<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/NCT02232737</url>
  </required_header>
  <id_info>
    <org_study_id>P50DA036114:P3S2</org_study_id>
    <secondary_id>P50DA036114</secondary_id>
    <nct_id>NCT02232737</nct_id>
  </id_info>
  <brief_title>Project 3, Study 2: Extended Exposure to Low Nicotine Content Cigarettes in People With Current Affective Disorders</brief_title>
  <official_title>Project 3, Study 2: Extended Exposure to Low Nicotine Content Cigarettes in People With Current Affective Disorders</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Brown University</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>University of Vermont</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>National Institute on Drug Abuse (NIDA)</agency>
      <agency_class>NIH</agency_class>
    </collaborator>
  </sponsors>
  <source>Brown University</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      This study will examine extended exposure to cigarettes varying in nicotine content among&#xD;
      disadvantaged women. Adults with affective disorders are at increased risk for smoking,&#xD;
      nicotine dependence, and using high nicotine yield cigarettes and are also at significantly&#xD;
      increased risk for smoking-related adverse health consequences, including site-specific&#xD;
      cancers, heart disease, and premature death. Studies testing an innovative regulatory&#xD;
      strategy of reducing the nicotine content of cigarettes to a non-addictive level have shown&#xD;
      promising beneficial effects (decreased smoking rate, reduced toxicant exposure, and&#xD;
      increased cessation) in the general population of smokers. However, these studies have&#xD;
      uniformly excluded vulnerable populations like those with affective disorders who may respond&#xD;
      differently considering their greater vulnerability to smoking and nicotine dependence. Thus,&#xD;
      little is known scientifically about how this highly vulnerable subgroup of smokers might&#xD;
      respond to a nicotine reduction policy. This project is designed to address that substantial&#xD;
      knowledge gap. This same study was also conducted in two additional vulnerable populations&#xD;
      under a similar protocol.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The primary overall objective of these studies is to evaluate the effects of extended&#xD;
      exposure to cigarettes differing in nicotine content in adult men and women with affective&#xD;
      disorders using a 3-condition, parallel groups design. After a baseline period in which daily&#xD;
      smoking rate and other baseline assessments are completed, participants will be randomly&#xD;
      assigned to one of three cigarette conditions (nicotine content: 0.03, 0.12, and 0.8 mg&#xD;
      nicotine of tobacco) for the 12-week experimental period.&#xD;
&#xD;
      The cigarettes to be used in this study were made under an NIH contract with production being&#xD;
      overseen by the Research Triangle Institute (referred to as &quot;Spectrum cigarettes&quot;). NIH&#xD;
      currently has approximately 10 million of these cigarettes (of varying types) for research&#xD;
      purposes. The cigarettes selected for the study span the range of yields likely to produce&#xD;
      the hypothesized effects, as described above. The Spectrum cigarettes are not currently&#xD;
      commercially available, although they are similar in many ways to marketed cigarettes (e.g.,&#xD;
      similar manufacturing, filter, paper, etc.).&#xD;
&#xD;
      The primary overall objective of this study is to evaluate the effects of extended exposure&#xD;
      to cigarettes differing in nicotine content in adult men and women with affective disorders&#xD;
      using a 3-condition, parallel groups design. After a baseline period in which daily smoking&#xD;
      rate and other baseline assessments are completed, participants will be randomly assigned to&#xD;
      one of three cigarette conditions (nicotine content: 0.03 mg, 0.12 mg, and 0.8 mg nicotine of&#xD;
      tobacco) for the 12-week experimental period.&#xD;
&#xD;
      Participants will be seen weekly throughout the 12-week experimental period to obtain&#xD;
      research cigarettes. Cigarettes smoked per day will be obtained by participants completing&#xD;
      daily Interactive Voice Response (IVR) reports of cigarettes in past 24 hours. This daily&#xD;
      data will be used to calculate weekly means, with week-12 means serving as the primary&#xD;
      outcome.&#xD;
&#xD;
      This same study was conducted in two additional vulnerable populations under a similar&#xD;
      protocol, with differences between protocols consisting of data collection specific to that&#xD;
      vulnerable population. This included information such as use and timing of opioid maintenance&#xD;
      therapy for individuals with opioid-use disorder and other measures relevant to disadvantaged&#xD;
      women of reproductive age. In order to explore potential differences across individuals with&#xD;
      different vulnerabilities, data from all three studies were combined for analysis. A&#xD;
      vulnerable population-by-condition or population-by-condition-by-time interaction term was&#xD;
      included in all analyses. In the event that these interaction terms were statistically&#xD;
      significant, all pairwise comparisons were conducted using a Bonferroni multiple comparison&#xD;
      adjustment.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">October 7, 2016</start_date>
  <completion_date type="Actual">January 14, 2019</completion_date>
  <primary_completion_date type="Actual">January 14, 2019</primary_completion_date>
  <phase>Phase 1/Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <intervention_model_description>This study was one of three multi-site clinical trials conducted in three different vulnerable populations under a similar protocol, with differences between protocols consisting of data collection specific to that vulnerable population. This included information such as use and timing of opioid maintenance therapy for individuals with opioid-use disorder or additional assessments related to disadvantaged women of reproductive age. In order to explore potential differences across individuals with different vulnerabilities, data from all three studies were combined for analysis. A vulnerable population-by-condition or population-by- condition-by-time interaction term was included in all analyses. In the event that these interaction terms were statistically significant, all pairwise comparisons were conducted using a Bonferroni multiple comparison adjustment. Please see Statistical Analysis Plan for more details.</intervention_model_description>
    <primary_purpose>Basic Science</primary_purpose>
    <masking>Double (Participant, Investigator)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Cigarettes Per Day (CPD)</measure>
    <time_frame>12 weeks</time_frame>
    <description>Participant reported number of cigarettes smoked per day at Week 12</description>
  </primary_outcome>
  <number_of_arms>3</number_of_arms>
  <enrollment type="Actual">775</enrollment>
  <condition>Tobacco Use Disorder</condition>
  <arm_group>
    <arm_group_label>0.8 mg nicotine</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>0.8 mg nicotine cigarettes</description>
  </arm_group>
  <arm_group>
    <arm_group_label>0.12 mg nicotine</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>0.12 mg nicotine cigarettes</description>
  </arm_group>
  <arm_group>
    <arm_group_label>0.03 mg nicotine</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>0.03 mg nicotine cigarettes</description>
  </arm_group>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Very low nicotine content cigarettes</intervention_name>
    <arm_group_label>0.03 mg nicotine</arm_group_label>
    <arm_group_label>0.12 mg nicotine</arm_group_label>
    <arm_group_label>0.8 mg nicotine</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Male or Female&#xD;
&#xD;
          -  Ages 18-70&#xD;
&#xD;
          -  Past-year major depressive disorder, dysthymic disorder, generalized anxiety disorder,&#xD;
             post-traumatic stress disorder, obsessive-compulsive disorder, phobia, or panic&#xD;
             disorder with or without agoraphobia, based on Mini-Neuropsychiatric Interview (MINI)&#xD;
             structured interview, OR lifetime diagnosis of one of the above based on MINI with a&#xD;
             self-report of currently receiving treatment (prescribed psychoactive medication,&#xD;
             behavioral therapy, etc.)&#xD;
&#xD;
          -  Report smoking 5 or more cigarettes per day for the past year&#xD;
&#xD;
          -  Provide an intake breath Carbon Monoxide (CO) sample &gt; 8 ppm&#xD;
&#xD;
          -  Be without current substance abuse/dependence other than nicotine&#xD;
&#xD;
          -  Be sufficiently literate to complete the research-related tasks&#xD;
&#xD;
          -  Be in good physical health without serious illness or change in health in the past 3&#xD;
             months as determined by the licensed medical professional at each site&#xD;
&#xD;
          -  Not pregnant or nursing and report using oral, implant, patch, ring, intrauterine&#xD;
             device (IUD), injection or barrier contraceptives or report being surgically sterile&#xD;
             or post-menopausal&#xD;
&#xD;
          -  Report no significant use of other tobacco or nicotine products within the past month&#xD;
             (&gt; 9 days in the past 30)&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Any prior regular use (used as primary cigarette outside of the laboratory) of&#xD;
             Spectrum cigarettes (i.e., research cigarettes with reduced nicotine content)&#xD;
&#xD;
          -  Exclusive use of roll-your-own cigarettes&#xD;
&#xD;
          -  Planning to quit smoking in the next 30 days&#xD;
&#xD;
          -  A quit attempt in the past 30 days resulting in &gt; 3 days of abstinence&#xD;
&#xD;
          -  Positive toxicology screen for illicit drugs not including marijuana (participants&#xD;
             with valid prescriptions will not be excluded and participants with a positive&#xD;
             toxicology screen will be allowed to re-screen once)&#xD;
&#xD;
          -  Breath alcohol level &gt; 0.01 (participants with a positive screen will be allowed to&#xD;
             re-screen once)&#xD;
&#xD;
          -  Self-report of binge drinking alcohol (&gt; 9 days in the past 30, 4/5 drinks in 2 hours&#xD;
             for women/men&#xD;
&#xD;
          -  Systolic blood pressure below 90 mmHg or greater than or equal to 160 mmHg&#xD;
             (participants outside the range will be allowed to re-screen once)&#xD;
&#xD;
          -  Diastolic blood pressure below 50 mmHg or greater than or equal to 100 mmHg&#xD;
             (participants outside the range will be allowed to re-screen once)&#xD;
&#xD;
          -  Breath CO &gt; 80 ppm&#xD;
&#xD;
          -  Heart rate below 45 or greater than or equal to 115 bpm (participants outside the&#xD;
             range will be allowed to re-screen once)&#xD;
&#xD;
          -  Currently seeking treatment for smoking cessation&#xD;
&#xD;
          -  Have used nicotine replacement, bupropion or other pharmacotherapies as cessation aids&#xD;
             in the past month (bupropion for treatment of depression will be allowed)&#xD;
&#xD;
          -  Unstable psychiatric conditions (psychiatric medication changes in the past 4 weeks)&#xD;
&#xD;
          -  Current symptoms of psychosis, dementia or mania&#xD;
&#xD;
          -  Suicidal ideation in past month&#xD;
&#xD;
          -  Suicide attempt in past 6 months&#xD;
&#xD;
          -  Participation in another research study in the past 30 days&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>70 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Stephen T Higgins, PhD</last_name>
    <role>Study Director</role>
    <affiliation>University of Vermont</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Brown University</name>
      <address>
        <city>Providence</city>
        <state>Rhode Island</state>
        <zip>02912</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Vermont</name>
      <address>
        <city>Burlington</city>
        <state>Vermont</state>
        <zip>05401</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>October 2022</verification_date>
  <study_first_submitted>September 3, 2014</study_first_submitted>
  <study_first_submitted_qc>September 4, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">September 5, 2014</study_first_posted>
  <results_first_submitted>October 11, 2022</results_first_submitted>
  <results_first_submitted_qc>November 15, 2022</results_first_submitted_qc>
  <results_first_posted type="Actual">December 7, 2022</results_first_posted>
  <last_update_submitted>November 15, 2022</last_update_submitted>
  <last_update_submitted_qc>November 15, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">December 7, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Brown University</investigator_affiliation>
    <investigator_full_name>Jennifer Tidey</investigator_full_name>
    <investigator_title>Professor (Research)</investigator_title>
  </responsible_party>
  <keyword>Biomarkers of exposure</keyword>
  <keyword>Compensatory smoking</keyword>
  <keyword>Nicotine dependence</keyword>
  <keyword>Reduced nicotine cigarettes</keyword>
  <keyword>Tobacco withdrawal</keyword>
  <keyword>Women</keyword>
  <keyword>Health disparities</keyword>
  <keyword>Vulnerable populations</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Tobacco Use Disorder</mesh_term>
    <mesh_term>Mood Disorders</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Nicotine</mesh_term>
  </intervention_browse>
  <provided_document_section>
    <provided_document>
      <document_type>Study Protocol and Statistical Analysis Plan</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>February 9, 2018</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/37/NCT02232737/Prot_SAP_000.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <group_list>
        <group group_id="P1">
          <title>0.8 mg Nicotine</title>
          <description>0.8 mg nicotine cigarettes&#xD;
Very low nicotine content cigarettes</description>
        </group>
        <group group_id="P2">
          <title>0.12 mg Nicotine</title>
          <description>0.12 mg nicotine cigarettes&#xD;
Very low nicotine content cigarettes</description>
        </group>
        <group group_id="P3">
          <title>0.03 mg Nicotine</title>
          <description>0.03 mg nicotine cigarettes&#xD;
Very low nicotine content cigarettes</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="254"/>
                <participants group_id="P2" count="235"/>
                <participants group_id="P3" count="286"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="218"/>
                <participants group_id="P2" count="190"/>
                <participants group_id="P3" count="224"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="36"/>
                <participants group_id="P2" count="45"/>
                <participants group_id="P3" count="62"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Lost to Follow-up</title>
              <participants_list>
                <participants group_id="P1" count="18"/>
                <participants group_id="P2" count="28"/>
                <participants group_id="P3" count="33"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Personal reasons</title>
              <participants_list>
                <participants group_id="P1" count="7"/>
                <participants group_id="P2" count="8"/>
                <participants group_id="P3" count="14"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Adverse Event</title>
              <participants_list>
                <participants group_id="P1" count="6"/>
                <participants group_id="P2" count="3"/>
                <participants group_id="P3" count="8"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Incarcerated</title>
              <participants_list>
                <participants group_id="P1" count="2"/>
                <participants group_id="P2" count="1"/>
                <participants group_id="P3" count="2"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Withdrawal by Subject</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="1"/>
                <participants group_id="P3" count="2"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Death</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="1"/>
                <participants group_id="P3" count="1"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Physician Decision</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="3"/>
                <participants group_id="P3" count="1"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Protocol Violation</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="1"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Reason unknown</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>0.8 mg Nicotine</title>
          <description>0.8 mg nicotine cigarettes&#xD;
Very low nicotine content cigarettes</description>
        </group>
        <group group_id="B2">
          <title>0.12 mg Nicotine</title>
          <description>0.12 mg nicotine cigarettes&#xD;
Very low nicotine content cigarettes</description>
        </group>
        <group group_id="B3">
          <title>0.03 mg Nicotine</title>
          <description>0.03 mg nicotine cigarettes&#xD;
Very low nicotine content cigarettes</description>
        </group>
        <group group_id="B4">
          <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="254"/>
            <count group_id="B2" value="235"/>
            <count group_id="B3" value="286"/>
            <count group_id="B4" value="775"/>
          </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="35.90" spread="10.82"/>
                    <measurement group_id="B2" value="35.18" spread="11.13"/>
                    <measurement group_id="B3" value="35.65" spread="11.21"/>
                    <measurement group_id="B4" value="35.59" spread="11.05"/>
                  </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="184"/>
                    <measurement group_id="B2" value="167"/>
                    <measurement group_id="B3" value="200"/>
                    <measurement group_id="B4" value="551"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="70"/>
                    <measurement group_id="B2" value="68"/>
                    <measurement group_id="B3" value="86"/>
                    <measurement group_id="B4" value="224"/>
                  </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>Non-Latino White</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="207"/>
                    <measurement group_id="B2" value="183"/>
                    <measurement group_id="B3" value="240"/>
                    <measurement group_id="B4" value="630"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Non-Latino Black</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="24"/>
                    <measurement group_id="B2" value="25"/>
                    <measurement group_id="B3" value="19"/>
                    <measurement group_id="B4" value="68"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Latino</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="7"/>
                    <measurement group_id="B2" value="8"/>
                    <measurement group_id="B3" value="8"/>
                    <measurement group_id="B4" value="23"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Non-Latino Other</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="12"/>
                    <measurement group_id="B2" value="18"/>
                    <measurement group_id="B3" value="16"/>
                    <measurement group_id="B4" value="46"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Unknown</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="4"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="3"/>
                    <measurement group_id="B4" value="8"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Region of Enrollment</title>
          <units>participants</units>
          <param>Number</param>
          <class_list>
            <class>
              <title>United States</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="254"/>
                    <measurement group_id="B2" value="235"/>
                    <measurement group_id="B3" value="286"/>
                    <measurement group_id="B4" value="775"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Cigarettes Per Day</title>
          <units>Cigarettes Per Day</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="19.63" spread="10.33"/>
                    <measurement group_id="B2" value="19.54" spread="10.56"/>
                    <measurement group_id="B3" value="19.91" spread="10.84"/>
                    <measurement group_id="B4" value="19.71" spread="10.58"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Cigarettes Per Day (CPD)</title>
        <description>Participant reported number of cigarettes smoked per day at Week 12</description>
        <time_frame>12 weeks</time_frame>
        <population>Participants who completed Week 12</population>
        <group_list>
          <group group_id="O1">
            <title>0.8 mg Nicotine</title>
            <description>0.8 mg nicotine cigarettes&#xD;
Very low nicotine content cigarettes</description>
          </group>
          <group group_id="O2">
            <title>0.12 mg Nicotine</title>
            <description>0.12 mg nicotine cigarettes&#xD;
Very low nicotine content cigarettes</description>
          </group>
          <group group_id="O3">
            <title>0.03 mg Nicotine</title>
            <description>0.03 mg nicotine cigarettes&#xD;
Very low nicotine content cigarettes</description>
          </group>
        </group_list>
        <measure>
          <title>Cigarettes Per Day (CPD)</title>
          <description>Participant reported number of cigarettes smoked per day at Week 12</description>
          <population>Participants who completed Week 12</population>
          <units>cigarettes per day</units>
          <param>Least Squares Mean</param>
          <dispersion>Standard Error</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="218"/>
                <count group_id="O2" value="190"/>
                <count group_id="O3" value="224"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="25.28" spread="0.77"/>
                    <measurement group_id="O2" value="19.95" spread="0.80"/>
                    <measurement group_id="O3" value="17.74" spread="0.74"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>The statistical analysis method was ANCOVA, in order to test for statistically significant differences between group means, while controlling for covariates of interest. It was calculated that 207 subjects per group would be required to have at least 90% power to detect a mean difference of 4.52 CPD between the 0.8 mg and 0.12 mg groups at week 12, with significance level alpha of 0.0167. The significance level reflects the Bonferroni correction needed for testing of all pairwise comparisons.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>&lt;0.0001</p_value>
            <p_value_desc>The p-value is Bonferroni-corrected for multiple comparisons with a priori threshold of significance P &lt; 0.0167</p_value_desc>
            <method>ANCOVA</method>
            <param_type>Mean Difference (Net)</param_type>
            <param_value>-5.33</param_value>
            <dispersion_type>Standard Error of the Mean</dispersion_type>
            <dispersion_value>1.06</dispersion_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-7.41</ci_lower_limit>
            <ci_upper_limit>-3.26</ci_upper_limit>
            <estimate_desc>Group difference = 0.12 mg nicotine - 0.8 mg nicotine</estimate_desc>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O3</group_id>
            </group_id_list>
            <groups_desc>The statistical analysis method was ANCOVA, in order to test for statistically significant differences between group means, while controlling for covariates of interest. It was calculated that 207 subjects per group would be required to have at least 90% power to detect a mean difference of 4.52 CPD between the 0.8 mg and 0.12 mg groups at week 12, with significance level alpha of 0.0167. The significance level reflects the Bonferroni correction needed for testing of all pairwise comparisons.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>&lt;0.0001</p_value>
            <p_value_desc>The p-value is Bonferroni-corrected for multiple comparisons with a priori threshold of significance P &lt; 0.0167</p_value_desc>
            <method>ANCOVA</method>
            <param_type>Mean Difference (Net)</param_type>
            <param_value>-7.54</param_value>
            <dispersion_type>Standard Error of the Mean</dispersion_type>
            <dispersion_value>1.00</dispersion_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-9.51</ci_lower_limit>
            <ci_upper_limit>-5.57</ci_upper_limit>
            <estimate_desc>Group difference = 0.03 mg nicotine - 0.8 mg nicotine</estimate_desc>
          </analysis>
        </analysis_list>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>12 weeks</time_frame>
      <group_list>
        <group group_id="E1">
          <title>0.8 mg Nicotine</title>
          <description>0.8 mg nicotine cigarettes&#xD;
Very low nicotine content cigarettes</description>
        </group>
        <group group_id="E2">
          <title>0.12 mg Nicotine</title>
          <description>0.12 mg nicotine cigarettes&#xD;
Very low nicotine content cigarettes</description>
        </group>
        <group group_id="E3">
          <title>0.03 mg Nicotine</title>
          <description>0.03 mg nicotine cigarettes&#xD;
Very low nicotine content cigarettes</description>
        </group>
      </group_list>
      <serious_events>
        <default_vocab>CTCAE (5.0)</default_vocab>
        <default_assessment>Systematic Assessment</default_assessment>
        <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="254"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="235"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="286"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="13" subjects_at_risk="254"/>
                <counts group_id="E2" subjects_affected="4" subjects_at_risk="235"/>
                <counts group_id="E3" subjects_affected="13" subjects_at_risk="286"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Cardiac disorders</title>
            <event_list>
              <event>
                <sub_title>Sudden onset of chest pain due to not enough blood going to the heart</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="254"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="235"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="286"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Eye disorders</title>
            <event_list>
              <event>
                <sub_title>Blurred vision</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="254"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="235"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="286"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Bloody stool</sub_title>
                <description>Diarrhea, stomach pain, vomiting</description>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="254"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="235"/>
                <counts group_id="E3" events="4" subjects_affected="1" subjects_at_risk="286"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Kidney infection</sub_title>
                <description>Cellulitis, Hepatitis B infection, Hepatitis C infection</description>
                <counts group_id="E1" events="4" subjects_affected="3" subjects_at_risk="254"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="235"/>
                <counts group_id="E3" events="2" subjects_affected="1" subjects_at_risk="286"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Injury, poisoning and procedural complications</title>
            <event_list>
              <event>
                <sub_title>Broken bone</sub_title>
                <description>Bruising</description>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="254"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="235"/>
                <counts group_id="E3" events="7" subjects_affected="2" subjects_at_risk="286"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>Frontal lobe lesion</sub_title>
                <description>Knee sprain</description>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="254"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="235"/>
                <counts group_id="E3" events="2" subjects_affected="1" subjects_at_risk="286"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Metabolism and nutrition disorders</title>
            <event_list>
              <event>
                <sub_title>Diabetes Type 2</sub_title>
                <description>Hyperglycemia</description>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="254"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="235"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="286"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Tenosynovitis of the Hand</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="254"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="235"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="286"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Seizure</sub_title>
                <description>Stroke</description>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="254"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="235"/>
                <counts group_id="E3" events="5" subjects_affected="3" subjects_at_risk="286"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Psychiatric disorders</title>
            <event_list>
              <event>
                <sub_title>Anxiety, feelings of dread or danger</sub_title>
                <description>Depression, Thoughts of taking one's own life</description>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="254"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="235"/>
                <counts group_id="E3" events="2" subjects_affected="2" subjects_at_risk="286"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Renal and urinary disorders</title>
            <event_list>
              <event>
                <sub_title>Acute renal failure</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="254"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="235"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="286"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Skin and subcutaneous tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Skin graft to wound on leg</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="254"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="235"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="286"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Surgical and medical procedures</title>
            <event_list>
              <event>
                <sub_title>Neurosurgery</sub_title>
                <description>Hospitalization due to increased pain</description>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="254"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="235"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="286"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Vascular disorders</title>
            <event_list>
              <event>
                <sub_title>High blood pressure</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="254"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="235"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="286"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>5</frequency_threshold>
        <default_vocab>CTCAE (5.0)</default_vocab>
        <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="241" subjects_at_risk="254"/>
                <counts group_id="E2" subjects_affected="203" subjects_at_risk="235"/>
                <counts group_id="E3" subjects_affected="226" subjects_at_risk="286"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Gastrointestinal disorders</sub_title>
                <counts group_id="E1" events="92" subjects_affected="63" subjects_at_risk="254"/>
                <counts group_id="E2" events="71" subjects_affected="49" subjects_at_risk="235"/>
                <counts group_id="E3" events="114" subjects_affected="77" subjects_at_risk="286"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>General disorders</sub_title>
                <counts group_id="E1" events="77" subjects_affected="58" subjects_at_risk="254"/>
                <counts group_id="E2" events="72" subjects_affected="46" subjects_at_risk="235"/>
                <counts group_id="E3" events="85" subjects_affected="67" subjects_at_risk="286"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Infections and infestations</sub_title>
                <counts group_id="E1" events="113" subjects_affected="89" subjects_at_risk="254"/>
                <counts group_id="E2" events="106" subjects_affected="79" subjects_at_risk="235"/>
                <counts group_id="E3" events="119" subjects_affected="92" subjects_at_risk="286"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Injury, poisoning and procedural complications</title>
            <event_list>
              <event>
                <sub_title>Injury, poisoning, and procedural complications</sub_title>
                <counts group_id="E1" events="28" subjects_affected="22" subjects_at_risk="254"/>
                <counts group_id="E2" events="13" subjects_affected="13" subjects_at_risk="235"/>
                <counts group_id="E3" events="23" subjects_affected="17" subjects_at_risk="286"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Musculoskeletal and connective tissue disorders</sub_title>
                <counts group_id="E1" events="52" subjects_affected="42" subjects_at_risk="254"/>
                <counts group_id="E2" events="34" subjects_affected="27" subjects_at_risk="235"/>
                <counts group_id="E3" events="41" subjects_affected="33" subjects_at_risk="286"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Nervous system disorders</sub_title>
                <counts group_id="E1" events="56" subjects_affected="49" subjects_at_risk="254"/>
                <counts group_id="E2" events="52" subjects_affected="38" subjects_at_risk="235"/>
                <counts group_id="E3" events="65" subjects_affected="46" subjects_at_risk="286"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Respiratory, thoracic, and mediastinal disorders</sub_title>
                <counts group_id="E1" events="112" subjects_affected="78" subjects_at_risk="254"/>
                <counts group_id="E2" events="111" subjects_affected="72" subjects_at_risk="235"/>
                <counts group_id="E3" events="114" subjects_affected="84" subjects_at_risk="286"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Surgical and medical procedures</title>
            <event_list>
              <event>
                <sub_title>Surgical and medical procedures</sub_title>
                <counts group_id="E1" events="28" subjects_affected="23" subjects_at_risk="254"/>
                <counts group_id="E2" events="25" subjects_affected="16" subjects_at_risk="235"/>
                <counts group_id="E3" events="31" subjects_affected="26" subjects_at_risk="286"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Vascular disorders</title>
            <event_list>
              <event>
                <sub_title>Vascular disorders</sub_title>
                <counts group_id="E1" events="30" subjects_affected="20" subjects_at_risk="254"/>
                <counts group_id="E2" events="31" subjects_affected="22" subjects_at_risk="235"/>
                <counts group_id="E3" events="34" subjects_affected="25" subjects_at_risk="286"/>
              </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>Stephen T. Higgins, PhD, Professor</name_or_title>
      <organization>University of Vermont</organization>
      <phone>802-735-6267</phone>
      <email>stephen.higgins@uvm.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/NCT02232737
org study id: P50DA036114:P3S2
secondary id: P50DA036114
nct id: NCT02232737
lead sponsor: 
collaborator: 
collaborator: 
has dmc: Yes
This study will examine extended exposure to cigarettes varying in nicotine content among
      disadvantaged women. Adults with affective disorders are at increased risk for smoking,
      nicotine dependence, and using high nicotine yield cigarettes and are also at significantly
      increased risk for smoking-related adverse health consequences, including site-specific
      cancers, heart disease, and premature death. Studies testing an innovative regulatory
      strategy of reducing the nicotine content of cigarettes to a non-addictive level have shown
      promising beneficial effects (decreased smoking rate, reduced toxicant exposure, and
      increased cessation) in the general population of smokers. However, these studies have
      uniformly excluded vulnerable populations like those with affective disorders who may respond
      differently considering their greater vulnerability to smoking and nicotine dependence. Thus,
      little is known scientifically about how this highly vulnerable subgroup of smokers might
      respond to a nicotine reduction policy. This project is designed to address that substantial
      knowledge gap. This same study was also conducted in two additional vulnerable populations
      under a similar protocol.
The primary overall objective of these studies is to evaluate the effects of extended
      exposure to cigarettes differing in nicotine content in adult men and women with affective
      disorders using a 3-condition, parallel groups design. After a baseline period in which daily
      smoking rate and other baseline assessments are completed, participants will be randomly
      assigned to one of three cigarette conditions (nicotine content: 0.03, 0.12, and 0.8 mg
      nicotine of tobacco) for the 12-week experimental period.

      The cigarettes to be used in this study were made under an NIH contract with production being
      overseen by the Research Triangle Institute (referred to as "Spectrum cigarettes"). NIH
      currently has approximately 10 million of these cigarettes (of varying types) for research
      purposes. The cigarettes selected for the study span the range of yields likely to produce
      the hypothesized effects, as described above. The Spectrum cigarettes are not currently
      commercially available, although they are similar in many ways to marketed cigarettes (e.g.,
      similar manufacturing, filter, paper, etc.).

      The primary overall objective of this study is to evaluate the effects of extended exposure
      to cigarettes differing in nicotine content in adult men and women with affective disorders
      using a 3-condition, parallel groups design. After a baseline period in which daily smoking
      rate and other baseline assessments are completed, participants will be randomly assigned to
      one of three cigarette conditions (nicotine content: 0.03 mg, 0.12 mg, and 0.8 mg nicotine of
      tobacco) for the 12-week experimental period.

      Participants will be seen weekly throughout the 12-week experimental period to obtain
      research cigarettes. Cigarettes smoked per day will be obtained by participants completing
      daily Interactive Voice Response (IVR) reports of cigarettes in past 24 hours. This daily
      data will be used to calculate weekly means, with week-12 means serving as the primary
      outcome.

      This same study was conducted in two additional vulnerable populations under a similar
      protocol, with differences between protocols consisting of data collection specific to that
      vulnerable population. This included information such as use and timing of opioid maintenance
      therapy for individuals with opioid-use disorder and other measures relevant to disadvantaged
      women of reproductive age. In order to explore potential differences across individuals with
      different vulnerabilities, data from all three studies were combined for analysis. A
      vulnerable population-by-condition or population-by-condition-by-time interaction term was
      included in all analyses. In the event that these interaction terms were statistically
      significant, all pairwise comparisons were conducted using a Bonferroni multiple comparison
      adjustment.
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: This study was one of three multi-site clinical trials conducted in three different vulnerable populations under a similar protocol, with differences between protocols consisting of data collection specific to that vulnerable population. This included information such as use and timing of opioid maintenance therapy for individuals with opioid-use disorder or additional assessments related to disadvantaged women of reproductive age. In order to explore potential differences across individuals with different vulnerabilities, data from all three studies were combined for analysis. A vulnerable population-by-condition or population-by- condition-by-time interaction term was included in all analyses. In the event that these interaction terms were statistically significant, all pairwise comparisons were conducted using a Bonferroni multiple comparison adjustment. Please see Statistical Analysis Plan for more details.
primary purpose: Basic Science
masking: Double (Participant, Investigator)
measure: Cigarettes Per Day (CPD)
time frame: 12 weeks
description: Participant reported number of cigarettes smoked per day at Week 12
arm group label: 0.8 mg nicotine
arm group type: Experimental
description: 0.8 mg nicotine cigarettes
arm group label: 0.12 mg nicotine
arm group type: Experimental
description: 0.12 mg nicotine cigarettes
arm group label: 0.03 mg nicotine
arm group type: Experimental
description: 0.03 mg nicotine cigarettes
intervention type: Other
intervention name: Very low nicotine content cigarettes
arm group label: 0.03 mg nicotine
arm group label: 0.12 mg nicotine
arm group label: 0.8 mg nicotine
criteria: 
gender: All
minimum age: 18 Years
maximum age: 70 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Stephen T Higgins, PhD
role: Study Director
affiliation: University of Vermont
facility: 
facility: 
country: United States
responsible party type: Principal Investigator
investigator affiliation: Brown University
investigator full name: Jennifer Tidey
investigator title: Professor (Research)
mesh term: Tobacco Use Disorder
mesh term: Mood Disorders
mesh term: Nicotine
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 