<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/NCT03262662</url>
  </required_header>
  <id_info>
    <org_study_id>STUDY00000911</org_study_id>
    <secondary_id>R01CA206193</secondary_id>
    <nct_id>NCT03262662</nct_id>
  </id_info>
  <brief_title>EVarQuit: Extended Pre-quit Varenicline to Assist in Quitting Smoking</brief_title>
  <acronym>EVarQuit</acronym>
  <official_title>EVarQuit: Extended Pre-quit Varenicline to Assist in Quitting Smoking</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>State University of New York at Buffalo</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>National Cancer Institute (NCI)</agency>
      <agency_class>NIH</agency_class>
    </collaborator>
    <collaborator>
      <agency>Pfizer</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>State University of New York at Buffalo</source>
  <oversight_info>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      Varenicline is the most effective smoking cessation therapy available. Nevertheless, most&#xD;
      smokers using varenicline relapse within the first few months after quitting. Varenicline is&#xD;
      hypothesized to help smokers to quit in part by reducing the reinforcing effects of smoking&#xD;
      during the standard 1-week pre-quitting treatment phase. Learning theory and previous human&#xD;
      and animal research support the hypothesis that a longer period of varenicline treatment&#xD;
      prior to the target quit date (TQD) will lead to greater reductions in smoking before&#xD;
      quitting, and higher long-term cessation rates, compared to standard varenicline treatment.&#xD;
      Building on promising preliminary clinical data, the study tests these hypotheses with a&#xD;
      full-scale randomized clinical trial (RCT). 320 treatment-seeking smokers will be randomized&#xD;
      to a standard run-in group (3 weeks of placebo, followed by the standard 1 week of pre-TQD&#xD;
      varenicline) or an extended run-in group (4 weeks of pre-TQD varenicline). Both groups will&#xD;
      receive brief individual cessation counseling and 11 weeks of post-TQD varenicline. The&#xD;
      primary outcome measure will be bio-verified continuous abstinence at end-of-treatment (weeks&#xD;
      8-11 post-quit; cessation at 26-weeks post TQD will also be examined. Hypothesized mediating&#xD;
      mechanisms (e.g., smoking reinforcement) will be evaluated by behavioral, physiological, and&#xD;
      subjective measures assessed both in the lab and using real-world, real-time electronic&#xD;
      momentary assessments (EMA). The investigators predict that long-term, bio-verified smoking&#xD;
      cessation will be improved among the extended run-in group compared to the standard run-in&#xD;
      group. The investigators further predict the improved clinical outcomes with extended run-in&#xD;
      varenicline will be explained (or mediated) by greater pre-quit reductions in smoking&#xD;
      reinforcement among the extended run-in group compared to the standard run-in group. The&#xD;
      significance of this work is clear: The project aims to make best available treatment for&#xD;
      smoking cessation even better, using a method that is ripe for dissemination and an approach&#xD;
      that will elucidate critical mechanisms to target in the next generation of treatment&#xD;
      enhancement.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">October 1, 2017</start_date>
  <completion_date type="Actual">July 8, 2021</completion_date>
  <primary_completion_date type="Actual">April 5, 2021</primary_completion_date>
  <phase>Phase 3</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>Treatment</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Number of Participants With Continuous Abstinence at End-of-Treatment (EOT) as Assessed by Self-Report and Bio-verification</measure>
    <time_frame>Self-report Treatment Weeks 12-15; bio-verification ~Week 16</time_frame>
    <description>Number of participants with bio-verified (cotinine level of 15 ng/mL or less) self-reported continuous abstinence from smoking (not even a puff) during the final four weeks of treatment</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Pre-quit Change in Cigarettes Smoked Per Day</measure>
    <time_frame>Treatment Week 1 vs. Treatment Week 4 (final week before TQD)</time_frame>
    <description>Percent change in smoking behavior (self-reported cigarettes per day; CPD) from timeline follow-back (TLFB) interviews during the pre-quit phase of the study.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of Participants With Continuous Abstinence at 6-Month Follow-Up as Assessed by Self-Report and Bio-verification</measure>
    <time_frame>Self-report Treatment Weeks 12-28; bio-verification ~Week 16 and ~Week 29</time_frame>
    <description>Number of participants with continuous abstinence at the 6-month follow-up (no self-reported smoking during weeks 12-28 AND cotinine level 15 ng/mL or less at EOT and 6 month follow-up)</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">320</enrollment>
  <condition>Tobacco Smoking</condition>
  <arm_group>
    <arm_group_label>Extended Run-In</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>** 4 weeks of varenicline prior to the target quit date (TQD) **&#xD;
+ 11 weeks of post-TQD varenicline&#xD;
Standard varenicline dosing titration in initial week of therapy (one 0.5 mg tablet orally daily x 3 days, then one 0.5 mg tablet twice daily x 4 days); then 1 mg twice daily thereafter.&#xD;
Brief individual counseling at clinic visits</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Standard Run-In</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>** 3 weeks of placebo followed by 1 week of varenicline prior to the target quit date (TQD) **&#xD;
+ 11 weeks of post-TQD varenicline&#xD;
Standard varenicline dosing titration in initial week of therapy (one 0.5 mg tablet orally daily x 3 days, then one 0.5 mg tablet twice daily x 4 days); then 1 mg twice daily thereafter.&#xD;
Brief individual counseling at clinic visits</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Varenicline</intervention_name>
    <description>oral varenicline tablets</description>
    <arm_group_label>Extended Run-In</arm_group_label>
    <arm_group_label>Standard Run-In</arm_group_label>
    <other_name>Chantix</other_name>
  </intervention>
  <intervention>
    <intervention_type>Behavioral</intervention_type>
    <intervention_name>Brief smoking cessation counseling</intervention_name>
    <description>~10-minute individual counseling at each of 6 clinic visits</description>
    <arm_group_label>Extended Run-In</arm_group_label>
    <arm_group_label>Standard Run-In</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Smoking at least 10 cigarettes per day (CPD) for the past 6 months and expired-air&#xD;
             carbon monoxide (CO) &gt;7 at intake. NOTE: To reduce exclusion of Black participants,&#xD;
             the CPD criterion was reduced to 5 and the carbon monoxide criterion was eliminated in&#xD;
             November, 2019.&#xD;
&#xD;
          -  At least moderately motivated to quit smoking and intention to make a quit attempt&#xD;
             with varenicline 1 month after treatment begins.&#xD;
&#xD;
          -  Planning to remain in western New York (NY) during the study period&#xD;
&#xD;
          -  Willing to use varenicline and to refrain from other cessation treatments and tobacco&#xD;
             products during the study period.&#xD;
&#xD;
          -  English speaker&#xD;
&#xD;
          -  To be intent-to-treat (ITT), the participant must complete Lab Visit 1 and meet&#xD;
             minimal completion rate for real-world (EMA) assessments.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Use of other tobacco products, including e-cigarettes, in past 7 days&#xD;
&#xD;
          -  Use of smoking cessation medication, including nicotine replacement therapy, in the&#xD;
             past 14 days&#xD;
&#xD;
          -  Prior allergy/hypersensitivity to varenicline&#xD;
&#xD;
          -  Pregnant or breast-feeding&#xD;
&#xD;
          -  Substance use:&#xD;
&#xD;
               -  Alcohol: AUDIT score &gt; 15 at intake, suggestive of alcohol dependence and&#xD;
                  warranting treatment; for those with scores between 8 and 15, the investigators&#xD;
                  will advise reducing drinking).&#xD;
&#xD;
               -  Medical treatment for substance use (SU) in past 3 months, including Suboxone&#xD;
                  (buprenorphine) and methadone (at phone screen)&#xD;
&#xD;
               -  Using a combination of the National Institute on Drug Abuse (NIDA) modified&#xD;
                  ASSIST (4-26 = moderate risk; 27+ = high risk) and urine toxicology screen (both&#xD;
                  at intake):&#xD;
&#xD;
                    -  Cannabis: ASSIST=27+ (tox screen not used)&#xD;
&#xD;
                    -  Cocaine: ASSIST=7+ OR positive tox screen&#xD;
&#xD;
                    -  Methamphetamine: ASSIST=7+ OR positive tox screen&#xD;
&#xD;
                    -  Inhalants, hallucinogens, sedatives, or sleeping pills: ASSIST score = 7+&#xD;
&#xD;
                    -  Prescription stimulants: With prescription, ASSIST 27+; Without&#xD;
                       prescription, ASSIST 7+&#xD;
&#xD;
                    -  Opioids: With prescription, ASSIST 27+ (note ineligible if prescription is&#xD;
                       for buprenorphine or methadone); Without prescription, ASSIST 7+ OR positive&#xD;
                       tox screen&#xD;
&#xD;
        (Note: ASSIST 4+ modified to 7+ in 2018 to avoid excluding people with past SU problems.&#xD;
        clinicaltrials.gov edited 12/18/18)&#xD;
&#xD;
          -  Psychiatric:&#xD;
&#xD;
               -  Antipsychotic medications&#xD;
&#xD;
               -  Lifetime history of schizophrenia or bipolar disorder&#xD;
&#xD;
               -  Evidence of current major depression (per Patient Health Questionnaire (PHQ-9) at&#xD;
                  intake&#xD;
&#xD;
               -  Past 10 years suicidal ideation (SI) / behavior. At intake, all of the following&#xD;
                  are exclusionary on the baseline Columbia-Suicide Severity Rating Scale (Posner&#xD;
                  et al., 2008): SI without intent (C-SSRS #1, #2, or #3), if any intensity rating&#xD;
                  (Frequency, Duration, Controllability, Deterrents, or Reasons for Ideation) is &gt;&#xD;
                  2; SI with intent (C-SSRS #4, or #5), regardless of intensity ratings; Suicidal&#xD;
                  Behavior (any suicide attempt, interrupted attempt, aborted attempt, or suicide&#xD;
                  preparatory acts or behavior on the C-SSRS).&#xD;
&#xD;
          -  Any medical condition, illness, disorder or concomitant medication that compromises&#xD;
             participant safety or treatment, as determined by the Principal Investigator and/or&#xD;
             Study Physician.&#xD;
&#xD;
          -  Inability to provide informed consent or complete any of the study tasks as determined&#xD;
             by the Principal Investigator and/or Study Physician.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <gender_based>Yes</gender_based>
    <gender_description>Approximately equal numbers of men and women will participate.</gender_description>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>70 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <location>
    <facility>
      <name>State University of New York at Buffalo</name>
      <address>
        <city>Buffalo</city>
        <state>New York</state>
        <zip>14260</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>July 2023</verification_date>
  <study_first_submitted>August 22, 2017</study_first_submitted>
  <study_first_submitted_qc>August 22, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">August 25, 2017</study_first_posted>
  <results_first_submitted>November 21, 2022</results_first_submitted>
  <results_first_submitted_qc>July 10, 2023</results_first_submitted_qc>
  <results_first_posted type="Actual">July 11, 2023</results_first_posted>
  <last_update_submitted>July 10, 2023</last_update_submitted>
  <last_update_submitted_qc>July 10, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">July 11, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>State University of New York at Buffalo</investigator_affiliation>
    <investigator_full_name>Larry Hawk, Ph.D.</investigator_full_name>
    <investigator_title>Professor, Department of Psychology</investigator_title>
  </responsible_party>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Varenicline</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Yes</sharing_ipd>
    <ipd_description>We plan to share study data through the NIDA-supported NAHDAP repository. IPD to be shared include baseline participant characteristics, intervention group, smoking abstinence, and adverse events.</ipd_description>
    <ipd_info_type>Study Protocol</ipd_info_type>
    <ipd_info_type>Informed Consent Form (ICF)</ipd_info_type>
    <ipd_time_frame>2023. We are currently awaiting confirmation from NAHDAP that our archival plan fits their expectations. Data will be available indefinitely (as long as NAHDAP is supported).</ipd_time_frame>
    <ipd_access_criteria>Public release; anyone who registers on the website.</ipd_access_criteria>
  </patient_data>
  <provided_document_section>
    <provided_document>
      <document_type>Study Protocol and Statistical Analysis Plan</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>June 30, 2020</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/62/NCT03262662/Prot_SAP_000.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <group_list>
        <group group_id="P1">
          <title>Extended Run-In</title>
          <description>** 4 weeks of varenicline prior to the target quit date (TQD) **&#xD;
+ 11 weeks of post-TQD varenicline&#xD;
Standard varenicline dosing titration in initial week of therapy (one 0.5 mg tablet orally daily x 3 days, then one 0.5 mg tablet twice daily x 4 days); then 1 mg twice daily thereafter.&#xD;
Brief individual counseling at clinic visits&#xD;
Varenicline: oral varenicline tablets&#xD;
Brief smoking cessation counseling: ~10-minute individual counseling at each of 6 clinic visits</description>
        </group>
        <group group_id="P2">
          <title>Standard Run-In</title>
          <description>** 3 weeks of placebo followed by 1 week of varenicline prior to the target quit date (TQD) **&#xD;
+ 11 weeks of post-TQD varenicline&#xD;
Standard varenicline dosing titration in initial week of therapy (one 0.5 mg tablet orally daily x 3 days, then one 0.5 mg tablet twice daily x 4 days); then 1 mg twice daily thereafter.&#xD;
Brief individual counseling at clinic visits&#xD;
Varenicline: oral varenicline tablets&#xD;
Brief smoking cessation counseling: ~10-minute individual counseling at each of 6 clinic visits</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="163"/>
                <participants group_id="P2" count="157"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>Retained at Wk 15 (EOT)</title>
              <participants_list>
                <participants group_id="P1" count="127"/>
                <participants group_id="P2" count="126"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>Retained at Wk 28 (6-month Follow-up)</title>
              <participants_list>
                <participants group_id="P1" count="124"/>
                <participants group_id="P2" count="121"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="163">Intent-to-treat</participants>
                <participants group_id="P2" count="157">Intent-to-treat</participants>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>Extended Run-In</title>
          <description>** 4 weeks of varenicline prior to the target quit date (TQD) **&#xD;
+ 11 weeks of post-TQD varenicline&#xD;
Standard varenicline dosing titration in initial week of therapy (one 0.5 mg tablet orally daily x 3 days, then one 0.5 mg tablet twice daily x 4 days); then 1 mg twice daily thereafter.&#xD;
Brief individual counseling at clinic visits&#xD;
Varenicline: oral varenicline tablets&#xD;
Brief smoking cessation counseling: ~10-minute individual counseling at each of 6 clinic visits</description>
        </group>
        <group group_id="B2">
          <title>Standard Run-In</title>
          <description>** 3 weeks of placebo followed by 1 week of varenicline prior to the target quit date (TQD) **&#xD;
+ 11 weeks of post-TQD varenicline&#xD;
Standard varenicline dosing titration in initial week of therapy (one 0.5 mg tablet orally daily x 3 days, then one 0.5 mg tablet twice daily x 4 days); then 1 mg twice daily thereafter.&#xD;
Brief individual counseling at clinic visits&#xD;
Varenicline: oral varenicline tablets&#xD;
Brief smoking cessation counseling: ~10-minute individual counseling at each of 6 clinic visits</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="163"/>
            <count group_id="B2" value="157"/>
            <count group_id="B3" value="320"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>years</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="163"/>
                    <count group_id="B2" value="157"/>
                    <count group_id="B3" value="320"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="53.8" spread="10.3"/>
                    <measurement group_id="B2" value="53.5" spread="10"/>
                    <measurement group_id="B3" value="53.7" spread="10.1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Sex: Female, Male</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="163"/>
                    <count group_id="B2" value="157"/>
                    <count group_id="B3" value="320"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <title>Female</title>
                  <measurement_list>
                    <measurement group_id="B1" value="90"/>
                    <measurement group_id="B2" value="89"/>
                    <measurement group_id="B3" value="179"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="73"/>
                    <measurement group_id="B2" value="68"/>
                    <measurement group_id="B3" value="141"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Ethnicity (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="163"/>
                    <count group_id="B2" value="157"/>
                    <count group_id="B3" value="320"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <title>Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="4"/>
                    <measurement group_id="B2" value="4"/>
                    <measurement group_id="B3" value="8"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Not Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="159"/>
                    <measurement group_id="B2" value="153"/>
                    <measurement group_id="B3" value="312"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Race/Ethnicity, Customized</title>
          <description>Self-reported race</description>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <title>Race</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="163"/>
                    <count group_id="B2" value="157"/>
                    <count group_id="B3" value="320"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <title>White/Caucasian</title>
                  <measurement_list>
                    <measurement group_id="B1" value="122"/>
                    <measurement group_id="B2" value="118"/>
                    <measurement group_id="B3" value="240"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Black/African American</title>
                  <measurement_list>
                    <measurement group_id="B1" value="33"/>
                    <measurement group_id="B2" value="34"/>
                    <measurement group_id="B3" value="67"/>
                  </measurement_list>
                </category>
                <category>
                  <title>American Indian / Alaska Native</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                    <measurement group_id="B2" value="2"/>
                    <measurement group_id="B3" value="3"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Other</title>
                  <measurement_list>
                    <measurement group_id="B1" value="4"/>
                    <measurement group_id="B2" value="3"/>
                    <measurement group_id="B3" value="7"/>
                  </measurement_list>
                </category>
                <category>
                  <title>More than 1 race</title>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="2"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Refused / prefer not to answer</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="1"/>
                  </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>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="163"/>
                    <count group_id="B2" value="157"/>
                    <count group_id="B3" value="320"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="163"/>
                    <measurement group_id="B2" value="157"/>
                    <measurement group_id="B3" value="320"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Cigarettes per day</title>
          <description>Self-reported cigarettes smoked per day, on average, over the past 6 months</description>
          <units>Cigarettes per day</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="163"/>
                    <count group_id="B2" value="157"/>
                    <count group_id="B3" value="320"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="17.9" spread="7.2"/>
                    <measurement group_id="B2" value="18.4" spread="7.3"/>
                    <measurement group_id="B3" value="18.1" spread="7.2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Salivary cotinine</title>
          <population>Baseline cotinine data were missing for one participant in the standard run-in group.</population>
          <units>ng/mL</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="163"/>
                    <count group_id="B2" value="156"/>
                    <count group_id="B3" value="319"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="312" spread="158"/>
                    <measurement group_id="B2" value="312" spread="164"/>
                    <measurement group_id="B3" value="312" spread="161"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Number of Participants With Continuous Abstinence at End-of-Treatment (EOT) as Assessed by Self-Report and Bio-verification</title>
        <description>Number of participants with bio-verified (cotinine level of 15 ng/mL or less) self-reported continuous abstinence from smoking (not even a puff) during the final four weeks of treatment</description>
        <time_frame>Self-report Treatment Weeks 12-15; bio-verification ~Week 16</time_frame>
        <population>Intent-to-treat analysis.</population>
        <group_list>
          <group group_id="O1">
            <title>Extended Run-In</title>
            <description>** 4 weeks of varenicline prior to the target quit date (TQD) **&#xD;
+ 11 weeks of post-TQD varenicline&#xD;
Standard varenicline dosing titration in initial week of therapy (one 0.5 mg tablet orally daily x 3 days, then one 0.5 mg tablet twice daily x 4 days); then 1 mg twice daily thereafter.&#xD;
Brief individual counseling at clinic visits&#xD;
Varenicline: oral varenicline tablets&#xD;
Brief smoking cessation counseling: ~10-minute individual counseling at each of 6 clinic visits</description>
          </group>
          <group group_id="O2">
            <title>Standard Run-In</title>
            <description>** 3 weeks of placebo followed by 1 week of varenicline prior to the target quit date (TQD) **&#xD;
+ 11 weeks of post-TQD varenicline&#xD;
Standard varenicline dosing titration in initial week of therapy (one 0.5 mg tablet orally daily x 3 days, then one 0.5 mg tablet twice daily x 4 days); then 1 mg twice daily thereafter.&#xD;
Brief individual counseling at clinic visits&#xD;
Varenicline: oral varenicline tablets&#xD;
Brief smoking cessation counseling: ~10-minute individual counseling at each of 6 clinic visits</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Participants With Continuous Abstinence at End-of-Treatment (EOT) as Assessed by Self-Report and Bio-verification</title>
          <description>Number of participants with bio-verified (cotinine level of 15 ng/mL or less) self-reported continuous abstinence from smoking (not even a puff) during the final four weeks of treatment</description>
          <population>Intent-to-treat analysis.</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="163"/>
                <count group_id="O2" value="157"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="64"/>
                    <measurement group_id="O2" value="57"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Pre-quit Change in Cigarettes Smoked Per Day</title>
        <description>Percent change in smoking behavior (self-reported cigarettes per day; CPD) from timeline follow-back (TLFB) interviews during the pre-quit phase of the study.</description>
        <time_frame>Treatment Week 1 vs. Treatment Week 4 (final week before TQD)</time_frame>
        <population>This analysis is not based on ITT, as only participants with complete TLFB data for Weeks 1 and 4 were included in the analysis; early in the trial, pre-quit TLFB was not consistently obtained due to staff error.</population>
        <group_list>
          <group group_id="O1">
            <title>Extended Run-In</title>
            <description>** 4 weeks of varenicline prior to the target quit date (TQD) **&#xD;
+ 11 weeks of post-TQD varenicline&#xD;
Standard varenicline dosing titration in initial week of therapy (one 0.5 mg tablet orally daily x 3 days, then one 0.5 mg tablet twice daily x 4 days); then 1 mg twice daily thereafter.&#xD;
Brief individual counseling at clinic visits&#xD;
Varenicline: oral varenicline tablets&#xD;
Brief smoking cessation counseling: ~10-minute individual counseling at each of 6 clinic visits</description>
          </group>
          <group group_id="O2">
            <title>Standard Run-In</title>
            <description>** 3 weeks of placebo followed by 1 week of varenicline prior to the target quit date (TQD) **&#xD;
+ 11 weeks of post-TQD varenicline&#xD;
Standard varenicline dosing titration in initial week of therapy (one 0.5 mg tablet orally daily x 3 days, then one 0.5 mg tablet twice daily x 4 days); then 1 mg twice daily thereafter.&#xD;
Brief individual counseling at clinic visits&#xD;
Varenicline: oral varenicline tablets&#xD;
Brief smoking cessation counseling: ~10-minute individual counseling at each of 6 clinic visits</description>
          </group>
        </group_list>
        <measure>
          <title>Pre-quit Change in Cigarettes Smoked Per Day</title>
          <description>Percent change in smoking behavior (self-reported cigarettes per day; CPD) from timeline follow-back (TLFB) interviews during the pre-quit phase of the study.</description>
          <population>This analysis is not based on ITT, as only participants with complete TLFB data for Weeks 1 and 4 were included in the analysis; early in the trial, pre-quit TLFB was not consistently obtained due to staff error.</population>
          <units>percent change in CPD</units>
          <param>Mean</param>
          <dispersion>Standard Error</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="128"/>
                <count group_id="O2" value="123"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-38.8" spread="2.7"/>
                    <measurement group_id="O2" value="-17.5" spread="2.8"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Number of Participants With Continuous Abstinence at 6-Month Follow-Up as Assessed by Self-Report and Bio-verification</title>
        <description>Number of participants with continuous abstinence at the 6-month follow-up (no self-reported smoking during weeks 12-28 AND cotinine level 15 ng/mL or less at EOT and 6 month follow-up)</description>
        <time_frame>Self-report Treatment Weeks 12-28; bio-verification ~Week 16 and ~Week 29</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Extended Run-In</title>
            <description>** 4 weeks of varenicline prior to the target quit date (TQD) **&#xD;
+ 11 weeks of post-TQD varenicline&#xD;
Standard varenicline dosing titration in initial week of therapy (one 0.5 mg tablet orally daily x 3 days, then one 0.5 mg tablet twice daily x 4 days); then 1 mg twice daily thereafter.&#xD;
Brief individual counseling at clinic visits&#xD;
Varenicline: oral varenicline tablets&#xD;
Brief smoking cessation counseling: ~10-minute individual counseling at each of 6 clinic visits</description>
          </group>
          <group group_id="O2">
            <title>Standard Run-In</title>
            <description>** 3 weeks of placebo followed by 1 week of varenicline prior to the target quit date (TQD) **&#xD;
+ 11 weeks of post-TQD varenicline&#xD;
Standard varenicline dosing titration in initial week of therapy (one 0.5 mg tablet orally daily x 3 days, then one 0.5 mg tablet twice daily x 4 days); then 1 mg twice daily thereafter.&#xD;
Brief individual counseling at clinic visits&#xD;
Varenicline: oral varenicline tablets&#xD;
Brief smoking cessation counseling: ~10-minute individual counseling at each of 6 clinic visits</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Participants With Continuous Abstinence at 6-Month Follow-Up as Assessed by Self-Report and Bio-verification</title>
          <description>Number of participants with continuous abstinence at the 6-month follow-up (no self-reported smoking during weeks 12-28 AND cotinine level 15 ng/mL or less at EOT and 6 month follow-up)</description>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="163"/>
                <count group_id="O2" value="157"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="37"/>
                    <measurement group_id="O2" value="29"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>Adverse events were assessed at intake and clinic visits which occurred across the first two months of treatment.</time_frame>
      <desc>At each visit, participants completed a 32-item symptom checklist, as in prior work.&#xD;
Suicidality was assessed at each visit with the Columbia Suicide Severity Rating Scale.&#xD;
Here, data on adverse events are reported for each of three treatment phasesphases (pre-treatment phase [intake visit &amp; clinic visit 1); pre-quit run-in manipulation phase [clinic visits 2&amp;3; extended run-in group taking varenicline, standard run-in group taking placebo], and early quit phase [clinic visits 4&amp;5]).</desc>
      <group_list>
        <group group_id="E1">
          <title>Pre-Treatment Phase (Intake Visit &amp; Clinic 1): Extended Run-In Group</title>
          <description>Pre-Treatment Phase: Intake Visit and Clinic 1 assessments occurred prior to initiating treatment&#xD;
Brief smoking cessation counseling: ~10-minute individual counseling at each clinic visit</description>
        </group>
        <group group_id="E2">
          <title>Pre-Treatment Phase (Intake Visit &amp; Clinic 1): Standard Run-In Group</title>
          <description>Pre-Treatment Phase: Intake Visit and Clinic 1 assessments occurred prior to initiating treatment&#xD;
Brief smoking cessation counseling: ~10-minute individual counseling at each clinic visit</description>
        </group>
        <group group_id="E3">
          <title>Pre-Quit Run-In Manip Phase (Clinic 2 &amp; 3): Extended Run-In Group</title>
          <description>Pre-Quit Run-In Manipulation Phase (3 weeks):&#xD;
All participants began taking study medication following Clinic 1&#xD;
The extended run-in group took varenicline:&#xD;
Varenicline dosing titration in initial week of therapy (one 0.5 mg tablet orally daily x 3 days, then one 0.5 mg tablet twice daily x 4 days); then 1 mg twice daily thereafter.&#xD;
Brief smoking cessation counseling: ~10-minute individual counseling at each clinic visit</description>
        </group>
        <group group_id="E4">
          <title>Pre-Quit Run-In Manip Phase (Clinic 2 &amp; 3): Standard Run-In Group</title>
          <description>Pre-Quit Run-In Manipulation Phase (3 weeks):&#xD;
All participants began taking study medication following Clinic 1&#xD;
The standard run-in group took placebo.&#xD;
Brief smoking cessation counseling: ~10-minute individual counseling at each clinic visit</description>
        </group>
        <group group_id="E5">
          <title>Early Quit Phase (Clinic 4 &amp; 5): Extended Run-In Group</title>
          <description>Early Quit Phase (3 weeks):&#xD;
The extended run-in group continued varenicline, two 0.5 mg varenicline twice daily during Week 4 (to match the placebo group and maintain the blind); 1 mg twice daily thereafter.&#xD;
Brief smoking cessation counseling: ~10-minute individual counseling at each clinic visit</description>
        </group>
        <group group_id="E6">
          <title>Early Quit Phase (Clinic 4 &amp; 5): Standard Run-In Group</title>
          <description>Early Quit Phase (3 weeks)&#xD;
Varenicline dosing titration in Week 4 (one 0.5 mg tablet and 3 placebo orally daily x 3 days, then one 0.5 mg tablet and 1 placebo twice daily x 4 days); then 1 mg twice daily thereafter.&#xD;
Brief smoking cessation counseling: ~10-minute individual counseling at each clinic visit</description>
        </group>
      </group_list>
      <serious_events>
        <default_assessment>Non-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="163"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="157"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="157"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="147"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="150"/>
                <counts group_id="E6" subjects_affected="0" subjects_at_risk="146"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="163"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="157"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="157"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="147"/>
                <counts group_id="E5" subjects_affected="2" subjects_at_risk="150"/>
                <counts group_id="E6" subjects_affected="2" subjects_at_risk="146"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Cardiac disorders</title>
            <event_list>
              <event>
                <sub_title>Bilateral hand swelling</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="163"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="157"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="157"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="147"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="150"/>
                <counts group_id="E6" subjects_affected="1" subjects_at_risk="146"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>bowel obstruction/laparotomy for lysis of adhesions</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="163"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="157"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="157"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="147"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="150"/>
                <counts group_id="E6" subjects_affected="0" subjects_at_risk="146"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>urinary frequency and incisional pain 3 days after elective inguinal hernia repair</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="163"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="157"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="157"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="147"/>
                <counts group_id="E5" subjects_affected="1" subjects_at_risk="150"/>
                <counts group_id="E6" subjects_affected="0" subjects_at_risk="146"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Renal and urinary disorders</title>
            <event_list>
              <event>
                <sub_title>pyelonephritis/nephrolithiasis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="163"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="157"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="157"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="147"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="150"/>
                <counts group_id="E6" subjects_affected="1" subjects_at_risk="146"/>
              </event>
              <event>
                <sub_title>urinary tract infection</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="163"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="157"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="157"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="147"/>
                <counts group_id="E5" subjects_affected="1" subjects_at_risk="150"/>
                <counts group_id="E6" subjects_affected="0" subjects_at_risk="146"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Skin and subcutaneous tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Scabies</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="163"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="157"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="157"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="147"/>
                <counts group_id="E5" subjects_affected="1" subjects_at_risk="150"/>
                <counts group_id="E6" subjects_affected="0" subjects_at_risk="146"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>5</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="125" subjects_at_risk="163"/>
                <counts group_id="E2" subjects_affected="121" subjects_at_risk="157"/>
                <counts group_id="E3" subjects_affected="131" subjects_at_risk="157"/>
                <counts group_id="E4" subjects_affected="104" subjects_at_risk="147"/>
                <counts group_id="E5" subjects_affected="116" subjects_at_risk="150"/>
                <counts group_id="E6" subjects_affected="104" subjects_at_risk="146"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Cardiac disorders</title>
            <event_list>
              <event>
                <sub_title>Increased Heart Rate</sub_title>
                <counts group_id="E1" subjects_affected="11" subjects_at_risk="163"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="157"/>
                <counts group_id="E3" subjects_affected="8" subjects_at_risk="157"/>
                <counts group_id="E4" subjects_affected="7" subjects_at_risk="147"/>
                <counts group_id="E5" subjects_affected="5" subjects_at_risk="150"/>
                <counts group_id="E6" subjects_affected="4" subjects_at_risk="146"/>
              </event>
              <event>
                <sub_title>Chest Pain</sub_title>
                <counts group_id="E1" subjects_affected="9" subjects_at_risk="163"/>
                <counts group_id="E2" subjects_affected="6" subjects_at_risk="157"/>
                <counts group_id="E3" subjects_affected="9" subjects_at_risk="157"/>
                <counts group_id="E4" subjects_affected="5" subjects_at_risk="147"/>
                <counts group_id="E5" subjects_affected="7" subjects_at_risk="150"/>
                <counts group_id="E6" subjects_affected="4" subjects_at_risk="146"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Nausea</sub_title>
                <counts group_id="E1" subjects_affected="13" subjects_at_risk="163"/>
                <counts group_id="E2" subjects_affected="13" subjects_at_risk="157"/>
                <counts group_id="E3" subjects_affected="45" subjects_at_risk="157"/>
                <counts group_id="E4" subjects_affected="26" subjects_at_risk="147"/>
                <counts group_id="E5" subjects_affected="48" subjects_at_risk="150"/>
                <counts group_id="E6" subjects_affected="42" subjects_at_risk="146"/>
              </event>
              <event>
                <sub_title>Vomiting</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="163"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="157"/>
                <counts group_id="E3" subjects_affected="11" subjects_at_risk="157"/>
                <counts group_id="E4" subjects_affected="5" subjects_at_risk="147"/>
                <counts group_id="E5" subjects_affected="10" subjects_at_risk="150"/>
                <counts group_id="E6" subjects_affected="9" subjects_at_risk="146"/>
              </event>
              <event>
                <sub_title>Abdominal Pain</sub_title>
                <counts group_id="E1" subjects_affected="8" subjects_at_risk="163"/>
                <counts group_id="E2" subjects_affected="9" subjects_at_risk="157"/>
                <counts group_id="E3" subjects_affected="19" subjects_at_risk="157"/>
                <counts group_id="E4" subjects_affected="8" subjects_at_risk="147"/>
                <counts group_id="E5" subjects_affected="13" subjects_at_risk="150"/>
                <counts group_id="E6" subjects_affected="12" subjects_at_risk="146"/>
              </event>
              <event>
                <sub_title>Indigestion</sub_title>
                <counts group_id="E1" subjects_affected="17" subjects_at_risk="163"/>
                <counts group_id="E2" subjects_affected="13" subjects_at_risk="157"/>
                <counts group_id="E3" subjects_affected="13" subjects_at_risk="157"/>
                <counts group_id="E4" subjects_affected="6" subjects_at_risk="147"/>
                <counts group_id="E5" subjects_affected="10" subjects_at_risk="150"/>
                <counts group_id="E6" subjects_affected="9" subjects_at_risk="146"/>
              </event>
              <event>
                <sub_title>Diarrhea</sub_title>
                <counts group_id="E1" subjects_affected="12" subjects_at_risk="163"/>
                <counts group_id="E2" subjects_affected="13" subjects_at_risk="157"/>
                <counts group_id="E3" subjects_affected="13" subjects_at_risk="157"/>
                <counts group_id="E4" subjects_affected="7" subjects_at_risk="147"/>
                <counts group_id="E5" subjects_affected="12" subjects_at_risk="150"/>
                <counts group_id="E6" subjects_affected="5" subjects_at_risk="146"/>
              </event>
              <event>
                <sub_title>Constipation</sub_title>
                <counts group_id="E1" subjects_affected="16" subjects_at_risk="163"/>
                <counts group_id="E2" subjects_affected="11" subjects_at_risk="157"/>
                <counts group_id="E3" subjects_affected="22" subjects_at_risk="157"/>
                <counts group_id="E4" subjects_affected="23" subjects_at_risk="147"/>
                <counts group_id="E5" subjects_affected="25" subjects_at_risk="150"/>
                <counts group_id="E6" subjects_affected="28" subjects_at_risk="146"/>
              </event>
              <event>
                <sub_title>Dry mouth</sub_title>
                <counts group_id="E1" subjects_affected="25" subjects_at_risk="163"/>
                <counts group_id="E2" subjects_affected="37" subjects_at_risk="157"/>
                <counts group_id="E3" subjects_affected="33" subjects_at_risk="157"/>
                <counts group_id="E4" subjects_affected="43" subjects_at_risk="147"/>
                <counts group_id="E5" subjects_affected="29" subjects_at_risk="150"/>
                <counts group_id="E6" subjects_affected="37" subjects_at_risk="146"/>
              </event>
              <event>
                <sub_title>Flatulence</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="163"/>
                <counts group_id="E2" subjects_affected="15" subjects_at_risk="157"/>
                <counts group_id="E3" subjects_affected="11" subjects_at_risk="157"/>
                <counts group_id="E4" subjects_affected="15" subjects_at_risk="147"/>
                <counts group_id="E5" subjects_affected="12" subjects_at_risk="150"/>
                <counts group_id="E6" subjects_affected="10" subjects_at_risk="146"/>
              </event>
              <event>
                <sub_title>Gas</sub_title>
                <counts group_id="E1" subjects_affected="19" subjects_at_risk="163"/>
                <counts group_id="E2" subjects_affected="23" subjects_at_risk="157"/>
                <counts group_id="E3" subjects_affected="28" subjects_at_risk="157"/>
                <counts group_id="E4" subjects_affected="20" subjects_at_risk="147"/>
                <counts group_id="E5" subjects_affected="25" subjects_at_risk="150"/>
                <counts group_id="E6" subjects_affected="23" subjects_at_risk="146"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Insomnia</sub_title>
                <counts group_id="E1" subjects_affected="25" subjects_at_risk="163"/>
                <counts group_id="E2" subjects_affected="29" subjects_at_risk="157"/>
                <counts group_id="E3" subjects_affected="29" subjects_at_risk="157"/>
                <counts group_id="E4" subjects_affected="27" subjects_at_risk="147"/>
                <counts group_id="E5" subjects_affected="33" subjects_at_risk="150"/>
                <counts group_id="E6" subjects_affected="29" subjects_at_risk="146"/>
              </event>
              <event>
                <sub_title>Abnormal dreams</sub_title>
                <counts group_id="E1" subjects_affected="6" subjects_at_risk="163"/>
                <counts group_id="E2" subjects_affected="9" subjects_at_risk="157"/>
                <counts group_id="E3" subjects_affected="41" subjects_at_risk="157"/>
                <counts group_id="E4" subjects_affected="15" subjects_at_risk="147"/>
                <counts group_id="E5" subjects_affected="35" subjects_at_risk="150"/>
                <counts group_id="E6" subjects_affected="24" subjects_at_risk="146"/>
              </event>
              <event>
                <sub_title>Other Sleep Problems</sub_title>
                <counts group_id="E1" subjects_affected="23" subjects_at_risk="163"/>
                <counts group_id="E2" subjects_affected="29" subjects_at_risk="157"/>
                <counts group_id="E3" subjects_affected="25" subjects_at_risk="157"/>
                <counts group_id="E4" subjects_affected="14" subjects_at_risk="147"/>
                <counts group_id="E5" subjects_affected="22" subjects_at_risk="150"/>
                <counts group_id="E6" subjects_affected="15" subjects_at_risk="146"/>
              </event>
              <event>
                <sub_title>Fatigue</sub_title>
                <counts group_id="E1" subjects_affected="39" subjects_at_risk="163"/>
                <counts group_id="E2" subjects_affected="43" subjects_at_risk="157"/>
                <counts group_id="E3" subjects_affected="28" subjects_at_risk="157"/>
                <counts group_id="E4" subjects_affected="33" subjects_at_risk="147"/>
                <counts group_id="E5" subjects_affected="28" subjects_at_risk="150"/>
                <counts group_id="E6" subjects_affected="32" subjects_at_risk="146"/>
              </event>
              <event>
                <sub_title>Weakness</sub_title>
                <counts group_id="E1" subjects_affected="14" subjects_at_risk="163"/>
                <counts group_id="E2" subjects_affected="9" subjects_at_risk="157"/>
                <counts group_id="E3" subjects_affected="8" subjects_at_risk="157"/>
                <counts group_id="E4" subjects_affected="7" subjects_at_risk="147"/>
                <counts group_id="E5" subjects_affected="8" subjects_at_risk="150"/>
                <counts group_id="E6" subjects_affected="10" subjects_at_risk="146"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Headache</sub_title>
                <counts group_id="E1" subjects_affected="39" subjects_at_risk="163"/>
                <counts group_id="E2" subjects_affected="47" subjects_at_risk="157"/>
                <counts group_id="E3" subjects_affected="31" subjects_at_risk="157"/>
                <counts group_id="E4" subjects_affected="39" subjects_at_risk="147"/>
                <counts group_id="E5" subjects_affected="26" subjects_at_risk="150"/>
                <counts group_id="E6" subjects_affected="29" subjects_at_risk="146"/>
              </event>
              <event>
                <sub_title>Dizziness</sub_title>
                <counts group_id="E1" subjects_affected="13" subjects_at_risk="163"/>
                <counts group_id="E2" subjects_affected="10" subjects_at_risk="157"/>
                <counts group_id="E3" subjects_affected="22" subjects_at_risk="157"/>
                <counts group_id="E4" subjects_affected="9" subjects_at_risk="147"/>
                <counts group_id="E5" subjects_affected="12" subjects_at_risk="150"/>
                <counts group_id="E6" subjects_affected="9" subjects_at_risk="146"/>
              </event>
              <event>
                <sub_title>Attention Disturbance</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="163"/>
                <counts group_id="E2" subjects_affected="10" subjects_at_risk="157"/>
                <counts group_id="E3" subjects_affected="10" subjects_at_risk="157"/>
                <counts group_id="E4" subjects_affected="6" subjects_at_risk="147"/>
                <counts group_id="E5" subjects_affected="4" subjects_at_risk="150"/>
                <counts group_id="E6" subjects_affected="10" subjects_at_risk="146"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Psychiatric disorders</title>
            <event_list>
              <event>
                <sub_title>Agitation</sub_title>
                <counts group_id="E1" subjects_affected="37" subjects_at_risk="163"/>
                <counts group_id="E2" subjects_affected="31" subjects_at_risk="157"/>
                <counts group_id="E3" subjects_affected="32" subjects_at_risk="157"/>
                <counts group_id="E4" subjects_affected="26" subjects_at_risk="147"/>
                <counts group_id="E5" subjects_affected="29" subjects_at_risk="150"/>
                <counts group_id="E6" subjects_affected="41" subjects_at_risk="146"/>
              </event>
              <event>
                <sub_title>Depressed Mood</sub_title>
                <counts group_id="E1" subjects_affected="20" subjects_at_risk="163"/>
                <counts group_id="E2" subjects_affected="27" subjects_at_risk="157"/>
                <counts group_id="E3" subjects_affected="21" subjects_at_risk="157"/>
                <counts group_id="E4" subjects_affected="16" subjects_at_risk="147"/>
                <counts group_id="E5" subjects_affected="23" subjects_at_risk="150"/>
                <counts group_id="E6" subjects_affected="14" subjects_at_risk="146"/>
              </event>
              <event>
                <sub_title>Irritability</sub_title>
                <counts group_id="E1" subjects_affected="58" subjects_at_risk="163"/>
                <counts group_id="E2" subjects_affected="50" subjects_at_risk="157"/>
                <counts group_id="E3" subjects_affected="55" subjects_at_risk="157"/>
                <counts group_id="E4" subjects_affected="47" subjects_at_risk="147"/>
                <counts group_id="E5" subjects_affected="49" subjects_at_risk="150"/>
                <counts group_id="E6" subjects_affected="56" subjects_at_risk="146"/>
              </event>
              <event>
                <sub_title>Hostility</sub_title>
                <counts group_id="E1" subjects_affected="9" subjects_at_risk="163"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="157"/>
                <counts group_id="E3" subjects_affected="10" subjects_at_risk="157"/>
                <counts group_id="E4" subjects_affected="5" subjects_at_risk="147"/>
                <counts group_id="E5" subjects_affected="11" subjects_at_risk="150"/>
                <counts group_id="E6" subjects_affected="6" subjects_at_risk="146"/>
              </event>
              <event>
                <sub_title>Anxiety</sub_title>
                <counts group_id="E1" subjects_affected="36" subjects_at_risk="163"/>
                <counts group_id="E2" subjects_affected="34" subjects_at_risk="157"/>
                <counts group_id="E3" subjects_affected="26" subjects_at_risk="157"/>
                <counts group_id="E4" subjects_affected="25" subjects_at_risk="147"/>
                <counts group_id="E5" subjects_affected="25" subjects_at_risk="150"/>
                <counts group_id="E6" subjects_affected="32" subjects_at_risk="146"/>
              </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>Larry Hawk, PhD</name_or_title>
      <organization>University at Buffalo</organization>
      <phone>716-829-2323</phone>
      <email>lhawk@buffalo.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/NCT03262662
org study id: STUDY00000911
secondary id: R01CA206193
nct id: NCT03262662
lead sponsor: 
collaborator: 
collaborator: 
is fda regulated drug: Yes
is fda regulated device: No
Varenicline is the most effective smoking cessation therapy available. Nevertheless, most
      smokers using varenicline relapse within the first few months after quitting. Varenicline is
      hypothesized to help smokers to quit in part by reducing the reinforcing effects of smoking
      during the standard 1-week pre-quitting treatment phase. Learning theory and previous human
      and animal research support the hypothesis that a longer period of varenicline treatment
      prior to the target quit date (TQD) will lead to greater reductions in smoking before
      quitting, and higher long-term cessation rates, compared to standard varenicline treatment.
      Building on promising preliminary clinical data, the study tests these hypotheses with a
      full-scale randomized clinical trial (RCT). 320 treatment-seeking smokers will be randomized
      to a standard run-in group (3 weeks of placebo, followed by the standard 1 week of pre-TQD
      varenicline) or an extended run-in group (4 weeks of pre-TQD varenicline). Both groups will
      receive brief individual cessation counseling and 11 weeks of post-TQD varenicline. The
      primary outcome measure will be bio-verified continuous abstinence at end-of-treatment (weeks
      8-11 post-quit; cessation at 26-weeks post TQD will also be examined. Hypothesized mediating
      mechanisms (e.g., smoking reinforcement) will be evaluated by behavioral, physiological, and
      subjective measures assessed both in the lab and using real-world, real-time electronic
      momentary assessments (EMA). The investigators predict that long-term, bio-verified smoking
      cessation will be improved among the extended run-in group compared to the standard run-in
      group. The investigators further predict the improved clinical outcomes with extended run-in
      varenicline will be explained (or mediated) by greater pre-quit reductions in smoking
      reinforcement among the extended run-in group compared to the standard run-in group. The
      significance of this work is clear: The project aims to make best available treatment for
      smoking cessation even better, using a method that is ripe for dissemination and an approach
      that will elucidate critical mechanisms to target in the next generation of treatment
      enhancement.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
measure: Number of Participants With Continuous Abstinence at End-of-Treatment (EOT) as Assessed by Self-Report and Bio-verification
time frame: Self-report Treatment Weeks 12-15; bio-verification ~Week 16
description: Number of participants with bio-verified (cotinine level of 15 ng/mL or less) self-reported continuous abstinence from smoking (not even a puff) during the final four weeks of treatment
measure: Pre-quit Change in Cigarettes Smoked Per Day
time frame: Treatment Week 1 vs. Treatment Week 4 (final week before TQD)
description: Percent change in smoking behavior (self-reported cigarettes per day; CPD) from timeline follow-back (TLFB) interviews during the pre-quit phase of the study.
measure: Number of Participants With Continuous Abstinence at 6-Month Follow-Up as Assessed by Self-Report and Bio-verification
time frame: Self-report Treatment Weeks 12-28; bio-verification ~Week 16 and ~Week 29
description: Number of participants with continuous abstinence at the 6-month follow-up (no self-reported smoking during weeks 12-28 AND cotinine level 15 ng/mL or less at EOT and 6 month follow-up)
arm group label: Extended Run-In
arm group type: Experimental
description: ** 4 weeks of varenicline prior to the target quit date (TQD) **
+ 11 weeks of post-TQD varenicline
Standard varenicline dosing titration in initial week of therapy (one 0.5 mg tablet orally daily x 3 days, then one 0.5 mg tablet twice daily x 4 days); then 1 mg twice daily thereafter.
Brief individual counseling at clinic visits
arm group label: Standard Run-In
arm group type: Active Comparator
description: ** 3 weeks of placebo followed by 1 week of varenicline prior to the target quit date (TQD) **
+ 11 weeks of post-TQD varenicline
Standard varenicline dosing titration in initial week of therapy (one 0.5 mg tablet orally daily x 3 days, then one 0.5 mg tablet twice daily x 4 days); then 1 mg twice daily thereafter.
Brief individual counseling at clinic visits
intervention type: Drug
intervention name: Varenicline
description: oral varenicline tablets
arm group label: Extended Run-In
arm group label: Standard Run-In
other name: Chantix
intervention type: Behavioral
intervention name: Brief smoking cessation counseling
description: ~10-minute individual counseling at each of 6 clinic visits
arm group label: Extended Run-In
arm group label: Standard Run-In
criteria: 
gender: All
gender based: Yes
gender description: Approximately equal numbers of men and women will participate.
minimum age: 18 Years
maximum age: 70 Years
healthy volunteers: Accepts Healthy Volunteers
facility: 
country: United States
responsible party type: Principal Investigator
investigator affiliation: State University of New York at Buffalo
investigator full name: Larry Hawk, Ph.D.
investigator title: Professor, Department of Psychology
mesh term: Varenicline
sharing ipd: Yes
ipd description: We plan to share study data through the NIDA-supported NAHDAP repository. IPD to be shared include baseline participant characteristics, intervention group, smoking abstinence, and adverse events.
ipd info type: Study Protocol
ipd info type: Informed Consent Form (ICF)
ipd time frame: 2023. We are currently awaiting confirmation from NAHDAP that our archival plan fits their expectations. Data will be available indefinitely (as long as NAHDAP is supported).
ipd access criteria: Public release; anyone who registers on the website.
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 