<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/NCT03283566</url>
  </required_header>
  <id_info>
    <org_study_id>17-912</org_study_id>
    <nct_id>NCT03283566</nct_id>
  </id_info>
  <brief_title>Hydroxychloroquine and Metabolic Outcomes in Patients Undergoing TPAIT</brief_title>
  <official_title>Hydroxychloroquine and Metabolic Outcomes in Patients Undergoing Total Pancreatectomy and Autologous Islet Transplantation: A Clinical, Molecular, and Genomic Study</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>The Cleveland Clinic</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Allegheny Singer Research Institute (also known as Allegheny Health Network Research Institute)</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Stanford University</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>The Cleveland Clinic</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 will be a pilot, 12-month phase II, open label, randomized, two-arm, single-blinded,&#xD;
      placebo-controlled, parallel clinical trial of individuals undergoing TPAIT (Total&#xD;
      Pancreatectomy and Autologous Islet Transplantation) for treatment of chronic pancreatitis&#xD;
      (CP). The two study arms consist of HCQ-treated (Hydroxychloroquine) and placebo-treated&#xD;
      individuals. The purpose of this study is to investigate the effects of HCQ administration&#xD;
      compared to placebo on islet cell function post-autologous transplantation.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      A compelling level of evidence exists on the effects of the innate immunity-driven&#xD;
      inflammation on the decline of functional beta cell mass in the autologous transplant&#xD;
      setting. The investigators hypothesize that HCQ administration during the peri-transplant&#xD;
      period will preserve islet mass and improve islet cell function in TPAIT by reducing&#xD;
      inflammation. The investigators specifically aim to demonstrate a higher stimulated C-peptide&#xD;
      level as well as greater glucose control in response to mixed meal tolerance testing (MMTT)&#xD;
      at 6 and 12 months following TPAIT in patients treated with HCQ compared to placebo. A better&#xD;
      response in the HCQ arm suggests improved islet survival and metabolic performance,&#xD;
      potentially facilitating higher rates of insulin independence.&#xD;
&#xD;
      HCQ administration:&#xD;
&#xD;
      Arm 1 (n=5): Subjects will receive a pre-transplant HCQ 200 mg daily dose 30 days prior TPAIT&#xD;
      followed by HCQ use for an additional 3 months post-surgery.&#xD;
&#xD;
      Arm 2 (n=5) subjects will receive placebo treatment following the same schedule as in Arm 1.&#xD;
&#xD;
      Exploratory mechanistic studies:&#xD;
&#xD;
      All subjects will undergo a MMTT to assess islet cell function at 6 and 12 months following&#xD;
      TPAIT (in addition to MMTT pre-surgery performed as standard of care, and whose results will&#xD;
      be used for pre-randomization in this pilot). Baseline metabolic tests obtained too early&#xD;
      after surgery may not be indicative of islet function, due to insulin supporting therapy&#xD;
      administered for several weeks after transplantation. Also, compelling data indicate that&#xD;
      stabilization of islet function may require up to 1 year to occur. Blood glucose and&#xD;
      C-peptide serum levels will be measured in peripheral blood samples immediately prior and&#xD;
      subsequent to MMTT. The research coordinator will contact the subjects at 3, 6 and 12 months&#xD;
      for interview on the course of follow up and will assist in scheduling the 6 and 12-month&#xD;
      appointments for MMTT.&#xD;
&#xD;
      Mitochondrial Function and Metabolic Outcomes in TPAIT:&#xD;
&#xD;
      Mitochondrial efficiency is important in the setting of TPAIT, where increase in metabolic&#xD;
      demand and decrease in oxygenation have been established. The investigators will assess&#xD;
      mitochondrial efficiency by measuring rates of mitochondrial respiration and glycolysis.&#xD;
      These measures will be obtained on islets procured for donation and after islet isolation.&#xD;
      Small amounts of digest left after islet isolation, that would normally be discarded, will be&#xD;
      used for this portion of the study. The islets from the digest will be collected and will&#xD;
      undergo extracellular efflux analysis through the Seahorse XF analyzer for mitochondrial&#xD;
      function assessment. Commercially available normal human islet cells for experiments will be&#xD;
      used as control. Controls will be compared simultaneously with islets isolated from study&#xD;
      subjects.&#xD;
&#xD;
      Genome-wide Gene Expression in TPAIT Patients:&#xD;
&#xD;
      On the genomic level, several genetic pathways have been implicated in islet cell function&#xD;
      and survival. The genetic profiles of islet cells from CP patients undergoing TPAIT have not&#xD;
      been evaluated yet. The investigators aim to build an RNA-gene sequence database for islet&#xD;
      cells of CP patients undergoing TPAIT, specifically targeting genes previously identified as&#xD;
      key players in islet function. Small amounts of digest from the procedure used for isolating&#xD;
      islets, and what remains in the circuit after the isolation process is complete, that would&#xD;
      normally be discarded, will also be used for islet gene expression assessment.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">October 3, 2017</start_date>
  <completion_date type="Actual">May 31, 2020</completion_date>
  <primary_completion_date type="Actual">May 31, 2020</primary_completion_date>
  <phase>Phase 2</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>
    <intervention_model_description>open label, randomized, two-arm, single-blinded, placebo-controlled, parallel</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Triple (Participant, Investigator, Outcomes Assessor)</masking>
    <masking_description>The study will be single-blinded. The PI, biostatistician who will analyze the data, consultants, and technicians running assays will be blinded to the study arm into which the subjects have been randomized. An alphanumeric identifier that refers to the study subject without any indicators of study arm allocation will be used. Only the surgeons and the research coordinator, but not the personnel conducting the metabolic studies, will be un-blinded as to the study arm randomization.</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>Quotient of Stimulated C-peptide/Glucose Level Normalized for IEQ/Kg Infused in Response to MMTT</measure>
    <time_frame>12 months</time_frame>
    <description>HCQ-treated compared to placebo arm. This outcome measure was reported in Mean and Standard deviation looking at C peptide/glucose secretion at 90 mins during mixed meal test adjusted for IEG/Kg (islet cell equivalency) infused to the patient.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>C-peptide AUC Response to MMTT</measure>
    <time_frame>12 months</time_frame>
    <description>HCQ-treated compared to placebo arm. We used a standard, 5 hour Mixed meal tolerance test (MMT). Blood draws were taken every 15 mins for the first hours, then every 30 mins the second hour, then hourly until completion.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Ratio of C-peptide AUC to Glucose AUC in Response to MMTT Adjusted for Infused Islet Cell Mass</measure>
    <time_frame>12 months</time_frame>
    <description>C-peptide, ng/mL/min/IEQ/kg iAUC post-MMTT. Our measurement can be reported in area under the curve for C-peptide normalized for glucose values as well as Islet cell mass infused to the patient in order to compare placebo vs intervention arms.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">9</enrollment>
  <condition>Chronic Pancreatitis</condition>
  <condition>Insulin Dependent Diabetes</condition>
  <arm_group>
    <arm_group_label>Hydroxychloroquine</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Administered pre-transplant through 3 months after surgery.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Placebo treatment following the same schedule as Arm 1 (i.e. Hydroxychloroquine).</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Hydroxychloroquine</intervention_name>
    <description>Subjects will receive a pre-transplant 200 mg daily dose of HCQ 30 days before TPAIT and will continue on the drug for 3 months after surgery.</description>
    <arm_group_label>Hydroxychloroquine</arm_group_label>
    <other_name>Plaquenil</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>Subjects will receive a pre-transplant placebo 30 days before TPAIT and will continue on the placebo for 3 months after surgery.</description>
    <arm_group_label>Placebo</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Clinically confirmed diagnosis of chronic pancreatitis (CP)&#xD;
&#xD;
          -  Intractable abdominal pain&#xD;
&#xD;
          -  History of failed operation(s) for CP&#xD;
&#xD;
          -  Recurrent acute pancreatitis&#xD;
&#xD;
          -  HbA1c &lt;8.0%&#xD;
&#xD;
          -  Sustained alcohol remission&#xD;
&#xD;
          -  Chronic narcotic use&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Insulin dependence&#xD;
&#xD;
          -  Pancreatic carcinoma&#xD;
&#xD;
          -  Pancreatic mass suspicious for carcinoma&#xD;
&#xD;
          -  Cirrhosis&#xD;
&#xD;
          -  Portal hypertension&#xD;
&#xD;
          -  Continued alcohol abuse&#xD;
&#xD;
          -  Manufacturer's product label-contraindicated use of HCQ&#xD;
&#xD;
          -  History of retinopathy&#xD;
&#xD;
          -  Actual weight at enrollment &lt;40 Kg&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>65 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Betul Hatipoglu, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Staff</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Cleveland Clinic</name>
      <address>
        <city>Cleveland</city>
        <state>Ohio</state>
        <zip>44195</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>April 2022</verification_date>
  <study_first_submitted>September 13, 2017</study_first_submitted>
  <study_first_submitted_qc>September 13, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">September 14, 2017</study_first_posted>
  <results_first_submitted>September 15, 2021</results_first_submitted>
  <results_first_submitted_qc>February 14, 2022</results_first_submitted_qc>
  <results_first_posted type="Actual">March 11, 2022</results_first_posted>
  <last_update_submitted>April 6, 2022</last_update_submitted>
  <last_update_submitted_qc>April 6, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">April 8, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Pancreatectomy</keyword>
  <keyword>Autologous Islet Transplantation</keyword>
  <keyword>Pancreatitis</keyword>
  <keyword>Diabetes</keyword>
  <keyword>Hydroxychloroquine</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Pancreatitis</mesh_term>
    <mesh_term>Pancreatitis, Chronic</mesh_term>
    <mesh_term>Diabetes Mellitus, Type 1</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Hydroxychloroquine</mesh_term>
  </intervention_browse>
  <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>November 25, 2016</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/66/NCT03283566/Prot_SAP_000.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <group_list>
        <group group_id="P1">
          <title>Hydroxychloroquine</title>
          <description>Administered pre-transplant through 3 months after surgery.&#xD;
Hydroxychloroquine: Subjects will receive a pre-transplant 200 mg daily dose of HCQ 30 days before TPAIT and will continue on the drug for 3 months after surgery.</description>
        </group>
        <group group_id="P2">
          <title>Placebo</title>
          <description>Placebo treatment following the same schedule as Arm 1 (i.e. Hydroxychloroquine).&#xD;
Placebo: Subjects will receive a pre-transplant placebo 30 days before TPAIT and will continue on the placebo for 3 months after surgery.</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="4"/>
                <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="3"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="2"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Lost to Follow-up</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="2"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>Hydroxychloroquine</title>
          <description>Administered pre-transplant through 3 months after surgery.&#xD;
Hydroxychloroquine: Subjects will receive a pre-transplant 200 mg daily dose of HCQ 30 days before TPAIT and will continue on the drug for 3 months after surgery.</description>
        </group>
        <group group_id="B2">
          <title>Placebo</title>
          <description>Placebo treatment following the same schedule as Arm 1 (i.e. Hydroxychloroquine).&#xD;
Placebo: Subjects will receive a pre-transplant placebo 30 days before TPAIT and will continue on the placebo for 3 months after surgery.</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="3"/>
            <count group_id="B3" value="6"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="3"/>
                    <count group_id="B2" value="3"/>
                    <count group_id="B3" value="6"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <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_list>
                </category>
                <category>
                  <title>Between 18 and 65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="3"/>
                    <measurement group_id="B2" value="3"/>
                    <measurement group_id="B3" value="6"/>
                  </measurement_list>
                </category>
                <category>
                  <title>&gt;=65 years</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>Age</title>
          <units>years</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="3"/>
                    <count group_id="B2" value="3"/>
                    <count group_id="B3" value="6"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="50" spread="12"/>
                    <measurement group_id="B2" value="37" spread="3"/>
                    <measurement group_id="B3" value="43.5" spread="7.5"/>
                  </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>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="3"/>
                    <count group_id="B2" value="3"/>
                    <count group_id="B3" value="6"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <title>Female</title>
                  <measurement_list>
                    <measurement group_id="B1" value="3"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="4"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="2"/>
                    <measurement group_id="B3" value="2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Race and Ethnicity Not Collected</title>
          <population>Race and Ethnicity were not collected from any participant.</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="0"/>
                    <count group_id="B2" value="0"/>
                    <count group_id="B3" value="0"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <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>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="3"/>
                    <count group_id="B2" value="3"/>
                    <count group_id="B3" value="6"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="3"/>
                    <measurement group_id="B2" value="3"/>
                    <measurement group_id="B3" value="6"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Quotient of Stimulated C-peptide/Glucose Level Normalized for IEQ/Kg Infused in Response to MMTT</title>
        <description>HCQ-treated compared to placebo arm. This outcome measure was reported in Mean and Standard deviation looking at C peptide/glucose secretion at 90 mins during mixed meal test adjusted for IEG/Kg (islet cell equivalency) infused to the patient.</description>
        <time_frame>12 months</time_frame>
        <population>C-peptide/Glucose = ng/mg glucose/IEQ/kg - Primary 12-month endpoint</population>
        <group_list>
          <group group_id="O1">
            <title>Hydroxychloroquine</title>
            <description>Administered pre-transplant through 3 months after surgery.&#xD;
Hydroxychloroquine: Subjects will receive a pre-transplant 200 mg daily dose of HCQ 30 days before TPAIT and will continue on the drug for 3 months after surgery.</description>
          </group>
          <group group_id="O2">
            <title>Placebo</title>
            <description>Placebo treatment following the same schedule as Arm 1 (i.e. Hydroxychloroquine).&#xD;
Placebo: Subjects will receive a pre-transplant placebo 30 days before TPAIT and will continue on the placebo for 3 months after surgery.</description>
          </group>
        </group_list>
        <measure>
          <title>Quotient of Stimulated C-peptide/Glucose Level Normalized for IEQ/Kg Infused in Response to MMTT</title>
          <description>HCQ-treated compared to placebo arm. This outcome measure was reported in Mean and Standard deviation looking at C peptide/glucose secretion at 90 mins during mixed meal test adjusted for IEG/Kg (islet cell equivalency) infused to the patient.</description>
          <population>C-peptide/Glucose = ng/mg glucose/IEQ/kg - Primary 12-month endpoint</population>
          <units>ng/mg glucose/IEQ/kg</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="3"/>
                <count group_id="O2" value="3"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value=".000000077" spread=".000000096"/>
                    <measurement group_id="O2" value="0.000000079" spread=".00000012"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>C-peptide AUC Response to MMTT</title>
        <description>HCQ-treated compared to placebo arm. We used a standard, 5 hour Mixed meal tolerance test (MMT). Blood draws were taken every 15 mins for the first hours, then every 30 mins the second hour, then hourly until completion.</description>
        <time_frame>12 months</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Hydroxychloroquine</title>
            <description>Administered pre-transplant through 3 months after surgery.&#xD;
Hydroxychloroquine: Subjects will receive a pre-transplant 200 mg daily dose of HCQ 30 days before TPAIT and will continue on the drug for 3 months after surgery.</description>
          </group>
          <group group_id="O2">
            <title>Placebo</title>
            <description>Placebo treatment following the same schedule as Arm 1 (i.e. Hydroxychloroquine).&#xD;
Placebo: Subjects will receive a pre-transplant placebo 30 days before TPAIT and will continue on the placebo for 3 months after surgery.</description>
          </group>
        </group_list>
        <measure>
          <title>C-peptide AUC Response to MMTT</title>
          <description>HCQ-treated compared to placebo arm. We used a standard, 5 hour Mixed meal tolerance test (MMT). Blood draws were taken every 15 mins for the first hours, then every 30 mins the second hour, then hourly until completion.</description>
          <units>ng/mL/min</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="3"/>
                <count group_id="O2" value="3"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="813" spread="463"/>
                    <measurement group_id="O2" value="588" spread="391"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Equivalence</non_inferiority_type>
            <non_inferiority_desc>Assuming a 20-30% difference in outcome (CP/G quotient) between study arms, which is equivalent to 0.08-0.12 CP/G difference and a 0.07 standard deviation, a sample size of 6 subjects (1:1 randomization) will detect a CP/G difference of at least 0.12, assuming 80% power, with a 0.05 significance level.</non_inferiority_desc>
            <p_value>0.739</p_value>
            <method>ANOVA</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Ratio of C-peptide AUC to Glucose AUC in Response to MMTT Adjusted for Infused Islet Cell Mass</title>
        <description>C-peptide, ng/mL/min/IEQ/kg iAUC post-MMTT. Our measurement can be reported in area under the curve for C-peptide normalized for glucose values as well as Islet cell mass infused to the patient in order to compare placebo vs intervention arms.</description>
        <time_frame>12 months</time_frame>
        <population>Treatment versus placebo</population>
        <group_list>
          <group group_id="O1">
            <title>Hydroxychloroquine</title>
            <description>Administered pre-transplant through 3 months after surgery.&#xD;
Hydroxychloroquine: Subjects will receive a pre-transplant 200 mg daily dose of HCQ 30 days before TPAIT and will continue on the drug for 3 months after surgery.</description>
          </group>
          <group group_id="O2">
            <title>Placebo</title>
            <description>Placebo treatment following the same schedule as Arm 1 (i.e. Hydroxychloroquine).&#xD;
Placebo: Subjects will receive a pre-transplant placebo 30 days before TPAIT and will continue on the placebo for 3 months after surgery.</description>
          </group>
        </group_list>
        <measure>
          <title>Ratio of C-peptide AUC to Glucose AUC in Response to MMTT Adjusted for Infused Islet Cell Mass</title>
          <description>C-peptide, ng/mL/min/IEQ/kg iAUC post-MMTT. Our measurement can be reported in area under the curve for C-peptide normalized for glucose values as well as Islet cell mass infused to the patient in order to compare placebo vs intervention arms.</description>
          <population>Treatment versus placebo</population>
          <units>ng/mL/min/IEQ/kg iAUC post-MMT</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="3"/>
                <count group_id="O2" value="3"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.00091" spread="0.0006"/>
                    <measurement group_id="O2" value="0.00222" spread="0.0029"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>About 3 years total study time. Each patient was assessed during a period of 12 months.</time_frame>
      <desc>No difference from clinicaltrials.gov definitions</desc>
      <group_list>
        <group group_id="E1">
          <title>Hydroxychloroquine</title>
          <description>Administered pre-transplant through 3 months after surgery.&#xD;
Hydroxychloroquine: Subjects will receive a pre-transplant 200 mg daily dose of HCQ 30 days before TPAIT and will continue on the drug for 3 months after surgery.</description>
        </group>
        <group group_id="E2">
          <title>Placebo</title>
          <description>Placebo treatment following the same schedule as Arm 1 (i.e. Hydroxychloroquine).&#xD;
Placebo: Subjects will receive a pre-transplant placebo 30 days before TPAIT and will continue on the placebo for 3 months after surgery.</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="3"/>
              </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="3"/>
              </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="3"/>
              </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>EMI Research Director</name_or_title>
      <organization>Cleveland Clinic Foundation, Department of Endocroine and Metabolism</organization>
      <phone>216 445-3757</phone>
      <email>jenkink@ccf.org</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/NCT03283566
org study id: 17-912
nct id: NCT03283566
lead sponsor: 
collaborator: 
collaborator: 
has dmc: No
is fda regulated drug: Yes
is fda regulated device: No
is us export: No
This will be a pilot, 12-month phase II, open label, randomized, two-arm, single-blinded,
      placebo-controlled, parallel clinical trial of individuals undergoing TPAIT (Total
      Pancreatectomy and Autologous Islet Transplantation) for treatment of chronic pancreatitis
      (CP). The two study arms consist of HCQ-treated (Hydroxychloroquine) and placebo-treated
      individuals. The purpose of this study is to investigate the effects of HCQ administration
      compared to placebo on islet cell function post-autologous transplantation.
A compelling level of evidence exists on the effects of the innate immunity-driven
      inflammation on the decline of functional beta cell mass in the autologous transplant
      setting. The investigators hypothesize that HCQ administration during the peri-transplant
      period will preserve islet mass and improve islet cell function in TPAIT by reducing
      inflammation. The investigators specifically aim to demonstrate a higher stimulated C-peptide
      level as well as greater glucose control in response to mixed meal tolerance testing (MMTT)
      at 6 and 12 months following TPAIT in patients treated with HCQ compared to placebo. A better
      response in the HCQ arm suggests improved islet survival and metabolic performance,
      potentially facilitating higher rates of insulin independence.

      HCQ administration:

      Arm 1 (n=5): Subjects will receive a pre-transplant HCQ 200 mg daily dose 30 days prior TPAIT
      followed by HCQ use for an additional 3 months post-surgery.

      Arm 2 (n=5) subjects will receive placebo treatment following the same schedule as in Arm 1.

      Exploratory mechanistic studies:

      All subjects will undergo a MMTT to assess islet cell function at 6 and 12 months following
      TPAIT (in addition to MMTT pre-surgery performed as standard of care, and whose results will
      be used for pre-randomization in this pilot). Baseline metabolic tests obtained too early
      after surgery may not be indicative of islet function, due to insulin supporting therapy
      administered for several weeks after transplantation. Also, compelling data indicate that
      stabilization of islet function may require up to 1 year to occur. Blood glucose and
      C-peptide serum levels will be measured in peripheral blood samples immediately prior and
      subsequent to MMTT. The research coordinator will contact the subjects at 3, 6 and 12 months
      for interview on the course of follow up and will assist in scheduling the 6 and 12-month
      appointments for MMTT.

      Mitochondrial Function and Metabolic Outcomes in TPAIT:

      Mitochondrial efficiency is important in the setting of TPAIT, where increase in metabolic
      demand and decrease in oxygenation have been established. The investigators will assess
      mitochondrial efficiency by measuring rates of mitochondrial respiration and glycolysis.
      These measures will be obtained on islets procured for donation and after islet isolation.
      Small amounts of digest left after islet isolation, that would normally be discarded, will be
      used for this portion of the study. The islets from the digest will be collected and will
      undergo extracellular efflux analysis through the Seahorse XF analyzer for mitochondrial
      function assessment. Commercially available normal human islet cells for experiments will be
      used as control. Controls will be compared simultaneously with islets isolated from study
      subjects.

      Genome-wide Gene Expression in TPAIT Patients:

      On the genomic level, several genetic pathways have been implicated in islet cell function
      and survival. The genetic profiles of islet cells from CP patients undergoing TPAIT have not
      been evaluated yet. The investigators aim to build an RNA-gene sequence database for islet
      cells of CP patients undergoing TPAIT, specifically targeting genes previously identified as
      key players in islet function. Small amounts of digest from the procedure used for isolating
      islets, and what remains in the circuit after the isolation process is complete, that would
      normally be discarded, will also be used for islet gene expression assessment.
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: open label, randomized, two-arm, single-blinded, placebo-controlled, parallel
primary purpose: Treatment
masking: Triple (Participant, Investigator, Outcomes Assessor)
masking description: The study will be single-blinded. The PI, biostatistician who will analyze the data, consultants, and technicians running assays will be blinded to the study arm into which the subjects have been randomized. An alphanumeric identifier that refers to the study subject without any indicators of study arm allocation will be used. Only the surgeons and the research coordinator, but not the personnel conducting the metabolic studies, will be un-blinded as to the study arm randomization.
measure: Quotient of Stimulated C-peptide/Glucose Level Normalized for IEQ/Kg Infused in Response to MMTT
time frame: 12 months
description: HCQ-treated compared to placebo arm. This outcome measure was reported in Mean and Standard deviation looking at C peptide/glucose secretion at 90 mins during mixed meal test adjusted for IEG/Kg (islet cell equivalency) infused to the patient.
measure: C-peptide AUC Response to MMTT
time frame: 12 months
description: HCQ-treated compared to placebo arm. We used a standard, 5 hour Mixed meal tolerance test (MMT). Blood draws were taken every 15 mins for the first hours, then every 30 mins the second hour, then hourly until completion.
measure: Ratio of C-peptide AUC to Glucose AUC in Response to MMTT Adjusted for Infused Islet Cell Mass
time frame: 12 months
description: C-peptide, ng/mL/min/IEQ/kg iAUC post-MMTT. Our measurement can be reported in area under the curve for C-peptide normalized for glucose values as well as Islet cell mass infused to the patient in order to compare placebo vs intervention arms.
arm group label: Hydroxychloroquine
arm group type: Active Comparator
description: Administered pre-transplant through 3 months after surgery.
arm group label: Placebo
arm group type: Placebo Comparator
description: Placebo treatment following the same schedule as Arm 1 (i.e. Hydroxychloroquine).
intervention type: Drug
intervention name: Hydroxychloroquine
description: Subjects will receive a pre-transplant 200 mg daily dose of HCQ 30 days before TPAIT and will continue on the drug for 3 months after surgery.
arm group label: Hydroxychloroquine
other name: Plaquenil
intervention type: Drug
intervention name: Placebo
description: Subjects will receive a pre-transplant placebo 30 days before TPAIT and will continue on the placebo for 3 months after surgery.
arm group label: Placebo
criteria: 
gender: All
minimum age: 18 Years
maximum age: 65 Years
healthy volunteers: No
last name: Betul Hatipoglu, MD
role: Principal Investigator
affiliation: Staff
facility: 
country: United States
responsible party type: Sponsor
mesh term: Pancreatitis
mesh term: Pancreatitis, Chronic
mesh term: Diabetes Mellitus, Type 1
mesh term: Hydroxychloroquine
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 