<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/NCT02228824</url>
  </required_header>
  <id_info>
    <org_study_id>3P30CA047904-25S4</org_study_id>
    <nct_id>NCT02228824</nct_id>
  </id_info>
  <brief_title>Very-Low Nicotine Cigarettes and Non-Daily Smokers</brief_title>
  <official_title>The Effect of Very-Low Nicotine Cigarettes on Smoking in Non-Daily Smokers</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Saul Shiffman</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>National Cancer Institute (NCI)</agency>
      <agency_class>NIH</agency_class>
    </collaborator>
  </sponsors>
  <source>University of Pittsburgh</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      The purpose of this research study is to investigate the impact of different nicotine levels&#xD;
      in cigarettes among non-daily smokers. This research may help inform the Food and Drug&#xD;
      Administration (FDA) on how best to regulate tobacco products in the future, with the goal of&#xD;
      improving public health.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The overall goal of the study is to assess the effects of switching to&#xD;
      Very-Low-Nicotine-Content cigarettes (VLNCCs) among non-daily, or intermittent smokers (ITS).&#xD;
      This is a two-arm randomized study with an own-cigarette baseline control. After a 2-week&#xD;
      baseline period smoking their own cigarettes, 455 ITS will be randomized (double-blind) for&#xD;
      10 weeks to smoke experimental cigarettes, either: (a) normal nicotine content cigarettes&#xD;
      (NNCCs; 0.8 mg) or (b) VLNCCs (0.07 mg), each matched to menthol status of subjects'&#xD;
      preferred brand. ITS are more likely to be African-American (AA) smokers; thus AA smokers&#xD;
      will be oversampled (to one third of the total sample). Change in cigarette consumption is&#xD;
      the primary end-point, and biomarkers of smoke exposure and measures of smoking intensity are&#xD;
      also assessed.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">June 2015</start_date>
  <completion_date type="Actual">July 31, 2017</completion_date>
  <primary_completion_date type="Actual">July 31, 2017</primary_completion_date>
  <phase>N/A</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Basic Science</primary_purpose>
    <masking>Double (Participant, Investigator)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Change in Cigarette Consumption</measure>
    <time_frame>Two-week pre-intervention baseline period compared to final two weeks of 10-week intervention period</time_frame>
    <description>Difference in mean daily cigarette consumption between initial two-week baseline period and final two weeks of experimental period, using imputed data</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Exposure Measure - Solanesol</measure>
    <time_frame>Post-randomization time points at study weeks 4, 8, 12</time_frame>
    <description>The concentration of solanesol, a stable marker indicator of how much smoke has passed through the filter of a smoked cigarette to the smoker, will be assayed as a measure of smoking intensity. The filter of a cigarette butts smoked during the baseline period will be compared to those smoked during the experimental period.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Exposure Measure - Smoking Topography</measure>
    <time_frame>Post-randomization study visits at study weeks 4, 8, 12</time_frame>
    <description>Difference between average puff volume per cigarette at laboratory smoking topography sessions at study weeks 4, 8, and 12 across all participants, comparing those assigned to the very-low-nicotine-content cigarette condition to those assigned to the normal-nicotine-content cigarette condition. Topography measures were averaged across all time points for each treatment group.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Exposure Measure - Cotinine (Logged)</measure>
    <time_frame>Post-randomization office visits weeks 2 (end of baseline period) and 12 (end of study)</time_frame>
    <description>Cotinine nicotine exposure measure, analyzed from urine samples taken at study office visits&#xD;
The natural logarithm (ln) of the cotinine measures was used for analysis.&#xD;
Difference in ln(cotinine) between baseline and end of study, from imputed data</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Exposure Measure - Cigarette Butt Weight</measure>
    <time_frame>Entire length of study, through completion, up to 12 weeks</time_frame>
    <description>Mean mass smoked per cigarette (calculated as the starting cigarette weight minus returned butt weight) aggregated for all cigarettes smoked among participants assigned to the very-low-nicotine-content cigarette, compared to those assigned to the normal-nicotine-content cigarette condition.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">312</enrollment>
  <condition>Smoking</condition>
  <arm_group>
    <arm_group_label>Very low nicotine content cigarettes</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
  </arm_group>
  <arm_group>
    <arm_group_label>Normal nicotine content cigarettes</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Very low nicotine content cigarettes</intervention_name>
    <description>0.07 mg nicotine delivery</description>
    <arm_group_label>Very low nicotine content cigarettes</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Normal nicotine content cigarettes</intervention_name>
    <description>0.8 mg nicotine delivery</description>
    <arm_group_label>Normal nicotine content cigarettes</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  age 18 years or older, and smoking cigarettes for at least 3 years&#xD;
&#xD;
          -  smoking, on average, 4-27 days per month&#xD;
&#xD;
          -  smoking at current rate for at least the previous 3 months&#xD;
&#xD;
          -  willingness to try novel cigarettes&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  active plans to quit or actively seeking smoking cessation treatment in the next 3&#xD;
             months&#xD;
&#xD;
          -  severe psychiatric disorders that may interfere with study procedures&#xD;
&#xD;
          -  current, regular (i.e., monthly or more) use of nicotine replacement or other tobacco&#xD;
             products, by self-report&#xD;
&#xD;
          -  exclusive use of roll-your-own cigarettes (since the study uses manufactured&#xD;
             cigarettes)&#xD;
&#xD;
          -  [for female participants] being pregnant or breastfeeding, or planning to become&#xD;
             pregnant, by self-report&#xD;
&#xD;
          -  current use of medications such as Chantix (varenicline), Zyban, Wellbutrin, or&#xD;
             bupropion for any purpose, including stopping smoking&#xD;
&#xD;
          -  occurrence of heart attack, stroke, or angina in the past 3 months&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Saul Shiffman, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Pittsburgh, Department of Psychology</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Smoking Research Group, University of Pittsburgh</name>
      <address>
        <city>Pittsburgh</city>
        <state>Pennsylvania</state>
        <zip>15213</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>October 2018</verification_date>
  <study_first_submitted>August 27, 2014</study_first_submitted>
  <study_first_submitted_qc>August 27, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">August 29, 2014</study_first_posted>
  <results_first_submitted>July 29, 2018</results_first_submitted>
  <results_first_submitted_qc>October 5, 2018</results_first_submitted_qc>
  <results_first_posted type="Actual">October 31, 2018</results_first_posted>
  <last_update_submitted>October 5, 2018</last_update_submitted>
  <last_update_submitted_qc>October 5, 2018</last_update_submitted_qc>
  <last_update_posted type="Actual">October 31, 2018</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor-Investigator</responsible_party_type>
    <investigator_affiliation>University of Pittsburgh</investigator_affiliation>
    <investigator_full_name>Saul Shiffman</investigator_full_name>
    <investigator_title>Research Professor</investigator_title>
  </responsible_party>
  <keyword>Smoking</keyword>
  <keyword>Non-daily smokers</keyword>
  <keyword>Ecological Momentary Assessment</keyword>
  <keyword>Biomarkers</keyword>
  <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>May 7, 2018</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/24/NCT02228824/Prot_SAP_000.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <recruitment_details>Participants were recruited from the greater Pittsburgh area from June 2015 through April 2017 via various channels (e.g., advertisements on local television stations, public transportation, and social media such as Facebook and Instagram), as well as through University-housed research registries and recruiting services.</recruitment_details>
      <pre_assignment_details>Participants may have been excluded from the study after enrollment but before assignment to an arm if they were found to be unable to adhere to the study protocol or were unable to attend study visits, opted to no longer participate, or if they became unable to contact (i.e., were lost to follow-up).</pre_assignment_details>
      <group_list>
        <group group_id="P1">
          <title>Very Low Nicotine Content Cigarettes</title>
          <description>Very low nicotine content cigarettes: 0.07 mg nicotine delivery</description>
        </group>
        <group group_id="P2">
          <title>Normal Nicotine Content Cigarettes</title>
          <description>Normal nicotine content cigarettes: 0.8 mg nicotine delivery</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="118"/>
                <participants group_id="P2" count="120"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="89"/>
                <participants group_id="P2" count="98"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="29"/>
                <participants group_id="P2" count="22"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>Very Low Nicotine Content Cigarettes</title>
          <description>Very low nicotine content cigarettes: 0.07 mg nicotine delivery</description>
        </group>
        <group group_id="B2">
          <title>Normal Nicotine Content Cigarettes</title>
          <description>Normal nicotine content cigarettes: 0.8 mg nicotine delivery</description>
        </group>
        <group group_id="B3">
          <title>Total</title>
          <description>Total of all reporting groups</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="118"/>
            <count group_id="B2" value="120"/>
            <count group_id="B3" value="238"/>
          </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="37.4" spread="13.5"/>
                    <measurement group_id="B2" value="38.4" spread="14.2"/>
                    <measurement group_id="B3" value="37.9" spread="13.8"/>
                  </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="59"/>
                    <measurement group_id="B2" value="71"/>
                    <measurement group_id="B3" value="130"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="59"/>
                    <measurement group_id="B2" value="49"/>
                    <measurement group_id="B3" value="108"/>
                  </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>Race</title>
              <category_list>
                <category>
                  <title>White</title>
                  <measurement_list>
                    <measurement group_id="B1" value="76"/>
                    <measurement group_id="B2" value="76"/>
                    <measurement group_id="B3" value="152"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Black</title>
                  <measurement_list>
                    <measurement group_id="B1" value="27"/>
                    <measurement group_id="B2" value="34"/>
                    <measurement group_id="B3" value="61"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Other</title>
                  <measurement_list>
                    <measurement group_id="B1" value="15"/>
                    <measurement group_id="B2" value="10"/>
                    <measurement group_id="B3" value="25"/>
                  </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="118"/>
                    <measurement group_id="B2" value="120"/>
                    <measurement group_id="B3" value="238"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Cigarettes per day at enrollment (across all days)</title>
          <description>Average cigarettes per day, across all calendar days in the month preceding initial visit, reported via calendar-based TimeLine Follow-Back</description>
          <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="1.9" spread="1.6"/>
                    <measurement group_id="B2" value="1.9" spread="1.7"/>
                    <measurement group_id="B3" value="1.9" spread="1.7"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Smoking days per week at enrollment</title>
          <description>Average smoking days per week, across all calendar days in the month preceding initial visit, reported via calendar-based TimeLine Follow-Back</description>
          <units>smoking days per week</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="3.7" spread="1.4"/>
                    <measurement group_id="B2" value="3.7" spread="1.4"/>
                    <measurement group_id="B3" value="3.7" spread="1.4"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Cigarettes per day at enrollment (smoking days only)</title>
          <description>Average cigarettes per day (across smoking days only) in the month preceding initial visit, reported via calendar-based TimeLine Follow-Back</description>
          <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="3.3" spread="2.3"/>
                    <measurement group_id="B2" value="3.5" spread="2.9"/>
                    <measurement group_id="B3" value="3.4" spread="2.6"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Previous history of daily smoking</title>
          <description>Those participants who reported having previously smoked daily, continuously for at least six months, were classified as past daily smokers</description>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="57"/>
                    <measurement group_id="B2" value="61"/>
                    <measurement group_id="B3" value="118"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Change in Cigarette Consumption</title>
        <description>Difference in mean daily cigarette consumption between initial two-week baseline period and final two weeks of experimental period, using imputed data</description>
        <time_frame>Two-week pre-intervention baseline period compared to final two weeks of 10-week intervention period</time_frame>
        <population>All participants who were randomized to an experimental condition (either very-low-nicotine-content cigarettes or normal-nicotine-content cigarettes)</population>
        <group_list>
          <group group_id="O1">
            <title>Very Low Nicotine Content Cigarettes</title>
            <description>Very low nicotine content cigarettes: 0.07 mg nicotine delivery</description>
          </group>
          <group group_id="O2">
            <title>Normal Nicotine Content Cigarettes</title>
            <description>Normal nicotine content cigarettes: 0.8 mg nicotine delivery</description>
          </group>
        </group_list>
        <measure>
          <title>Change in Cigarette Consumption</title>
          <description>Difference in mean daily cigarette consumption between initial two-week baseline period and final two weeks of experimental period, using imputed data</description>
          <population>All participants who were randomized to an experimental condition (either very-low-nicotine-content cigarettes or normal-nicotine-content cigarettes)</population>
          <units>cigarettes per day</units>
          <param>Least Squares Mean</param>
          <dispersion>95% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="118"/>
                <count group_id="O2" value="120"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-1.6" lower_limit="-2.0" upper_limit="-1.1"/>
                    <measurement group_id="O2" value="-0.05" lower_limit="-0.5" upper_limit="0.4"/>
                  </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>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>&lt;0.001</p_value>
            <method>ANCOVA</method>
            <method_desc>ANCOVA was performed on 25 sets of imputed data and then analyzed using SAS PROC MIANALYZE</method_desc>
            <param_type>Mean Difference (Final Values)</param_type>
            <param_value>1.51</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>0.86</ci_lower_limit>
            <ci_upper_limit>2.17</ci_upper_limit>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Exposure Measure - Solanesol</title>
        <description>The concentration of solanesol, a stable marker indicator of how much smoke has passed through the filter of a smoked cigarette to the smoker, will be assayed as a measure of smoking intensity. The filter of a cigarette butts smoked during the baseline period will be compared to those smoked during the experimental period.</description>
        <time_frame>Post-randomization time points at study weeks 4, 8, 12</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Very Low Nicotine Content Cigarettes</title>
            <description>Very low nicotine content cigarettes: 0.07 mg nicotine delivery</description>
          </group>
          <group group_id="O2">
            <title>Normal Nicotine Content Cigarettes</title>
            <description>Normal nicotine content cigarettes: 0.8 mg nicotine delivery</description>
          </group>
        </group_list>
        <measure>
          <title>Exposure Measure - Solanesol</title>
          <description>The concentration of solanesol, a stable marker indicator of how much smoke has passed through the filter of a smoked cigarette to the smoker, will be assayed as a measure of smoking intensity. The filter of a cigarette butts smoked during the baseline period will be compared to those smoked during the experimental period.</description>
          <units>mg/butt</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="118"/>
                <count group_id="O2" value="120"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="NA" spread="NA">Data for this measure will not be analyzed due to the inability of the laboratory at which the analysis was to be performed to conduct these assays, as a result of cuts in CDC funding.</measurement>
                    <measurement group_id="O2" value="NA" spread="NA">Data for this measure will not be analyzed due to the inability of the laboratory at which the analysis was to be performed to conduct these assays, as a result of cuts in CDC funding.</measurement>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Exposure Measure - Smoking Topography</title>
        <description>Difference between average puff volume per cigarette at laboratory smoking topography sessions at study weeks 4, 8, and 12 across all participants, comparing those assigned to the very-low-nicotine-content cigarette condition to those assigned to the normal-nicotine-content cigarette condition. Topography measures were averaged across all time points for each treatment group.</description>
        <time_frame>Post-randomization study visits at study weeks 4, 8, 12</time_frame>
        <population>Analysis consists of those participants who contributed data to the study through at least study week 4.</population>
        <group_list>
          <group group_id="O1">
            <title>Very Low Nicotine Content Cigarettes</title>
            <description>Very low nicotine content cigarettes: 0.07 mg nicotine delivery</description>
          </group>
          <group group_id="O2">
            <title>Normal Nicotine Content Cigarettes</title>
            <description>Normal nicotine content cigarettes: 0.8 mg nicotine delivery</description>
          </group>
        </group_list>
        <measure>
          <title>Exposure Measure - Smoking Topography</title>
          <description>Difference between average puff volume per cigarette at laboratory smoking topography sessions at study weeks 4, 8, and 12 across all participants, comparing those assigned to the very-low-nicotine-content cigarette condition to those assigned to the normal-nicotine-content cigarette condition. Topography measures were averaged across all time points for each treatment group.</description>
          <population>Analysis consists of those participants who contributed data to the study through at least study week 4.</population>
          <units>mL</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="99"/>
                <count group_id="O2" value="101"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="501.20" spread="13.5"/>
                    <measurement group_id="O2" value="539.70" spread="12.83"/>
                  </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>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.041</p_value>
            <method>Mixed Models Analysis</method>
            <param_type>Mean Difference (Final Values)</param_type>
            <param_value>-38.50</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-75.21</ci_lower_limit>
            <ci_upper_limit>-1.78</ci_upper_limit>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Exposure Measure - Cotinine (Logged)</title>
        <description>Cotinine nicotine exposure measure, analyzed from urine samples taken at study office visits&#xD;
The natural logarithm (ln) of the cotinine measures was used for analysis.&#xD;
Difference in ln(cotinine) between baseline and end of study, from imputed data</description>
        <time_frame>Post-randomization office visits weeks 2 (end of baseline period) and 12 (end of study)</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Very Low Nicotine Content Cigarettes</title>
            <description>Very low nicotine content cigarettes: 0.07 mg nicotine delivery</description>
          </group>
          <group group_id="O2">
            <title>Normal Nicotine Content Cigarettes</title>
            <description>Normal nicotine content cigarettes: 0.8 mg nicotine delivery</description>
          </group>
        </group_list>
        <measure>
          <title>Exposure Measure - Cotinine (Logged)</title>
          <description>Cotinine nicotine exposure measure, analyzed from urine samples taken at study office visits&#xD;
The natural logarithm (ln) of the cotinine measures was used for analysis.&#xD;
Difference in ln(cotinine) between baseline and end of study, from imputed data</description>
          <units>log ng/mL</units>
          <param>Mean</param>
          <dispersion>95% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="118"/>
                <count group_id="O2" value="120"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-0.84" lower_limit="-1.29" upper_limit="-0.39"/>
                    <measurement group_id="O2" value="-0.15" lower_limit="-0.49" upper_limit="0.18"/>
                  </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>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.016</p_value>
            <method>ANCOVA</method>
            <method_desc>ANCOVA was performed on 25 sets of imputed data and then analyzed using SAS PROC MIANALYZE</method_desc>
            <param_type>Mean Difference (Final Values)</param_type>
            <param_value>-0.70</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-1.26</ci_lower_limit>
            <ci_upper_limit>-0.13</ci_upper_limit>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Exposure Measure - Cigarette Butt Weight</title>
        <description>Mean mass smoked per cigarette (calculated as the starting cigarette weight minus returned butt weight) aggregated for all cigarettes smoked among participants assigned to the very-low-nicotine-content cigarette, compared to those assigned to the normal-nicotine-content cigarette condition.</description>
        <time_frame>Entire length of study, through completion, up to 12 weeks</time_frame>
        <population>Analysis population consists of those participants who contributed data to the study for (at minimum) the two-week baseline study period block as well as the first two-week block post-randomization</population>
        <group_list>
          <group group_id="O1">
            <title>Very Low Nicotine Content Cigarettes</title>
            <description>Very low nicotine content cigarettes: 0.07 mg nicotine delivery</description>
          </group>
          <group group_id="O2">
            <title>Normal Nicotine Content Cigarettes</title>
            <description>Normal nicotine content cigarettes: 0.8 mg nicotine delivery</description>
          </group>
        </group_list>
        <measure>
          <title>Exposure Measure - Cigarette Butt Weight</title>
          <description>Mean mass smoked per cigarette (calculated as the starting cigarette weight minus returned butt weight) aggregated for all cigarettes smoked among participants assigned to the very-low-nicotine-content cigarette, compared to those assigned to the normal-nicotine-content cigarette condition.</description>
          <population>Analysis population consists of those participants who contributed data to the study for (at minimum) the two-week baseline study period block as well as the first two-week block post-randomization</population>
          <units>grams</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="111"/>
                <count group_id="O2" value="114"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.58" spread="0.01"/>
                    <measurement group_id="O2" value="0.60" spread="0.01"/>
                  </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>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.03</p_value>
            <method>Mixed Models Analysis</method>
            <param_type>Mean Difference (Final Values)</param_type>
            <param_value>-0.02</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-0.04</ci_lower_limit>
            <ci_upper_limit>-0.002</ci_upper_limit>
          </analysis>
        </analysis_list>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>Adverse event data was collected for each participant during the time of enrollment to completion of the study. Enrollment of study participants began in June 2015 and data collection concluded in July 2017. Thus, adverse event data for the entire study was collected over a 26 month span. Each individual participant participated in the study for 12 weeks.</time_frame>
      <desc>Adverse events were assessed during study visits via in-session interactions in which study participants were prompted to describe their experiences since the prior visit in an open-ended form, as well as via the self-completed Respiratory Health Questionnaire administered to participants at study visits.</desc>
      <group_list>
        <group group_id="E1">
          <title>Very Low Nicotine Content Cigarettes</title>
          <description>Very low nicotine content cigarettes: 0.07 mg nicotine delivery</description>
        </group>
        <group group_id="E2">
          <title>Normal Nicotine Content Cigarettes</title>
          <description>Normal nicotine content cigarettes: 0.8 mg nicotine delivery</description>
        </group>
      </group_list>
      <serious_events>
        <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="118"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="120"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="118"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="120"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Hospitalization for acute change in mental status (tranisient, unknown etiology)</sub_title>
                <assessment>Non-systematic Assessment</assessment>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="118"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="120"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Hospitalization for mini-seizures</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="118"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="120"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Psychiatric disorders</title>
            <event_list>
              <event>
                <sub_title>Hospitalization for psychiatric medication management</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="118"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="120"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>0</frequency_threshold>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="41" subjects_at_risk="118"/>
                <counts group_id="E2" subjects_affected="42" subjects_at_risk="120"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Nausea / flu</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="118"/>
                <counts group_id="E2" subjects_affected="8" subjects_at_risk="120"/>
              </event>
              <event>
                <sub_title>Acid reflux</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="118"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="120"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Immune system disorders</title>
            <event_list>
              <event>
                <sub_title>Seasonal allergies</sub_title>
                <counts group_id="E1" subjects_affected="8" subjects_at_risk="118"/>
                <counts group_id="E2" subjects_affected="9" subjects_at_risk="120"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Headache</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="118"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="120"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Respiratory (cough, cold)</sub_title>
                <counts group_id="E1" subjects_affected="33" subjects_at_risk="118"/>
                <counts group_id="E2" subjects_affected="30" subjects_at_risk="120"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>All Principal Investigators ARE employed by the organization sponsoring the study.</pi_employee>
      <restrictive_agreement>There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed. </restrictive_agreement>
    </certain_agreements>
    <point_of_contact>
      <name_or_title>Dr. Saul Shiffman</name_or_title>
      <organization>University of Pittsburgh</organization>
      <phone>412-567-1761</phone>
      <email>shiffman@pinneyassociates.com</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/NCT02228824
org study id: 3P30CA047904-25S4
nct id: NCT02228824
lead sponsor: 
collaborator: 
has dmc: Yes
The purpose of this research study is to investigate the impact of different nicotine levels
      in cigarettes among non-daily smokers. This research may help inform the Food and Drug
      Administration (FDA) on how best to regulate tobacco products in the future, with the goal of
      improving public health.
The overall goal of the study is to assess the effects of switching to
      Very-Low-Nicotine-Content cigarettes (VLNCCs) among non-daily, or intermittent smokers (ITS).
      This is a two-arm randomized study with an own-cigarette baseline control. After a 2-week
      baseline period smoking their own cigarettes, 455 ITS will be randomized (double-blind) for
      10 weeks to smoke experimental cigarettes, either: (a) normal nicotine content cigarettes
      (NNCCs; 0.8 mg) or (b) VLNCCs (0.07 mg), each matched to menthol status of subjects'
      preferred brand. ITS are more likely to be African-American (AA) smokers; thus AA smokers
      will be oversampled (to one third of the total sample). Change in cigarette consumption is
      the primary end-point, and biomarkers of smoke exposure and measures of smoking intensity are
      also assessed.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Basic Science
masking: Double (Participant, Investigator)
measure: Change in Cigarette Consumption
time frame: Two-week pre-intervention baseline period compared to final two weeks of 10-week intervention period
description: Difference in mean daily cigarette consumption between initial two-week baseline period and final two weeks of experimental period, using imputed data
measure: Exposure Measure - Solanesol
time frame: Post-randomization time points at study weeks 4, 8, 12
description: The concentration of solanesol, a stable marker indicator of how much smoke has passed through the filter of a smoked cigarette to the smoker, will be assayed as a measure of smoking intensity. The filter of a cigarette butts smoked during the baseline period will be compared to those smoked during the experimental period.
measure: Exposure Measure - Smoking Topography
time frame: Post-randomization study visits at study weeks 4, 8, 12
description: Difference between average puff volume per cigarette at laboratory smoking topography sessions at study weeks 4, 8, and 12 across all participants, comparing those assigned to the very-low-nicotine-content cigarette condition to those assigned to the normal-nicotine-content cigarette condition. Topography measures were averaged across all time points for each treatment group.
measure: Exposure Measure - Cotinine (Logged)
time frame: Post-randomization office visits weeks 2 (end of baseline period) and 12 (end of study)
description: Cotinine nicotine exposure measure, analyzed from urine samples taken at study office visits
The natural logarithm (ln) of the cotinine measures was used for analysis.
Difference in ln(cotinine) between baseline and end of study, from imputed data
measure: Exposure Measure - Cigarette Butt Weight
time frame: Entire length of study, through completion, up to 12 weeks
description: Mean mass smoked per cigarette (calculated as the starting cigarette weight minus returned butt weight) aggregated for all cigarettes smoked among participants assigned to the very-low-nicotine-content cigarette, compared to those assigned to the normal-nicotine-content cigarette condition.
arm group label: Very low nicotine content cigarettes
arm group type: Experimental
arm group label: Normal nicotine content cigarettes
arm group type: Active Comparator
intervention type: Drug
intervention name: Very low nicotine content cigarettes
description: 0.07 mg nicotine delivery
arm group label: Very low nicotine content cigarettes
intervention type: Drug
intervention name: Normal nicotine content cigarettes
description: 0.8 mg nicotine delivery
arm group label: Normal nicotine content cigarettes
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Saul Shiffman, PhD
role: Principal Investigator
affiliation: University of Pittsburgh, Department of Psychology
facility: 
country: United States
responsible party type: Sponsor-Investigator
investigator affiliation: University of Pittsburgh
investigator full name: Saul Shiffman
investigator title: Research Professor
mesh term: Nicotine
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 