<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/NCT02243631</url>
  </required_header>
  <id_info>
    <org_study_id>IMMA-022-13F</org_study_id>
    <nct_id>NCT02243631</nct_id>
  </id_info>
  <brief_title>Effect of Probenecid on Synovial Fluid ATP Levels in CPPD</brief_title>
  <official_title>ANK-dependent ATP Efflux Causes Calcium Pyrophosphate Deposition in Cartilage</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>VA Office of Research and Development</agency>
      <agency_class>U.S. Fed</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>VA Office of Research and Development</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 will investigate the hypothesis that probenecid, a medication currently used for&#xD;
      gout, reduces levels of ATP in the joint fluid of patients with calcium pyrophosphate&#xD;
      deposition disease (CPPD), another common type of crystal-related arthritis. There is good&#xD;
      evidence that CPPD results from an excess of ATP in joints. The investigators will measure&#xD;
      levels of ATP in joint fluid before and after 5 days of treatment with probenecid. This study&#xD;
      will serve to rationalize larger studies of probenecid in CPPD.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Objective: The objective of this study is to determine whether pharmacologic doses of the&#xD;
      drug probenecid significantly decrease ATP and inorganic pyrophosphate (PPi) levels in the&#xD;
      synovial fluid of patients with calcium pyrophosphate deposition disease (CPPD). The&#xD;
      investigators have considerable evidence that synovial fluid ATP levels are high in patients&#xD;
      with this disease and these high levels lead to calcium pyrophosphate (CPP) crystal formation&#xD;
      which then produces acute and chronic arthritis. The investigators have identified the&#xD;
      transmembrane protein known as ANK as the chief regulator of ATP levels in and around&#xD;
      cartilage. Probenecid blocks function of ANK in vitro. The purpose of this study is to&#xD;
      determine if probenecid used at normal doses are sufficient to block ANK function in vivo and&#xD;
      whether this results in reduced ATP and PPi levels in synovial fluid.&#xD;
&#xD;
      Research design: This is a randomized un-controlled trial of probenecid vs. no drug in&#xD;
      patients with a joint effusion and known CPPD.&#xD;
&#xD;
      Methodology: Power analysis based on an 80% chance to show a 20% difference in ATP levels in&#xD;
      the treatment group resulted in a sample size of 20 patients in each group. Patients with&#xD;
      known CPPD and a joint effusion will have an arthrocentesis to remove 2 ml of synovial fluid&#xD;
      from their joint. Fluid will be sent to the investigators' research laboratory and ATP and&#xD;
      PPi levels will be measured. Patients will be randomized to treatment with 2 grams/day of&#xD;
      probenecid or no therapy. After 5 days, the remainder of the joint fluid will be removed and&#xD;
      tested for ATP and PPi levels. The investigators will compare differences in ATP and PPi&#xD;
      levels in the probenecid treated and the untreated group.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">October 15, 2014</start_date>
  <completion_date type="Actual">April 8, 2021</completion_date>
  <primary_completion_date type="Actual">April 8, 2021</primary_completion_date>
  <phase>Early Phase 1</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>ATP Levels in Synovial Fluid</measure>
    <time_frame>5 days</time_frame>
    <description>The investigators will measure levels of ATP in synovial fluid from patients with CPPD before and after treatment with probenecid compared to patients receiving no therapy. ATP levels are measured with a standard bioluminescent assay.</description>
  </primary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">8</enrollment>
  <condition>Calcium Pyrophosphate Deposition Disease</condition>
  <arm_group>
    <arm_group_label>Probenecid</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>These patients will receive 5 days of probenecid.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>No intervention</arm_group_label>
    <arm_group_type>No Intervention</arm_group_type>
    <description>These patients will receive no intervention.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Probenecid</intervention_name>
    <description>Treatment</description>
    <arm_group_label>Probenecid</arm_group_label>
    <other_name>uricosuric</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Age &gt;21 years,&#xD;
&#xD;
          -  CPPD diagnosed by Ryan /McCarty criteria&#xD;
&#xD;
          -  Joint effusion in a shoulder or knee&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Inability to sign informed consent&#xD;
&#xD;
          -  Age &lt;21 years&#xD;
&#xD;
          -  History of renal stones&#xD;
&#xD;
          -  Significant renal dysfunction (CKD &gt;stage 2)&#xD;
&#xD;
          -  Blood dyscrasias&#xD;
&#xD;
          -  Current use of drugs which interact with probenecid&#xD;
&#xD;
          -  Concurrent gout&#xD;
&#xD;
          -  Active infection, including bacteremia and overlying cellulitis&#xD;
&#xD;
          -  Recent joint trauma&#xD;
&#xD;
          -  Intra-articular corticosteroids in the affected joint within three months&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>21 Years</minimum_age>
    <maximum_age>99 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Ann K Rosenthal, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Clement J. Zablocki VA Medical Center, Milwaukee, WI</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Clement J. Zablocki VA Medical Center, Milwaukee, WI</name>
      <address>
        <city>Milwaukee</city>
        <state>Wisconsin</state>
        <zip>53295-1000</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>July 2022</verification_date>
  <study_first_submitted>September 16, 2014</study_first_submitted>
  <study_first_submitted_qc>September 16, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">September 18, 2014</study_first_posted>
  <results_first_submitted>March 24, 2022</results_first_submitted>
  <results_first_submitted_qc>July 22, 2022</results_first_submitted_qc>
  <results_first_posted type="Actual">July 26, 2022</results_first_posted>
  <last_update_submitted>July 22, 2022</last_update_submitted>
  <last_update_submitted_qc>July 22, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">July 26, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>ATP</keyword>
  <keyword>Probenecid</keyword>
  <keyword>Chondrocalcinosis</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Chondrocalcinosis</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Probenecid</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>February 28, 2022</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/31/NCT02243631/Prot_SAP_000.pdf</document_url>
    </provided_document>
    <provided_document>
      <document_type>Informed Consent Form</document_type>
      <document_has_protocol>No</document_has_protocol>
      <document_has_icf>Yes</document_has_icf>
      <document_has_sap>No</document_has_sap>
      <document_date>May 27, 2016</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/31/NCT02243631/ICF_001.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <group_list>
        <group group_id="P1">
          <title>Probenecid</title>
          <description>These patients will receive 5 days of probenecid.&#xD;
Probenecid: Treatment</description>
        </group>
        <group group_id="P2">
          <title>No Intervention</title>
          <description>These patients will receive no intervention.</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="3"/>
                <participants group_id="P2" count="5"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="3"/>
                <participants group_id="P2" count="4"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="1"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>no synovial fluid on second aspirate</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="1"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>Probenecid</title>
          <description>These patients will receive 5 days of probenecid.&#xD;
Probenecid: Treatment</description>
        </group>
        <group group_id="B2">
          <title>No Intervention</title>
          <description>These patients will receive no intervention.</description>
        </group>
        <group group_id="B3">
          <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="3"/>
            <count group_id="B2" value="5"/>
            <count group_id="B3" value="8"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <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="77.6" spread="12.3"/>
                    <measurement group_id="B2" value="68.4" spread="10.4"/>
                    <measurement group_id="B3" value="71.8" spread="11.3"/>
                  </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="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="3"/>
                    <measurement group_id="B2" value="5"/>
                    <measurement group_id="B3" value="8"/>
                  </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 group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Asian</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Native Hawaiian or Other Pacific Islander</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Black or African American</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>White</title>
                  <measurement_list>
                    <measurement group_id="B1" value="3"/>
                    <measurement group_id="B2" value="5"/>
                    <measurement group_id="B3" value="8"/>
                  </measurement_list>
                </category>
                <category>
                  <title>More than one race</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Region of Enrollment</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <title>United States</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="3"/>
                    <measurement group_id="B2" value="5"/>
                    <measurement group_id="B3" value="8"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>ATP levels in synovial fluid at day 0</title>
          <units>nanomoles/ml</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="1.2" spread="0.9"/>
                    <measurement group_id="B2" value="4.5" spread="6.7"/>
                    <measurement group_id="B3" value="2.85" spread="2.33"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>ATP Levels in Synovial Fluid</title>
        <description>The investigators will measure levels of ATP in synovial fluid from patients with CPPD before and after treatment with probenecid compared to patients receiving no therapy. ATP levels are measured with a standard bioluminescent assay.</description>
        <time_frame>5 days</time_frame>
        <population>Two subjects ( one in probenecid and one in no intervention group) had no measurable ATP on the second aspirate, and one subject in the no intervention group did not have any synovial fluid on the second visit.</population>
        <group_list>
          <group group_id="O1">
            <title>Probenecid</title>
            <description>probenecid group after 5 days of drug</description>
          </group>
          <group group_id="O2">
            <title>no Intervention</title>
            <description>no intervention after 5 days</description>
          </group>
        </group_list>
        <measure>
          <title>ATP Levels in Synovial Fluid</title>
          <description>The investigators will measure levels of ATP in synovial fluid from patients with CPPD before and after treatment with probenecid compared to patients receiving no therapy. ATP levels are measured with a standard bioluminescent assay.</description>
          <population>Two subjects ( one in probenecid and one in no intervention group) had no measurable ATP on the second aspirate, and one subject in the no intervention group did not have any synovial fluid on the second visit.</population>
          <units>nanomoles/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="2"/>
                <count group_id="O2" value="3"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="4.4" spread="2.5"/>
                    <measurement group_id="O2" value="31.4" spread="56.6"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>7 days</time_frame>
      <group_list>
        <group group_id="E1">
          <title>Probenecid</title>
          <description>These patients will receive 5 days of probenecid.&#xD;
Probenecid: Treatment</description>
        </group>
        <group group_id="E2">
          <title>No Intervention</title>
          <description>These patients will receive no intervention.</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="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="5"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>0</frequency_threshold>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="5"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>All Principal Investigators ARE 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. Ann Rosenthal , MD ACOS/Research</name_or_title>
      <organization>Zablocki VA Medical Center</organization>
      <phone>414-384-2000 ext 41430</phone>
      <email>ann.rosenthal@va.gov</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/NCT02243631
org study id: IMMA-022-13F
nct id: NCT02243631
lead sponsor: 
has dmc: No
is fda regulated drug: Yes
is fda regulated device: No
is us export: No
This study will investigate the hypothesis that probenecid, a medication currently used for
      gout, reduces levels of ATP in the joint fluid of patients with calcium pyrophosphate
      deposition disease (CPPD), another common type of crystal-related arthritis. There is good
      evidence that CPPD results from an excess of ATP in joints. The investigators will measure
      levels of ATP in joint fluid before and after 5 days of treatment with probenecid. This study
      will serve to rationalize larger studies of probenecid in CPPD.
Objective: The objective of this study is to determine whether pharmacologic doses of the
      drug probenecid significantly decrease ATP and inorganic pyrophosphate (PPi) levels in the
      synovial fluid of patients with calcium pyrophosphate deposition disease (CPPD). The
      investigators have considerable evidence that synovial fluid ATP levels are high in patients
      with this disease and these high levels lead to calcium pyrophosphate (CPP) crystal formation
      which then produces acute and chronic arthritis. The investigators have identified the
      transmembrane protein known as ANK as the chief regulator of ATP levels in and around
      cartilage. Probenecid blocks function of ANK in vitro. The purpose of this study is to
      determine if probenecid used at normal doses are sufficient to block ANK function in vivo and
      whether this results in reduced ATP and PPi levels in synovial fluid.

      Research design: This is a randomized un-controlled trial of probenecid vs. no drug in
      patients with a joint effusion and known CPPD.

      Methodology: Power analysis based on an 80% chance to show a 20% difference in ATP levels in
      the treatment group resulted in a sample size of 20 patients in each group. Patients with
      known CPPD and a joint effusion will have an arthrocentesis to remove 2 ml of synovial fluid
      from their joint. Fluid will be sent to the investigators' research laboratory and ATP and
      PPi levels will be measured. Patients will be randomized to treatment with 2 grams/day of
      probenecid or no therapy. After 5 days, the remainder of the joint fluid will be removed and
      tested for ATP and PPi levels. The investigators will compare differences in ATP and PPi
      levels in the probenecid treated and the untreated group.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: ATP Levels in Synovial Fluid
time frame: 5 days
description: The investigators will measure levels of ATP in synovial fluid from patients with CPPD before and after treatment with probenecid compared to patients receiving no therapy. ATP levels are measured with a standard bioluminescent assay.
arm group label: Probenecid
arm group type: Experimental
description: These patients will receive 5 days of probenecid.
arm group label: No intervention
arm group type: No Intervention
description: These patients will receive no intervention.
intervention type: Drug
intervention name: Probenecid
description: Treatment
arm group label: Probenecid
other name: uricosuric
criteria: 
gender: All
minimum age: 21 Years
maximum age: 99 Years
healthy volunteers: No
last name: Ann K Rosenthal, MD
role: Principal Investigator
affiliation: Clement J. Zablocki VA Medical Center, Milwaukee, WI
facility: 
country: United States
responsible party type: Sponsor
mesh term: Chondrocalcinosis
mesh term: Probenecid
sharing ipd: No
provided document: 
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 