<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/NCT03043560</url>
  </required_header>
  <id_info>
    <org_study_id>GCO 16-0374</org_study_id>
    <secondary_id>1R61MH111932-01</secondary_id>
    <nct_id>NCT03043560</nct_id>
  </id_info>
  <brief_title>Study to Treat Major Depressive Disorder With a New Medication</brief_title>
  <official_title>Developing Neuronal KCNQ Channel Modulators for Mood Disorders</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>James Murrough</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>National Institute of Mental Health (NIMH)</agency>
      <agency_class>NIH</agency_class>
    </collaborator>
    <collaborator>
      <agency>Baylor College of Medicine</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Icahn School of Medicine at Mount Sinai</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>
      This project is designed to examine the neuronal KCNQ2/3 potassium (K+) channel subtype as a&#xD;
      novel treatment target for mood disorders through the administration of the KCNQ-selective&#xD;
      channel opener ezogabine (Potiga, GlaxoSmithKline; FDA-approved for the treatment of seizure&#xD;
      disorders).&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Depressive disorders are among the most disabling medical conditions worldwide and currently&#xD;
      available treatments fall short of addressing this large public health burden. Dysfunction&#xD;
      within the brain reward system is emerging as a core feature of depressive disorders, in&#xD;
      particular related to deficits in motivation, interest, and response to pleasure (e.g.,&#xD;
      anhedonia: markedly diminished response to pleasure). Evidences from a series of preclinical&#xD;
      studies from our group highlighted the KCNQ subtype of neuronal potassium (K+) channel as a&#xD;
      novel target for the treatment of depressive disorders and our human pilot study showed a&#xD;
      reduction in anhedonia and related symptoms, and an increased brain response to reward (as&#xD;
      measured by functional magnetic resonance imaging [fMRI]) following treatment with ezogabine.&#xD;
      Building on this data, the current project will assess reward circuit activity following&#xD;
      treatment with ezogabine in depressed patients with a current depressive disorder (Major&#xD;
      depressive disorder [MDD], persistent depressive disorder, other specified depressive&#xD;
      disorder) and anhedonia (defined by a score ≥ 20 on the Snaith-Hamilton Pleasure Scale&#xD;
      [SHAPS]), using fMRI to investigate the cortico-striatal circuit to reward.&#xD;
&#xD;
      This study represents the first part of the R61/R33 National Institutes of Health (NIH)&#xD;
      founded project. A clear increase in reward circuit activation in at least one ezogabine&#xD;
      treatment group compared to placebo, given acceptable tolerability, will constitute a &quot;go&quot;&#xD;
      and the project will move to the next phase (R33), where we aim to examine the relationship&#xD;
      between treatment, reward circuit activity, and behavioral and clinical outcomes in a larger,&#xD;
      confirmatory efficacy trial of ezogabine for depression with anhedonia.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">September 25, 2017</start_date>
  <completion_date type="Actual">August 30, 2019</completion_date>
  <primary_completion_date type="Actual">August 30, 2019</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>
    <primary_purpose>Other</primary_purpose>
    <masking>Double (Participant, Investigator)</masking>
    <masking_description>Double blind</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>Change in Ventral Striatum (VS) Activation</measure>
    <time_frame>baseline and 5 weeks</time_frame>
    <description>change in activation during reward anticipation within the bilateral VS from baseline (Study Visit 0) to the primary outcome visit (Study Visit 5) as measured by functional MRI during the incentive flanker task (IFT). The IFT, like the Monetary Incentive Delay task, permits discrete modeling of brain activity during anticipation of an incentive.&#xD;
Functional scans were preprocessed and denoised for motion and physiological noise using multi-echo independent component analysis (ME-ICA). Task-based modeling was conducted using AFNI and FSL software. The primary outcome for reward anticipation was the contrast of reward cue compared to neutral cue (reward&gt;neutral cue). The primary imaging outcome was analyzed using a linear mixed model with a single random intercept term treating time as discrete or continuous as appropriate.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Change in Snaith-Hamilton Pleasure Scale (SHAPS)</measure>
    <time_frame>baseline and 5 weeks</time_frame>
    <description>The SHAPS is a well-validated 14-item self-report questionnaire commonly used to assess anhedonia. Each item on the SHAPS is worded so that higher scores indicate greater pleasure capacity. A total score can be derived by summing the responses to each item. Items answered with &quot;strongly agree&quot; are coded as &quot;1&quot;, while a &quot;strongly disagree&quot; response was assigned a score of &quot;4.&quot; Total scores on the SHAPS can range from 14 to 56, with higher scores corresponding to higher levels of anhedonia.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Clinical Global Impression - Improvement (CGI-I)</measure>
    <time_frame>baseline and 5 weeks</time_frame>
    <description>A widely administered clinician rated global measure of the degree of improvement from the initial assessment in subject overall illness severity. 7 point scale rated as: 1, very much improved; 2, much improved; 3, minimally improved; 4, no change; 5, minimally worse; 6, much worse; or 7, very much worse.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Clinical Global Impression - Severity (CGI-S)</measure>
    <time_frame>baseline and 5 weeks</time_frame>
    <description>Clinician rated global measure of subject overall illness severity. a 7-point scale rated as 1, normal, not at all ill; 2, borderline mentally ill; 3, mildly ill; 4, moderately ill; 5, markedly ill; 6, severely ill; or 7, extremely ill.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Anticipatory and Consummatory Interpersonal Pleasure Scale (ACIPS)</measure>
    <time_frame>baseline and 5 weeks</time_frame>
    <description>A measure specifically designed to assess hedonic capacity for social and interpersonal pleasure.The ACIPS is a 17-item self-report measure scored on a likert scale, ranging from 1 (very false for me) to 6 (very true for me). Full scale from 17-102, higher score indicates higher hedonic capacity</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Montgomery-Asberg Depression Rating Scale (MADRS)</measure>
    <time_frame>baseline and 5 weeks</time_frame>
    <description>A 10-item instrument used for the evaluation of depressive symptoms in adults and for the assessment of any changes to those symptoms. Each items is scored 0 (normal) to 6 (severe depression) with overall score ranges from 0 (normal) to 60 (severe depression).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>World Health Organization Disability Assessment Schedule 2.0 (WHODAS 2.0)</measure>
    <time_frame>baseline and 5 weeks</time_frame>
    <description>A 12-item generic assessment instrument that measures the level of functioning. Each item is scored from 0 to 4 and the items are summed to provide a total score. The score therefore ranges from 0 to 48, with higher scores indicating greater disability.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Temporal Experience of Pleasure Scale (TEPS)</measure>
    <time_frame>baseline and 5 weeks</time_frame>
    <description>The TEPS is composed of 18-items rated on a likert-type scale ranging from 1 (Very True for me) to 6 (Very False for me), and yields two subscales. Ten items make up the TEPS-Anticipatory Pleasure (TEPS-ANT) scale with a range from 10 (not motivated) to 60 (highly motivated). The other eight TEPS items make up the TEPS-Consummatory Pleasure (TEPS-CON) scale; range from 8 (not responsive) to 48 (highly responsive). Total scores range is 18-108. Lower scores indicate greater levels of anhedonia.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Specific Loss of Interest and Pleasure Scale (SLIPS)</measure>
    <time_frame>baseline 5 weeks</time_frame>
    <description>The SLIPS is a recently developed and validated measure of anhedonia that is tailored to detect recent changes in anhedonia. A 23-item measure, each item range from 0-3. Full scale from 0 to 69, higher score indicates more recent changes.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">45</enrollment>
  <condition>Depressive Disorder</condition>
  <condition>Anhedonia</condition>
  <arm_group>
    <arm_group_label>Ezogabine</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Participants will receive treatment with ezogabine up to 900mg/day.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Participants will receive treatment with a matching placebo pill.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Ezogabine</intervention_name>
    <description>daily for 5 weeks</description>
    <arm_group_label>Ezogabine</arm_group_label>
    <other_name>Potiga</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebos</intervention_name>
    <description>placebo pill daily for 5 weeks</description>
    <arm_group_label>Placebo</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Written informed consent obtained from subject and ability for subject to comply with&#xD;
             the requirements of the study;&#xD;
&#xD;
          -  Men and women, age 18-65;&#xD;
&#xD;
          -  Participants must meet DSM-V criteria for current depressive disorder (major&#xD;
             depressive disorder [MDD], persistent depressive disorder, other specified depressive&#xD;
             disorder) as determined by a study psychiatrist and confirmed using the Structured&#xD;
             Clinical Interview for DSM-V (SCID);&#xD;
&#xD;
          -  Clinically significant anhedonia as determined by a SHAPS score ≥ 20 at screening;&#xD;
&#xD;
          -  Current illness severity is at least moderate, defined as a score of ≥4 on the&#xD;
             Clinical Global Impression-Severity (CGI-S) Scale;&#xD;
&#xD;
          -  If female of childbearing potential, must agree to use of a medically accepted form of&#xD;
             contraception, or else agree to abstinence.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  A primary psychiatric diagnosis other than a depressive disorder as defined by DSM-V&#xD;
             [co-morbid anxiety disorders (including agoraphobia, generalized anxiety disorder,&#xD;
             social anxiety disorder and panic disorder) and Posttraumatic Stress Disorder (PTSD)&#xD;
             are allowed] or major cognitive disorder;&#xD;
&#xD;
          -  Meets criteria for a substance or alcohol use disorder in the past 6 months;&#xD;
&#xD;
          -  Female participants who are pregnant, breastfeeding, or may become pregnant, or&#xD;
             unwilling to practice birth control during participation in the study;&#xD;
&#xD;
          -  Positive urine toxicology screen for drugs of abuse at the time of screening;&#xD;
&#xD;
          -  Any unstable medical illnesses including hepatic, renal, gastroenterologic,&#xD;
             respiratory, cardiovascular (including ischemic heart disease), endocrinologic,&#xD;
             neurologic, immunologic, or hematologic disease;&#xD;
&#xD;
          -  Clinically significant abnormalities of laboratory tests, physical examination, or&#xD;
             ECG;&#xD;
&#xD;
          -  Prolonged QT Interval at screening, operationalized as a QTc of &gt; 480 ms;&#xD;
&#xD;
          -  A history of retinal abnormalities (i.e., pigment changes, retinal dystrophy) or&#xD;
             findings of retinal pathology on ophthalmological exam at baseline;&#xD;
&#xD;
          -  Presence of a condition or abnormality that in the opinion of the Investigator would&#xD;
             compromise the safety of the patient or the quality of the data;&#xD;
&#xD;
          -  Use of any dis-allowed medication according to the study protocol;&#xD;
&#xD;
          -  Serious and imminent risk of self harm or violence as determined by the PI;&#xD;
&#xD;
          -  Extreme illness severity as defined by a GCI-S score &gt;6;&#xD;
&#xD;
          -  Any contraindication to MRI including claustrophobia, any trauma or surgery which may&#xD;
             have left magnetic material in the body, magnetic implants or pacemakers, and&#xD;
             inability to lie still for 1 hour or more;&#xD;
&#xD;
          -  History of non-response to electroconvulsive therapy in the current depressive episode&#xD;
&#xD;
               -  Exceptions:&#xD;
&#xD;
                    1. Subjects with a positive urine drug screen for cannabinoids, barbiturates,&#xD;
                       opiates, amphetamines, or benzodiazepines may be allowed in the study&#xD;
                       provided that the drug was used for a documented, legitimate medical purpose&#xD;
                       and/or the use of such products may be discontinued (documented by a&#xD;
                       negative repeat test) prior to randomization;&#xD;
&#xD;
                    2. Medically appropriate episodic use (up to 3 days) of narcotic analgesics for&#xD;
                       acute medical indications is allowed (Discussion with PI required)&#xD;
&#xD;
                         -  Potential participants will not be discontinued from medication for the&#xD;
                            purposes of this study. If a patient is taking a protocol dis-allowed&#xD;
                            medication at the time of screening, the patient may discontinue the&#xD;
                            medication under the supervision of the treating physician in the case&#xD;
                            that the patient is not benefiting from the medication or otherwise&#xD;
                            wishes to discontinue the medication. In no case will a dis-allowed&#xD;
                            medication be discontinued for the purpose of study participation if&#xD;
                            the patient is receiving clinical benefit from the medication.&#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>James Murrough, MD, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Icahn School of Medicine at Mount Sinai</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Icahn School of Medicine at Mount Sinai</name>
      <address>
        <city>New York</city>
        <state>New York</state>
        <zip>10029</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Baylor College of Medicine</name>
      <address>
        <city>Houston</city>
        <state>Texas</state>
        <zip>77030</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>September 2020</verification_date>
  <study_first_submitted>February 2, 2017</study_first_submitted>
  <study_first_submitted_qc>February 3, 2017</study_first_submitted_qc>
  <study_first_posted type="Estimate">February 6, 2017</study_first_posted>
  <results_first_submitted>August 29, 2020</results_first_submitted>
  <results_first_submitted_qc>September 25, 2020</results_first_submitted_qc>
  <results_first_posted type="Actual">October 23, 2020</results_first_posted>
  <last_update_submitted>September 25, 2020</last_update_submitted>
  <last_update_submitted_qc>September 25, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">October 23, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor-Investigator</responsible_party_type>
    <investigator_affiliation>Icahn School of Medicine at Mount Sinai</investigator_affiliation>
    <investigator_full_name>James Murrough</investigator_full_name>
    <investigator_title>Associate Professor</investigator_title>
  </responsible_party>
  <keyword>depression</keyword>
  <keyword>anhedonia</keyword>
  <keyword>reward</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Anhedonia</mesh_term>
    <mesh_term>Depressive Disorder</mesh_term>
    <mesh_term>Depression</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Ezogabine</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Yes</sharing_ipd>
    <ipd_description>Data from this study may be submitted to the National Database for Clinical Research Related to Mental Illness (NDCT). NDCT isa data repository run by the National Institute of Mental Health (NIMH) that allows researchers studying mental illness to collect and share deidentified information with each other. During and after the study, the researchers will send deidentified information about health and behavior and in some cases, genetic information, to NDCT. Other researchers nationwide can then file an application with the NIMH to obtain access to deidentified study data for research purposes.</ipd_description>
  </patient_data>
  <provided_document_section>
    <provided_document>
      <document_type>Statistical Analysis Plan</document_type>
      <document_has_protocol>No</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>June 1, 2018</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/60/NCT03043560/SAP_000.pdf</document_url>
    </provided_document>
    <provided_document>
      <document_type>Study Protocol</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>No</document_has_sap>
      <document_date>June 12, 2019</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/60/NCT03043560/Prot_001.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <recruitment_details>Participants recruited from Sept 2017 through August 2019</recruitment_details>
      <group_list>
        <group group_id="P1">
          <title>Ezogabine</title>
          <description>Ezogabine up to 900mg/day daily for 5 weeks</description>
        </group>
        <group group_id="P2">
          <title>Placebo</title>
          <description>Matching placebo pill daily for 5 weeks</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="21"/>
                <participants group_id="P2" count="24"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="20"/>
                <participants group_id="P2" count="21"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="3"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Discontinued Intervention</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="2"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Lost to Follow-up</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="1"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>Ezogabine</title>
          <description>Ezogabine up to 900mg/day daily for 5 weeks</description>
        </group>
        <group group_id="B2">
          <title>Placebo</title>
          <description>Matching placebo pill daily for 5 weeks</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="21"/>
            <count group_id="B2" value="24"/>
            <count group_id="B3" value="45"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>years</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="44.4" spread="13.6"/>
                    <measurement group_id="B2" value="38.9" spread="14.3"/>
                    <measurement group_id="B3" value="41.5" spread="14.1"/>
                  </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="10"/>
                    <measurement group_id="B2" value="12"/>
                    <measurement group_id="B3" value="22"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="11"/>
                    <measurement group_id="B2" value="12"/>
                    <measurement group_id="B3" value="23"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Race/Ethnicity, Customized</title>
          <description>as reported by the study participant</description>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <title>White/Caucasian</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="12"/>
                    <measurement group_id="B2" value="12"/>
                    <measurement group_id="B3" value="24"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Black/African American</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="5"/>
                    <measurement group_id="B2" value="7"/>
                    <measurement group_id="B3" value="12"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Hispanic/Latino</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="6"/>
                    <measurement group_id="B2" value="9"/>
                    <measurement group_id="B3" value="15"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Employment at least Part-Time</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="9"/>
                    <measurement group_id="B2" value="14"/>
                    <measurement group_id="B3" value="23"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Educational Attainment - ast least some college</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="15"/>
                    <measurement group_id="B2" value="21"/>
                    <measurement group_id="B3" value="36"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Relationship Status - Single, Never Married</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="8"/>
                    <measurement group_id="B2" value="13"/>
                    <measurement group_id="B3" value="21"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Primary Diagnosis</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <title>Major Depressive Disorder</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="21"/>
                    <measurement group_id="B2" value="23"/>
                    <measurement group_id="B3" value="44"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Persistent Depressive Disorder</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Current Major Depressive Episode</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="21"/>
                    <measurement group_id="B2" value="22"/>
                    <measurement group_id="B3" value="43"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Age at Onset of Depression</title>
          <units>years</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="28.3" spread="15.6"/>
                    <measurement group_id="B2" value="21.7" spread="11.5"/>
                    <measurement group_id="B3" value="24.3" spread="14.0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Current Depressive Episode Duration</title>
          <units>months</units>
          <param>Median</param>
          <dispersion>Inter-Quartile Range</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="72" lower_limit="6" upper_limit="180"/>
                    <measurement group_id="B2" value="24" lower_limit="9.5" upper_limit="54"/>
                    <measurement group_id="B3" value="30" lower_limit="10" upper_limit="120"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Generalized Anxiety Disorder</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="11"/>
                    <measurement group_id="B2" value="10"/>
                    <measurement group_id="B3" value="21"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Posttraumatic Stress Disorder (PTSD)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="4"/>
                    <measurement group_id="B2" value="8"/>
                    <measurement group_id="B3" value="12"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Change in Ventral Striatum (VS) Activation</title>
        <description>change in activation during reward anticipation within the bilateral VS from baseline (Study Visit 0) to the primary outcome visit (Study Visit 5) as measured by functional MRI during the incentive flanker task (IFT). The IFT, like the Monetary Incentive Delay task, permits discrete modeling of brain activity during anticipation of an incentive.&#xD;
Functional scans were preprocessed and denoised for motion and physiological noise using multi-echo independent component analysis (ME-ICA). Task-based modeling was conducted using AFNI and FSL software. The primary outcome for reward anticipation was the contrast of reward cue compared to neutral cue (reward&gt;neutral cue). The primary imaging outcome was analyzed using a linear mixed model with a single random intercept term treating time as discrete or continuous as appropriate.</description>
        <time_frame>baseline and 5 weeks</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Ezogabine</title>
            <description>Ezogabine up to 900mg/day daily for 5 weeks</description>
          </group>
          <group group_id="O2">
            <title>Placebo</title>
            <description>Matching placebo pill daily for 5 weeks</description>
          </group>
        </group_list>
        <measure>
          <title>Change in Ventral Striatum (VS) Activation</title>
          <description>change in activation during reward anticipation within the bilateral VS from baseline (Study Visit 0) to the primary outcome visit (Study Visit 5) as measured by functional MRI during the incentive flanker task (IFT). The IFT, like the Monetary Incentive Delay task, permits discrete modeling of brain activity during anticipation of an incentive.&#xD;
Functional scans were preprocessed and denoised for motion and physiological noise using multi-echo independent component analysis (ME-ICA). Task-based modeling was conducted using AFNI and FSL software. The primary outcome for reward anticipation was the contrast of reward cue compared to neutral cue (reward&gt;neutral cue). The primary imaging outcome was analyzed using a linear mixed model with a single random intercept term treating time as discrete or continuous as appropriate.</description>
          <units>Bold Oxygen-level Dependent (BOLD) Signa</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="21"/>
                <count group_id="O2" value="24"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>baseline</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-0.26" spread="0.69"/>
                    <measurement group_id="O2" value="0.95" spread="0.79"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>5 weeks</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.176" spread="0.81"/>
                    <measurement group_id="O2" value="0.015" spread="0.68"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change in Snaith-Hamilton Pleasure Scale (SHAPS)</title>
        <description>The SHAPS is a well-validated 14-item self-report questionnaire commonly used to assess anhedonia. Each item on the SHAPS is worded so that higher scores indicate greater pleasure capacity. A total score can be derived by summing the responses to each item. Items answered with &quot;strongly agree&quot; are coded as &quot;1&quot;, while a &quot;strongly disagree&quot; response was assigned a score of &quot;4.&quot; Total scores on the SHAPS can range from 14 to 56, with higher scores corresponding to higher levels of anhedonia.</description>
        <time_frame>baseline and 5 weeks</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Ezogabine</title>
            <description>Ezogabine up to 900mg/day daily for 5 weeks</description>
          </group>
          <group group_id="O2">
            <title>Placebo</title>
            <description>Matching placebo pill daily for 5 weeks</description>
          </group>
        </group_list>
        <measure>
          <title>Change in Snaith-Hamilton Pleasure Scale (SHAPS)</title>
          <description>The SHAPS is a well-validated 14-item self-report questionnaire commonly used to assess anhedonia. Each item on the SHAPS is worded so that higher scores indicate greater pleasure capacity. A total score can be derived by summing the responses to each item. Items answered with &quot;strongly agree&quot; are coded as &quot;1&quot;, while a &quot;strongly disagree&quot; response was assigned a score of &quot;4.&quot; Total scores on the SHAPS can range from 14 to 56, with higher scores corresponding to higher levels of anhedonia.</description>
          <units>score on a scale</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="21"/>
                <count group_id="O2" value="24"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Baseline</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="38.7" spread="8.1"/>
                    <measurement group_id="O2" value="33.7" spread="6"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>5 weeks</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="27.5" spread="8.5"/>
                    <measurement group_id="O2" value="30" spread="10.9"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Clinical Global Impression - Improvement (CGI-I)</title>
        <description>A widely administered clinician rated global measure of the degree of improvement from the initial assessment in subject overall illness severity. 7 point scale rated as: 1, very much improved; 2, much improved; 3, minimally improved; 4, no change; 5, minimally worse; 6, much worse; or 7, very much worse.</description>
        <time_frame>baseline and 5 weeks</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Ezogabine</title>
            <description>Ezogabine up to 900mg/day daily for 5 weeks</description>
          </group>
          <group group_id="O2">
            <title>Placebo</title>
            <description>Matching placebo pill daily for 5 weeks</description>
          </group>
        </group_list>
        <measure>
          <title>Clinical Global Impression - Improvement (CGI-I)</title>
          <description>A widely administered clinician rated global measure of the degree of improvement from the initial assessment in subject overall illness severity. 7 point scale rated as: 1, very much improved; 2, much improved; 3, minimally improved; 4, no change; 5, minimally worse; 6, much worse; or 7, very much worse.</description>
          <units>score on a scale</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="21"/>
                <count group_id="O2" value="24"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>baseline</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="4" spread="0.2"/>
                    <measurement group_id="O2" value="4" spread="0.4"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>5 weeks</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2.1" spread="1"/>
                    <measurement group_id="O2" value="2.8" spread="1.3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Clinical Global Impression - Severity (CGI-S)</title>
        <description>Clinician rated global measure of subject overall illness severity. a 7-point scale rated as 1, normal, not at all ill; 2, borderline mentally ill; 3, mildly ill; 4, moderately ill; 5, markedly ill; 6, severely ill; or 7, extremely ill.</description>
        <time_frame>baseline and 5 weeks</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Ezogabine</title>
            <description>Ezogabine up to 900mg/day daily for 5 weeks</description>
          </group>
          <group group_id="O2">
            <title>Placebo</title>
            <description>Matching placebo pill daily for 5 weeks</description>
          </group>
        </group_list>
        <measure>
          <title>Clinical Global Impression - Severity (CGI-S)</title>
          <description>Clinician rated global measure of subject overall illness severity. a 7-point scale rated as 1, normal, not at all ill; 2, borderline mentally ill; 3, mildly ill; 4, moderately ill; 5, markedly ill; 6, severely ill; or 7, extremely ill.</description>
          <units>score on a scale</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="21"/>
                <count group_id="O2" value="24"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>baseline</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="4.4" spread="0.5"/>
                    <measurement group_id="O2" value="4.6" spread="0.6"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>5 weeks</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2.6" spread="1.2"/>
                    <measurement group_id="O2" value="3.3" spread="1.2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Anticipatory and Consummatory Interpersonal Pleasure Scale (ACIPS)</title>
        <description>A measure specifically designed to assess hedonic capacity for social and interpersonal pleasure.The ACIPS is a 17-item self-report measure scored on a likert scale, ranging from 1 (very false for me) to 6 (very true for me). Full scale from 17-102, higher score indicates higher hedonic capacity</description>
        <time_frame>baseline and 5 weeks</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Ezogabine</title>
            <description>Ezogabine up to 900mg/day daily for 5 weeks</description>
          </group>
          <group group_id="O2">
            <title>Placebo</title>
            <description>Matching placebo pill daily for 5 weeks</description>
          </group>
        </group_list>
        <measure>
          <title>Anticipatory and Consummatory Interpersonal Pleasure Scale (ACIPS)</title>
          <description>A measure specifically designed to assess hedonic capacity for social and interpersonal pleasure.The ACIPS is a 17-item self-report measure scored on a likert scale, ranging from 1 (very false for me) to 6 (very true for me). Full scale from 17-102, higher score indicates higher hedonic capacity</description>
          <units>score on a scale</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="21"/>
                <count group_id="O2" value="24"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>baseline</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="46.1" spread="15.1"/>
                    <measurement group_id="O2" value="53.7" spread="15"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>5 weeks</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="65.1" spread="22.8"/>
                    <measurement group_id="O2" value="59" spread="23.5"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Montgomery-Asberg Depression Rating Scale (MADRS)</title>
        <description>A 10-item instrument used for the evaluation of depressive symptoms in adults and for the assessment of any changes to those symptoms. Each items is scored 0 (normal) to 6 (severe depression) with overall score ranges from 0 (normal) to 60 (severe depression).</description>
        <time_frame>baseline and 5 weeks</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Ezogabine</title>
            <description>Ezogabine up to 900mg/day daily for 5 weeks</description>
          </group>
          <group group_id="O2">
            <title>Placebo</title>
            <description>Matching placebo pill daily for 5 weeks</description>
          </group>
        </group_list>
        <measure>
          <title>Montgomery-Asberg Depression Rating Scale (MADRS)</title>
          <description>A 10-item instrument used for the evaluation of depressive symptoms in adults and for the assessment of any changes to those symptoms. Each items is scored 0 (normal) to 6 (severe depression) with overall score ranges from 0 (normal) to 60 (severe depression).</description>
          <units>score on a scale</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="21"/>
                <count group_id="O2" value="24"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>baseline</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="28.3" spread="6.1"/>
                    <measurement group_id="O2" value="26.8" spread="5.1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>5 weeks</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="12.7" spread="8.7"/>
                    <measurement group_id="O2" value="18.5" spread="10.1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>World Health Organization Disability Assessment Schedule 2.0 (WHODAS 2.0)</title>
        <description>A 12-item generic assessment instrument that measures the level of functioning. Each item is scored from 0 to 4 and the items are summed to provide a total score. The score therefore ranges from 0 to 48, with higher scores indicating greater disability.</description>
        <time_frame>baseline and 5 weeks</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Ezogabine</title>
            <description>Ezogabine up to 900mg/day daily for 5 weeks</description>
          </group>
          <group group_id="O2">
            <title>Placebo</title>
            <description>Matching placebo pill daily for 5 weeks</description>
          </group>
        </group_list>
        <measure>
          <title>World Health Organization Disability Assessment Schedule 2.0 (WHODAS 2.0)</title>
          <description>A 12-item generic assessment instrument that measures the level of functioning. Each item is scored from 0 to 4 and the items are summed to provide a total score. The score therefore ranges from 0 to 48, with higher scores indicating greater disability.</description>
          <units>score on a scale</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="21"/>
                <count group_id="O2" value="24"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>baseline</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="15.5" spread="7.5"/>
                    <measurement group_id="O2" value="16.5" spread="9.4"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>5 weeks</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="10.2" spread="9.5"/>
                    <measurement group_id="O2" value="11.6" spread="9.8"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Temporal Experience of Pleasure Scale (TEPS)</title>
        <description>The TEPS is composed of 18-items rated on a likert-type scale ranging from 1 (Very True for me) to 6 (Very False for me), and yields two subscales. Ten items make up the TEPS-Anticipatory Pleasure (TEPS-ANT) scale with a range from 10 (not motivated) to 60 (highly motivated). The other eight TEPS items make up the TEPS-Consummatory Pleasure (TEPS-CON) scale; range from 8 (not responsive) to 48 (highly responsive). Total scores range is 18-108. Lower scores indicate greater levels of anhedonia.</description>
        <time_frame>baseline and 5 weeks</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Ezogabine</title>
            <description>Ezogabine up to 900mg/day daily for 5 weeks</description>
          </group>
          <group group_id="O2">
            <title>Placebo</title>
            <description>Matching placebo pill daily for 5 weeks</description>
          </group>
        </group_list>
        <measure>
          <title>Temporal Experience of Pleasure Scale (TEPS)</title>
          <description>The TEPS is composed of 18-items rated on a likert-type scale ranging from 1 (Very True for me) to 6 (Very False for me), and yields two subscales. Ten items make up the TEPS-Anticipatory Pleasure (TEPS-ANT) scale with a range from 10 (not motivated) to 60 (highly motivated). The other eight TEPS items make up the TEPS-Consummatory Pleasure (TEPS-CON) scale; range from 8 (not responsive) to 48 (highly responsive). Total scores range is 18-108. Lower scores indicate greater levels of anhedonia.</description>
          <units>score on a scale</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="21"/>
                <count group_id="O2" value="24"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>TEPS-ANT baseline</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="26.3" spread="8.3"/>
                    <measurement group_id="O2" value="28.6" spread="8.7"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>TEPS-ANT 5 weeks</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="37.3" spread="10.5"/>
                    <measurement group_id="O2" value="32.4" spread="11.5"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>TEPS-CON baseline</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="24.8" spread="8.1"/>
                    <measurement group_id="O2" value="25.6" spread="7.6"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>TEPS-CON 5 weeks</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="32.2" spread="6"/>
                    <measurement group_id="O2" value="29.9" spread="10.5"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Specific Loss of Interest and Pleasure Scale (SLIPS)</title>
        <description>The SLIPS is a recently developed and validated measure of anhedonia that is tailored to detect recent changes in anhedonia. A 23-item measure, each item range from 0-3. Full scale from 0 to 69, higher score indicates more recent changes.</description>
        <time_frame>baseline 5 weeks</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Ezogabine</title>
            <description>Ezogabine up to 900mg/day daily for 5 weeks</description>
          </group>
          <group group_id="O2">
            <title>Placebo</title>
            <description>Matching placebo pill daily for 5 weeks</description>
          </group>
        </group_list>
        <measure>
          <title>Specific Loss of Interest and Pleasure Scale (SLIPS)</title>
          <description>The SLIPS is a recently developed and validated measure of anhedonia that is tailored to detect recent changes in anhedonia. A 23-item measure, each item range from 0-3. Full scale from 0 to 69, higher score indicates more recent changes.</description>
          <units>score on a scale</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="21"/>
                <count group_id="O2" value="24"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>baseline</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="32.3" spread="9.8"/>
                    <measurement group_id="O2" value="28.8" spread="10.4"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>5 weeks</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="16.3" spread="16.7"/>
                    <measurement group_id="O2" value="21.5" spread="16.8"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>8 weeks</time_frame>
      <group_list>
        <group group_id="E1">
          <title>Ezogabine</title>
          <description>Ezogabine up to 900mg/day daily for 5 weeks</description>
        </group>
        <group group_id="E2">
          <title>Placebo</title>
          <description>Matching placebo pill daily for 5 weeks</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="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="24"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="24"/>
              </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="21" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="19" subjects_at_risk="24"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Cardiac disorders</title>
            <event_list>
              <event>
                <sub_title>Palpitations</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="24"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Eye disorders</title>
            <event_list>
              <event>
                <sub_title>Vision blurred</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="24"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Abdominal Pain</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="24"/>
              </event>
              <event>
                <sub_title>Constipation</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="24"/>
              </event>
              <event>
                <sub_title>Diarrhea</sub_title>
                <counts group_id="E1" subjects_affected="5" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="24"/>
              </event>
              <event>
                <sub_title>Dry mouth</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="24"/>
              </event>
              <event>
                <sub_title>Nausea</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="5" subjects_at_risk="24"/>
              </event>
              <event>
                <sub_title>Vomiting</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="24"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Malaise</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="24"/>
              </event>
              <event>
                <sub_title>Other</sub_title>
                <counts group_id="E1" subjects_affected="9" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="8" subjects_at_risk="24"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Upper respiratory tract infection</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="24"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Metabolism and nutrition disorders</title>
            <event_list>
              <event>
                <sub_title>Increased appetite</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="24"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Back Pain</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="24"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Disturbance in attention</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="24"/>
              </event>
              <event>
                <sub_title>Dizziness</sub_title>
                <counts group_id="E1" subjects_affected="21" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="5" subjects_at_risk="24"/>
              </event>
              <event>
                <sub_title>Headache</sub_title>
                <counts group_id="E1" subjects_affected="5" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="7" subjects_at_risk="24"/>
              </event>
              <event>
                <sub_title>Memory impairment</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="24"/>
              </event>
              <event>
                <sub_title>Sedation</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="24"/>
              </event>
              <event>
                <sub_title>Somnolence</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="24"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Psychiatric disorders</title>
            <event_list>
              <event>
                <sub_title>Anxiety</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="24"/>
              </event>
              <event>
                <sub_title>Confusional state</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="24"/>
              </event>
              <event>
                <sub_title>Panic attack</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="24"/>
              </event>
              <event>
                <sub_title>Restlessness</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="24"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Renal and urinary disorders</title>
            <event_list>
              <event>
                <sub_title>Polyuria</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="24"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Cough</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="24"/>
              </event>
              <event>
                <sub_title>Nasal Congestion</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="24"/>
              </event>
              <event>
                <sub_title>Oropharyngeal pain</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="24"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Skin and subcutaneous tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Rash</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="24"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>Principal Investigators are NOT employed by the organization sponsoring the study.</pi_employee>
      <restrictive_agreement>There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed. </restrictive_agreement>
    </certain_agreements>
    <limitations_and_caveats>The relatively small sample size and termination of enrollment prior to the planned target limit conclusions regarding efficacy and generalizability.</limitations_and_caveats>
    <point_of_contact>
      <name_or_title>Dr, James Murrough</name_or_title>
      <organization>Icahn School of Medicine at Mount Sinai</organization>
      <phone>212-585-4640</phone>
      <email>james.murrough@mssm.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/NCT03043560
org study id: GCO 16-0374
secondary id: 1R61MH111932-01
nct id: NCT03043560
lead sponsor: 
collaborator: 
collaborator: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
This project is designed to examine the neuronal KCNQ2/3 potassium (K+) channel subtype as a
      novel treatment target for mood disorders through the administration of the KCNQ-selective
      channel opener ezogabine (Potiga, GlaxoSmithKline; FDA-approved for the treatment of seizure
      disorders).
Depressive disorders are among the most disabling medical conditions worldwide and currently
      available treatments fall short of addressing this large public health burden. Dysfunction
      within the brain reward system is emerging as a core feature of depressive disorders, in
      particular related to deficits in motivation, interest, and response to pleasure (e.g.,
      anhedonia: markedly diminished response to pleasure). Evidences from a series of preclinical
      studies from our group highlighted the KCNQ subtype of neuronal potassium (K+) channel as a
      novel target for the treatment of depressive disorders and our human pilot study showed a
      reduction in anhedonia and related symptoms, and an increased brain response to reward (as
      measured by functional magnetic resonance imaging [fMRI]) following treatment with ezogabine.
      Building on this data, the current project will assess reward circuit activity following
      treatment with ezogabine in depressed patients with a current depressive disorder (Major
      depressive disorder [MDD], persistent depressive disorder, other specified depressive
      disorder) and anhedonia (defined by a score ≥ 20 on the Snaith-Hamilton Pleasure Scale
      [SHAPS]), using fMRI to investigate the cortico-striatal circuit to reward.

      This study represents the first part of the R61/R33 National Institutes of Health (NIH)
      founded project. A clear increase in reward circuit activation in at least one ezogabine
      treatment group compared to placebo, given acceptable tolerability, will constitute a "go"
      and the project will move to the next phase (R33), where we aim to examine the relationship
      between treatment, reward circuit activity, and behavioral and clinical outcomes in a larger,
      confirmatory efficacy trial of ezogabine for depression with anhedonia.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Other
masking: Double (Participant, Investigator)
masking description: Double blind
measure: Change in Ventral Striatum (VS) Activation
time frame: baseline and 5 weeks
description: change in activation during reward anticipation within the bilateral VS from baseline (Study Visit 0) to the primary outcome visit (Study Visit 5) as measured by functional MRI during the incentive flanker task (IFT). The IFT, like the Monetary Incentive Delay task, permits discrete modeling of brain activity during anticipation of an incentive.
Functional scans were preprocessed and denoised for motion and physiological noise using multi-echo independent component analysis (ME-ICA). Task-based modeling was conducted using AFNI and FSL software. The primary outcome for reward anticipation was the contrast of reward cue compared to neutral cue (reward>neutral cue). The primary imaging outcome was analyzed using a linear mixed model with a single random intercept term treating time as discrete or continuous as appropriate.
measure: Change in Snaith-Hamilton Pleasure Scale (SHAPS)
time frame: baseline and 5 weeks
description: The SHAPS is a well-validated 14-item self-report questionnaire commonly used to assess anhedonia. Each item on the SHAPS is worded so that higher scores indicate greater pleasure capacity. A total score can be derived by summing the responses to each item. Items answered with "strongly agree" are coded as "1", while a "strongly disagree" response was assigned a score of "4." Total scores on the SHAPS can range from 14 to 56, with higher scores corresponding to higher levels of anhedonia.
measure: Clinical Global Impression - Improvement (CGI-I)
time frame: baseline and 5 weeks
description: A widely administered clinician rated global measure of the degree of improvement from the initial assessment in subject overall illness severity. 7 point scale rated as: 1, very much improved; 2, much improved; 3, minimally improved; 4, no change; 5, minimally worse; 6, much worse; or 7, very much worse.
measure: Clinical Global Impression - Severity (CGI-S)
time frame: baseline and 5 weeks
description: Clinician rated global measure of subject overall illness severity. a 7-point scale rated as 1, normal, not at all ill; 2, borderline mentally ill; 3, mildly ill; 4, moderately ill; 5, markedly ill; 6, severely ill; or 7, extremely ill.
measure: Anticipatory and Consummatory Interpersonal Pleasure Scale (ACIPS)
time frame: baseline and 5 weeks
description: A measure specifically designed to assess hedonic capacity for social and interpersonal pleasure.The ACIPS is a 17-item self-report measure scored on a likert scale, ranging from 1 (very false for me) to 6 (very true for me). Full scale from 17-102, higher score indicates higher hedonic capacity
measure: Montgomery-Asberg Depression Rating Scale (MADRS)
time frame: baseline and 5 weeks
description: A 10-item instrument used for the evaluation of depressive symptoms in adults and for the assessment of any changes to those symptoms. Each items is scored 0 (normal) to 6 (severe depression) with overall score ranges from 0 (normal) to 60 (severe depression).
measure: World Health Organization Disability Assessment Schedule 2.0 (WHODAS 2.0)
time frame: baseline and 5 weeks
description: A 12-item generic assessment instrument that measures the level of functioning. Each item is scored from 0 to 4 and the items are summed to provide a total score. The score therefore ranges from 0 to 48, with higher scores indicating greater disability.
measure: Temporal Experience of Pleasure Scale (TEPS)
time frame: baseline and 5 weeks
description: The TEPS is composed of 18-items rated on a likert-type scale ranging from 1 (Very True for me) to 6 (Very False for me), and yields two subscales. Ten items make up the TEPS-Anticipatory Pleasure (TEPS-ANT) scale with a range from 10 (not motivated) to 60 (highly motivated). The other eight TEPS items make up the TEPS-Consummatory Pleasure (TEPS-CON) scale; range from 8 (not responsive) to 48 (highly responsive). Total scores range is 18-108. Lower scores indicate greater levels of anhedonia.
measure: Specific Loss of Interest and Pleasure Scale (SLIPS)
time frame: baseline 5 weeks
description: The SLIPS is a recently developed and validated measure of anhedonia that is tailored to detect recent changes in anhedonia. A 23-item measure, each item range from 0-3. Full scale from 0 to 69, higher score indicates more recent changes.
arm group label: Ezogabine
arm group type: Experimental
description: Participants will receive treatment with ezogabine up to 900mg/day.
arm group label: Placebo
arm group type: Placebo Comparator
description: Participants will receive treatment with a matching placebo pill.
intervention type: Drug
intervention name: Ezogabine
description: daily for 5 weeks
arm group label: Ezogabine
other name: Potiga
intervention type: Drug
intervention name: Placebos
description: placebo pill daily for 5 weeks
arm group label: Placebo
criteria: 
gender: All
minimum age: 18 Years
maximum age: 65 Years
healthy volunteers: No
last name: James Murrough, MD, PhD
role: Principal Investigator
affiliation: Icahn School of Medicine at Mount Sinai
facility: 
facility: 
country: United States
responsible party type: Sponsor-Investigator
investigator affiliation: Icahn School of Medicine at Mount Sinai
investigator full name: James Murrough
investigator title: Associate Professor
mesh term: Anhedonia
mesh term: Depressive Disorder
mesh term: Depression
mesh term: Ezogabine
sharing ipd: Yes
ipd description: Data from this study may be submitted to the National Database for Clinical Research Related to Mental Illness (NDCT). NDCT isa data repository run by the National Institute of Mental Health (NIMH) that allows researchers studying mental illness to collect and share deidentified information with each other. During and after the study, the researchers will send deidentified information about health and behavior and in some cases, genetic information, to NDCT. Other researchers nationwide can then file an application with the NIMH to obtain access to deidentified study data for research purposes.
provided document: 
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
limitations and caveats: The relatively small sample size and termination of enrollment prior to the planned target limit conclusions regarding efficacy and generalizability.
point of contact: 