<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/NCT03243630</url>
  </required_header>
  <id_info>
    <org_study_id>2000021591</org_study_id>
    <secondary_id>1P50DA036151-01</secondary_id>
    <nct_id>NCT03243630</nct_id>
  </id_info>
  <brief_title>Effects of Flavors on Nicotine Reinforcement in Smokers</brief_title>
  <official_title>Effects of Flavors on Nicotine Reinforcement in Smokers</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Yale University</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>National Institute on Drug Abuse (NIDA)</agency>
      <agency_class>NIH</agency_class>
    </collaborator>
  </sponsors>
  <source>Yale 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>
      To examine the acute reinforcing effects of menthol, a fruit flavor (green apple) or a fruit&#xD;
      flavor plus menthol, alone or in combination with nicotine in smokers. Flavors will be&#xD;
      administered by inhalation via electronic cigarettes (e-cigarettes) and nicotine will be&#xD;
      administered intravenously. The reinforcing drug effects will be measured with the drug&#xD;
      effects questionnaire (DEQ).&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This is a proposed double-blind, crossover study that enrolls young adult smokers who prefer&#xD;
      menthol cigarettes. The study will consist of an adaptation session and three test sessions.&#xD;
      In the adaptation session, participants will practice using the e-cigarette by sampling the&#xD;
      flavors to be used in the test sessions. The test sessions will be performed following&#xD;
      overnight abstinence from tobacco. Across the three test sessions, participants will be&#xD;
      assigned to a random sequence of the three different e-cigarette conditions: menthol, green&#xD;
      apple or menthol plus green apple, a different flavor condition for each test session. In&#xD;
      each test session, just after the assigned flavor is delivered via the e-cigarette,&#xD;
      participants will receive a random order of one intravenous delivery of saline, and two&#xD;
      intravenous deliveries of nicotine (3.6 mcg/kg and 7 mcg/kg or 0.25 mg/70 kg and 0.5&#xD;
      mg/70kg), one hour apart. The test sessions will be performed at least 24 hours apart to&#xD;
      minimize carryover nicotine effects. The main outcome measure will be subjective drug effects&#xD;
      as measured with the Drug Effects Questionnaire (DEQ). Other outcomes include cardiovascular&#xD;
      measures, cognitive performance, and self-report measures of nicotine withdrawal and craving.&#xD;
      Cardiovascular measures include heart rate, systolic and diastolic blood pressure. Cognitive&#xD;
      performance will be assessed with the Stroop test, mathematical processing test (MPT), and&#xD;
      continuous performance test (CPT). Nicotine withdrawal measures will be measured with the&#xD;
      Minnesota Nicotine Withdrawal Symptom Checklist (M-NWSC) and the Brief Questionnaire on&#xD;
      Smoking Urges (BQSU).&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">April 23, 2018</start_date>
  <completion_date type="Actual">January 31, 2019</completion_date>
  <primary_completion_date type="Actual">December 19, 2018</primary_completion_date>
  <phase>Early Phase 1</phase>
  <study_type>Interventional</study_type>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Crossover Assignment</intervention_model>
    <intervention_model_description>Mixed-effects models will be used to test the study hypotheses. These models allow for different numbers of observations per subject, use all available data on each subject, and are unaffected by randomly missing data.</intervention_model_description>
    <primary_purpose>Health Services Research</primary_purpose>
    <masking>Double (Participant, Investigator)</masking>
    <masking_description>The participant and medical professional will be blinded to the condition per day.</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>The Reinforcing Drug Effects Will be Measured With the Drug Effects Questionnaire (DEQ).</measure>
    <time_frame>up to 3 hours per test session.</time_frame>
    <description>The (DEQ) Drug Effects Questionnaire has eleven questions with a minimum score of 0 to a maximum score of 100.&#xD;
Peak values from each time points were calculated for the change in the intensity of positive subjective effects as measured with these peak values for like and want more were averaged to obtain a summary score to represent the feel &quot;good drug effects&quot; composite factor. Higher scores for each DEQ represent greater endorsement of that subjective effect (e.g., on the &quot;like drug&quot; scale a response of 90 represents greater liking than a response of 50).</description>
  </primary_outcome>
  <number_of_arms>3</number_of_arms>
  <enrollment type="Actual">26</enrollment>
  <condition>Nicotine Dependence</condition>
  <arm_group>
    <arm_group_label>Menthol e-liquid</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Menthol Flavor + IV saline Menthol Flavor + IV nicotine (0.25mg/70kg) Menthol Flavor + IV nicotine (0.5mg/70kg)</description>
  </arm_group>
  <arm_group>
    <arm_group_label>green apple e-liquid</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Green apple + IV saline Green apple + IV nicotine (0.25mg/70kg) Green apple + IV nicotine (0.5mg/70kg)</description>
  </arm_group>
  <arm_group>
    <arm_group_label>green apple and menthol e-liquid</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Green apple and menthol + IV saline Green apple and menthol + IV nicotine (0.25mg/70kg) Green apple and menthol + IV nicotine (0.5mg/70kg)</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>IV nicotine</intervention_name>
    <description>Subjects in each arm will receive three infusions in a random order one hour apart. The infusions will be saline, 0.25mg/70kg and 0.5mg/70kg</description>
    <arm_group_label>Menthol e-liquid</arm_group_label>
    <arm_group_label>green apple and menthol e-liquid</arm_group_label>
    <arm_group_label>green apple e-liquid</arm_group_label>
    <other_name>nicotine, e-liquid</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Menthol flavor</intervention_name>
    <description>American e-liquids' menthol flavor used in e-cigarettes will be used as the placebo comparator</description>
    <arm_group_label>Menthol e-liquid</arm_group_label>
    <arm_group_label>green apple and menthol e-liquid</arm_group_label>
    <arm_group_label>green apple e-liquid</arm_group_label>
    <other_name>menthol American e-liquids</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>green apple</intervention_name>
    <description>green apple will be added to the menthol flavor</description>
    <arm_group_label>Menthol e-liquid</arm_group_label>
    <arm_group_label>green apple and menthol e-liquid</arm_group_label>
    <arm_group_label>green apple e-liquid</arm_group_label>
    <other_name>green apple American e-liquids</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>green apple and menthol</intervention_name>
    <description>menthol and green apple will be the active intervention</description>
    <arm_group_label>Menthol e-liquid</arm_group_label>
    <arm_group_label>green apple and menthol e-liquid</arm_group_label>
    <arm_group_label>green apple e-liquid</arm_group_label>
    <other_name>green apple and menthol flavor American e-liquids</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
        Female and male mentholated cigarette smokers, aged 18 to 30 years; history of smoking for&#xD;
        the past 12 months, at least one cigarette per day; smoking status is verified with urinary&#xD;
        cotinine levels above 10 ng/ml; not seeking treatment for nicotine dependence at the time&#xD;
        of study entry in good health as verified by medical history, screening examination, and&#xD;
        screening laboratory tests; for women, not pregnant as determined by pregnancy screening,&#xD;
        nor breast feeding, and using acceptable birth control methods.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
        History of major medical illnesses that the physician investigator deems as contraindicated&#xD;
        for the patient to be in the study; regular use of psychotropic medication&#xD;
        (antidepressants, antipsychotics, or anxiolytics); psychiatric diagnosis and / or treatment&#xD;
        for Axis I disorders including major depression, bipolar affective disorder, schizophrenia&#xD;
        or panic disorder in the past month; abuse of alcohol or any other recreational or&#xD;
        prescription drugs in the past 30 days; any allergy to propylene glycol or menthol; and 6)&#xD;
        aversion to green apple flavor.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>30 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Mehmet Sofuoglu, M.D.Ph.D.</last_name>
    <role>Principal Investigator</role>
    <affiliation>Yale University</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Veterans Affairs</name>
      <address>
        <city>West Haven</city>
        <state>Connecticut</state>
        <zip>06516</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>November 2020</verification_date>
  <study_first_submitted>August 4, 2017</study_first_submitted>
  <study_first_submitted_qc>August 8, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">August 9, 2017</study_first_posted>
  <results_first_submitted>July 31, 2020</results_first_submitted>
  <results_first_submitted_qc>October 20, 2020</results_first_submitted_qc>
  <results_first_posted type="Actual">November 13, 2020</results_first_posted>
  <last_update_submitted>November 18, 2020</last_update_submitted>
  <last_update_submitted_qc>November 18, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">December 3, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Yale University</investigator_affiliation>
    <investigator_full_name>Mehmet Sofuoglu</investigator_full_name>
    <investigator_title>Professor of Psychiatry</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Tobacco Use Disorder</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Menthol</mesh_term>
    <mesh_term>Nicotine</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>July 26, 2017</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/30/NCT03243630/Prot_SAP_000.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <recruitment_details>A total of 26 subjects were eligible for participation with 24 randomized after completion of the adaptation session. Reasons for exclusion after adaptation session included poor venous access (n=1) and a positive drug screen (n=1).</recruitment_details>
      <pre_assignment_details>A total of 26 subjects were eligible for participation with 24 randomized after completion of the adaptation session.</pre_assignment_details>
      <group_list>
        <group group_id="P1">
          <title>Study Cohort</title>
          <description>In each test session, the flavor was randomly assigned and delivered via the e-cigarette. Then, participants were randomly assigned to receive one intravenous delivery of saline, and two intravenous deliveries of nicotine (3.6 mcg/kg and 7 mcg/kg or 0.25 mg/70 kg and 0.5 mg/70kg), one hour apart.&#xD;
Menthol Flavor + IV saline Menthol Flavor + IV nicotine (0.25mg/70kg) Menthol Flavor + IV nicotine (0.5mg/70kg)&#xD;
Green Apple Flavor + IV saline Green Apple Flavor + IV nicotine (0.25mg/70kg) Green Apple Flavor + IV nicotine (0.5mg/70kg)&#xD;
Menthol plus Green Apple Flavor + IV saline Menthol plus Green Apple Flavor + IV nicotine (0.25mg/70kg) Menthol plus Green Apple Flavor + IV nicotine (0.5mg/70kg)</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="24"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>Menthol E-liquid Saline</title>
              <participants_list>
                <participants group_id="P1" count="22"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>Menthol E-liquid Higher</title>
              <participants_list>
                <participants group_id="P1" count="22"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>Menthol E-liquid Lower</title>
              <participants_list>
                <participants group_id="P1" count="22"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>Green Apple E-liquid Saline</title>
              <participants_list>
                <participants group_id="P1" count="20"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>Green Apple E-liquid Higher</title>
              <participants_list>
                <participants group_id="P1" count="20"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>Green Apple E-liquid Lower</title>
              <participants_list>
                <participants group_id="P1" count="20"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>Green Apple and Menthol E-liquid Saline</title>
              <participants_list>
                <participants group_id="P1" count="21"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>Green Apple and Menthol E-liquid Higher</title>
              <participants_list>
                <participants group_id="P1" count="21"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>Green Apple and Menthol E-liquid Lower</title>
              <participants_list>
                <participants group_id="P1" count="21"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="22"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="2"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Protocol Violation</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Physician Decision</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>Overall Study</title>
          <description>The baseline characteristics has been provided for the entire study. Test sessions were randomized by arm, each test session was a different arm.</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="24"/>
          </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="26.2" spread="2.4"/>
                  </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="9"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="15"/>
                  </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="6"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Not Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="18"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Race/Ethnicity, Customized</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <title>African American</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="15"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Caucasian</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="7"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Other</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="4"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Hispanic ethnicity</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="6"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Fagerstrom Test of Nicotine Dependence</title>
          <description>The test was designed to provide an ordinal measure of nicotine dependence related to cigarette smoking. It contains six items that evaluate the quantity of cigarette consumption, the compulsion to use, and dependence.&#xD;
In scoring the Fagerstrom Test for Nicotine Dependence, yes/no items are scored from 0 to 1 and multiple-choice items are scored from 0 to 3. A score of 3 greater indicates dependence on nicotine The items are summed to yield a total score of 0-10. The higher the total Fagerström score, the more intense is the patient's physical dependence on nicotine.</description>
          <units>units on a scale</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="3.2" spread="2.1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Average cigarette consumption per day</title>
          <units>cigarette</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="8.3" spread="4.5"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Years of smoking</title>
          <units>years</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="13.2" spread="2.4"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>serum cotinine level</title>
          <units>ng/ml</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="194.4" spread="123.8"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Positive THC at screen</title>
          <units>participants</units>
          <param>Number</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="15"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>The Reinforcing Drug Effects Will be Measured With the Drug Effects Questionnaire (DEQ).</title>
        <description>The (DEQ) Drug Effects Questionnaire has eleven questions with a minimum score of 0 to a maximum score of 100.&#xD;
Peak values from each time points were calculated for the change in the intensity of positive subjective effects as measured with these peak values for like and want more were averaged to obtain a summary score to represent the feel &quot;good drug effects&quot; composite factor. Higher scores for each DEQ represent greater endorsement of that subjective effect (e.g., on the &quot;like drug&quot; scale a response of 90 represents greater liking than a response of 50).</description>
        <time_frame>up to 3 hours per test session.</time_frame>
        <population>Data was analyzed as Intention to Treat</population>
        <group_list>
          <group group_id="O1">
            <title>Menthol E-liquid</title>
            <description>Menthol Flavor + IV saline Menthol Flavor + IV nicotine (0.25mg/70kg) Menthol Flavor + IV nicotine (0.5mg/70kg)&#xD;
IV nicotine: Subjects in each arm will receive three infusions in a random order one hour apart. The infusions will be saline, 0.25mg/70kg and 0.5mg/70kg&#xD;
Menthol flavor: American e-liquids' menthol flavor used in e-cigarettes will be used as the placebo comparator&#xD;
green apple: green apple will be added to the menthol flavor&#xD;
green apple and menthol: menthol and green apple will be the active intervention</description>
          </group>
          <group group_id="O2">
            <title>Green Apple E-liquid</title>
            <description>Green apple + IV saline Green apple + IV nicotine (0.25mg/70kg) Green apple + IV nicotine (0.5mg/70kg)&#xD;
IV nicotine: Subjects in each arm will receive three infusions in a random order one hour apart. The infusions will be saline, 0.25mg/70kg and 0.5mg/70kg&#xD;
Menthol flavor: American e-liquids' menthol flavor used in e-cigarettes will be used as the placebo comparator&#xD;
green apple: green apple will be added to the menthol flavor&#xD;
green apple and menthol: menthol and green apple will be the active intervention</description>
          </group>
          <group group_id="O3">
            <title>Green Apple and Menthol E-liquid</title>
            <description>Green apple and menthol + IV saline Green apple and menthol + IV nicotine (0.25mg/70kg) Green apple and menthol + IV nicotine (0.5mg/70kg)&#xD;
IV nicotine: Subjects in each arm will receive three infusions in a random order one hour apart. The infusions will be saline, 0.25mg/70kg and 0.5mg/70kg&#xD;
Menthol flavor: American e-liquids' menthol flavor used in e-cigarettes will be used as the placebo comparator&#xD;
green apple: green apple will be added to the menthol flavor&#xD;
green apple and menthol: menthol and green apple will be the active intervention</description>
          </group>
        </group_list>
        <measure>
          <title>The Reinforcing Drug Effects Will be Measured With the Drug Effects Questionnaire (DEQ).</title>
          <description>The (DEQ) Drug Effects Questionnaire has eleven questions with a minimum score of 0 to a maximum score of 100.&#xD;
Peak values from each time points were calculated for the change in the intensity of positive subjective effects as measured with these peak values for like and want more were averaged to obtain a summary score to represent the feel &quot;good drug effects&quot; composite factor. Higher scores for each DEQ represent greater endorsement of that subjective effect (e.g., on the &quot;like drug&quot; scale a response of 90 represents greater liking than a response of 50).</description>
          <population>Data was analyzed as Intention to Treat</population>
          <units>units 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="22"/>
                <count group_id="O2" value="20"/>
                <count group_id="O3" value="20"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Higher Nicotine : Max_Cool</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="22"/>
                    <count group_id="O2" value="18"/>
                    <count group_id="O3" value="20"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="43.18" spread="26.49"/>
                    <measurement group_id="O2" value="26.22" spread="25.83"/>
                    <measurement group_id="O3" value="25.20" spread="21.38"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Higher Nicotine : Max_Like</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="22"/>
                    <count group_id="O2" value="18"/>
                    <count group_id="O3" value="20"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="56.00" spread="28.14"/>
                    <measurement group_id="O2" value="53.44" spread="28.03"/>
                    <measurement group_id="O3" value="50.80" spread="34.69"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Higher Nicotine : Max_Dislike</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="22"/>
                    <count group_id="O2" value="18"/>
                    <count group_id="O3" value="20"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="24.36" spread="29.86"/>
                    <measurement group_id="O2" value="25.88" spread="31.41"/>
                    <measurement group_id="O3" value="20.80" spread="27.59"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Higher Nicotine : Max_Craving</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="22"/>
                    <count group_id="O2" value="18"/>
                    <count group_id="O3" value="20"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="41.27" spread="35.29"/>
                    <measurement group_id="O2" value="46.00" spread="36.57"/>
                    <measurement group_id="O3" value="49.90" spread="36.90"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Lower Nicotine: Max_Cool</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="22"/>
                    <count group_id="O2" value="19"/>
                    <count group_id="O3" value="20"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="33.27" spread="26.16"/>
                    <measurement group_id="O2" value="17.47" spread="22.45"/>
                    <measurement group_id="O3" value="25.90" spread="26.66"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Lower Nicotine: Max_Like</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="22"/>
                    <count group_id="O2" value="19"/>
                    <count group_id="O3" value="20"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="46.09" spread="31.02"/>
                    <measurement group_id="O2" value="50.11" spread="30.44"/>
                    <measurement group_id="O3" value="42.90" spread="32.40"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Lower Nicotine: Max_Dislike</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="22"/>
                    <count group_id="O2" value="19"/>
                    <count group_id="O3" value="20"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="13.63" spread="17.48"/>
                    <measurement group_id="O2" value="13.36" spread="21.65"/>
                    <measurement group_id="O3" value="14.50" spread="23.45"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Lower Nicotine: Max_Craving</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="22"/>
                    <count group_id="O2" value="20"/>
                    <count group_id="O3" value="20"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="48.00" spread="35.69"/>
                    <measurement group_id="O2" value="53.16" spread="37.34"/>
                    <measurement group_id="O3" value="49.00" spread="37.95"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Saline: Max_Cool</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="22"/>
                    <count group_id="O2" value="20"/>
                    <count group_id="O3" value="20"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="31.45" spread="21.97"/>
                    <measurement group_id="O2" value="15.50" spread="20.56"/>
                    <measurement group_id="O3" value="24.60" spread="22.96"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Saline: Max_Like</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="22"/>
                    <count group_id="O2" value="20"/>
                    <count group_id="O3" value="20"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="33.00" spread="30.67"/>
                    <measurement group_id="O2" value="35.80" spread="31.65"/>
                    <measurement group_id="O3" value="32.90" spread="27.04"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Saline: Max_Dislike</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="22"/>
                    <count group_id="O2" value="20"/>
                    <count group_id="O3" value="20"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="8.72" spread="12.64"/>
                    <measurement group_id="O2" value="15.50" spread="23.75"/>
                    <measurement group_id="O3" value="14.40" spread="23.79"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Saline: Max_Craving</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="22"/>
                    <count group_id="O2" value="20"/>
                    <count group_id="O3" value="20"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="46.09" spread="39.44"/>
                    <measurement group_id="O2" value="57.70" spread="36.60"/>
                    <measurement group_id="O3" value="55.80" spread="38.24"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>The SAFTEE is a technique for the systematic assessment of side effects in clinical trials developed by National Institute of Mental Health This was used before each Test Session and after each test session participants were observed no more than one month. There were no adverse events reported.</time_frame>
      <desc>The SAFTEE is a technique for the systematic assessment of side effects in clinical trials developed by National Institute of Mental Health</desc>
      <group_list>
        <group group_id="E1">
          <title>Menthol E-liquid</title>
          <description>Menthol Flavor + IV saline Menthol Flavor + IV nicotine (0.25mg/70kg) Menthol Flavor + IV nicotine (0.5mg/70kg)&#xD;
IV nicotine: Subjects in each arm will receive three infusions in a random order one hour apart. The infusions will be saline, 0.25mg/70kg and 0.5mg/70kg&#xD;
Menthol flavor: American e-liquids' menthol flavor used in e-cigarettes will be used as the placebo comparator&#xD;
green apple: green apple will be added to the menthol flavor&#xD;
green apple and menthol: menthol and green apple will be the active intervention</description>
        </group>
        <group group_id="E2">
          <title>Green Apple E-liquid</title>
          <description>Green apple + IV saline Green apple + IV nicotine (0.25mg/70kg) Green apple + IV nicotine (0.5mg/70kg)&#xD;
IV nicotine: Subjects in each arm will receive three infusions in a random order one hour apart. The infusions will be saline, 0.25mg/70kg and 0.5mg/70kg&#xD;
Menthol flavor: American e-liquids' menthol flavor used in e-cigarettes will be used as the placebo comparator&#xD;
green apple: green apple will be added to the menthol flavor&#xD;
green apple and menthol: menthol and green apple will be the active intervention</description>
        </group>
        <group group_id="E3">
          <title>Green Apple and Menthol E-liquid</title>
          <description>Green apple and menthol + IV saline Green apple and menthol + IV nicotine (0.25mg/70kg) Green apple and menthol + IV nicotine (0.5mg/70kg)&#xD;
IV nicotine: Subjects in each arm will receive three infusions in a random order one hour apart. The infusions will be saline, 0.25mg/70kg and 0.5mg/70kg&#xD;
Menthol flavor: American e-liquids' menthol flavor used in e-cigarettes will be used as the placebo comparator&#xD;
green apple: green apple will be added to the menthol flavor&#xD;
green apple and menthol: menthol and green apple will be the active intervention</description>
        </group>
      </group_list>
      <serious_events>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, all-cause mortality</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="22"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="20"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="22"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="20"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="20"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>0</frequency_threshold>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="22"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="18"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="20"/>
              </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>
    <point_of_contact>
      <name_or_title>Mehmet Sofuoglu</name_or_title>
      <organization>Yale University</organization>
      <phone>203-932-5711 ext 4809</phone>
      <email>mehmet.sofuoglu@yale.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/NCT03243630
org study id: 2000021591
secondary id: 1P50DA036151-01
nct id: NCT03243630
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
To examine the acute reinforcing effects of menthol, a fruit flavor (green apple) or a fruit
      flavor plus menthol, alone or in combination with nicotine in smokers. Flavors will be
      administered by inhalation via electronic cigarettes (e-cigarettes) and nicotine will be
      administered intravenously. The reinforcing drug effects will be measured with the drug
      effects questionnaire (DEQ).
This is a proposed double-blind, crossover study that enrolls young adult smokers who prefer
      menthol cigarettes. The study will consist of an adaptation session and three test sessions.
      In the adaptation session, participants will practice using the e-cigarette by sampling the
      flavors to be used in the test sessions. The test sessions will be performed following
      overnight abstinence from tobacco. Across the three test sessions, participants will be
      assigned to a random sequence of the three different e-cigarette conditions: menthol, green
      apple or menthol plus green apple, a different flavor condition for each test session. In
      each test session, just after the assigned flavor is delivered via the e-cigarette,
      participants will receive a random order of one intravenous delivery of saline, and two
      intravenous deliveries of nicotine (3.6 mcg/kg and 7 mcg/kg or 0.25 mg/70 kg and 0.5
      mg/70kg), one hour apart. The test sessions will be performed at least 24 hours apart to
      minimize carryover nicotine effects. The main outcome measure will be subjective drug effects
      as measured with the Drug Effects Questionnaire (DEQ). Other outcomes include cardiovascular
      measures, cognitive performance, and self-report measures of nicotine withdrawal and craving.
      Cardiovascular measures include heart rate, systolic and diastolic blood pressure. Cognitive
      performance will be assessed with the Stroop test, mathematical processing test (MPT), and
      continuous performance test (CPT). Nicotine withdrawal measures will be measured with the
      Minnesota Nicotine Withdrawal Symptom Checklist (M-NWSC) and the Brief Questionnaire on
      Smoking Urges (BQSU).
allocation: Randomized
intervention model: Crossover Assignment
intervention model description: Mixed-effects models will be used to test the study hypotheses. These models allow for different numbers of observations per subject, use all available data on each subject, and are unaffected by randomly missing data.
primary purpose: Health Services Research
masking: Double (Participant, Investigator)
masking description: The participant and medical professional will be blinded to the condition per day.
measure: The Reinforcing Drug Effects Will be Measured With the Drug Effects Questionnaire (DEQ).
time frame: up to 3 hours per test session.
description: The (DEQ) Drug Effects Questionnaire has eleven questions with a minimum score of 0 to a maximum score of 100.
Peak values from each time points were calculated for the change in the intensity of positive subjective effects as measured with these peak values for like and want more were averaged to obtain a summary score to represent the feel "good drug effects" composite factor. Higher scores for each DEQ represent greater endorsement of that subjective effect (e.g., on the "like drug" scale a response of 90 represents greater liking than a response of 50).
arm group label: Menthol e-liquid
arm group type: Placebo Comparator
description: Menthol Flavor + IV saline Menthol Flavor + IV nicotine (0.25mg/70kg) Menthol Flavor + IV nicotine (0.5mg/70kg)
arm group label: green apple e-liquid
arm group type: Active Comparator
description: Green apple + IV saline Green apple + IV nicotine (0.25mg/70kg) Green apple + IV nicotine (0.5mg/70kg)
arm group label: green apple and menthol e-liquid
arm group type: Active Comparator
description: Green apple and menthol + IV saline Green apple and menthol + IV nicotine (0.25mg/70kg) Green apple and menthol + IV nicotine (0.5mg/70kg)
intervention type: Drug
intervention name: IV nicotine
description: Subjects in each arm will receive three infusions in a random order one hour apart. The infusions will be saline, 0.25mg/70kg and 0.5mg/70kg
arm group label: Menthol e-liquid
arm group label: green apple and menthol e-liquid
arm group label: green apple e-liquid
other name: nicotine, e-liquid
intervention type: Drug
intervention name: Menthol flavor
description: American e-liquids' menthol flavor used in e-cigarettes will be used as the placebo comparator
arm group label: Menthol e-liquid
arm group label: green apple and menthol e-liquid
arm group label: green apple e-liquid
other name: menthol American e-liquids
intervention type: Drug
intervention name: green apple
description: green apple will be added to the menthol flavor
arm group label: Menthol e-liquid
arm group label: green apple and menthol e-liquid
arm group label: green apple e-liquid
other name: green apple American e-liquids
intervention type: Drug
intervention name: green apple and menthol
description: menthol and green apple will be the active intervention
arm group label: Menthol e-liquid
arm group label: green apple and menthol e-liquid
arm group label: green apple e-liquid
other name: green apple and menthol flavor American e-liquids
criteria: 
gender: All
minimum age: 18 Years
maximum age: 30 Years
healthy volunteers: No
last name: Mehmet Sofuoglu, M.D.Ph.D.
role: Principal Investigator
affiliation: Yale University
facility: 
country: United States
responsible party type: Principal Investigator
investigator affiliation: Yale University
investigator full name: Mehmet Sofuoglu
investigator title: Professor of Psychiatry
mesh term: Tobacco Use Disorder
mesh term: Menthol
mesh term: Nicotine
sharing ipd: No
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 