<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/NCT04411914</url>
  </required_header>
  <id_info>
    <org_study_id>26876</org_study_id>
    <secondary_id>U01DA048517</secondary_id>
    <nct_id>NCT04411914</nct_id>
  </id_info>
  <brief_title>Pharmaco-Magnetic Resonance Spectroscopy (MRS) Study of Clavulanic Acid</brief_title>
  <official_title>A Phase 1B Double Blind, Placebo (PBO) Controlled, Pharmaco- Magnetic Resonance Spectroscopy (MRS) Inpatient Study of Clavulanic Acid (CLAV) 500, 750, 1000 mg Daily Repeated Administration in Early Remitted Cocaine Use Disorder Subjects</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Temple University</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Beth Israel Deaconess Medical Center</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>University of Pennsylvania</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>National Institute on Drug Abuse (NIDA)</agency>
      <agency_class>NIH</agency_class>
    </collaborator>
  </sponsors>
  <source>Temple University</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      A dose-escalation study to determine the optimum dose of Clavulanic Acid (CLAV) for effects&#xD;
      on craving and efficacy.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This is a randomized, double-blind, placebo-controlled, parallel group inpatient study of&#xD;
      clavulanic acid for 10 days in adults (18-65) seeking treatment for cocaine use disorder. For&#xD;
      those subjects who can tolerate 500 mg/day for 3 days (or matched placebo), there will be a&#xD;
      forced dose escalation to 750 mg/day for 3 days. Subjects who can tolerate 750 mg/day for&#xD;
      three days will have a forced dose escalation to 1000 mg/day for 4 days until the study ends.&#xD;
&#xD;
      Thus, there are 3 Periods for each participant:&#xD;
&#xD;
      Period 1: 500 mg CLAV per day for days 1-3; Period 2: 750 mg per day for days 4-6; Period 3:&#xD;
      1000 mg/day for days 7-10.&#xD;
&#xD;
      Subjective, cognitive, and adverse effect assessments, blood pressure and pulse will be&#xD;
      performed daily. Structural MRI, resting state MRI (rs-fMRI), functional MRI (fMRI) and&#xD;
      Magnetic Resonance Spectroscopy (MRS) scans will be done at baseline and on Days 3, 6 and 10&#xD;
      of the study. At the time of each scan, safety of the subject to complete the scan will be&#xD;
      re-assessed. fMRI was not done at baseline.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">September 1, 2020</start_date>
  <completion_date type="Actual">March 31, 2022</completion_date>
  <primary_completion_date type="Actual">November 23, 2021</primary_completion_date>
  <phase>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>
    <intervention_model_description>Randomized, double-blind, placebo-controlled, parallel group inpatient study</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Brain Glutamate Concentration in the Anterior Cingulate Cortex (ACC) in Subjects With Cocaine Use Disorder (CUD) Treated With Escalating Doses of Clavulanate (CLAV)</measure>
    <time_frame>ACC glutamate and CCQ will be measured and correlated on Day 10 of treatment with CLAV compared with baseline.</time_frame>
    <description>Brain glutamate concentration in the ACC (based on Magnetic Resonance Spectroscopy (MRS)) will be correlated with cocaine craving (measured by Cocaine Craving Questionnaire (CCQ)) in subjects receiving escalating doses of CLAV for 10 days. Measurement will be made at baseline and Day 10 of CLAV (1000 mg/day) in subjects with cocaine use disorder.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Changes in Resting State Network Connectivity From Baseline</measure>
    <time_frame>Assessment was done at the end of Period 1, 2 and 3 detailed above. Data from the end of Period 3 (Day 10, 1000mg CLAV) are reported.</time_frame>
    <description>Craving-associated neurocircuitry (frontal-striatal-thalamic connectivity) will be examined with resting state functional Magnetic Resonance Imaging (rs-fMRI) and Cocaine Craving Questionnaire (CCQ-45). The CCQ is comprised of five 9-item sub-scales (desire to use cocaine, intention and planning to use cocaine, anticipation of positive outcome from use, anticipation of relief from withdrawal or dysphoria, and lack of control over use) measured on a scale of 1 to 7, total scores ranging from 45 to 315 with higher numbers indicating increased craving.. The rs-fMRI activity and CCQ were assessed in the 9 participants at baseline and at the end of each of 3 periods. rs-fMRI activity and CCQ were correlated using the Spearman Correlation Coefficient calculation. A negative correlation coefficient indicates an inverse relationship between the assessments; higher rs-fMRI activity correlates with lower craving.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Craving</measure>
    <time_frame>CCQ-45 questionnaires were completed daily during the study. Data from day 10 adjusted for baseline score are reported.</time_frame>
    <description>Craving will be evaluated by Cocaine Craving Questionnaire (CCQ-45). The CCQ is comprised of five 9-item sub-scales (desire to use cocaine, intention and planning to use cocaine, anticipation of positive outcome from use, anticipation of relief from withdrawal or dysphoria, and lack of control over use) measured on a scale of 1 to 7, total scores ranging from 45 to 315 with higher numbers indicating increased craving. The results are the CCQ scores on day 10 minus the baseline scores before starting study drug.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in Brain Glutamine From Baseline</measure>
    <time_frame>Brain glutamine will be analyzed at baseline (Day 1 prior to CLAV or PBO dose) and at Day 10 day (having completed Periods 1, 2 and 3 (CLAV 500mg/day for 3 days, 750 mg/day for 3 days and 1000 mg/day for 4 days).</time_frame>
    <description>Change in brain glutamine (Gln) concentration in the ACC at Day 10 compared to baseline as assessed by MRS in the ACC.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of Participants With Treatment-related Adverse Events (AEs)</measure>
    <time_frame>1-24 days (during and up to 2 weeks after study dosing period)</time_frame>
    <description>Adverse events (AES) will be defined as any clinically significant changes in vital signs, clinically significant change in Electrocardiogram (EKG) from baseline measurement, clinically significant changes in laboratory bloodwork (Complete blood count, comprehensive metabolic panel, urinalysis), or any self reported side effects compared with baseline. AEs will be collected throughout the study and reviewed by a physician. An evaluation of AE severity (mild, moderate, severe) will be evaluated by a physician based on participant self-report. AEs per subject will be listed by organ system, and the number of AEs within the subject population will be totaled.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">13</enrollment>
  <condition>Cocaine Dependence</condition>
  <arm_group>
    <arm_group_label>Clavulanic Acid</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Participants will receive 10 days of CLAV-- Period 1: 500 mg/day for days 1-3; Period 2: 750 mg/day for days 4-6; Period 3: 1000 mg/day for days 7-10.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Participants will receive 10 days of placebo and will have a &quot;dose&quot; escalation at the same time as the experimental group. They will be given additional placebo pills to match the number given to the experimental group (i.e. 2 PBO capsules/day for days 1-3, 3 PBO capsules/day days 4-6 and 4 PBO capsules/day for days 7-10).</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Clavulanic Acid</intervention_name>
    <description>Drug will be given in 250mg capsules.</description>
    <arm_group_label>Clavulanic Acid</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>Placebo</description>
    <arm_group_label>Placebo</arm_group_label>
    <other_name>microcrystalline cellulose</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Be able to verbalize understanding of consent form&#xD;
&#xD;
          2. Be male or female adult volunteers ages 18-65 inclusive.&#xD;
&#xD;
          3. Have a Diagnostic and Statistical Manual-5 (DSM-5) diagnosis of cocaine use disorder,&#xD;
             moderate to severe in early remission&#xD;
&#xD;
          4. Have a Body Mass Index (BMI) of 17.5 to 39.9 kg/m2; and a total body weight of at&#xD;
             least 45 kg (99 lbs.)&#xD;
&#xD;
          5. Have a history and brief physical examination that demonstrate no clinically&#xD;
             significant contraindication for participating in the study, and/ or significant or&#xD;
             unstable medical or psychiatric illness.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Have a current DSM-5 substance use disorder, mild, moderate, or severe, on any drug of&#xD;
             abuse other than nicotine, caffeine, and cocaine use disorder in early remission&#xD;
             verified by Urine Drug Screen (UDS). Alcohol use disorder and marijuana use disorder,&#xD;
             mild without withdrawal symptoms, will be permitted.&#xD;
&#xD;
          2. Have any previous medically adverse reaction to CLAV, Augmentin, penicillin,&#xD;
             Ticarcillin, cephalosporin, or any beta-lactam drug.&#xD;
&#xD;
          3. Have any illness, condition, and use of medications, in the opinion of the principal&#xD;
             investigator, sub-investigators which would preclude safe and/or successful completion&#xD;
             of the study.&#xD;
&#xD;
          4. Report having human immunodeficiency virus (HIV) infection or test positive for HIV&#xD;
             during screening&#xD;
&#xD;
          5. Be pregnant (females).&#xD;
&#xD;
          6. Unable to tolerate MRI scan for duration of 60 minutes for physical or psychological&#xD;
             reasons.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>70 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <location>
    <facility>
      <name>Temple University Episcopal Hospital</name>
      <address>
        <city>Philadelphia</city>
        <state>Pennsylvania</state>
        <zip>19125</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <reference>
    <citation>Kim J, John J, Langford D, Walker E, Ward S, Rawls SM. Clavulanic acid enhances glutamate transporter subtype I (GLT-1) expression and decreases reinforcing efficacy of cocaine in mice. Amino Acids. 2016 Mar;48(3):689-696. doi: 10.1007/s00726-015-2117-8. Epub 2015 Nov 5.</citation>
    <PMID>26543027</PMID>
  </reference>
  <verification_date>June 2023</verification_date>
  <study_first_submitted>May 20, 2020</study_first_submitted>
  <study_first_submitted_qc>May 28, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">June 2, 2020</study_first_posted>
  <results_first_submitted>January 20, 2023</results_first_submitted>
  <results_first_submitted_qc>June 15, 2023</results_first_submitted_qc>
  <results_first_posted type="Actual">June 22, 2023</results_first_posted>
  <last_update_submitted>June 15, 2023</last_update_submitted>
  <last_update_submitted_qc>June 15, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">June 22, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Cocaine-Related Disorders</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Clavulanic Acids</mesh_term>
    <mesh_term>Clavulanic Acid</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>November 15, 2021</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/14/NCT04411914/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>December 1, 2021</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/14/NCT04411914/ICF_001.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <recruitment_details>Recruitment materials included newspapers, facebook, and word of mouth. Participants were recruited from the local community between 9/2020 and 11/2021.</recruitment_details>
      <group_list>
        <group group_id="P1">
          <title>Clavulanic Acid</title>
          <description>10 Participants will receive CLAV for 10 days over 3 Periods with no CLAV for Day 11.&#xD;
Period 1 CLAV 500 mg/day for 3 days dose Period 2- CLAV 750 mg/day for 3 days. Period 3 CLAV 1000mg for 4 days&#xD;
Clavulanic Acid Only Product: Drug will be given in 250mg capsules.</description>
        </group>
        <group group_id="P2">
          <title>Placebo</title>
          <description>3 participants will receive placebo and serve as a control group. They will be blinded to their condition and will have a &quot;dose&quot; escalation at the same time as the experimental group, and be given additional placebo pills to match the number given to the experimental group.&#xD;
Placebo: Placebo</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>CLAV 500mg/Day for Days 1-3</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="10"/>
                <participants group_id="P2" count="3"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="9"/>
                <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="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Adverse Event</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
        <period>
          <title>CLAV 750mg/Day for Days 4-6</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="9">9 participants who completed Period 1 (3 days of CLAV 500mg for 3 days) had dose escalation to 750mg/d for 3 days in Period 2.</participants>
                <participants group_id="P2" count="3"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="9"/>
                <participants group_id="P2" count="3"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
        <period>
          <title>CLAV 1000m/d for Days 7-10</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="9">The same 9 participants who started the study and received 3days of CLAV 500mg/day and 3 days of CLAV 750mg/day were then dose escalated to CLAV 1000mg/day for 4 days.</participants>
                <participants group_id="P2" count="3"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="9"/>
                <participants group_id="P2" count="3"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>Clavulanic Acid</title>
          <description>10 participants randomized to the CLAV group&#xD;
Clavulanic Acid will be given in 250mg capsules according to the 3 Periods</description>
        </group>
        <group group_id="B2">
          <title>Placebo</title>
          <description>3 participants will receive placebo (PBO) and serve as a control group. They will have a &quot;dose&quot; escalation at the same time as the experimental group, and be given additional placebo pills to match the number given to the experimental group.&#xD;
Placebo: Placebo</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="10"/>
            <count group_id="B2" value="3"/>
            <count group_id="B3" value="13"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>years</units>
          <param>Median</param>
          <dispersion>Inter-Quartile Range</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="54.2" lower_limit="49.8" upper_limit="57.8"/>
                    <measurement group_id="B2" value="57.8" lower_limit="45.3" upper_limit="60.9"/>
                    <measurement group_id="B3" value="55.6" lower_limit="47.6" upper_limit="57.9"/>
                  </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="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="7"/>
                    <measurement group_id="B2" value="2"/>
                    <measurement group_id="B3" value="9"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Ethnicity (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Not Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="10"/>
                    <measurement group_id="B2" value="3"/>
                    <measurement group_id="B3" value="13"/>
                  </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>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="7"/>
                    <measurement group_id="B2" value="3"/>
                    <measurement group_id="B3" value="10"/>
                  </measurement_list>
                </category>
                <category>
                  <title>White</title>
                  <measurement_list>
                    <measurement group_id="B1" value="3"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="3"/>
                  </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>Number</param>
          <class_list>
            <class>
              <title>United States</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="10"/>
                    <measurement group_id="B2" value="3"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Handedness</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>left-handed</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="1"/>
                  </measurement_list>
                </category>
                <category>
                  <title>right-handed</title>
                  <measurement_list>
                    <measurement group_id="B1" value="10"/>
                    <measurement group_id="B2" value="2"/>
                    <measurement group_id="B3" value="12"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Education</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Left formal education at 16</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="1"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Left formal education at 17-18</title>
                  <measurement_list>
                    <measurement group_id="B1" value="5"/>
                    <measurement group_id="B2" value="2"/>
                    <measurement group_id="B3" value="7"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Undergraduate or Equivalent</title>
                  <measurement_list>
                    <measurement group_id="B1" value="4"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="4"/>
                  </measurement_list>
                </category>
                <category>
                  <title>unknown</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Brain Glutamate Concentration in the Anterior Cingulate Cortex (ACC) in Subjects With Cocaine Use Disorder (CUD) Treated With Escalating Doses of Clavulanate (CLAV)</title>
        <description>Brain glutamate concentration in the ACC (based on Magnetic Resonance Spectroscopy (MRS)) will be correlated with cocaine craving (measured by Cocaine Craving Questionnaire (CCQ)) in subjects receiving escalating doses of CLAV for 10 days. Measurement will be made at baseline and Day 10 of CLAV (1000 mg/day) in subjects with cocaine use disorder.</description>
        <time_frame>ACC glutamate and CCQ will be measured and correlated on Day 10 of treatment with CLAV compared with baseline.</time_frame>
        <population>Glutamate (Glu) level (MR-Spectroscopy) in the ACC (9 scans at baseline and 9 scans at Day 10, adjusted for baseline) are correlated with CCQ results (9 baseline questionnaires and 9 day 10 questionnaires). Spearman Correlation Coefficients were calculated. Higher concentrations of ACC glutamate on day 10 correlated with decreased cocaine craving.</population>
        <group_list>
          <group group_id="O1">
            <title>Clavulanic Acid Day 10</title>
            <description>9 participants who completed Periods 1, 2 and 3 were assessed for brain Glutamate levels in the ACC using MRS at the end of Period 3 (Day 10.)This measure was correlated with CCQ on day 10 adjusted for the baseline.</description>
          </group>
          <group group_id="O2">
            <title>Clavulanic Acid Baseline</title>
            <description>Same 9 subjects underwent CCQ and MRS on Day 1 prior to receiving CLAV 500 mg.</description>
          </group>
        </group_list>
        <measure>
          <title>Brain Glutamate Concentration in the Anterior Cingulate Cortex (ACC) in Subjects With Cocaine Use Disorder (CUD) Treated With Escalating Doses of Clavulanate (CLAV)</title>
          <description>Brain glutamate concentration in the ACC (based on Magnetic Resonance Spectroscopy (MRS)) will be correlated with cocaine craving (measured by Cocaine Craving Questionnaire (CCQ)) in subjects receiving escalating doses of CLAV for 10 days. Measurement will be made at baseline and Day 10 of CLAV (1000 mg/day) in subjects with cocaine use disorder.</description>
          <population>Glutamate (Glu) level (MR-Spectroscopy) in the ACC (9 scans at baseline and 9 scans at Day 10, adjusted for baseline) are correlated with CCQ results (9 baseline questionnaires and 9 day 10 questionnaires). Spearman Correlation Coefficients were calculated. Higher concentrations of ACC glutamate on day 10 correlated with decreased cocaine craving.</population>
          <units>Spearman Correlation Coefficient</units>
          <param>Number</param>
          <units_analyzed>MRS Scans and CCQ</units_analyzed>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="9"/>
                <count group_id="O2" value="9"/>
              </count_list>
            </analyzed>
            <analyzed>
              <units>MRS Scans and CCQ</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="18"/>
                <count group_id="O2" value="18"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-0.9000"/>
                    <measurement group_id="O2" value="0.3333"/>
                  </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>Superiority</non_inferiority_type>
            <p_value>0.0009</p_value>
            <method>Spearman Correlation Coefficient</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Changes in Resting State Network Connectivity From Baseline</title>
        <description>Craving-associated neurocircuitry (frontal-striatal-thalamic connectivity) will be examined with resting state functional Magnetic Resonance Imaging (rs-fMRI) and Cocaine Craving Questionnaire (CCQ-45). The CCQ is comprised of five 9-item sub-scales (desire to use cocaine, intention and planning to use cocaine, anticipation of positive outcome from use, anticipation of relief from withdrawal or dysphoria, and lack of control over use) measured on a scale of 1 to 7, total scores ranging from 45 to 315 with higher numbers indicating increased craving.. The rs-fMRI activity and CCQ were assessed in the 9 participants at baseline and at the end of each of 3 periods. rs-fMRI activity and CCQ were correlated using the Spearman Correlation Coefficient calculation. A negative correlation coefficient indicates an inverse relationship between the assessments; higher rs-fMRI activity correlates with lower craving.</description>
        <time_frame>Assessment was done at the end of Period 1, 2 and 3 detailed above. Data from the end of Period 3 (Day 10, 1000mg CLAV) are reported.</time_frame>
        <population>9 participants completed Period 1 (3 days of CLAV 500mg) Period 2 (3 days of CLAV 750mg) and then Period 3 (4 days of CLAV 1000mg). The rs-fMRI activity in the executive control network and CCQ were correlated using the Spearman Correlation calculation at the end of this course of study drug (Day 10) and are reported.</population>
        <group_list>
          <group group_id="O1">
            <title>Rs-fMRI and CCQ on Day 10 CLAV</title>
            <description>rs-fMRI activity of the Executive Control Network at the end of Period 3 (day 10 of CLAV (dose 1000mg/day)) adjusted for baseline was correlated with CCQ day 10. Subjects had a baseline scan on Day 1 prior to receiving CLAV 500mg. They received CLAV 500mg/day days 1-3. CLAV 750 mg/day days 4-6 and CLAV 1000 mg/day on days 7-10 and then did the CCQ and had repeat rs-fMRI on day 10.</description>
          </group>
        </group_list>
        <measure>
          <title>Changes in Resting State Network Connectivity From Baseline</title>
          <description>Craving-associated neurocircuitry (frontal-striatal-thalamic connectivity) will be examined with resting state functional Magnetic Resonance Imaging (rs-fMRI) and Cocaine Craving Questionnaire (CCQ-45). The CCQ is comprised of five 9-item sub-scales (desire to use cocaine, intention and planning to use cocaine, anticipation of positive outcome from use, anticipation of relief from withdrawal or dysphoria, and lack of control over use) measured on a scale of 1 to 7, total scores ranging from 45 to 315 with higher numbers indicating increased craving.. The rs-fMRI activity and CCQ were assessed in the 9 participants at baseline and at the end of each of 3 periods. rs-fMRI activity and CCQ were correlated using the Spearman Correlation Coefficient calculation. A negative correlation coefficient indicates an inverse relationship between the assessments; higher rs-fMRI activity correlates with lower craving.</description>
          <population>9 participants completed Period 1 (3 days of CLAV 500mg) Period 2 (3 days of CLAV 750mg) and then Period 3 (4 days of CLAV 1000mg). The rs-fMRI activity in the executive control network and CCQ were correlated using the Spearman Correlation calculation at the end of this course of study drug (Day 10) and are reported.</population>
          <units>Spearman Correlation Coefficient</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="9"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-0.8333"/>
                  </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>Other</non_inferiority_type>
            <p_value>0.0053</p_value>
            <method>Spearman Correlation Coefficient</method>
            <method_desc>Spearman Correlation Coefficient, N=9 Prob &gt; |r| under H0: Rho=0</method_desc>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Craving</title>
        <description>Craving will be evaluated by Cocaine Craving Questionnaire (CCQ-45). The CCQ is comprised of five 9-item sub-scales (desire to use cocaine, intention and planning to use cocaine, anticipation of positive outcome from use, anticipation of relief from withdrawal or dysphoria, and lack of control over use) measured on a scale of 1 to 7, total scores ranging from 45 to 315 with higher numbers indicating increased craving. The results are the CCQ scores on day 10 minus the baseline scores before starting study drug.</description>
        <time_frame>CCQ-45 questionnaires were completed daily during the study. Data from day 10 adjusted for baseline score are reported.</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Male CLAV Subjects--CCQ on Day 10</title>
            <description>CCQ-45 scores on Day 10 in male subjects (who took CLAV 500mg/day for 3 days, then 750 mg/day for 3 days and 1000mg/day for 4 days) minus the baseline CCQ scores.</description>
          </group>
          <group group_id="O2">
            <title>Male PBO Subjects--CCQ Score Day 10</title>
            <description>CCQ scores on Day 10 minus the baseline CCQ scores in male subjects who took matched PBO for 10 days.</description>
          </group>
          <group group_id="O3">
            <title>Female CLAV Subjects--CCQ Score Day 10</title>
            <description>CCQ-45 scores from day 10 in female subjects (they took CLAV 500mg/3 for the first 3 days, then 750 mg/day for days for 3 days and 1000mg/day for 4 days) minus the baseline scores.</description>
          </group>
          <group group_id="O4">
            <title>Femaile PBO Subjects--CCQ Scores Day 10</title>
            <description>The CCQ scores day 10 minus the baseline scores in female submects who took matched PBO for 10 days.</description>
          </group>
        </group_list>
        <measure>
          <title>Craving</title>
          <description>Craving will be evaluated by Cocaine Craving Questionnaire (CCQ-45). The CCQ is comprised of five 9-item sub-scales (desire to use cocaine, intention and planning to use cocaine, anticipation of positive outcome from use, anticipation of relief from withdrawal or dysphoria, and lack of control over use) measured on a scale of 1 to 7, total scores ranging from 45 to 315 with higher numbers indicating increased craving. The results are the CCQ scores on day 10 minus the baseline scores before starting study drug.</description>
          <units>difference in 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="6"/>
                <count group_id="O2" value="2"/>
                <count group_id="O3" value="3"/>
                <count group_id="O4" value="1"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="7" spread="16"/>
                    <measurement group_id="O2" value="-22" spread="10"/>
                    <measurement group_id="O3" value="-15" spread="21"/>
                    <measurement group_id="O4" value="49" spread="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change in Brain Glutamine From Baseline</title>
        <description>Change in brain glutamine (Gln) concentration in the ACC at Day 10 compared to baseline as assessed by MRS in the ACC.</description>
        <time_frame>Brain glutamine will be analyzed at baseline (Day 1 prior to CLAV or PBO dose) and at Day 10 day (having completed Periods 1, 2 and 3 (CLAV 500mg/day for 3 days, 750 mg/day for 3 days and 1000 mg/day for 4 days).</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Clavulanic Acid (CLAV) Group Baseline</title>
            <description>Glutamine (Gln) levels measured in 9 participants by MRS in the ACC at baseline (prior to receiving any dose of CLA V)</description>
          </group>
          <group group_id="O2">
            <title>Clavulanic Acid Day 10</title>
            <description>Gln levels measured in 9 participants by MRS in the ACC on Day 10 of CLAV dosing having taken CLAV 500mg for 3 days, 750 mg for 3 days and 1000 mg for 4 days.</description>
          </group>
          <group group_id="O3">
            <title>Placebo Group Baseline</title>
            <description>Gln levels measured in 3 participants by MRS in the ACC at baseline (prior to receiving any dose of Placebo)</description>
          </group>
          <group group_id="O4">
            <title>Placebo Group Day 10</title>
            <description>Gln levels measured in 3 participants by MRS in the ACC on Day 10 of matching Placebo.</description>
          </group>
        </group_list>
        <measure>
          <title>Change in Brain Glutamine From Baseline</title>
          <description>Change in brain glutamine (Gln) concentration in the ACC at Day 10 compared to baseline as assessed by MRS in the ACC.</description>
          <units>mmol/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="9"/>
                <count group_id="O2" value="9"/>
                <count group_id="O3" value="3"/>
                <count group_id="O4" value="3"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1.5" spread="1.0"/>
                    <measurement group_id="O2" value="2.1" spread="2.0"/>
                    <measurement group_id="O3" value="0.8" spread="0.3"/>
                    <measurement group_id="O4" value="0.7" spread="0.6"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Number of Participants With Treatment-related Adverse Events (AEs)</title>
        <description>Adverse events (AES) will be defined as any clinically significant changes in vital signs, clinically significant change in Electrocardiogram (EKG) from baseline measurement, clinically significant changes in laboratory bloodwork (Complete blood count, comprehensive metabolic panel, urinalysis), or any self reported side effects compared with baseline. AEs will be collected throughout the study and reviewed by a physician. An evaluation of AE severity (mild, moderate, severe) will be evaluated by a physician based on participant self-report. AEs per subject will be listed by organ system, and the number of AEs within the subject population will be totaled.</description>
        <time_frame>1-24 days (during and up to 2 weeks after study dosing period)</time_frame>
        <population>see adverse events report; Blood Pressure, heart rate, EKG were not statistically different between the two groups.</population>
        <group_list>
          <group group_id="O1">
            <title>Clavulanic Acid</title>
            <description>9 Participants will receive 500 mg of CLAV at baseline. Subjects who can tolerate 500 mg/day for 3 days (or matched placebo) will have a dose escalation to 750 mg/day for 3 days. Subjects who can tolerate 750mg/day for three days will have a dose escalation to 1000mg for 4 days.&#xD;
Clavulanic Acid Only Product: Drug will be given in 250mg capsules.</description>
          </group>
          <group group_id="O2">
            <title>Placebo</title>
            <description>3 participants will receive placebo and serve as a control group. They will be blinded to their condition and will have a &quot;dose&quot; escalation at the same time as the experimental group, and be given additional placebo pills to match the number given to the experimental group.&#xD;
Placebo: Placebo</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Participants With Treatment-related Adverse Events (AEs)</title>
          <description>Adverse events (AES) will be defined as any clinically significant changes in vital signs, clinically significant change in Electrocardiogram (EKG) from baseline measurement, clinically significant changes in laboratory bloodwork (Complete blood count, comprehensive metabolic panel, urinalysis), or any self reported side effects compared with baseline. AEs will be collected throughout the study and reviewed by a physician. An evaluation of AE severity (mild, moderate, severe) will be evaluated by a physician based on participant self-report. AEs per subject will be listed by organ system, and the number of AEs within the subject population will be totaled.</description>
          <population>see adverse events report; Blood Pressure, heart rate, EKG were not statistically different between the two groups.</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="10"/>
                <count group_id="O2" value="3"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="6"/>
                    <measurement group_id="O2" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>24 days</time_frame>
      <desc>9 subjects in the CLAV group and 3 subjects in the PBO group will be assessed throughout the study for Adverse Events (AE).&#xD;
Subjects in the CLAV group are treated in 3 periods: CLAV 500 mg for 3 days, 750mg for the next 3 days and then 1000mg for the last 4 days to complete the 10 days of the study. AEs were reported by period/dose though the same person may have had several AE or the same AE at different doses.</desc>
      <group_list>
        <group group_id="E1">
          <title>Clavulanic Acid Treatment Period 1-500mg/Day</title>
          <description>10 Participants will be treated with CLAV (500mg/day for 3 days)</description>
        </group>
        <group group_id="E2">
          <title>CLavulanic Acid Treatment Period 2-750mg.Day</title>
          <description>9 Participants who completed Period 1 treated with CLAV (750mg/day for 3 days)</description>
        </group>
        <group group_id="E3">
          <title>Clavulanic Acid Treatment Period 3--1000mg/Day</title>
          <description>9 Participants who completed Period 1 treated with CLAV (1000mg/day for 3 days)</description>
        </group>
        <group group_id="E4">
          <title>Placebo</title>
          <description>3 participants received matched placebo. They will be given additional placebo capsules to match the number given to the CLAV group.</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="10"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="9"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="9"/>
                <counts group_id="E4" 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="10"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="9"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="9"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="3"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>0</frequency_threshold>
        <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="6" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="5" subjects_at_risk="9"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="9"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="3"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Nausea</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
                <counts group_id="E2" events="3" subjects_affected="3" subjects_at_risk="9"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="9"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>flatulence</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="9"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="9"/>
                <counts group_id="E4" events="1" subjects_affected="1" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>loose stool</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="9"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="9"/>
                <counts group_id="E4" events="1" subjects_affected="1" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>stomach pain</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="9"/>
                <counts group_id="E3" events="2" subjects_affected="1" subjects_at_risk="9"/>
                <counts group_id="E4" events="2" subjects_affected="1" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>Heartburn</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="9"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="9"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="3"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Hepatobiliary disorders</title>
            <event_list>
              <event>
                <sub_title>Elevated Liver Function Tests</sub_title>
                <description>Drug induced hepatitis, asymptomatic, resolved in 2 weeks, discontinued from study</description>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="9"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="9"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="3"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Joint pain</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="9"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="9"/>
                <counts group_id="E4" events="1" subjects_affected="1" subjects_at_risk="3"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Headache</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="9"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="9"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>Lightheaded</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="9"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="9"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="3"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Reproductive system and breast disorders</title>
            <event_list>
              <event>
                <sub_title>Priapism</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="9"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="9"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="3"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Skin and subcutaneous tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Itching</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="9"/>
                <counts group_id="E3" events="2" subjects_affected="1" subjects_at_risk="9"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>Swollen feet</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="9"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="9"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="3"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Vascular disorders</title>
            <event_list>
              <event>
                <sub_title>High blood pressure</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="9"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="9"/>
                <counts group_id="E4" events="0" 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>Mary Morrison, MD, MS</name_or_title>
      <organization>Temple University</organization>
      <phone>215=707=4037</phone>
      <email>mary.morrison@temple.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/NCT04411914
org study id: 26876
secondary id: U01DA048517
nct id: NCT04411914
lead sponsor: 
collaborator: 
collaborator: 
collaborator: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
A dose-escalation study to determine the optimum dose of Clavulanic Acid (CLAV) for effects
      on craving and efficacy.
This is a randomized, double-blind, placebo-controlled, parallel group inpatient study of
      clavulanic acid for 10 days in adults (18-65) seeking treatment for cocaine use disorder. For
      those subjects who can tolerate 500 mg/day for 3 days (or matched placebo), there will be a
      forced dose escalation to 750 mg/day for 3 days. Subjects who can tolerate 750 mg/day for
      three days will have a forced dose escalation to 1000 mg/day for 4 days until the study ends.

      Thus, there are 3 Periods for each participant:

      Period 1: 500 mg CLAV per day for days 1-3; Period 2: 750 mg per day for days 4-6; Period 3:
      1000 mg/day for days 7-10.

      Subjective, cognitive, and adverse effect assessments, blood pressure and pulse will be
      performed daily. Structural MRI, resting state MRI (rs-fMRI), functional MRI (fMRI) and
      Magnetic Resonance Spectroscopy (MRS) scans will be done at baseline and on Days 3, 6 and 10
      of the study. At the time of each scan, safety of the subject to complete the scan will be
      re-assessed. fMRI was not done at baseline.
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: Randomized, double-blind, placebo-controlled, parallel group inpatient study
primary purpose: Treatment
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
measure: Brain Glutamate Concentration in the Anterior Cingulate Cortex (ACC) in Subjects With Cocaine Use Disorder (CUD) Treated With Escalating Doses of Clavulanate (CLAV)
time frame: ACC glutamate and CCQ will be measured and correlated on Day 10 of treatment with CLAV compared with baseline.
description: Brain glutamate concentration in the ACC (based on Magnetic Resonance Spectroscopy (MRS)) will be correlated with cocaine craving (measured by Cocaine Craving Questionnaire (CCQ)) in subjects receiving escalating doses of CLAV for 10 days. Measurement will be made at baseline and Day 10 of CLAV (1000 mg/day) in subjects with cocaine use disorder.
measure: Changes in Resting State Network Connectivity From Baseline
time frame: Assessment was done at the end of Period 1, 2 and 3 detailed above. Data from the end of Period 3 (Day 10, 1000mg CLAV) are reported.
description: Craving-associated neurocircuitry (frontal-striatal-thalamic connectivity) will be examined with resting state functional Magnetic Resonance Imaging (rs-fMRI) and Cocaine Craving Questionnaire (CCQ-45). The CCQ is comprised of five 9-item sub-scales (desire to use cocaine, intention and planning to use cocaine, anticipation of positive outcome from use, anticipation of relief from withdrawal or dysphoria, and lack of control over use) measured on a scale of 1 to 7, total scores ranging from 45 to 315 with higher numbers indicating increased craving.. The rs-fMRI activity and CCQ were assessed in the 9 participants at baseline and at the end of each of 3 periods. rs-fMRI activity and CCQ were correlated using the Spearman Correlation Coefficient calculation. A negative correlation coefficient indicates an inverse relationship between the assessments; higher rs-fMRI activity correlates with lower craving.
measure: Craving
time frame: CCQ-45 questionnaires were completed daily during the study. Data from day 10 adjusted for baseline score are reported.
description: Craving will be evaluated by Cocaine Craving Questionnaire (CCQ-45). The CCQ is comprised of five 9-item sub-scales (desire to use cocaine, intention and planning to use cocaine, anticipation of positive outcome from use, anticipation of relief from withdrawal or dysphoria, and lack of control over use) measured on a scale of 1 to 7, total scores ranging from 45 to 315 with higher numbers indicating increased craving. The results are the CCQ scores on day 10 minus the baseline scores before starting study drug.
measure: Change in Brain Glutamine From Baseline
time frame: Brain glutamine will be analyzed at baseline (Day 1 prior to CLAV or PBO dose) and at Day 10 day (having completed Periods 1, 2 and 3 (CLAV 500mg/day for 3 days, 750 mg/day for 3 days and 1000 mg/day for 4 days).
description: Change in brain glutamine (Gln) concentration in the ACC at Day 10 compared to baseline as assessed by MRS in the ACC.
measure: Number of Participants With Treatment-related Adverse Events (AEs)
time frame: 1-24 days (during and up to 2 weeks after study dosing period)
description: Adverse events (AES) will be defined as any clinically significant changes in vital signs, clinically significant change in Electrocardiogram (EKG) from baseline measurement, clinically significant changes in laboratory bloodwork (Complete blood count, comprehensive metabolic panel, urinalysis), or any self reported side effects compared with baseline. AEs will be collected throughout the study and reviewed by a physician. An evaluation of AE severity (mild, moderate, severe) will be evaluated by a physician based on participant self-report. AEs per subject will be listed by organ system, and the number of AEs within the subject population will be totaled.
arm group label: Clavulanic Acid
arm group type: Experimental
description: Participants will receive 10 days of CLAV-- Period 1: 500 mg/day for days 1-3; Period 2: 750 mg/day for days 4-6; Period 3: 1000 mg/day for days 7-10.
arm group label: Placebo
arm group type: Placebo Comparator
description: Participants will receive 10 days of placebo and will have a "dose" escalation at the same time as the experimental group. They will be given additional placebo pills to match the number given to the experimental group (i.e. 2 PBO capsules/day for days 1-3, 3 PBO capsules/day days 4-6 and 4 PBO capsules/day for days 7-10).
intervention type: Drug
intervention name: Clavulanic Acid
description: Drug will be given in 250mg capsules.
arm group label: Clavulanic Acid
intervention type: Other
intervention name: Placebo
description: Placebo
arm group label: Placebo
other name: microcrystalline cellulose
criteria: 
gender: All
minimum age: 18 Years
maximum age: 70 Years
healthy volunteers: No
facility: 
country: United States
citation: Kim J, John J, Langford D, Walker E, Ward S, Rawls SM. Clavulanic acid enhances glutamate transporter subtype I (GLT-1) expression and decreases reinforcing efficacy of cocaine in mice. Amino Acids. 2016 Mar;48(3):689-696. doi: 10.1007/s00726-015-2117-8. Epub 2015 Nov 5.
PMID: 26543027
responsible party type: Sponsor
mesh term: Cocaine-Related Disorders
mesh term: Clavulanic Acids
mesh term: Clavulanic Acid
sharing ipd: No
provided document: 
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 