<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/NCT03783715</url>
  </required_header>
  <id_info>
    <org_study_id>49078</org_study_id>
    <nct_id>NCT03783715</nct_id>
  </id_info>
  <brief_title>Characterization of Treatment Responses in Lymphedema</brief_title>
  <official_title>Characterization of Treatment Responses in Lymphedema</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>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      This study is designed to investigate the treatment response of lymphedema, of the upper or&#xD;
      lower extremity, during clinical, pharmacologic treatment of lymphedema with oral ketoprofen.&#xD;
      Correlation of clinical responses (changes in limb volume and skin thickness) with changes in&#xD;
      the inflammasome will help to define the molecular substrate of treatment response.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Patients presenting to the Investigator's Clinic for evaluation and treatment of (upper or&#xD;
      lower extremity) lymphedema, will be assessed for their suitability (of low risk) for medical&#xD;
      treatment with ketoprofen. If there are no contra-indications to taking ketoprofen, after&#xD;
      discussion of FDA warnings, including provision of a written copy of the FDA language to the&#xD;
      patient, and with the recommendation to discuss with the primary physician-of-record,&#xD;
      patients will be provided with a prescription for ketoprofen 200 mg daily (one capsule taken&#xD;
      orally, once daily) or if obtained from a compound pharmacy, ketoprofen 210 mg daily (one&#xD;
      capsule taken orally, once daily).&#xD;
&#xD;
      Participation in this study will be offered. Two study visits, at baseline and month 6 are&#xD;
      required. Measurements (circumferential and skin thickness) and a blood sample will be taken&#xD;
      at each study visit.&#xD;
&#xD;
      The investigators will try to determine how ketoprofen affects the body tissue by obtaining&#xD;
      blood samples and measurements, before starting treatment and at month 6.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Suspended</overall_status>
  <why_stopped>
    Study has been halted due to Covid-19 pandemic and unavailability of ketoprofen.&#xD;
  </why_stopped>
  <start_date type="Actual">June 21, 2019</start_date>
  <completion_date type="Anticipated">August 31, 2023</completion_date>
  <primary_completion_date type="Anticipated">March 31, 2023</primary_completion_date>
  <study_type>Observational</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <observational_model>Cohort</observational_model>
    <time_perspective>Prospective</time_perspective>
  </study_design_info>
  <primary_outcome>
    <measure>Change in Systemic Inflammatory Mediator Granulocyte Colony Stimulating Factor (G-CSF)</measure>
    <time_frame>baseline and month 6.</time_frame>
    <description>The systemic inflammatory response of G-CSF, in patients treated with Ketoprofen will be assessed with Luminex-bead inflammasome analysis at baseline and 6 months 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 arachidonate 5-lipoxygenase (5-LO). Measurement using median fluorescence intensity (MFI) will be employed.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Change in Measurement of Skin Thickness</measure>
    <time_frame>baseline and month 6.</time_frame>
    <description>Caliper-measured skin thickness (mm) of upper or lower extremities, at 3 points, will be performed and recorded. Quantitative assessment of skin thickness (mm) of the affected limb at month 6 will be compared to baseline value.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in Limb Volume</measure>
    <time_frame>baseline and month 6.</time_frame>
    <description>Upper or lower limbs will be marked and measured at 4 cm intervals and circumferential measurements, with tape, will be performed and recorded.&#xD;
Quantitative assessment of limb volume (ml) of the affected limb at month 6 will be compared to baseline value.</description>
  </secondary_outcome>
  <number_of_groups>1</number_of_groups>
  <enrollment type="Anticipated">60</enrollment>
  <condition>Lymphedema</condition>
  <arm_group>
    <arm_group_label>Ketoprofen</arm_group_label>
    <description>Participants will take ketoprofen for six months. They will have evaluations at baseline and month 6.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Ketoprofen</intervention_name>
    <description>Ketoprofen 200 mg ER, taken orally, once a day for 6 months. If medication, if obtained from a compound pharmacy, dose will be 210 mg ER, taken orally once a day for 6 months.</description>
    <arm_group_label>Ketoprofen</arm_group_label>
  </intervention>
  <biospec_retention>Samples Without DNA</biospec_retention>
  <biospec_descr>
    <textblock>
      Plasma samples&#xD;
    </textblock>
  </biospec_descr>
  <eligibility>
    <study_pop>
      <textblock>
        Patients presenting to the Investigator's Stanford Center for Lymphatic and Venous&#xD;
        Disorders, for evaluation and treatment of their condition, lymphedema, will be assessed&#xD;
        for their suitability for medical treatment with ketoprofen. The use of ketoprofen in these&#xD;
        patients is predicated upon clinical presentation and evidence-based practice, not any&#xD;
        investigational consideration of therapy.&#xD;
&#xD;
        If there are no contra-indications to taking ketoprofen, after discussion of FDA black box&#xD;
        warnings, including provision of a written copy of the Medication Guide for Non-Steroidal&#xD;
        Anti-Inflammatory Drugs (NSAIDs), approved by FDA, will be provided to the patient, and&#xD;
        with the recommendation to discuss with the primary physician-of-record, patients will be&#xD;
        provided with a prescription for ketoprofen. The opportunity to participate in this&#xD;
        observational study will be presented.&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Non-Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Participants with a history of acquired lymphedema&#xD;
&#xD;
          -  Stage 1, 2, or 3&#xD;
&#xD;
          -  18-75 years&#xD;
&#xD;
          -  Clinical use of ketoprofen for lymphedema&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Active cancer, infection, bleeding tendency, inflammatory disease and/or taking&#xD;
             anti-inflammatory or anti-leukotriene medication will be excluded.&#xD;
&#xD;
          -  Pregnant or lactating females&#xD;
&#xD;
          -  Inability to take ketoprofen (contra-indicated, e.g patients with known CV, GI, renal,&#xD;
             hepatic disease).&#xD;
&#xD;
          -  Other severe acute or chronic medical or psychiatric condition or laboratory&#xD;
             abnormality that may increase the risk associated with study participation, may&#xD;
             interfere with interpretation of study results, and in the judgement of the&#xD;
             investigator, would make the participation inappropriate for entry into this study.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>75 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Stanley G Rockson</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>
  <reference>
    <citation>Rockson SG, Tian W, Jiang X, Kuznetsova T, Haddad F, Zampell J, Mehrara B, Sampson JP, Roche L, Kim J, Nicolls MR. Pilot studies demonstrate the potential benefits of antiinflammatory therapy in human lymphedema. JCI Insight. 2018 Oct 18;3(20):e123775. doi: 10.1172/jci.insight.123775.</citation>
    <PMID>30333315</PMID>
  </reference>
  <reference>
    <citation>Tian W, Rockson SG, Jiang X, Kim J, Begaye A, Shuffle EM, Tu AB, Cribb M, Nepiyushchikh Z, Feroze AH, Zamanian RT, Dhillon GS, Voelkel NF, Peters-Golden M, Kitajewski J, Dixon JB, Nicolls MR. Leukotriene B4 antagonism ameliorates experimental lymphedema. Sci Transl Med. 2017 May 10;9(389):eaal3920. doi: 10.1126/scitranslmed.aal3920.</citation>
    <PMID>28490670</PMID>
  </reference>
  <reference>
    <citation>Nakamura K, Radhakrishnan K, Wong YM, Rockson SG. Anti-inflammatory pharmacotherapy with ketoprofen ameliorates experimental lymphatic vascular insufficiency in mice. PLoS One. 2009 Dec 21;4(12):e8380. doi: 10.1371/journal.pone.0008380.</citation>
    <PMID>20027220</PMID>
  </reference>
  <reference>
    <citation>Tabibiazar R, Cheung L, Han J, Swanson J, Beilhack A, An A, Dadras SS, Rockson N, Joshi S, Wagner R, Rockson SG. Inflammatory manifestations of experimental lymphatic insufficiency. PLoS Med. 2006 Jul;3(7):e254. doi: 10.1371/journal.pmed.0030254.</citation>
    <PMID>16834456</PMID>
  </reference>
  <verification_date>August 2022</verification_date>
  <study_first_submitted>December 19, 2018</study_first_submitted>
  <study_first_submitted_qc>December 19, 2018</study_first_submitted_qc>
  <study_first_posted type="Actual">December 21, 2018</study_first_posted>
  <last_update_submitted>August 4, 2022</last_update_submitted>
  <last_update_submitted_qc>August 4, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">August 8, 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</investigator_title>
  </responsible_party>
  <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>
  <patient_data>
    <sharing_ipd>Yes</sharing_ipd>
    <ipd_description>De-identified participant data, for study endpoints, will be made available.</ipd_description>
    <ipd_info_type>Study Protocol</ipd_info_type>
    <ipd_info_type>Statistical Analysis Plan (SAP)</ipd_info_type>
    <ipd_info_type>Informed Consent Form (ICF)</ipd_info_type>
    <ipd_time_frame>Data will become available 12 months after completion of the last enrollment in the trial.</ipd_time_frame>
    <ipd_access_criteria>Data access requests will be reviewed by PI and Stanford IRB. If approved, requestors will be required to sign a data use agreement (DUA).</ipd_access_criteria>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</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/NCT03783715
org study id: 49078
nct id: NCT03783715
lead sponsor: 
has dmc: No
is fda regulated drug: Yes
is fda regulated device: No
is us export: No
This study is designed to investigate the treatment response of lymphedema, of the upper or
      lower extremity, during clinical, pharmacologic treatment of lymphedema with oral ketoprofen.
      Correlation of clinical responses (changes in limb volume and skin thickness) with changes in
      the inflammasome will help to define the molecular substrate of treatment response.
Patients presenting to the Investigator's Clinic for evaluation and treatment of (upper or
      lower extremity) lymphedema, will be assessed for their suitability (of low risk) for medical
      treatment with ketoprofen. If there are no contra-indications to taking ketoprofen, after
      discussion of FDA warnings, including provision of a written copy of the FDA language to the
      patient, and with the recommendation to discuss with the primary physician-of-record,
      patients will be provided with a prescription for ketoprofen 200 mg daily (one capsule taken
      orally, once daily) or if obtained from a compound pharmacy, ketoprofen 210 mg daily (one
      capsule taken orally, once daily).

      Participation in this study will be offered. Two study visits, at baseline and month 6 are
      required. Measurements (circumferential and skin thickness) and a blood sample will be taken
      at each study visit.

      The investigators will try to determine how ketoprofen affects the body tissue by obtaining
      blood samples and measurements, before starting treatment and at month 6.
observational model: Cohort
time perspective: Prospective
measure: Change in Systemic Inflammatory Mediator Granulocyte Colony Stimulating Factor (G-CSF)
time frame: baseline and month 6.
description: The systemic inflammatory response of G-CSF, in patients treated with Ketoprofen will be assessed with Luminex-bead inflammasome analysis at baseline and 6 months 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 arachidonate 5-lipoxygenase (5-LO). Measurement using median fluorescence intensity (MFI) will be employed.
measure: Change in Measurement of Skin Thickness
time frame: baseline and month 6.
description: Caliper-measured skin thickness (mm) of upper or lower extremities, at 3 points, will be performed and recorded. Quantitative assessment of skin thickness (mm) of the affected limb at month 6 will be compared to baseline value.
measure: Change in Limb Volume
time frame: baseline and month 6.
description: Upper or lower limbs will be marked and measured at 4 cm intervals and circumferential measurements, with tape, will be performed and recorded.
Quantitative assessment of limb volume (ml) of the affected limb at month 6 will be compared to baseline value.
arm group label: Ketoprofen
description: Participants will take ketoprofen for six months. They will have evaluations at baseline and month 6.
intervention type: Drug
intervention name: Ketoprofen
description: Ketoprofen 200 mg ER, taken orally, once a day for 6 months. If medication, if obtained from a compound pharmacy, dose will be 210 mg ER, taken orally once a day for 6 months.
arm group label: Ketoprofen
Plasma samples
study pop: 
sampling method: Non-Probability Sample
criteria: 
gender: All
minimum age: 18 Years
maximum age: 75 Years
healthy volunteers: No
last name: Stanley G Rockson
role: Principal Investigator
affiliation: Stanford University
facility: 
country: United States
citation: Rockson SG, Tian W, Jiang X, Kuznetsova T, Haddad F, Zampell J, Mehrara B, Sampson JP, Roche L, Kim J, Nicolls MR. Pilot studies demonstrate the potential benefits of antiinflammatory therapy in human lymphedema. JCI Insight. 2018 Oct 18;3(20):e123775. doi: 10.1172/jci.insight.123775.
PMID: 30333315
citation: Tian W, Rockson SG, Jiang X, Kim J, Begaye A, Shuffle EM, Tu AB, Cribb M, Nepiyushchikh Z, Feroze AH, Zamanian RT, Dhillon GS, Voelkel NF, Peters-Golden M, Kitajewski J, Dixon JB, Nicolls MR. Leukotriene B4 antagonism ameliorates experimental lymphedema. Sci Transl Med. 2017 May 10;9(389):eaal3920. doi: 10.1126/scitranslmed.aal3920.
PMID: 28490670
citation: Nakamura K, Radhakrishnan K, Wong YM, Rockson SG. Anti-inflammatory pharmacotherapy with ketoprofen ameliorates experimental lymphatic vascular insufficiency in mice. PLoS One. 2009 Dec 21;4(12):e8380. doi: 10.1371/journal.pone.0008380.
PMID: 20027220
citation: Tabibiazar R, Cheung L, Han J, Swanson J, Beilhack A, An A, Dadras SS, Rockson N, Joshi S, Wagner R, Rockson SG. Inflammatory manifestations of experimental lymphatic insufficiency. PLoS Med. 2006 Jul;3(7):e254. doi: 10.1371/journal.pmed.0030254.
PMID: 16834456
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
mesh term: Lymphedema
mesh term: Ketoprofen
sharing ipd: Yes
ipd description: De-identified participant data, for study endpoints, will be made available.
ipd info type: Study Protocol
ipd info type: Statistical Analysis Plan (SAP)
ipd info type: Informed Consent Form (ICF)
ipd time frame: Data will become available 12 months after completion of the last enrollment in the trial.
ipd access criteria: Data access requests will be reviewed by PI and Stanford IRB. If approved, requestors will be required to sign a data use agreement (DUA).