to six months</description>
          </group>
        </group_list>
        <measure>
          <title>Part 1: Count of Participants Able to Complete Ketoprofen Treatment</title>
          <description>Participants who were able to complete ketoprofen treatment and experienced no treatment-related serious adverse events.</description>
          <population>This outcome was assessed in Part 1 participants only.</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="50"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="50"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Part 2: Change From Baseline in Cutaneous Histological Architecture</title>
        <description>Quantitative assessment of paired histological specimens of lymphedema skin pre- and post-treatment with ketoprofen. The impact of treatment on cutaneous histopathology was evaluated through the use of an empirically-derived scoring system (comprised of dermal thickness, intercellular mucin content, deep dermal collagen content, and perivascular infiltrate); this quantitative assessment was developed and performed by a dermatopathologist. Each characteristic was weighted equally and each specimen was assigned a cumulative subscale score of 0-5. The scores were summed for a total score (range: 0-20) which is presented here. Higher scores indicate a higher degree of pathology. A quantitatively higher negative change indicates a more favorable therapeutic response in the histology.</description>
        <time_frame>Baseline; Month 4</time_frame>
        <population>This primary endpoint outcome was assessed in Part 2 participants only.</population>
        <group_list>
          <group group_id="O1">
            <title>Part 2: Open-label Group</title>
            <description>Ketoprofen 225 mg daily, taken orally&#xD;
Open-label group: 75 mgs, three times daily, for four months</description>
          </group>
          <group group_id="O2">
            <title>Part 2: Unaffected Tissue Samples</title>
            <description>Results from normal samples from Part 2 participants are presented in this reporting group.</description>
          </group>
        </group_list>
        <measure>
          <title>Part 2: Change From Baseline in Cutaneous Histological Architecture</title>
          <description>Quantitative assessment of paired histological specimens of lymphedema skin pre- and post-treatment with ketoprofen. The impact of treatment on cutaneous histopathology was evaluated through the use of an empirically-derived scoring system (comprised of dermal thickness, intercellular mucin content, deep dermal collagen content, and perivascular infiltrate); this quantitative assessment was developed and performed by a dermatopathologist. Each characteristic was weighted equally and each specimen was assigned a cumulative subscale score of 0-5. The scores were summed for a total score (range: 0-20) which is presented here. Higher scores indicate a higher degree of pathology. A quantitatively higher negative change indicates a more favorable therapeutic response in the histology.</description>
          <population>This primary endpoint outcome was assessed in Part 2 participants only.</population>
          <units>score on a scale</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="16"/>
                <count group_id="O2" value="16"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Baseline</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="6.125" spread="2.247"/>
                    <measurement group_id="O2" value="0.8" spread="1.2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Month 4</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2.688" spread="1.401"/>
                    <measurement group_id="O2" value="0.6" spread="1.0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
            </group_id_list>
            <groups_desc>For the analysis, the 4-month post-minus-pre change in this score for ketoprofen was compared.</groups_desc>
            <non_inferiority_type>Equivalence</non_inferiority_type>
            <non_inferiority_desc>The likelihood of rejecting the null hypothesis (equivalence between the two groups) was defined as P&lt;0.05</non_inferiority_desc>
            <p_value>&lt;0.0001</p_value>
            <method>t-test, 2 sided</method>
            <method_desc>paired t-test</method_desc>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Part 3: Measurement of Skin Thickness</title>
        <description>Caliper-measured skin thickness (mm) was serially assessed and pre-to-post paired analysis was performed for both arms (Placebo and Ketoprofen) of the study.</description>
        <time_frame>Baseline and 4 months</time_frame>
        <population>Data for this outcome were collected in Part 3 participants only and for lymphedema-affected limbs only.</population>
        <group_list>
          <group group_id="O1">
            <title>Part 3: Placebo Group</title>
            <description>Participants randomized to receive placebo: placebo, three times daily, taken orally Placebo: 1 capsule, three times daily, for four months</description>
          </group>
          <group group_id="O2">
            <title>Part 3: Ketoprofen Group</title>
            <description>Participants randomized to receive active medication: ketoprofen 75 mgs., three times daily, taken orally Ketoprofen: 1 capsule, three times daily, for four months</description>
          </group>
        </group_list>
        <measure>
          <title>Part 3: Measurement of Skin Thickness</title>
          <description>Caliper-measured skin thickness (mm) was serially assessed and pre-to-post paired analysis was performed for both arms (Placebo and Ketoprofen) of the study.</description>
          <population>Data for this outcome were collected in Part 3 participants only and for lymphedema-affected limbs only.</population>
          <units>mm</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="16"/>
                <count group_id="O2" value="14"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Baseline</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="47" spread="28"/>
                    <measurement group_id="O2" value="49" spread="21"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Month 4</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="45" spread="31"/>
                    <measurement group_id="O2" value="41" spread="21"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
            </group_id_list>
            <non_inferiority_type>Equivalence</non_inferiority_type>
            <non_inferiority_desc>Pre-to-post comparison: the likelihood of rejecting the null hypothesis (equivalence between the two groups) was defined as P&lt;0.05</non_inferiority_desc>
            <p_value>=0.6</p_value>
            <method>t-test, 2 sided</method>
            <method_desc>Paired t-test</method_desc>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Equivalence</non_inferiority_type>
            <non_inferiority_desc>Pre-to-Post comparison: The likelihood of rejecting the null hypothesis (equivalence between the two groups) was defined as P&lt;0.05</non_inferiority_desc>
            <p_value>=0.01</p_value>
            <method>t-test, 2 sided</method>
            <method_desc>paired t-test</method_desc>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Part 2: Measurement of Skin Thickness</title>
        <description>Caliper measured skin thickness (mm) of lymphedema-affected limb was serially assessed and pre-to-post paired analysis was performed.</description>
        <time_frame>Baseline and 4 months</time_frame>
        <population>Data for this outcome were collected in Part 2 participants only and for lymphedema-affected limbs only.</population>
        <group_list>
          <group group_id="O1">
            <title>Part 2: Open-label Group</title>
            <description>Ketoprofen 225 mg daily, taken orally&#xD;
Open-label group: 75 mgs, three times daily, for four months</description>
          </group>
        </group_list>
        <measure>
          <title>Part 2: Measurement of Skin Thickness</title>
          <description>Caliper measured skin thickness (mm) of lymphedema-affected limb was serially assessed and pre-to-post paired analysis was performed.</description>
          <population>Data for this outcome were collected in Part 2 participants only and for lymphedema-affected limbs only.</population>
          <units>mm</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="16"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Baseline</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="62" spread="34"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Month 4</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="27" spread="22"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Part 3: Change From Baseline in Cutaneous Histological Architecture</title>
        <description>Quantitative assessment of paired histological specimens of lymphedema skin pre- and post-treatment with ketoprofen or placebo, respectively. The impact of treatment on cutaneous histopathology was evaluated through the use of an empirically-derived scoring system (comprised of dermal thickness, intercellular mucin content, deep dermal collagen content, and perivascular infiltrate); this quantitative assessment was developed and performed by a dermatopathologist. Each characteristic was weighted equally and each specimen was assigned a cumulative subscale score of 0-5. The scores were summed for a total score (range: 0-20) which is presented here. Higher scores indicate a higher degree of pathology. For the analysis, the 4-month post-minus-pre change in this score for ketoprofen- and placebo-recipients, respectively, was compared. A quantitatively higher negative change indicates a more favorable therapeutic response in the histology.</description>
        <time_frame>Baseline; 4 months</time_frame>
        <population>Data for this outcome were collected in Part 3 participants only and for lymphedema tissue samples only.</population>
        <group_list>
          <group group_id="O1">
            <title>Part 3 Placebo</title>
            <description>Placebo, 1 capsule taken orally, three times daily, for four months</description>
          </group>
          <group group_id="O2">
            <title>Part 3: Ketoprofen Group</title>
            <description>Ketoprofen, 75 mgs, 1 capsule taken orally, three times daily, for four months</description>
          </group>
          <group group_id="O3">
            <title>Part 3: Unaffected Tissue Samples</title>
            <description>Results from normal samples from Part 3 participants are presented in this reporting group.</description>
          </group>
        </group_list>
        <measure>
          <title>Part 3: Change From Baseline in Cutaneous Histological Architecture</title>
          <description>Quantitative assessment of paired histological specimens of lymphedema skin pre- and post-treatment with ketoprofen or placebo, respectively. The impact of treatment on cutaneous histopathology was evaluated through the use of an empirically-derived scoring system (comprised of dermal thickness, intercellular mucin content, deep dermal collagen content, and perivascular infiltrate); this quantitative assessment was developed and performed by a dermatopathologist. Each characteristic was weighted equally and each specimen was assigned a cumulative subscale score of 0-5. The scores were summed for a total score (range: 0-20) which is presented here. Higher scores indicate a higher degree of pathology. For the analysis, the 4-month post-minus-pre change in this score for ketoprofen- and placebo-recipients, respectively, was compared. A quantitatively higher negative change indicates a more favorable therapeutic response in the histology.</description>
          <population>Data for this outcome were collected in Part 3 participants only and for lymphedema tissue samples only.</population>
          <units>score on a scale</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="16"/>
                <count group_id="O2" value="14"/>
                <count group_id="O3" value="30"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Baseline</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2.7" spread="2.1"/>
                    <measurement group_id="O2" value="4.1" spread="1.8"/>
                    <measurement group_id="O3" value="0.8" spread="1.2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Month 4</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1.0" spread="1.1"/>
                    <measurement group_id="O2" value="1.18" spread="1.08"/>
                    <measurement group_id="O3" value="0.6" spread="1.0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Part 2/Part 3: Change From Baseline in Bioimpedance Spectroscopy</title>
        <description>A four-electrode configuration was used to non-invasively assess the extracellular and intracellular fluid contents of the limb. Data were analyzed according to Cole theory, using the manufacturer's software (Impedimed Ltd.), to provide values for a bioimpedance ratio (Ro), the resistance of the extracellular fluid including lymph, R∞ the resistance of total tissue fluid and Ri, the resistance of the intracellular fluid. For the purposes of these investigations, in patients with unilateral lymphedema, the ratio of Ro in the affected:unaffected limbs was analyzed in each patient, as a measure of the bioimpedance attributable to the extracellular fluid content. An Ro level of 1.034 was considered normal; values ≥1.034 were considered abnormal.</description>
        <time_frame>Baseline; 4 months</time_frame>
        <population>Data for this outcome were collected for Part 2 and Part 3 participants with unilateral lymphedema-affected limbs only.</population>
        <group_list>
          <group group_id="O1">
            <title>Part 2: Open-label Group</title>
            <description>Ketoprofen 225 mg daily, taken orally&#xD;
Open-label group: 75 mgs, three times daily, for four months</description>
          </group>
          <group group_id="O2">
            <title>Part 3: Placebo Group</title>
            <description>Participants randomized to receive placebo:&#xD;
1 capsule, three times daily, for four months</description>
          </group>
          <group group_id="O3">
            <title>Part 3: Ketoprofen Group</title>
            <description>Participants randomized to receive active medication:&#xD;
Ketoprofen 75 mgs., 1 capsule, taken orally, three times daily, for four months</description>
          </group>
        </group_list>
        <measure>
          <title>Part 2/Part 3: Change From Baseline in Bioimpedance Spectroscopy</title>
          <description>A four-electrode configuration was used to non-invasively assess the extracellular and intracellular fluid contents of the limb. Data were analyzed according to Cole theory, using the manufacturer's software (Impedimed Ltd.), to provide values for a bioimpedance ratio (Ro), the resistance of the extracellular fluid including lymph, R∞ the resistance of total tissue fluid and Ri, the resistance of the intracellular fluid. For the purposes of these investigations, in patients with unilateral lymphedema, the ratio of Ro in the affected:unaffected limbs was analyzed in each patient, as a measure of the bioimpedance attributable to the extracellular fluid content. An Ro level of 1.034 was considered normal; values ≥1.034 were considered abnormal.</description>
          <population>Data for this outcome were collected for Part 2 and Part 3 participants with unilateral lymphedema-affected limbs only.</population>
          <units>ratio of Ro values</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <units_analyzed>limbs</units_analyzed>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="10"/>
                <count group_id="O2" value="12"/>
                <count group_id="O3" value="13"/>
              </count_list>
            </analyzed>
            <analyzed>
              <units>limbs</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="20"/>
                <count group_id="O2" value="24"/>
                <count group_id="O3" value="26"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Baseline</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1.5" spread="0.5"/>
                    <measurement group_id="O2" value="1.5" spread="0.4"/>
                    <measurement group_id="O3" value="1.4" spread="0.2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Month 4</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1.6" spread="0.3"/>
                    <measurement group_id="O2" value="1.5" spread="0.3"/>
                    <measurement group_id="O3" value="1.4" spread="0.2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Part 2/Part 3: Change in Limb Volume</title>
        <description>Quantitative assessment of limb volume (ml) of the affected limb at study end compared to pre-treatment values.</description>
        <time_frame>Baseline; 4 months</time_frame>
        <population>Data for this outcome were collected only for lymphedema-affected limbs only.</population>
        <group_list>
          <group group_id="O1">
            <title>Part 2: Open-label Group</title>
            <description>Ketoprofen 225 mg daily&#xD;
Open-label group: 75 mgs, 1 capsule, taken orally, three times daily, for four months</description>
          </group>
          <group group_id="O2">
            <title>Part 3: Placebo Group</title>
            <description>Participants randomized to receive placebo:&#xD;
1 capsule, taken orally, three times daily, for four months</description>
          </group>
          <group group_id="O3">
            <title>Part 3: Ketoprofen Group</title>
            <description>Participants randomized to receive active medication:&#xD;
Ketoprofen 75 mgs., 1 capsule, taken orally, three times daily, for four months</description>
          </group>
        </group_list>
        <measure>
          <title>Part 2/Part 3: Change in Limb Volume</title>
          <description>Quantitative assessment of limb volume (ml) of the affected limb at study end compared to pre-treatment values.</description>
          <population>Data for this outcome were collected only for lymphedema-affected limbs only.</population>
          <units>ml</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="16"/>
                <count group_id="O2" value="16"/>
                <count group_id="O3" value="14"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Baseline</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="9866" spread="5821"/>
                    <measurement group_id="O2" value="7196" spread="3519"/>
                    <measurement group_id="O3" value="8598" spread="3066"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Month 4</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="9465" spread="5115"/>
                    <measurement group_id="O2" value="7256" spread="3496"/>
                    <measurement group_id="O3" value="8675" spread="3103"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Part 3: Change in Systemic Inflammatory Mediator Granulocyte Colony Stimulating Factor (G-CSF)</title>
        <description>The systemic inflammatory response of G-CSF, in the two treatment groups, Ketoprofen and Placebo, will be assessed with Luminex-bead inflammasome analysis of pre- and post-treatment plasma samples. G-CSF, a glycoprotein, is an inflammatory cytokine produced by endothelium and immune cells. Ketoprofen is a unique NSAID possessing dual pathways of inflammatory inhibition, blocking cyclooxygenase (COX) and 5-LO. Measurement using median fluorescence intensity (MFI) was employed.</description>
        <time_frame>Baseline; 4 months</time_frame>
        <population>Data for this outcome was collected for Part 3 participants only.</population>
        <group_list>
          <group group_id="O1">
            <title>Part 3: Placebo</title>
            <description>Placebo, 1 capsule taken orally, three times daily, for four months</description>
          </group>
          <group group_id="O2">
            <title>Part 3: Ketoprofen Group</title>
            <description>Ketoprofen, 75 mgs, 1 capsule taken orally, three times daily, for four months</description>
          </group>
        </group_list>
        <measure>
          <title>Part 3: Change in Systemic Inflammatory Mediator Granulocyte Colony Stimulating Factor (G-CSF)</title>
          <description>The systemic inflammatory response of G-CSF, in the two treatment groups, Ketoprofen and Placebo, will be assessed with Luminex-bead inflammasome analysis of pre- and post-treatment plasma samples. G-CSF, a glycoprotein, is an inflammatory cytokine produced by endothelium and immune cells. Ketoprofen is a unique NSAID possessing dual pathways of inflammatory inhibition, blocking cyclooxygenase (COX) and 5-LO. Measurement using median fluorescence intensity (MFI) was employed.</description>
          <population>Data for this outcome was collected for Part 3 participants only.</population>
          <units>MFI (log10)</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="16"/>
                <count group_id="O2" value="14"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Baseline</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="121" spread="90"/>
                    <measurement group_id="O2" value="131" spread="76"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Month 4</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="209" spread="214"/>
                    <measurement group_id="O2" value="126" spread="107"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>Four months</time_frame>
      <group_list>
        <group group_id="E1">
          <title>Part 1: Exploratory Group</title>
          <description>Ketoprofen 225-300 mgs daily, taken orally&#xD;
Ketoprofen-exploratory group: 225-300 mgs daily for four to six months</description>
        </group>
        <group group_id="E2">
          <title>Part 2: Open-label Group</title>
          <description>Ketoprofen 225 mg daily, taken orally&#xD;
Open-label group: 75 mgs, three times daily, for four months</description>
        </group>
        <group group_id="E3">
          <title>Part 3: Placebo Group</title>
          <description>Participants randomized to receive placebo: placebo, three times daily, taken orally&#xD;
Placebo: 1 capsule, three times daily, for four months</description>
        </group>
        <group group_id="E4">
          <title>Part 3: Ketoprofen Group</title>
          <description>Participants randomized to receive active medication: ketoprofen 75 mgs., three times daily, taken orally&#xD;
Ketoprofen: 1 capsule, three times daily, for four months</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="50"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="23"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="23"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="21"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="50"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="23"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="23"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="21"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>1</frequency_threshold>
        <default_vocab>CTCAE (4.0)</default_vocab>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="50"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="23"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="23"/>
                <counts group_id="E4" subjects_affected="2" subjects_at_risk="21"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Hemorrhoidal hemorrhag</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="50"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="23"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="23"/>
                <counts group_id="E4" events="1" subjects_affected="1" subjects_at_risk="21"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Skin and subcutaneous tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Cellulitis</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="50"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="23"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="23"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="21"/>
              </event>
              <event>
                <sub_title>Rash</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="50"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="23"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="23"/>
                <counts group_id="E4" events="1" subjects_affected="1" subjects_at_risk="19"/>
              </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>Dr. Stanley Rockson</name_or_title>
      <organization>Stanford University, School of Medicine</organization>
      <phone>650-725-7571</phone>
      <email>rockson@stanford.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/NCT02257970
org study id: 7781
nct id: NCT02257970
lead sponsor: 
has dmc: No
This study compares the effectiveness of a study drug versus placebo in the treatment of
      lymphedema.
Part 1 is feasibility, exploratory, open-label study of ketoprofen, to document effects.

      Part 2, is open-label trial of ketoprofen to document histological response. Part 3 is
      double-blind randomized trial of receive placebo or ketoprofen to evaluate safety and
      efficacy.

      We will try to determine how the study drug affects the body tissue by obtaining tissue
      biopsies (small pieces of skin from the arm or leg) before treatment and after treatment.
allocation: Randomized
intervention model: Sequential Assignment
primary purpose: Treatment
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
measure: Part 1: Count of Participants Able to Complete Ketoprofen Treatment
time frame: Baseline to month 6
description: Participants who were able to complete ketoprofen treatment and experienced no treatment-related serious adverse events.
measure: Part 2: Change From Baseline in Cutaneous Histological Architecture
time frame: Baseline; Month 4
description: Quantitative assessment of paired histological specimens of lymphedema skin pre- and post-treatment with ketoprofen. The impact of treatment on cutaneous histopathology was evaluated through the use of an empirically-derived scoring system (comprised of dermal thickness, intercellular mucin content, deep dermal collagen content, and perivascular infiltrate); this quantitative assessment was developed and performed by a dermatopathologist. Each characteristic was weighted equally and each specimen was assigned a cumulative subscale score of 0-5. The scores were summed for a total score (range: 0-20) which is presented here. Higher scores indicate a higher degree of pathology. A quantitatively higher negative change indicates a more favorable therapeutic response in the histology.
measure: Part 3: Measurement of Skin Thickness
time frame: Baseline and 4 months
description: Caliper-measured skin thickness (mm) was serially assessed and pre-to-post paired analysis was performed for both arms (Placebo and Ketoprofen) of the study.
measure: Part 2: Measurement of Skin Thickness
time frame: Baseline and 4 months
description: Caliper measured skin thickness (mm) of lymphedema-affected limb was serially assessed and pre-to-post paired analysis was performed.
measure: Part 3: Change From Baseline in Cutaneous Histological Architecture
time frame: Baseline; 4 months
description: Quantitative assessment of paired histological specimens of lymphedema skin pre- and post-treatment with ketoprofen or placebo, respectively. The impact of treatment on cutaneous histopathology was evaluated through the use of an empirically-derived scoring system (comprised of dermal thickness, intercellular mucin content, deep dermal collagen content, and perivascular infiltrate); this quantitative assessment was developed and performed by a dermatopathologist. Each characteristic was weighted equally and each specimen was assigned a cumulative subscale score of 0-5. The scores were summed for a total score (range: 0-20) which is presented here. Higher scores indicate a higher degree of pathology. For the analysis, the 4-month post-minus-pre change in this score for ketoprofen- and placebo-recipients, respectively, was compared. A quantitatively higher negative change indicates a more favorable therapeutic response in the histology.
measure: Part 2/Part 3: Change From Baseline in Bioimpedance Spectroscopy
time frame: Baseline; 4 months
description: A four-electrode configuration was used to non-invasively assess the extracellular and intracellular fluid contents of the limb. Data were analyzed according to Cole theory, using the manufacturer's software (Impedimed Ltd.), to provide values for a bioimpedance ratio (Ro), the resistance of the extracellular fluid including lymph, R∞ the resistance of total tissue fluid and Ri, the resistance of the intracellular fluid. For the purposes of these investigations, in patients with unilateral lymphedema, the ratio of Ro in the affected:unaffected limbs was analyzed in each patient, as a measure of the bioimpedance attributable to the extracellular fluid content. An Ro level of 1.034 was considered normal; values ≥1.034 were considered abnormal.
measure: Part 2/Part 3: Change in Limb Volume
time frame: Baseline; 4 months
description: Quantitative assessment of limb volume (ml) of the affected limb at study end compared to pre-treatment values.
measure: Part 3: Change in Systemic Inflammatory Mediator Granulocyte Colony Stimulating Factor (G-CSF)
time frame: Baseline; 4 months
description: The systemic inflammatory response of G-CSF, in the two treatment groups, Ketoprofen and Placebo, will be assessed with Luminex-bead inflammasome analysis of pre- and post-treatment plasma samples. G-CSF, a glycoprotein, is an inflammatory cytokine produced by endothelium and immune cells. Ketoprofen is a unique NSAID possessing dual pathways of inflammatory inhibition, blocking cyclooxygenase (COX) and 5-LO. Measurement using median fluorescence intensity (MFI) was employed.
arm group label: Part 1: Exploratory Group
arm group type: Experimental
description: Ketoprofen 225-300 mgs daily, taken orally
Ketoprofen-exploratory group: 225-300 mgs daily for four to six months
arm group label: Part 2: Open-label Group
arm group type: Experimental
description: Ketoprofen 225 mg daily, taken orally
Open-label group: 75 mgs, three times daily, for four months
arm group label: Part 3: Placebo Group
arm group type: Placebo Comparator
description: Participants randomized to receive placebo: placebo, three times daily, taken orally
Placebo: 1 capsule, three times daily, for four months
arm group label: Part 3: Ketoprofen Group
arm group type: Active Comparator
description: Participants randomized to receive active medication: ketoprofen 75 mgs., three times daily, taken orally
Ketoprofen: 1 capsule, three times daily, for four months
intervention type: Drug
intervention name: Ketoprofen
arm group label: Part 1: Exploratory Group
arm group label: Part 2: Open-label Group
arm group label: Part 3: Ketoprofen Group
intervention type: Drug
intervention name: Placebo
description: Placebo to match ketoprofen.
arm group label: Part 3: Placebo Group
criteria: 
gender: All
minimum age: 18 Years
maximum age: 90 Years
healthy volunteers: No
last name: Stanley G Rockson, MD
role: Principal Investigator
affiliation: Stanford University
facility: 
country: United States
url: http://stanfordhealthcare.org/medical-clinics/center-lymphatic-venous-disorders.html
description: Stanford Health Care: Center for Lymphatic and Venous Disorders
responsible party type: Principal Investigator
investigator affiliation: Stanford University
investigator full name: Stanley Rockson
investigator title: Allan and Tina Neill Professor of Lymphatic Research and Medicine; Professor of Cardiovascular Medicine
mesh term: Lymphedema
mesh term: Ketoprofen
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 