<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/NCT02250534</url>
  </required_header>
  <id_info>
    <org_study_id>P50DA036114:P1S2</org_study_id>
    <secondary_id>P50DA036114</secondary_id>
    <nct_id>NCT02250534</nct_id>
  </id_info>
  <brief_title>Project 1, Study 2: Extended Exposure to Low Nicotine Content Cigarettes in Childbearing Age Women</brief_title>
  <official_title>Project 1, Study 2: Extended Exposure to Low Nicotine Content Cigarettes in Childbearing Age Women</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Vermont</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Johns Hopkins University</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>National Institute on Drug Abuse (NIDA)</agency>
      <agency_class>NIH</agency_class>
    </collaborator>
  </sponsors>
  <source>University of Vermont</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. Disadvantaged women are at increased risk for smoking, nicotine&#xD;
      dependence, and using high nicotine yield cigarettes and are also at significantly increased&#xD;
      risk for smoking-related adverse health consequences, including cervical cancer, thrombosis&#xD;
      related to hormone-based contraception, infertility, and early menopause. Studies testing an&#xD;
      innovative regulatory strategy of reducing the nicotine content of cigarettes to a&#xD;
      non-addictive level have shown promising beneficial effects (decreased smoking rate, reduced&#xD;
      toxicant exposure, and increased cessation) in the general population of smokers. However,&#xD;
      these studies have uniformly excluded vulnerable populations like disadvantaged women who may&#xD;
      respond differently considering their greater vulnerability to smoking and nicotine&#xD;
      dependence. Thus, little is known scientifically about how this highly vulnerable subgroup of&#xD;
      smokers might respond to a nicotine reduction policy. This project is designed to address&#xD;
      that substantial knowledge gap. This same study was also conducted in two additional&#xD;
      vulnerable populations 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 socioeconomically disadvantaged (&lt;&#xD;
      high school educational attainment) women of childbearing age using a 3-condition, parallel&#xD;
      groups design. After a baseline period in which daily smoking rate and other baseline&#xD;
      assessments are completed, participants will be randomly assigned to one of three cigarette&#xD;
      conditions (nicotine content: 0.04, 2.4, and 15.8 mg nicotine/gram of tobacco) for the&#xD;
      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 female adult smokers of childbearing age&#xD;
      (18-44 yrs) whose highest academic degree is high school using a 3-condition, parallel groups&#xD;
      design. After a baseline period in which daily smoking rate and other baseline assessments&#xD;
      are completed, participants will be randomly assigned to one of three cigarette conditions&#xD;
      (nicotine content: 0.04 mg, 2.4 mg, and 15.8 mg nicotine/g of tobacco) for the 12-week&#xD;
      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 or additional assessments of anxiety and&#xD;
      depression for individuals with affective disorders. In order to explore potential&#xD;
      differences across individuals with different vulnerabilities, data from all three studies&#xD;
      were combined for analysis. A vulnerable population-by-condition or&#xD;
      population-by-condition-by-time interaction term was included in all analyses. In the event&#xD;
      that these interaction terms were statistically significant, all pairwise comparisons were&#xD;
      conducted using a Bonferroni multiple comparison adjustment.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date>October 2016</start_date>
  <completion_date type="Actual">October 2019</completion_date>
  <primary_completion_date type="Actual">October 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 of anxiety and depression for individuals with affective disorders. 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 very low nicotine content 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 very low nicotine content 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 very low nicotine content 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;
          -  Female&#xD;
&#xD;
          -  Ages 18-44 years&#xD;
&#xD;
          -  Less than an Associate's degree&#xD;
&#xD;
          -  Report smoking ≥ 5 cigarettes per day&#xD;
&#xD;
          -  Provide an intake breath carbon monoxide (CO) sample &gt; 8 ppm&#xD;
&#xD;
          -  Be without current (within the past year) serious mental disorder that would interfere&#xD;
             with study results or completion as determined by the Licensed Medical Professional or&#xD;
             PI&#xD;
&#xD;
          -  Be without current substance abuse/dependence other than nicotine&#xD;
&#xD;
          -  Be sufficiently literate to complete research-related tasks&#xD;
&#xD;
          -  Be in good physical health without serious illness or change in health or medication&#xD;
             in the past three months as determined by the Licensed Medical Professional at each&#xD;
             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;
          -  Currently taking anticonvulsant medications&#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 past 30, 4 drinks in 2 hours )&#xD;
&#xD;
          -  Systolic blood pressure &lt; 90 or ≥ 160 mmHg (participants outside the range will be&#xD;
             allowed to re-screen once)&#xD;
&#xD;
          -  Diastolic blood pressure &lt; 50 or ≥ 100 mmHg (participants outside the range will be&#xD;
             allowed to re-screen once)&#xD;
&#xD;
          -  Breath CO &gt; 80 ppm&#xD;
&#xD;
          -  Heart rate &lt; 45 or ≥ 115 bpm (participants outside the range will be allowed to&#xD;
             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;
          -  Current symptoms of psychosis, dementia or mania&#xD;
&#xD;
          -  Suicidal ideation in the 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>Female</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>44 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Stephen T. Higgins, Ph.D.</last_name>
    <role>Study Director</role>
    <affiliation>University of Vermont</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Sarah H. Heil, Ph.D.</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Vermont</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Johns Hopkins University</name>
      <address>
        <city>Baltimore</city>
        <state>Maryland</state>
        <zip>21224</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>November 2022</verification_date>
  <study_first_submitted>September 23, 2014</study_first_submitted>
  <study_first_submitted_qc>September 23, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">September 26, 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 1, 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 1, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>University of Vermont</investigator_affiliation>
    <investigator_full_name>Stephen T. Higgins, PhD</investigator_full_name>
    <investigator_title>Professor</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>
  </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/34/NCT02250534/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 very low nicotine content cigarettes&#xD;
Very low nicotine content cigarettes</description>
        </group>
        <group group_id="P2">
          <title>0.12 mg Nicotine</title>
          <description>0.12 mg nicotine very low nicotine content cigarettes&#xD;
Very low nicotine content cigarettes</description>
        </group>
        <group group_id="P3">
          <title>0.03 mg Nicotine</title>
          <description>0.03 mg nicotine very low nicotine content 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 very low nicotine content cigarettes&#xD;
Very low nicotine content cigarettes</description>
        </group>
        <group group_id="B2">
          <title>0.12 mg Nicotine</title>
          <description>0.12 mg nicotine very low nicotine content cigarettes&#xD;
Very low nicotine content cigarettes</description>
        </group>
        <group group_id="B3">
          <title>0.03 mg Nicotine</title>
          <description>0.03 mg nicotine very low nicotine content 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>Count of Participants</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 very low nicotine content cigarettes&#xD;
Very low nicotine content cigarettes</description>
          </group>
          <group group_id="O2">
            <title>0.12 mg Nicotine</title>
            <description>0.12 mg nicotine very low nicotine content cigarettes&#xD;
Very low nicotine content cigarettes</description>
          </group>
          <group group_id="O3">
            <title>0.03 mg Nicotine</title>
            <description>0.03 mg nicotine very low nicotine content 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 6.07 CPD between the 0.8 mg and 0.03 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 very low nicotine content cigarettes&#xD;
Very low nicotine content cigarettes</description>
        </group>
        <group group_id="E2">
          <title>0.12 mg Nicotine</title>
          <description>0.12 mg nicotine very low nicotine content cigarettes&#xD;
Very low nicotine content cigarettes</description>
        </group>
        <group group_id="E3">
          <title>0.03 mg Nicotine</title>
          <description>0.03 mg nicotine very low nicotine content 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 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 ones 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, Department of Psychiatry</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/NCT02250534
org study id: P50DA036114:P1S2
secondary id: P50DA036114
nct id: NCT02250534
lead sponsor: 
collaborator: 
collaborator: 
has dmc: Yes
This study will examine extended exposure to cigarettes varying in nicotine content among
      disadvantaged women. Disadvantaged women 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 cervical cancer, thrombosis
      related to hormone-based contraception, infertility, and early menopause. 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 disadvantaged women 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 socioeconomically disadvantaged (<
      high school educational attainment) women of childbearing age 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: 0.04, 2.4, and 15.8 mg nicotine/gram 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 female adult smokers of childbearing age
      (18-44 yrs) whose highest academic degree is high school 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: 0.04 mg, 2.4 mg, and 15.8 mg nicotine/g 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 or additional assessments of anxiety and
      depression for individuals with affective disorders. 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 of anxiety and depression for individuals with affective disorders. 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 very low nicotine content cigarettes
arm group label: 0.12 mg nicotine
arm group type: Experimental
description: 0.12 mg nicotine very low nicotine content cigarettes
arm group label: 0.03 mg nicotine
arm group type: Experimental
description: 0.03 mg nicotine very low nicotine content 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: Female
minimum age: 18 Years
maximum age: 44 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Stephen T. Higgins, Ph.D.
role: Study Director
affiliation: University of Vermont
last name: Sarah H. Heil, Ph.D.
role: Principal Investigator
affiliation: University of Vermont
facility: 
facility: 
country: United States
responsible party type: Principal Investigator
investigator affiliation: University of Vermont
investigator full name: Stephen T. Higgins, PhD
investigator title: Professor
mesh term: Tobacco Use Disorder
mesh term: Nicotine
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