<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/NCT02239770</url>
  </required_header>
  <id_info>
    <org_study_id>00000873</org_study_id>
    <nct_id>NCT02239770</nct_id>
  </id_info>
  <brief_title>Pharmacokinetics of Nicotine Film in Smokers</brief_title>
  <official_title>Pharmacokinetics of Nicotine Film in Smokers</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Milton S. Hershey Medical Center</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Milton S. Hershey Medical Center</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      The objective of this study is to test the effect of a range of doses of a novel nicotine&#xD;
      film on plasma nicotine levels, expired carbon monoxide and, via a questionnaire, subjective&#xD;
      ratings of the film and side effects. The nicotine film is not part of standard of care and&#xD;
      is not available in a non-investigational setting. The investigators hypothesize that plasma&#xD;
      nicotine levels will be in keeping with those induced by other oral nicotine replacement&#xD;
      therapies (NRTs) and by the smoking of a cigarette. Thus, the investigators predict that&#xD;
      random delivery of nicotine via the oral film will be safe and well-tolerated by the human&#xD;
      subjects.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Briefly, this will be a two-part pharmacokinetic study, each part involving 12 participants.&#xD;
&#xD;
      In Part 1, 4 volunteer smokers (both male, and female) each will each abstain from all&#xD;
      tobacco/nicotine products for 16 hours before attending the Penn State Clinical Research&#xD;
      Center for the measurement of the blood nicotine pharmacokinetic response to a randomly&#xD;
      allocated dose of either (a) 0mg, (b) 2mg or (c) 4mg oral nicotine film. A trained nurse will&#xD;
      implant an intravenous indwelling catheter in each participant, through which they will&#xD;
      provide a baseline blood sample after 16 hours of abstinence, confirmed by an exhaled&#xD;
      carbon-monoxide &lt; 6 ppm, and then will place a nicotine film in their mouth and have blood&#xD;
      drawn every 10 minutes for the next 60 minutes, and then every 30 minutes for the next 2&#xD;
      hours plus one blood draw one minute after the film dissolves (11 blood draws in all over 3&#xD;
      hours after using the nicotine film). Subjective measures of (a) nicotine withdrawal and&#xD;
      craving and (b) potential nicotine effects, including symptoms of nicotine intoxication, will&#xD;
      be recorded at scheduled intervals through the study visit, and blood pressure and heart rate&#xD;
      will be measured every 30 minutes. The investigators expect to find peak blood nicotine&#xD;
      concentrations of around 3-4 ng/ml and 5-6 ng/ml from each of the two active doses of&#xD;
      nicotine film, with the peak occurring approximately 30 minutes after film administration,&#xD;
      and the level having dropped by at least half by 2 hours later. These peak blood nicotine&#xD;
      levels are all within the range that a smoker might obtain after smoking a single cigarette.&#xD;
      Upon completion of all blood draws, a trained nurse will remove the catheter and treat the&#xD;
      puncture wound. The participant will receive $120 for this visit.&#xD;
&#xD;
      In Part 2, 12 participants will again attend the Penn State Clinical Research Center after 16&#xD;
      hours of abstinence, confirmed by an exhaled carbon monoxide &lt; 12 ppm. On this visit&#xD;
      participants will consume repeated doses of nicotine films intended to mimic the patterns of&#xD;
      delivery that will be used in smoking cessation study 2 and fMRI study 3. The primary issue&#xD;
      here is to determine peak blood nicotine concentrations and safety resulting from (a) the&#xD;
      highest dose schedule that could be used in study 2 and 3, (b) the steady state levels&#xD;
      produced by repeated administration of the 2mg nicotine film, and (c) to compare the&#xD;
      subjective effects to placebo. In order to mimic the most aggressive dosing schedule possible&#xD;
      in the &quot;random nicotine&quot; arm of study 2 and 3, the investigators will assess blood nicotine,&#xD;
      subjective and basic cardiovascular responses to consuming nicotine film every 3 hours&#xD;
      beginning at 8:00 a.m. on the following schedule: 4mg, 4mg, 0mg, 4mg.&#xD;
&#xD;
      All 12 participants will attend after 16 hours nicotine abstinence. 4 subjects each will be&#xD;
      randomly allocated to consume 4 films over 12 hours in each of the following orders (a)&#xD;
      0,0,0,0 mg (b) 2,2,2,2 or (c) 4,4,0,4. A blood sample will be drawn at baseline prior to each&#xD;
      film administration, and then at 30, 60 and 120 minutes after each film administration as&#xD;
      well as one minute after film dissolution (20 blood draws in total), with heart rate and BP&#xD;
      being assessed every 30 minutes. Nicotine has a half-life of approximately 2 hours, so the&#xD;
      investigators expect that with 3-hourly administration there will not be much build-up of&#xD;
      nicotine levels and these levels will be on the low end of the typical levels experienced by&#xD;
      smokers every day. The participants will each receive $240 for this visit.&#xD;
&#xD;
      At clinic visits, in addition to providing blood samples for measurement of plasma nicotine&#xD;
      concentration, participants will be asked to complete a battery of survey instruments&#xD;
      assessing subjective effects (e.g. withdrawal and craving) and physical symptoms (e.g.&#xD;
      dizziness and nausea) that could be caused by either nicotine withdrawal or nicotine&#xD;
      exposure.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">September 2015</start_date>
  <completion_date type="Actual">October 2017</completion_date>
  <primary_completion_date type="Actual">October 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>Peak Plasma Nicotine Concentrations Following Ingestion of a Single (Phase 1) or Repeated (Phase 2) Doses of Nicotine Film</measure>
    <time_frame>10 min - 12 hours</time_frame>
    <description>In Phase 1, a trained nurse will implant an intravenous (IV) indwelling catheter in each participant. Participants will place a film containing zero, 2, or 4 mg of nicotine in their mouths and blood will be drawn every 10 minutes thereafter for the next 60 minutes, and then every 30 minutes for the next 2 hours (11 blood draws in all over 3 hours after using the nicotine film).&#xD;
In Phase 2, all 12 participants will receive an IV catheter and randomly allocated to consume 4 films over 12 hours in each of the following orders (a) 0,0,0,0 mg (b) 2,2,2,2 or (c) 4,4,0,4. A blood sample will be drawn at baseline prior to each film administration, and then at 30, 45, 60 and 120 minutes after each film administration and when the film is reported dissolved (20 blood draws in total).</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Questionnaire of Smoking Urges-Brief Mean Total Score by Dose Group</measure>
    <time_frame>Part 1: The QSU-Brief was measured at baseline and at 15, 35, 55, 80, 140, and 200 minutes post film administration. Part 2: The QSU-Brief was measured at baseline and at 50, 110, 230, 290, 410, 470, 590, and 690 minutes post FIRST film administration.</time_frame>
    <description>The Questionnaire of Smoking Urges-Brief (QSU-Brief) with a possible total score range of 10 to 70 was used to measure cigarette craving at baseline and at several points throughout the study visit for each participant. A score of 10 on this scale indicates very low cigarette craving, while a score of 70 indicates very high cigarette craving.&#xD;
Part 1: The QSU-Brief was measured at baseline and at 15, 35, 55, 80, 140, and 200 minutes post film administration.&#xD;
Part 2: The QSU-Brief was measured at baseline and at 50, 110, 230, 290, 410, 470, 590, and 690 minutes post FIRST film administration.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Mean Systolic Blood Pressure</measure>
    <time_frame>Part 1: Systolic blood pressure was measured at baseline and at every 30 minutes, up to 180 minutes post film administration. Part 2: Systolic blood pressure was measured at baseline and at every 30 minutes, up to 660 minutes post film administration.</time_frame>
    <description>Systolic blood pressure was measured using an electronic sphygmomanometer just prior to film administration and at every 30 minutes after film administration for the duration of each study visit.</description>
  </secondary_outcome>
  <number_of_arms>6</number_of_arms>
  <enrollment type="Actual">24</enrollment>
  <condition>Smoking Cessation</condition>
  <arm_group>
    <arm_group_label>0 mg Nicotine Film</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>In Part 1, 4 participants will be allocated to this arm and receive one placebo nicotine film.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>2 mg Nicotine Film</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>In Part 1, 4 participants will be allocated to this arm and receive one 2 mg nicotine film.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>4 mg Nicotine Film</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>In Part 1, 4 participants will be allocated to this arm and receive one 4 mg nicotine film.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>0, 0, 0, 0mg Nicotine Film Regimen</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>In Part 2, 4 participants will be allocated to this arm and receive one nicotine film every 3 hours (for a total of 4 films over 12 hours) in the following order: 0, 0, 0, 0 mg.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>2, 2, 2, 2mg Nicotine Film Regimen</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>In Part 2, 4 participants will be allocated to this arm and receive one nicotine film every 3 hours (for a total of 4 films over 12 hours) in the following order: 2, 2, 2, 2 mg.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>4, 4, 0, 4mg Nicotine Film Regimen</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>In Part 2, 4 participants will be allocated to this arm and receive one nicotine film every 3 hours (for a total of 4 films over 12 hours) in the following order: 4, 4, 0, 4 mg.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Nicotine Film</intervention_name>
    <description>Nicotine orally dissolving films (ODF) are films containing nicotine (0, 2, or 4 mg). The active pharmaceutical ingredient in Nicotine ODF is nicotine polacrilex (20%, USP). The film used in Nicotine ODF has a muco-adhesive property, i.e. it can adhere to the oral mucosa and allow the drug to be absorbed through oral mucosa. After placement in the oral cavity, nicotine ODF dissolves over a 5-10 minute period.The unit-dose dosage is in the form of 1 in x 1 in square and weighs about 100 mg. Nicotine films are not available in the United States in a non-investigational setting.</description>
    <arm_group_label>2 mg Nicotine Film</arm_group_label>
    <arm_group_label>2, 2, 2, 2mg Nicotine Film Regimen</arm_group_label>
    <arm_group_label>4 mg Nicotine Film</arm_group_label>
    <arm_group_label>4, 4, 0, 4mg Nicotine Film Regimen</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo Nicotine Film</intervention_name>
    <description>Nicotine orally dissolving films (ODF) are films containing nicotine (0, 2, or 4 mg). The active pharmaceutical ingredient in Nicotine ODF is nicotine polacrilex (20%, USP). The film used in Nicotine ODF has a muco-adhesive property, i.e. it can adhere to the oral mucosa and allow the drug to be absorbed through oral mucosa. After placement in the oral cavity, nicotine ODF dissolves over a 5-10 minute period.The unit-dose dosage is in the form of 1 in x 1 in square and weighs about 100 mg. Nicotine films are not available in the United States in a non-investigational setting.</description>
    <arm_group_label>0 mg Nicotine Film</arm_group_label>
    <arm_group_label>0, 0, 0, 0mg Nicotine Film Regimen</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Aged 18 - 55&#xD;
&#xD;
          2. Smoke &gt;9 cigarettes/day for at least the past 12 months&#xD;
&#xD;
          3. Able to understand and consent to study procedures&#xD;
&#xD;
          4. Able to read and write in English&#xD;
&#xD;
          5. Exhaled Carbon Monoxide &lt;12 ppm at in-person screening&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Unstable or significant medical conditions and conditions such as elevated blood&#xD;
             pressure (Systolic &gt;140 mm Hg or diastolic &gt;90mm Hg at baseline), COPD and those that&#xD;
             are likely to affect biomarker data such as kidney or liver disease.&#xD;
&#xD;
          2. Individuals with sodium-restricted diet, heart disease, recent heart attack, irregular&#xD;
             heartbeat, stomach ulcers, or diabetes as well as those taking prescription&#xD;
             medications for depression or asthma as indicated under &quot;Warnings&quot; section on FDA&#xD;
             approved NRT Drug Facts Label.&#xD;
&#xD;
          3. More than weekly use in the past 3 months of illegal drugs or prescription drugs that&#xD;
             are not being used for medically prescribed purposes or inpatient treatment for these&#xD;
             in the past 6 months.&#xD;
&#xD;
          4. Use of non-cigarette nicotine delivery product in the prior week (including cigars,&#xD;
             pipes, chew, snus, hookah, electronic cigarette and marijuana mixed with tobacco).&#xD;
&#xD;
          5. Use of an FDA approved cessation medication in past week (any NRT, Chantix,&#xD;
             Wellbutrin)&#xD;
&#xD;
          6. Women who are pregnant (verified by urine pregnancy test at visit), trying to become&#xD;
             pregnant (not using a medically acceptable form of birth control for at least one&#xD;
             month prior to visit i.e., oral contraceptives, intrauterine device, double barrier),&#xD;
             or nursing.&#xD;
&#xD;
          7. Uncontrolled serious psychiatric illness or inpatient treatment in the past 6 months.&#xD;
&#xD;
          8. Unwillingness to provide blood samples or history of repeatedly fainting during blood&#xD;
             draws&#xD;
&#xD;
          9. Any previous adverse reaction to NRT.&#xD;
&#xD;
         10. Any other condition, serious illness, or situation that would, in the investigator's&#xD;
             opinion, make it unlikely that the participant could comply with the study protocol.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>55 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Patricia S. Grigson, Ph.D.</last_name>
    <role>Principal Investigator</role>
    <affiliation>Penn State College of Medicine</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Jonathan A Foulds, Ph.D.</last_name>
    <role>Principal Investigator</role>
    <affiliation>Penn State College of Medicine</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Christopher N Sciamanna, MD, MPH</last_name>
    <role>Study Director</role>
    <affiliation>Penn State College of Medicine</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Penn State College of Medicine/Milton S. Hershey Medical Center</name>
      <address>
        <city>Hershey</city>
        <state>Pennsylvania</state>
        <zip>17033</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>August 2018</verification_date>
  <study_first_submitted>September 11, 2014</study_first_submitted>
  <study_first_submitted_qc>September 12, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">September 15, 2014</study_first_posted>
  <results_first_submitted>May 9, 2018</results_first_submitted>
  <results_first_submitted_qc>August 29, 2018</results_first_submitted_qc>
  <results_first_posted type="Actual">August 31, 2018</results_first_posted>
  <last_update_submitted>August 29, 2018</last_update_submitted>
  <last_update_submitted_qc>August 29, 2018</last_update_submitted_qc>
  <last_update_posted type="Actual">August 31, 2018</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Milton S. Hershey Medical Center</investigator_affiliation>
    <investigator_full_name>Patricia Sue Grigson</investigator_full_name>
    <investigator_title>Professor</investigator_title>
  </responsible_party>
  <keyword>Nicotine</keyword>
  <keyword>Random Delivery</keyword>
  <keyword>Smoking Cessation</keyword>
  <keyword>Plasma Nicotine</keyword>
  <keyword>Oral Film</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>January 26, 2017</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/70/NCT02239770/Prot_SAP_000.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <pre_assignment_details>In-person screening procedures included a review of medications and medical history, an assessment of drug use, a blood pressure measurement, a urine pregnancy test (if applicable), and an exhaled CO measurement to confirm prior 16 hour smoking abstinence. Those who did not satisfy inclusion criteria were excluded prior to randomization.</pre_assignment_details>
      <group_list>
        <group group_id="P1">
          <title>0 mg Nicotine Film</title>
          <description>In Part 1, 4 participants were allocated to this arm and received one placebo nicotine film.&#xD;
Placebo Nicotine Film: Nicotine orally dissolving films (ODF) are films containing nicotine (0, 2, or 4 mg). The active pharmaceutical ingredient in Nicotine ODF is nicotine polacrilex (20%, USP). The film used in Nicotine ODF has a muco-adhesive property, i.e. it can adhere to the oral mucosa and allow the drug to be absorbed through oral mucosa. After placement in the oral cavity, nicotine ODF dissolves over a 5-10 minute period.The unit-dose dosage is in the form of 1 in x 1 in square and weighs about 100 mg. Nicotine films are not available in the United States in a non-investigational setting.</description>
        </group>
        <group group_id="P2">
          <title>2 mg Nicotine Film</title>
          <description>In Part 1, 4 participants were allocated to this arm and received one 2mg nicotine film.&#xD;
Nicotine Film: Nicotine orally dissolving films (ODF) are films containing nicotine (0, 2, or 4 mg). The active pharmaceutical ingredient in Nicotine ODF is nicotine polacrilex (20%, USP). The film used in Nicotine ODF has a muco-adhesive property, i.e. it can adhere to the oral mucosa and allow the drug to be absorbed through oral mucosa. After placement in the oral cavity, nicotine ODF dissolves over a 5-10 minute period.The unit-dose dosage is in the form of 1 in x 1 in square and weighs about 100 mg. Nicotine films are not available in the United States in a non-investigational setting.</description>
        </group>
        <group group_id="P3">
          <title>4 mg Nicotine Film</title>
          <description>In Part 1, 4 participants were allocated to this arm and received one 4mg nicotine film.&#xD;
Nicotine Film: Nicotine orally dissolving films (ODF) are films containing nicotine (0, 2, or 4 mg). The active pharmaceutical ingredient in Nicotine ODF is nicotine polacrilex (20%, USP). The film used in Nicotine ODF has a muco-adhesive property, i.e. it can adhere to the oral mucosa and allow the drug to be absorbed through oral mucosa. After placement in the oral cavity, nicotine ODF dissolves over a 5-10 minute period.The unit-dose dosage is in the form of 1 in x 1 in square and weighs about 100 mg. Nicotine films are not available in the United States in a non-investigational setting.</description>
        </group>
        <group group_id="P4">
          <title>0, 0, 0, 0mg Nicotine Film Regimen</title>
          <description>In Part 2, 4 participants were allocated to this arm and received one nicotine film every 3 hours (for a total of 4 films over 12 hours) in the following order: 0, 0, 0, 0 mg.&#xD;
Placebo Nicotine Film: Nicotine orally dissolving films (ODF) are films containing nicotine (0, 2, or 4 mg). The active pharmaceutical ingredient in Nicotine ODF is nicotine polacrilex (20%, USP). The film used in Nicotine ODF has a muco-adhesive property, i.e. it can adhere to the oral mucosa and allow the drug to be absorbed through oral mucosa. After placement in the oral cavity, nicotine ODF dissolves over a 5-10 minute period.The unit-dose dosage is in the form of 1 in x 1 in square and weighs about 100 mg. Nicotine films are not available in the United States in a non-investigational setting.</description>
        </group>
        <group group_id="P5">
          <title>2, 2, 2, 2mg Nicotine Film Regimen</title>
          <description>In Part 2, 4 participants were allocated to this arm and received one nicotine film every 3 hours (for a total of 4 films over 12 hours) in the following order: 2, 2, 2, 2 mg.&#xD;
Nicotine Film: Nicotine orally dissolving films (ODF) are films containing nicotine (0, 2, or 4 mg). The active pharmaceutical ingredient in Nicotine ODF is nicotine polacrilex (20%, USP). The film used in Nicotine ODF has a muco-adhesive property, i.e. it can adhere to the oral mucosa and allow the drug to be absorbed through oral mucosa. After placement in the oral cavity, nicotine ODF dissolves over a 5-10 minute period.The unit-dose dosage is in the form of 1 in x 1 in square and weighs about 100 mg. Nicotine films are not available in the United States in a non-investigational setting.</description>
        </group>
        <group group_id="P6">
          <title>4, 4, 0, 4mg Nicotine Film Regimen</title>
          <description>In Part 2, 4 participants were allocated to this arm and received one nicotine film every 3 hours (for a total of 4 films over 12 hours) in the following order: 4, 4, 0, 4 mg.&#xD;
Nicotine Film: Nicotine orally dissolving films (ODF) are films containing nicotine (0, 2, or 4 mg). The active pharmaceutical ingredient in Nicotine ODF is nicotine polacrilex (20%, USP). The film used in Nicotine ODF has a muco-adhesive property, i.e. it can adhere to the oral mucosa and allow the drug to be absorbed through oral mucosa. After placement in the oral cavity, nicotine ODF dissolves over a 5-10 minute period.The unit-dose dosage is in the form of 1 in x 1 in square and weighs about 100 mg. Nicotine films are not available in the United States in a non-investigational setting.</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Part 1</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="4"/>
                <participants group_id="P2" count="4"/>
                <participants group_id="P3" count="4"/>
                <participants group_id="P4" count="0"/>
                <participants group_id="P5" count="0"/>
                <participants group_id="P6" count="0"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="4"/>
                <participants group_id="P2" count="4"/>
                <participants group_id="P3" count="4"/>
                <participants group_id="P4" count="0"/>
                <participants group_id="P5" count="0"/>
                <participants group_id="P6" count="0"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="0"/>
                <participants group_id="P4" count="0"/>
                <participants group_id="P5" count="0"/>
                <participants group_id="P6" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
        <period>
          <title>Part 2</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="0"/>
                <participants group_id="P4" count="4"/>
                <participants group_id="P5" count="4"/>
                <participants group_id="P6" count="4"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="0"/>
                <participants group_id="P4" count="4"/>
                <participants group_id="P5" count="4"/>
                <participants group_id="P6" count="4"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="0"/>
                <participants group_id="P4" count="0"/>
                <participants group_id="P5" count="0"/>
                <participants group_id="P6" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>0 mg Nicotine Film</title>
          <description>In Part 1, 4 participants were allocated to this arm and received one placebo nicotine film.&#xD;
Placebo Nicotine Film: Nicotine orally dissolving films (ODF) are films containing nicotine (0, 2, or 4 mg). The active pharmaceutical ingredient in Nicotine ODF is nicotine polacrilex (20%, USP). The film used in Nicotine ODF has a muco-adhesive property, i.e. it can adhere to the oral mucosa and allow the drug to be absorbed through oral mucosa. After placement in the oral cavity, nicotine ODF dissolves over a 5-10 minute period.The unit-dose dosage is in the form of 1 in x 1 in square and weighs about 100 mg. Nicotine films are not available in the United States in a non-investigational setting.</description>
        </group>
        <group group_id="B2">
          <title>2 mg Nicotine Film</title>
          <description>In Part 1, 4 participants were allocated to this arm and received one 2 mg nicotine film.&#xD;
Nicotine Film: Nicotine orally dissolving films (ODF) are films containing nicotine (0, 2, or 4 mg). The active pharmaceutical ingredient in Nicotine ODF is nicotine polacrilex (20%, USP). The film used in Nicotine ODF has a muco-adhesive property, i.e. it can adhere to the oral mucosa and allow the drug to be absorbed through oral mucosa. After placement in the oral cavity, nicotine ODF dissolves over a 5-10 minute period.The unit-dose dosage is in the form of 1 in x 1 in square and weighs about 100 mg. Nicotine films are not available in the United States in a non-investigational setting.</description>
        </group>
        <group group_id="B3">
          <title>4 mg Nicotine Film</title>
          <description>In Part 1, 4 participants were allocated to this arm and received one 4 mg nicotine film.&#xD;
Nicotine Film: Nicotine orally dissolving films (ODF) are films containing nicotine (0, 2, or 4 mg). The active pharmaceutical ingredient in Nicotine ODF is nicotine polacrilex (20%, USP). The film used in Nicotine ODF has a muco-adhesive property, i.e. it can adhere to the oral mucosa and allow the drug to be absorbed through oral mucosa. After placement in the oral cavity, nicotine ODF dissolves over a 5-10 minute period.The unit-dose dosage is in the form of 1 in x 1 in square and weighs about 100 mg. Nicotine films are not available in the United States in a non-investigational setting.</description>
        </group>
        <group group_id="B4">
          <title>0, 0, 0, 0mg Nicotine Film Regimen</title>
          <description>In Part 2, 4 participants were allocated to this arm and received one nicotine film every 3 hours (for a total of 4 films over 12 hours) in the following order: 0, 0, 0, 0 mg.&#xD;
Placebo Nicotine Film: Nicotine orally dissolving films (ODF) are films containing nicotine (0, 2, or 4 mg). The active pharmaceutical ingredient in Nicotine ODF is nicotine polacrilex (20%, USP). The film used in Nicotine ODF has a muco-adhesive property, i.e. it can adhere to the oral mucosa and allow the drug to be absorbed through oral mucosa. After placement in the oral cavity, nicotine ODF dissolves over a 5-10 minute period.The unit-dose dosage is in the form of 1 in x 1 in square and weighs about 100 mg. Nicotine films are not available in the United States in a non-investigational setting.</description>
        </group>
        <group group_id="B5">
          <title>2, 2, 2, 2mg Nicotine Film Regimen</title>
          <description>In Part 2, 4 participants were allocated to this arm and received one nicotine film every 3 hours (for a total of 4 films over 12 hours) in the following order: 2, 2, 2, 2 mg.&#xD;
Nicotine Film: Nicotine orally dissolving films (ODF) are films containing nicotine (0, 2, or 4 mg). The active pharmaceutical ingredient in Nicotine ODF is nicotine polacrilex (20%, USP). The film used in Nicotine ODF has a muco-adhesive property, i.e. it can adhere to the oral mucosa and allow the drug to be absorbed through oral mucosa. After placement in the oral cavity, nicotine ODF dissolves over a 5-10 minute period.The unit-dose dosage is in the form of 1 in x 1 in square and weighs about 100 mg. Nicotine films are not available in the United States in a non-investigational setting.</description>
        </group>
        <group group_id="B6">
          <title>4, 4, 0, 4mg Nicotine Film Regimen</title>
          <description>In Part 2, 4 participants were allocated to this arm and received one nicotine film every 3 hours (for a total of 4 films over 12 hours) in the following order: 4, 4, 0, 4 mg.&#xD;
Nicotine Film: Nicotine orally dissolving films (ODF) are films containing nicotine (0, 2, or 4 mg). The active pharmaceutical ingredient in Nicotine ODF is nicotine polacrilex (20%, USP). The film used in Nicotine ODF has a muco-adhesive property, i.e. it can adhere to the oral mucosa and allow the drug to be absorbed through oral mucosa. After placement in the oral cavity, nicotine ODF dissolves over a 5-10 minute period.The unit-dose dosage is in the form of 1 in x 1 in square and weighs about 100 mg. Nicotine films are not available in the United States in a non-investigational setting.</description>
        </group>
        <group group_id="B7">
          <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="4"/>
            <count group_id="B2" value="4"/>
            <count group_id="B3" value="4"/>
            <count group_id="B4" value="4"/>
            <count group_id="B5" value="4"/>
            <count group_id="B6" value="4"/>
            <count group_id="B7" value="24"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>years</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="37.3" spread="11.8"/>
                    <measurement group_id="B2" value="40.8" spread="13.6"/>
                    <measurement group_id="B3" value="31.8" spread="11.0"/>
                    <measurement group_id="B4" value="44.8" spread="6.5"/>
                    <measurement group_id="B5" value="36.0" spread="12.3"/>
                    <measurement group_id="B6" value="37.5" spread="14.7"/>
                    <measurement group_id="B7" value="38.0" spread="11.3"/>
                  </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="2"/>
                    <measurement group_id="B2" value="2"/>
                    <measurement group_id="B3" value="1"/>
                    <measurement group_id="B4" value="3"/>
                    <measurement group_id="B5" value="1"/>
                    <measurement group_id="B6" value="1"/>
                    <measurement group_id="B7" value="10"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                    <measurement group_id="B2" value="2"/>
                    <measurement group_id="B3" value="3"/>
                    <measurement group_id="B4" value="1"/>
                    <measurement group_id="B5" value="3"/>
                    <measurement group_id="B6" value="3"/>
                    <measurement group_id="B7" value="14"/>
                  </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>Caucasian/white</title>
                  <measurement_list>
                    <measurement group_id="B1" value="4"/>
                    <measurement group_id="B2" value="3"/>
                    <measurement group_id="B3" value="4"/>
                    <measurement group_id="B4" value="2"/>
                    <measurement group_id="B5" value="2"/>
                    <measurement group_id="B6" value="2"/>
                    <measurement group_id="B7" value="17"/>
                  </measurement_list>
                </category>
                <category>
                  <title>African American/black</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="1"/>
                    <measurement group_id="B5" value="1"/>
                    <measurement group_id="B6" value="2"/>
                    <measurement group_id="B7" value="5"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Other</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="1"/>
                    <measurement group_id="B5" value="1"/>
                    <measurement group_id="B6" value="0"/>
                    <measurement group_id="B7" value="2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Region of Enrollment</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <title>United States</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="4"/>
                    <measurement group_id="B2" value="4"/>
                    <measurement group_id="B3" value="4"/>
                    <measurement group_id="B4" value="4"/>
                    <measurement group_id="B5" value="4"/>
                    <measurement group_id="B6" value="4"/>
                    <measurement group_id="B7" value="24"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Less than a college degree</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="3"/>
                    <measurement group_id="B2" value="3"/>
                    <measurement group_id="B3" value="2"/>
                    <measurement group_id="B4" value="2"/>
                    <measurement group_id="B5" value="2"/>
                    <measurement group_id="B6" value="3"/>
                    <measurement group_id="B7" value="15"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Cigarettes smoked per day</title>
          <units>cigarettes per day</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="20" spread="8.0"/>
                    <measurement group_id="B2" value="20" spread="0.0"/>
                    <measurement group_id="B3" value="14" spread="3.0"/>
                    <measurement group_id="B4" value="18.8" spread="5.1"/>
                    <measurement group_id="B5" value="18.5" spread="8.6"/>
                    <measurement group_id="B6" value="14.8" spread="6.3"/>
                    <measurement group_id="B7" value="17.7" spread="5.8"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>BMI</title>
          <units>kg/m^2</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="28.7" spread="6.4"/>
                    <measurement group_id="B2" value="30.1" spread="10.0"/>
                    <measurement group_id="B3" value="27.2" spread="2.1"/>
                    <measurement group_id="B4" value="28.7" spread="3.5"/>
                    <measurement group_id="B5" value="26.9" spread="4.2"/>
                    <measurement group_id="B6" value="27.4" spread="5.3"/>
                    <measurement group_id="B7" value="28.2" spread="5.3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Exhaled carbon monoxide</title>
          <units>parts per million</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="5.0" spread="3.0"/>
                    <measurement group_id="B2" value="6.0" spread="2.0"/>
                    <measurement group_id="B3" value="4.0" spread="3.0"/>
                    <measurement group_id="B4" value="7.0" spread="2.2"/>
                    <measurement group_id="B5" value="6.3" spread="3.3"/>
                    <measurement group_id="B6" value="5.8" spread="3.2"/>
                    <measurement group_id="B7" value="5.6" spread="2.8"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Penn State Cigarette Dependence Index Total Score</title>
          <description>The total score of the Penn State Cigarette Dependence Index can range from 0 (no dependence/better outcome) to 20 (high dependence/worse outcome).&#xD;
A score of 0 to 3 indicates no dependence on cigarettes. A score of 4 to 8 indicates low dependence on cigarettes. A score of 9 to 12 indicates medium dependence on cigarettes. A score of 13 or higher indicates a high dependence on cigarettes.</description>
          <units>units on a scale</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="14" spread="3.0"/>
                    <measurement group_id="B2" value="12" spread="1.0"/>
                    <measurement group_id="B3" value="11" spread="2.0"/>
                    <measurement group_id="B4" value="11.8" spread="2.9"/>
                    <measurement group_id="B5" value="10.8" spread="3.8"/>
                    <measurement group_id="B6" value="11.0" spread="2.2"/>
                    <measurement group_id="B7" value="11.6" spread="2.6"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Peak Plasma Nicotine Concentrations Following Ingestion of a Single (Phase 1) or Repeated (Phase 2) Doses of Nicotine Film</title>
        <description>In Phase 1, a trained nurse will implant an intravenous (IV) indwelling catheter in each participant. Participants will place a film containing zero, 2, or 4 mg of nicotine in their mouths and blood will be drawn every 10 minutes thereafter for the next 60 minutes, and then every 30 minutes for the next 2 hours (11 blood draws in all over 3 hours after using the nicotine film).&#xD;
In Phase 2, all 12 participants will receive an IV catheter and randomly allocated to consume 4 films over 12 hours in each of the following orders (a) 0,0,0,0 mg (b) 2,2,2,2 or (c) 4,4,0,4. A blood sample will be drawn at baseline prior to each film administration, and then at 30, 45, 60 and 120 minutes after each film administration and when the film is reported dissolved (20 blood draws in total).</description>
        <time_frame>10 min - 12 hours</time_frame>
        <population>Because the placebo nicotine film does not deliver any nicotine to the blood, peak plasma nicotine levels cannot be observed in the 0 mg Nicotine Film arm (Part 1) and 0, 0, 0, 0 mg Nicotine Film Regimen (Part 2).</population>
        <group_list>
          <group group_id="O1">
            <title>0 mg Nicotine Film</title>
            <description>In Part 1, 4 participants were allocated to this arm and received one placebo nicotine film.&#xD;
Placebo Nicotine Film: Nicotine orally dissolving films (ODF) are films containing nicotine (0, 2, or 4 mg). The active pharmaceutical ingredient in Nicotine ODF is nicotine polacrilex (20%, USP). The film used in Nicotine ODF has a muco-adhesive property, i.e. it can adhere to the oral mucosa and allow the drug to be absorbed through oral mucosa. After placement in the oral cavity, nicotine ODF dissolves over a 5-10 minute period.The unit-dose dosage is in the form of 1 in x 1 in square and weighs about 100 mg. Nicotine films are not available in the United States in a non-investigational setting.</description>
          </group>
          <group group_id="O2">
            <title>2 mg Nicotine Film</title>
            <description>In Part 1, 4 participants were allocated to this arm and received one 2 mg nicotine film.&#xD;
Nicotine Film: Nicotine orally dissolving films (ODF) are films containing nicotine (0, 2, or 4 mg). The active pharmaceutical ingredient in Nicotine ODF is nicotine polacrilex (20%, USP). The film used in Nicotine ODF has a muco-adhesive property, i.e. it can adhere to the oral mucosa and allow the drug to be absorbed through oral mucosa. After placement in the oral cavity, nicotine ODF dissolves over a 5-10 minute period.The unit-dose dosage is in the form of 1 in x 1 in square and weighs about 100 mg. Nicotine films are not available in the United States in a non-investigational setting.</description>
          </group>
          <group group_id="O3">
            <title>4 mg Nicotine Film</title>
            <description>In Part 1, 4 participants were allocated to this arm and received one 4 mg nicotine film.&#xD;
Nicotine Film: Nicotine orally dissolving films (ODF) are films containing nicotine (0, 2, or 4 mg). The active pharmaceutical ingredient in Nicotine ODF is nicotine polacrilex (20%, USP). The film used in Nicotine ODF has a muco-adhesive property, i.e. it can adhere to the oral mucosa and allow the drug to be absorbed through oral mucosa. After placement in the oral cavity, nicotine ODF dissolves over a 5-10 minute period.The unit-dose dosage is in the form of 1 in x 1 in square and weighs about 100 mg. Nicotine films are not available in the United States in a non-investigational setting.</description>
          </group>
          <group group_id="O4">
            <title>0, 0, 0, 0mg Nicotine Film Regimen</title>
            <description>In Part 2, 4 participants were allocated to this arm and received one nicotine film every 3 hours (for a total of 4 films over 12 hours) in the following order: 0, 0, 0, 0 mg.&#xD;
Placebo Nicotine Film: Nicotine orally dissolving films (ODF) are films containing nicotine (0, 2, or 4 mg). The active pharmaceutical ingredient in Nicotine ODF is nicotine polacrilex (20%, USP). The film used in Nicotine ODF has a muco-adhesive property, i.e. it can adhere to the oral mucosa and allow the drug to be absorbed through oral mucosa. After placement in the oral cavity, nicotine ODF dissolves over a 5-10 minute period.The unit-dose dosage is in the form of 1 in x 1 in square and weighs about 100 mg. Nicotine films are not available in the United States in a non-investigational setting.</description>
          </group>
          <group group_id="O5">
            <title>2, 2, 2, 2mg Nicotine Film Regimen</title>
            <description>In Part 2, 4 participants were allocated to this arm and received one nicotine film every 3 hours (for a total of 4 films over 12 hours) in the following order: 2, 2, 2, 2 mg.&#xD;
Nicotine Film: Nicotine orally dissolving films (ODF) are films containing nicotine (0, 2, or 4 mg). The active pharmaceutical ingredient in Nicotine ODF is nicotine polacrilex (20%, USP). The film used in Nicotine ODF has a muco-adhesive property, i.e. it can adhere to the oral mucosa and allow the drug to be absorbed through oral mucosa. After placement in the oral cavity, nicotine ODF dissolves over a 5-10 minute period.The unit-dose dosage is in the form of 1 in x 1 in square and weighs about 100 mg. Nicotine films are not available in the United States in a non-investigational setting.</description>
          </group>
          <group group_id="O6">
            <title>4, 4, 0, 4mg Nicotine Film Regimen</title>
            <description>In Part 2, 4 participants were allocated to this arm and received one nicotine film every 3 hours (for a total of 4 films over 12 hours) in the following order: 4, 4, 0, 4 mg.&#xD;
Nicotine Film: Nicotine orally dissolving films (ODF) are films containing nicotine (0, 2, or 4 mg). The active pharmaceutical ingredient in Nicotine ODF is nicotine polacrilex (20%, USP). The film used in Nicotine ODF has a muco-adhesive property, i.e. it can adhere to the oral mucosa and allow the drug to be absorbed through oral mucosa. After placement in the oral cavity, nicotine ODF dissolves over a 5-10 minute period.The unit-dose dosage is in the form of 1 in x 1 in square and weighs about 100 mg. Nicotine films are not available in the United States in a non-investigational setting.</description>
          </group>
        </group_list>
        <measure>
          <title>Peak Plasma Nicotine Concentrations Following Ingestion of a Single (Phase 1) or Repeated (Phase 2) Doses of Nicotine Film</title>
          <description>In Phase 1, a trained nurse will implant an intravenous (IV) indwelling catheter in each participant. Participants will place a film containing zero, 2, or 4 mg of nicotine in their mouths and blood will be drawn every 10 minutes thereafter for the next 60 minutes, and then every 30 minutes for the next 2 hours (11 blood draws in all over 3 hours after using the nicotine film).&#xD;
In Phase 2, all 12 participants will receive an IV catheter and randomly allocated to consume 4 films over 12 hours in each of the following orders (a) 0,0,0,0 mg (b) 2,2,2,2 or (c) 4,4,0,4. A blood sample will be drawn at baseline prior to each film administration, and then at 30, 45, 60 and 120 minutes after each film administration and when the film is reported dissolved (20 blood draws in total).</description>
          <population>Because the placebo nicotine film does not deliver any nicotine to the blood, peak plasma nicotine levels cannot be observed in the 0 mg Nicotine Film arm (Part 1) and 0, 0, 0, 0 mg Nicotine Film Regimen (Part 2).</population>
          <units>ng/mL</units>
          <param>Mean</param>
          <dispersion>Full Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="0"/>
                <count group_id="O2" value="4"/>
                <count group_id="O3" value="4"/>
                <count group_id="O4" value="0"/>
                <count group_id="O5" value="4"/>
                <count group_id="O6" value="4"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O2" value="5.78" lower_limit="3.7" upper_limit="8.2"/>
                    <measurement group_id="O3" value="20.5" lower_limit="15.9" upper_limit="31.0"/>
                    <measurement group_id="O5" value="8.71" lower_limit="5.25" upper_limit="15.5"/>
                    <measurement group_id="O6" value="8.80" lower_limit="3.96" upper_limit="14.86"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Questionnaire of Smoking Urges-Brief Mean Total Score by Dose Group</title>
        <description>The Questionnaire of Smoking Urges-Brief (QSU-Brief) with a possible total score range of 10 to 70 was used to measure cigarette craving at baseline and at several points throughout the study visit for each participant. A score of 10 on this scale indicates very low cigarette craving, while a score of 70 indicates very high cigarette craving.&#xD;
Part 1: The QSU-Brief was measured at baseline and at 15, 35, 55, 80, 140, and 200 minutes post film administration.&#xD;
Part 2: The QSU-Brief was measured at baseline and at 50, 110, 230, 290, 410, 470, 590, and 690 minutes post FIRST film administration.</description>
        <time_frame>Part 1: The QSU-Brief was measured at baseline and at 15, 35, 55, 80, 140, and 200 minutes post film administration. Part 2: The QSU-Brief was measured at baseline and at 50, 110, 230, 290, 410, 470, 590, and 690 minutes post FIRST film administration.</time_frame>
        <population>This was a two part study. Participants in Part 1 and Part 2 were not assessed on the QSU-Brief measure at the same time intervals due to the differing study visit structures.</population>
        <group_list>
          <group group_id="O1">
            <title>0 mg Nicotine Film</title>
            <description>In Part 1, 4 participants will be allocated to this arm and receive one placebo nicotine film.&#xD;
Placebo Nicotine Film: Nicotine orally dissolving films (ODF) are films containing nicotine (0, 2, or 4 mg). The active pharmaceutical ingredient in Nicotine ODF is nicotine polacrilex (20%, USP). The film used in Nicotine ODF has a muco-adhesive property, i.e. it can adhere to the oral mucosa and allow the drug to be absorbed through oral mucosa. After placement in the oral cavity, nicotine ODF dissolves over a 5-10 minute period.The unit-dose dosage is in the form of 1 in x 1 in square and weighs about 100 mg. Nicotine films are not available in the United States in a non-investigational setting.</description>
          </group>
          <group group_id="O2">
            <title>2 mg Nicotine Film</title>
            <description>In Part 1, 4 participants will be allocated to this arm and receive one 2 mg nicotine film.&#xD;
Nicotine Film: Nicotine orally dissolving films (ODF) are films containing nicotine (0, 2, or 4 mg). The active pharmaceutical ingredient in Nicotine ODF is nicotine polacrilex (20%, USP). The film used in Nicotine ODF has a muco-adhesive property, i.e. it can adhere to the oral mucosa and allow the drug to be absorbed through oral mucosa. After placement in the oral cavity, nicotine ODF dissolves over a 5-10 minute period.The unit-dose dosage is in the form of 1 in x 1 in square and weighs about 100 mg. Nicotine films are not available in the United States in a non-investigational setting.</description>
          </group>
          <group group_id="O3">
            <title>4 mg Nicotine Film</title>
            <description>In Part 1, 4 participants will be allocated to this arm and receive one 4 mg nicotine film.&#xD;
Nicotine Film: Nicotine orally dissolving films (ODF) are films containing nicotine (0, 2, or 4 mg). The active pharmaceutical ingredient in Nicotine ODF is nicotine polacrilex (20%, USP). The film used in Nicotine ODF has a muco-adhesive property, i.e. it can adhere to the oral mucosa and allow the drug to be absorbed through oral mucosa. After placement in the oral cavity, nicotine ODF dissolves over a 5-10 minute period.The unit-dose dosage is in the form of 1 in x 1 in square and weighs about 100 mg. Nicotine films are not available in the United States in a non-investigational setting.</description>
          </group>
          <group group_id="O4">
            <title>0, 0, 0, 0mg Nicotine Film Regimen</title>
            <description>In Part 2, 4 participants will be allocated to this arm and receive one nicotine film every 3 hours (for a total of 4 films over 12 hours) in the following order: 0, 0, 0, 0 mg.&#xD;
Placebo Nicotine Film: Nicotine orally dissolving films (ODF) are films containing nicotine (0, 2, or 4 mg). The active pharmaceutical ingredient in Nicotine ODF is nicotine polacrilex (20%, USP). The film used in Nicotine ODF has a muco-adhesive property, i.e. it can adhere to the oral mucosa and allow the drug to be absorbed through oral mucosa. After placement in the oral cavity, nicotine ODF dissolves over a 5-10 minute period.The unit-dose dosage is in the form of 1 in x 1 in square and weighs about 100 mg. Nicotine films are not available in the United States in a non-investigational setting.</description>
          </group>
          <group group_id="O5">
            <title>2, 2, 2, 2mg Nicotine Film Regimen</title>
            <description>In Part 2, 4 participants will be allocated to this arm and receive one nicotine film every 3 hours (for a total of 4 films over 12 hours) in the following order: 2, 2, 2, 2 mg.&#xD;
Nicotine Film: Nicotine orally dissolving films (ODF) are films containing nicotine (0, 2, or 4 mg). The active pharmaceutical ingredient in Nicotine ODF is nicotine polacrilex (20%, USP). The film used in Nicotine ODF has a muco-adhesive property, i.e. it can adhere to the oral mucosa and allow the drug to be absorbed through oral mucosa. After placement in the oral cavity, nicotine ODF dissolves over a 5-10 minute period.The unit-dose dosage is in the form of 1 in x 1 in square and weighs about 100 mg. Nicotine films are not available in the United States in a non-investigational setting.</description>
          </group>
          <group group_id="O6">
            <title>4, 4, 0, 4mg Nicotine Film Regimen</title>
            <description>In Part 2, 4 participants will be allocated to this arm and receive one nicotine film every 3 hours (for a total of 4 films over 12 hours) in the following order: 4, 4, 0, 4 mg.&#xD;
Nicotine Film: Nicotine orally dissolving films (ODF) are films containing nicotine (0, 2, or 4 mg). The active pharmaceutical ingredient in Nicotine ODF is nicotine polacrilex (20%, USP). The film used in Nicotine ODF has a muco-adhesive property, i.e. it can adhere to the oral mucosa and allow the drug to be absorbed through oral mucosa. After placement in the oral cavity, nicotine ODF dissolves over a 5-10 minute period.The unit-dose dosage is in the form of 1 in x 1 in square and weighs about 100 mg. Nicotine films are not available in the United States in a non-investigational setting.</description>
          </group>
        </group_list>
        <measure>
          <title>Questionnaire of Smoking Urges-Brief Mean Total Score by Dose Group</title>
          <description>The Questionnaire of Smoking Urges-Brief (QSU-Brief) with a possible total score range of 10 to 70 was used to measure cigarette craving at baseline and at several points throughout the study visit for each participant. A score of 10 on this scale indicates very low cigarette craving, while a score of 70 indicates very high cigarette craving.&#xD;
Part 1: The QSU-Brief was measured at baseline and at 15, 35, 55, 80, 140, and 200 minutes post film administration.&#xD;
Part 2: The QSU-Brief was measured at baseline and at 50, 110, 230, 290, 410, 470, 590, and 690 minutes post FIRST film administration.</description>
          <population>This was a two part study. Participants in Part 1 and Part 2 were not assessed on the QSU-Brief measure at the same time intervals due to the differing study visit structures.</population>
          <units>score on a scale</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="4"/>
                <count group_id="O2" value="4"/>
                <count group_id="O3" value="4"/>
                <count group_id="O4" value="4"/>
                <count group_id="O5" value="4"/>
                <count group_id="O6" value="4"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>0 minute</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="4"/>
                    <count group_id="O2" value="4"/>
                    <count group_id="O3" value="4"/>
                    <count group_id="O4" value="4"/>
                    <count group_id="O5" value="4"/>
                    <count group_id="O6" value="4"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="56.3" spread="8.4"/>
                    <measurement group_id="O2" value="35.0" spread="16.4"/>
                    <measurement group_id="O3" value="46.0" spread="8.3"/>
                    <measurement group_id="O4" value="51.8" spread="19.3"/>
                    <measurement group_id="O5" value="46.3" spread="23.0"/>
                    <measurement group_id="O6" value="39.3" spread="15.6"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>15 minutes</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="4"/>
                    <count group_id="O2" value="4"/>
                    <count group_id="O3" value="4"/>
                    <count group_id="O4" value="0"/>
                    <count group_id="O5" value="0"/>
                    <count group_id="O6" value="0"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="43.3" spread="14.2"/>
                    <measurement group_id="O2" value="22.8" spread="8.5"/>
                    <measurement group_id="O3" value="26.5" spread="7.1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>35 minutes</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="4"/>
                    <count group_id="O2" value="4"/>
                    <count group_id="O3" value="4"/>
                    <count group_id="O4" value="0"/>
                    <count group_id="O5" value="0"/>
                    <count group_id="O6" value="0"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="35.0" spread="10.8"/>
                    <measurement group_id="O2" value="23.8" spread="12"/>
                    <measurement group_id="O3" value="22.5" spread="9.9"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>50 minutes</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="0"/>
                    <count group_id="O2" value="0"/>
                    <count group_id="O3" value="0"/>
                    <count group_id="O4" value="4"/>
                    <count group_id="O5" value="4"/>
                    <count group_id="O6" value="4"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O4" value="40.5" spread="15.9"/>
                    <measurement group_id="O5" value="30.8" spread="15.4"/>
                    <measurement group_id="O6" value="25.5" spread="15.6"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>55 minutes</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="4"/>
                    <count group_id="O2" value="4"/>
                    <count group_id="O3" value="4"/>
                    <count group_id="O4" value="0"/>
                    <count group_id="O5" value="0"/>
                    <count group_id="O6" value="0"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="29.8" spread="14.7"/>
                    <measurement group_id="O2" value="18.0" spread="5.7"/>
                    <measurement group_id="O3" value="19.0" spread="9.2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>80 minutes</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="4"/>
                    <count group_id="O2" value="4"/>
                    <count group_id="O3" value="4"/>
                    <count group_id="O4" value="0"/>
                    <count group_id="O5" value="0"/>
                    <count group_id="O6" value="0"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="31.5" spread="16.8"/>
                    <measurement group_id="O2" value="16.8" spread="4.8"/>
                    <measurement group_id="O3" value="24.3" spread="9.7"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>110 minutes</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="0"/>
                    <count group_id="O2" value="0"/>
                    <count group_id="O3" value="0"/>
                    <count group_id="O4" value="4"/>
                    <count group_id="O5" value="4"/>
                    <count group_id="O6" value="4"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O4" value="39.5" spread="3.8"/>
                    <measurement group_id="O5" value="31.5" spread="16.0"/>
                    <measurement group_id="O6" value="27.0" spread="15.6"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>140 minutes</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="4"/>
                    <count group_id="O2" value="4"/>
                    <count group_id="O3" value="4"/>
                    <count group_id="O4" value="0"/>
                    <count group_id="O5" value="0"/>
                    <count group_id="O6" value="0"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="36.0" spread="19.4"/>
                    <measurement group_id="O2" value="16.5" spread="3.9"/>
                    <measurement group_id="O3" value="22.0" spread="10.4"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>200 minutes</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="4"/>
                    <count group_id="O2" value="4"/>
                    <count group_id="O3" value="4"/>
                    <count group_id="O4" value="0"/>
                    <count group_id="O5" value="0"/>
                    <count group_id="O6" value="0"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="37.3" spread="25.4"/>
                    <measurement group_id="O2" value="18.3" spread="6.4"/>
                    <measurement group_id="O3" value="26.0" spread="13.3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>230 minutes</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="0"/>
                    <count group_id="O2" value="0"/>
                    <count group_id="O3" value="0"/>
                    <count group_id="O4" value="4"/>
                    <count group_id="O5" value="4"/>
                    <count group_id="O6" value="4"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O4" value="35.5" spread="11.4"/>
                    <measurement group_id="O5" value="32.0" spread="21.4"/>
                    <measurement group_id="O6" value="24.0" spread="13.0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>290 minutes</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="0"/>
                    <count group_id="O2" value="0"/>
                    <count group_id="O3" value="0"/>
                    <count group_id="O4" value="4"/>
                    <count group_id="O5" value="4"/>
                    <count group_id="O6" value="4"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O4" value="42.3" spread="11.3"/>
                    <measurement group_id="O5" value="34.5" spread="23.9"/>
                    <measurement group_id="O6" value="28.0" spread="20.6"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>410 minutes</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="0"/>
                    <count group_id="O2" value="0"/>
                    <count group_id="O3" value="0"/>
                    <count group_id="O4" value="4"/>
                    <count group_id="O5" value="4"/>
                    <count group_id="O6" value="4"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O4" value="36.0" spread="18.0"/>
                    <measurement group_id="O5" value="29.0" spread="19.7"/>
                    <measurement group_id="O6" value="28.5" spread="14.1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>470 minutes</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="0"/>
                    <count group_id="O2" value="0"/>
                    <count group_id="O3" value="0"/>
                    <count group_id="O4" value="4"/>
                    <count group_id="O5" value="4"/>
                    <count group_id="O6" value="4"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O4" value="32.8" spread="17.2"/>
                    <measurement group_id="O5" value="29.3" spread="18.9"/>
                    <measurement group_id="O6" value="31.3" spread="18.2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>590 minutes</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="0"/>
                    <count group_id="O2" value="0"/>
                    <count group_id="O3" value="0"/>
                    <count group_id="O4" value="4"/>
                    <count group_id="O5" value="4"/>
                    <count group_id="O6" value="4"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O4" value="29.8" spread="14.4"/>
                    <measurement group_id="O5" value="36.0" spread="27.1"/>
                    <measurement group_id="O6" value="23.5" spread="18.4"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>690 minutes</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="0"/>
                    <count group_id="O2" value="0"/>
                    <count group_id="O3" value="0"/>
                    <count group_id="O4" value="4"/>
                    <count group_id="O5" value="4"/>
                    <count group_id="O6" value="4"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O4" value="30.3" spread="16.6"/>
                    <measurement group_id="O5" value="31.5" spread="20.9"/>
                    <measurement group_id="O6" value="26.8" spread="18.8"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Mean Systolic Blood Pressure</title>
        <description>Systolic blood pressure was measured using an electronic sphygmomanometer just prior to film administration and at every 30 minutes after film administration for the duration of each study visit.</description>
        <time_frame>Part 1: Systolic blood pressure was measured at baseline and at every 30 minutes, up to 180 minutes post film administration. Part 2: Systolic blood pressure was measured at baseline and at every 30 minutes, up to 660 minutes post film administration.</time_frame>
        <population>Participants in Part 1 of the study were not assessed past 180 minutes post film administration, as this was the extent of the study visit.</population>
        <group_list>
          <group group_id="O1">
            <title>0 mg Nicotine Film</title>
            <description>In Part 1, 4 participants were allocated to this arm and received one placebo nicotine film.&#xD;
Placebo Nicotine Film: Nicotine orally dissolving films (ODF) are films containing nicotine (0, 2, or 4 mg). The active pharmaceutical ingredient in Nicotine ODF is nicotine polacrilex (20%, USP). The film used in Nicotine ODF has a muco-adhesive property, i.e. it can adhere to the oral mucosa and allow the drug to be absorbed through oral mucosa. After placement in the oral cavity, nicotine ODF dissolves over a 5-10 minute period.The unit-dose dosage is in the form of 1 in x 1 in square and weighs about 100 mg. Nicotine films are not available in the United States in a non-investigational setting.</description>
          </group>
          <group group_id="O2">
            <title>2 mg Nicotine Film</title>
            <description>In Part 1, 4 participants were allocated to this arm and received one 2mg nicotine film.&#xD;
Nicotine Film: Nicotine orally dissolving films (ODF) are films containing nicotine (0, 2, or 4 mg). The active pharmaceutical ingredient in Nicotine ODF is nicotine polacrilex (20%, USP). The film used in Nicotine ODF has a muco-adhesive property, i.e. it can adhere to the oral mucosa and allow the drug to be absorbed through oral mucosa. After placement in the oral cavity, nicotine ODF dissolves over a 5-10 minute period.The unit-dose dosage is in the form of 1 in x 1 in square and weighs about 100 mg. Nicotine films are not available in the United States in a non-investigational setting.</description>
          </group>
          <group group_id="O3">
            <title>4 mg Nicotine Film</title>
            <description>In Part 1, 4 participants were allocated to this arm and received one 4mg nicotine film.&#xD;
Nicotine Film: Nicotine orally dissolving films (ODF) are films containing nicotine (0, 2, or 4 mg). The active pharmaceutical ingredient in Nicotine ODF is nicotine polacrilex (20%, USP). The film used in Nicotine ODF has a muco-adhesive property, i.e. it can adhere to the oral mucosa and allow the drug to be absorbed through oral mucosa. After placement in the oral cavity, nicotine ODF dissolves over a 5-10 minute period.The unit-dose dosage is in the form of 1 in x 1 in square and weighs about 100 mg. Nicotine films are not available in the United States in a non-investigational setting.</description>
          </group>
          <group group_id="O4">
            <title>0, 0, 0, 0mg Nicotine Film Regimen</title>
            <description>In Part 2, 4 participants were allocated to this arm and received one nicotine film every 3 hours (for a total of 4 films over 12 hours) in the following order: 0, 0, 0, 0 mg.&#xD;
Placebo Nicotine Film: Nicotine orally dissolving films (ODF) are films containing nicotine (0, 2, or 4 mg). The active pharmaceutical ingredient in Nicotine ODF is nicotine polacrilex (20%, USP). The film used in Nicotine ODF has a muco-adhesive property, i.e. it can adhere to the oral mucosa and allow the drug to be absorbed through oral mucosa. After placement in the oral cavity, nicotine ODF dissolves over a 5-10 minute period.The unit-dose dosage is in the form of 1 in x 1 in square and weighs about 100 mg. Nicotine films are not available in the United States in a non-investigational setting.</description>
          </group>
          <group group_id="O5">
            <title>2, 2, 2, 2mg Nicotine Film Regimen</title>
            <description>In Part 2, 4 participants were allocated to this arm and received one nicotine film every 3 hours (for a total of 4 films over 12 hours) in the following order: 2, 2, 2, 2 mg.&#xD;
Nicotine Film: Nicotine orally dissolving films (ODF) are films containing nicotine (0, 2, or 4 mg). The active pharmaceutical ingredient in Nicotine ODF is nicotine polacrilex (20%, USP). The film used in Nicotine ODF has a muco-adhesive property, i.e. it can adhere to the oral mucosa and allow the drug to be absorbed through oral mucosa. After placement in the oral cavity, nicotine ODF dissolves over a 5-10 minute period.The unit-dose dosage is in the form of 1 in x 1 in square and weighs about 100 mg. Nicotine films are not available in the United States in a non-investigational setting.</description>
          </group>
          <group group_id="O6">
            <title>4, 4, 0, 4mg Nicotine Film Regimen</title>
            <description>In Part 2, 4 participants were allocated to this arm and received one nicotine film every 3 hours (for a total of 4 films over 12 hours) in the following order: 4, 4, 0, 4 mg.&#xD;
Nicotine Film: Nicotine orally dissolving films (ODF) are films containing nicotine (0, 2, or 4 mg). The active pharmaceutical ingredient in Nicotine ODF is nicotine polacrilex (20%, USP). The film used in Nicotine ODF has a muco-adhesive property, i.e. it can adhere to the oral mucosa and allow the drug to be absorbed through oral mucosa. After placement in the oral cavity, nicotine ODF dissolves over a 5-10 minute period.The unit-dose dosage is in the form of 1 in x 1 in square and weighs about 100 mg. Nicotine films are not available in the United States in a non-investigational setting.</description>
          </group>
        </group_list>
        <measure>
          <title>Mean Systolic Blood Pressure</title>
          <description>Systolic blood pressure was measured using an electronic sphygmomanometer just prior to film administration and at every 30 minutes after film administration for the duration of each study visit.</description>
          <population>Participants in Part 1 of the study were not assessed past 180 minutes post film administration, as this was the extent of the study visit.</population>
          <units>mmHg</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="4"/>
                <count group_id="O2" value="4"/>
                <count group_id="O3" value="4"/>
                <count group_id="O4" value="4"/>
                <count group_id="O5" value="4"/>
                <count group_id="O6" value="4"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Baseline</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="4"/>
                    <count group_id="O2" value="4"/>
                    <count group_id="O3" value="4"/>
                    <count group_id="O4" value="4"/>
                    <count group_id="O5" value="4"/>
                    <count group_id="O6" value="4"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="118.0" spread="12.8"/>
                    <measurement group_id="O2" value="115.8" spread="17.3"/>
                    <measurement group_id="O3" value="118.0" spread="17.1"/>
                    <measurement group_id="O4" value="114.8" spread="12.2"/>
                    <measurement group_id="O5" value="123.0" spread="8.8"/>
                    <measurement group_id="O6" value="125.5" spread="5.8"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>30 minutes</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="4"/>
                    <count group_id="O2" value="4"/>
                    <count group_id="O3" value="4"/>
                    <count group_id="O4" value="4"/>
                    <count group_id="O5" value="4"/>
                    <count group_id="O6" value="4"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="120.5" spread="15.8"/>
                    <measurement group_id="O2" value="110.8" spread="13.6"/>
                    <measurement group_id="O3" value="125.8" spread="11.4"/>
                    <measurement group_id="O4" value="110.3" spread="10.8"/>
                    <measurement group_id="O5" value="128.8" spread="6.8"/>
                    <measurement group_id="O6" value="129.5" spread="9.9"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>60 minutes</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="4"/>
                    <count group_id="O2" value="4"/>
                    <count group_id="O3" value="4"/>
                    <count group_id="O4" value="4"/>
                    <count group_id="O5" value="4"/>
                    <count group_id="O6" value="4"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="121.8" spread="17.0"/>
                    <measurement group_id="O2" value="117.8" spread="14.5"/>
                    <measurement group_id="O3" value="118.5" spread="20.0"/>
                    <measurement group_id="O4" value="108.3" spread="12.8"/>
                    <measurement group_id="O5" value="129.5" spread="5.5"/>
                    <measurement group_id="O6" value="131.3" spread="8.3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>90 minutes</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="4"/>
                    <count group_id="O2" value="4"/>
                    <count group_id="O3" value="4"/>
                    <count group_id="O4" value="4"/>
                    <count group_id="O5" value="4"/>
                    <count group_id="O6" value="4"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="120.8" spread="16.1"/>
                    <measurement group_id="O2" value="116.0" spread="14.1"/>
                    <measurement group_id="O3" value="120.3" spread="11.8"/>
                    <measurement group_id="O4" value="108.8" spread="9.2"/>
                    <measurement group_id="O5" value="121.0" spread="11.5"/>
                    <measurement group_id="O6" value="128.3" spread="17.9"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>120 minutes</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="4"/>
                    <count group_id="O2" value="4"/>
                    <count group_id="O3" value="4"/>
                    <count group_id="O4" value="4"/>
                    <count group_id="O5" value="4"/>
                    <count group_id="O6" value="4"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="118.5" spread="10.5"/>
                    <measurement group_id="O2" value="114.5" spread="15.9"/>
                    <measurement group_id="O3" value="115.3" spread="12.5"/>
                    <measurement group_id="O4" value="110.3" spread="2.5"/>
                    <measurement group_id="O5" value="125.8" spread="8.7"/>
                    <measurement group_id="O6" value="127.5" spread="3.1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>150 minutes</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="4"/>
                    <count group_id="O2" value="4"/>
                    <count group_id="O3" value="4"/>
                    <count group_id="O4" value="4"/>
                    <count group_id="O5" value="4"/>
                    <count group_id="O6" value="4"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="116.3" spread="10.6"/>
                    <measurement group_id="O2" value="110.5" spread="14.5"/>
                    <measurement group_id="O3" value="113.3" spread="16.1"/>
                    <measurement group_id="O4" value="99.0" spread="8.0"/>
                    <measurement group_id="O5" value="126.5" spread="12.2"/>
                    <measurement group_id="O6" value="123.0" spread="10.9"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>180 minutes</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="4"/>
                    <count group_id="O2" value="4"/>
                    <count group_id="O3" value="4"/>
                    <count group_id="O4" value="4"/>
                    <count group_id="O5" value="4"/>
                    <count group_id="O6" value="4"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="114.3" spread="4.1"/>
                    <measurement group_id="O2" value="118.8" spread="14.8"/>
                    <measurement group_id="O3" value="115.5" spread="13.8"/>
                    <measurement group_id="O4" value="104.5" spread="3.1"/>
                    <measurement group_id="O5" value="127.0" spread="7.3"/>
                    <measurement group_id="O6" value="122.8" spread="10.4"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>210 minutes</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="0"/>
                    <count group_id="O2" value="0"/>
                    <count group_id="O3" value="0"/>
                    <count group_id="O4" value="4"/>
                    <count group_id="O5" value="4"/>
                    <count group_id="O6" value="4"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O4" value="104.8" spread="7.2"/>
                    <measurement group_id="O5" value="124.0" spread="11.3"/>
                    <measurement group_id="O6" value="125.5" spread="9.4"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>240 minutes</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="0"/>
                    <count group_id="O2" value="0"/>
                    <count group_id="O3" value="0"/>
                    <count group_id="O4" value="4"/>
                    <count group_id="O5" value="4"/>
                    <count group_id="O6" value="4"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O4" value="116.0" spread="8.9"/>
                    <measurement group_id="O5" value="127.8" spread="13.7"/>
                    <measurement group_id="O6" value="122.8" spread="4.5"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>270 minutes</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="0"/>
                    <count group_id="O2" value="0"/>
                    <count group_id="O3" value="0"/>
                    <count group_id="O4" value="4"/>
                    <count group_id="O5" value="4"/>
                    <count group_id="O6" value="4"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O4" value="115.0" spread="8.9"/>
                    <measurement group_id="O5" value="129.8" spread="11.0"/>
                    <measurement group_id="O6" value="122.5" spread="6.5"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>300 minutes</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="0"/>
                    <count group_id="O2" value="0"/>
                    <count group_id="O3" value="0"/>
                    <count group_id="O4" value="4"/>
                    <count group_id="O5" value="4"/>
                    <count group_id="O6" value="4"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O4" value="109.3" spread="8.0"/>
                    <measurement group_id="O5" value="122.0" spread="14.3"/>
                    <measurement group_id="O6" value="124.8" spread="3.3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>330 minutes</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="0"/>
                    <count group_id="O2" value="0"/>
                    <count group_id="O3" value="0"/>
                    <count group_id="O4" value="4"/>
                    <count group_id="O5" value="4"/>
                    <count group_id="O6" value="4"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O4" value="109.0" spread="5.9"/>
                    <measurement group_id="O5" value="124.3" spread="6.7"/>
                    <measurement group_id="O6" value="120.0" spread="3.6"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>360 minutes</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="0"/>
                    <count group_id="O2" value="0"/>
                    <count group_id="O3" value="0"/>
                    <count group_id="O4" value="4"/>
                    <count group_id="O5" value="4"/>
                    <count group_id="O6" value="4"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O4" value="109.0" spread="8.8"/>
                    <measurement group_id="O5" value="120.5" spread="15.6"/>
                    <measurement group_id="O6" value="125.8" spread="4.1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>390 minutes</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="0"/>
                    <count group_id="O2" value="0"/>
                    <count group_id="O3" value="0"/>
                    <count group_id="O4" value="4"/>
                    <count group_id="O5" value="4"/>
                    <count group_id="O6" value="4"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O4" value="106.8" spread="11.0"/>
                    <measurement group_id="O5" value="124.0" spread="5.4"/>
                    <measurement group_id="O6" value="123.3" spread="3.5"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>420 minutes</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="0"/>
                    <count group_id="O2" value="0"/>
                    <count group_id="O3" value="0"/>
                    <count group_id="O4" value="4"/>
                    <count group_id="O5" value="4"/>
                    <count group_id="O6" value="4"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O4" value="115.5" spread="6.9"/>
                    <measurement group_id="O5" value="126.5" spread="11.4"/>
                    <measurement group_id="O6" value="124.8" spread="14.3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>450 minutes</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="0"/>
                    <count group_id="O2" value="0"/>
                    <count group_id="O3" value="0"/>
                    <count group_id="O4" value="4"/>
                    <count group_id="O5" value="4"/>
                    <count group_id="O6" value="4"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O4" value="112.8" spread="9.7"/>
                    <measurement group_id="O5" value="131.3" spread="3.3"/>
                    <measurement group_id="O6" value="123.8" spread="13.8"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>480 minutes</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="0"/>
                    <count group_id="O2" value="0"/>
                    <count group_id="O3" value="0"/>
                    <count group_id="O4" value="4"/>
                    <count group_id="O5" value="4"/>
                    <count group_id="O6" value="4"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O4" value="107.5" spread="5.2"/>
                    <measurement group_id="O5" value="127.8" spread="11.4"/>
                    <measurement group_id="O6" value="121.3" spread="6.3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>510 minutes</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="0"/>
                    <count group_id="O2" value="0"/>
                    <count group_id="O3" value="0"/>
                    <count group_id="O4" value="4"/>
                    <count group_id="O5" value="4"/>
                    <count group_id="O6" value="4"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O4" value="111.3" spread="5.6"/>
                    <measurement group_id="O5" value="124.5" spread="7.0"/>
                    <measurement group_id="O6" value="122.8" spread="7.6"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>540 minutes</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="0"/>
                    <count group_id="O2" value="0"/>
                    <count group_id="O3" value="0"/>
                    <count group_id="O4" value="4"/>
                    <count group_id="O5" value="4"/>
                    <count group_id="O6" value="4"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O4" value="113.8" spread="11.8"/>
                    <measurement group_id="O5" value="129.0" spread="8.0"/>
                    <measurement group_id="O6" value="115.5" spread="5.0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>570 minutes</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="0"/>
                    <count group_id="O2" value="0"/>
                    <count group_id="O3" value="0"/>
                    <count group_id="O4" value="4"/>
                    <count group_id="O5" value="4"/>
                    <count group_id="O6" value="4"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O4" value="151.0" spread="11.3"/>
                    <measurement group_id="O5" value="129.3" spread="10.2"/>
                    <measurement group_id="O6" value="115.5" spread="3.8"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>600 minutes</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="0"/>
                    <count group_id="O2" value="0"/>
                    <count group_id="O3" value="0"/>
                    <count group_id="O4" value="4"/>
                    <count group_id="O5" value="4"/>
                    <count group_id="O6" value="4"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O4" value="111.3" spread="9.1"/>
                    <measurement group_id="O5" value="125.0" spread="12.9"/>
                    <measurement group_id="O6" value="123.0" spread="8.3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>630 minutes</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="0"/>
                    <count group_id="O2" value="0"/>
                    <count group_id="O3" value="0"/>
                    <count group_id="O4" value="4"/>
                    <count group_id="O5" value="4"/>
                    <count group_id="O6" value="4"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O4" value="108.3" spread="14.5"/>
                    <measurement group_id="O5" value="134.8" spread="7.0"/>
                    <measurement group_id="O6" value="121.5" spread="1.7"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>660 minutes</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="0"/>
                    <count group_id="O2" value="0"/>
                    <count group_id="O3" value="0"/>
                    <count group_id="O4" value="4"/>
                    <count group_id="O5" value="4"/>
                    <count group_id="O6" value="4"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O4" value="109.5" spread="15.9"/>
                    <measurement group_id="O5" value="134.5" spread="7.8"/>
                    <measurement group_id="O6" value="121.3" spread="3.9"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>In Part 1, adverse event data were collected throughout the entirety of the study visit lasting approximately 4 hours in length. In Part 2, adverse event data were collected throughout the entirety of the study visit lasting approximately 12 hours in length.</time_frame>
      <group_list>
        <group group_id="E1">
          <title>0 mg Nicotine Film</title>
          <description>In Part 1, 4 participants were allocated to this arm and received one placebo nicotine film.&#xD;
Placebo Nicotine Film: Nicotine orally dissolving films (ODF) are films containing nicotine (0, 2, or 4 mg). The active pharmaceutical ingredient in Nicotine ODF is nicotine polacrilex (20%, USP). The film used in Nicotine ODF has a muco-adhesive property, i.e. it can adhere to the oral mucosa and allow the drug to be absorbed through oral mucosa. After placement in the oral cavity, nicotine ODF dissolves over a 5-10 minute period.The unit-dose dosage is in the form of 1 in x 1 in square and weighs about 100 mg. Nicotine films are not available in the United States in a non-investigational setting.</description>
        </group>
        <group group_id="E2">
          <title>2 mg Nicotine Film</title>
          <description>In Part 1, 4 participants were allocated to this arm and received one 2mg nicotine film.&#xD;
Nicotine Film: Nicotine orally dissolving films (ODF) are films containing nicotine (0, 2, or 4 mg). The active pharmaceutical ingredient in Nicotine ODF is nicotine polacrilex (20%, USP). The film used in Nicotine ODF has a muco-adhesive property, i.e. it can adhere to the oral mucosa and allow the drug to be absorbed through oral mucosa. After placement in the oral cavity, nicotine ODF dissolves over a 5-10 minute period.The unit-dose dosage is in the form of 1 in x 1 in square and weighs about 100 mg. Nicotine films are not available in the United States in a non-investigational setting.</description>
        </group>
        <group group_id="E3">
          <title>4 mg Nicotine Film</title>
          <description>In Part 1, 4 participants were allocated to this arm and received one 4mg nicotine film.&#xD;
Nicotine Film: Nicotine orally dissolving films (ODF) are films containing nicotine (0, 2, or 4 mg). The active pharmaceutical ingredient in Nicotine ODF is nicotine polacrilex (20%, USP). The film used in Nicotine ODF has a muco-adhesive property, i.e. it can adhere to the oral mucosa and allow the drug to be absorbed through oral mucosa. After placement in the oral cavity, nicotine ODF dissolves over a 5-10 minute period.The unit-dose dosage is in the form of 1 in x 1 in square and weighs about 100 mg. Nicotine films are not available in the United States in a non-investigational setting.</description>
        </group>
        <group group_id="E4">
          <title>0, 0, 0, 0mg Nicotine Film Regimen</title>
          <description>In Part 2, 4 participants were allocated to this arm and received one nicotine film every 3 hours (for a total of 4 films over 12 hours) in the following order: 0, 0, 0, 0 mg.&#xD;
Placebo Nicotine Film: Nicotine orally dissolving films (ODF) are films containing nicotine (0, 2, or 4 mg). The active pharmaceutical ingredient in Nicotine ODF is nicotine polacrilex (20%, USP). The film used in Nicotine ODF has a muco-adhesive property, i.e. it can adhere to the oral mucosa and allow the drug to be absorbed through oral mucosa. After placement in the oral cavity, nicotine ODF dissolves over a 5-10 minute period.The unit-dose dosage is in the form of 1 in x 1 in square and weighs about 100 mg. Nicotine films are not available in the United States in a non-investigational setting.</description>
        </group>
        <group group_id="E5">
          <title>2, 2, 2, 2mg Nicotine Film Regimen</title>
          <description>In Part 2, 4 participants were allocated to this arm and received one nicotine film every 3 hours (for a total of 4 films over 12 hours) in the following order: 2, 2, 2, 2 mg.&#xD;
Nicotine Film: Nicotine orally dissolving films (ODF) are films containing nicotine (0, 2, or 4 mg). The active pharmaceutical ingredient in Nicotine ODF is nicotine polacrilex (20%, USP). The film used in Nicotine ODF has a muco-adhesive property, i.e. it can adhere to the oral mucosa and allow the drug to be absorbed through oral mucosa. After placement in the oral cavity, nicotine ODF dissolves over a 5-10 minute period.The unit-dose dosage is in the form of 1 in x 1 in square and weighs about 100 mg. Nicotine films are not available in the United States in a non-investigational setting.</description>
        </group>
        <group group_id="E6">
          <title>4, 4, 0, 4mg Nicotine Film Regimen</title>
          <description>In Part 2, 4 participants were allocated to this arm and received one nicotine film every 3 hours (for a total of 4 films over 12 hours) in the following order: 4, 4, 0, 4 mg.&#xD;
Nicotine Film: Nicotine orally dissolving films (ODF) are films containing nicotine (0, 2, or 4 mg). The active pharmaceutical ingredient in Nicotine ODF is nicotine polacrilex (20%, USP). The film used in Nicotine ODF has a muco-adhesive property, i.e. it can adhere to the oral mucosa and allow the drug to be absorbed through oral mucosa. After placement in the oral cavity, nicotine ODF dissolves over a 5-10 minute period.The unit-dose dosage is in the form of 1 in x 1 in square and weighs about 100 mg. Nicotine films are not available in the United States in a non-investigational setting.</description>
        </group>
      </group_list>
      <serious_events>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, all-cause mortality</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E6" subjects_affected="0" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E6" subjects_affected="0" subjects_at_risk="4"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>0</frequency_threshold>
        <default_assessment>Non-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="1" subjects_at_risk="4"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="4"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E5" subjects_affected="3" subjects_at_risk="4"/>
                <counts group_id="E6" subjects_affected="2" subjects_at_risk="4"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Nausea</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E5" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E6" events="1" subjects_affected="1" subjects_at_risk="4"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Dizziness</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E5" events="1" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E6" events="0" subjects_affected="0" subjects_at_risk="4"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Hiccups</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E5" events="1" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E6" events="0" subjects_affected="0" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>Sore throat</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E5" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E6" events="0" subjects_affected="0" subjects_at_risk="4"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Vascular disorders</title>
            <event_list>
              <event>
                <sub_title>Hypertension</sub_title>
                <assessment>Systematic Assessment</assessment>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E5" events="2" subjects_affected="2" subjects_at_risk="4"/>
                <counts group_id="E6" events="1" subjects_affected="1" subjects_at_risk="4"/>
              </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. Patricia Sue Grigson</name_or_title>
      <organization>Penn State College of Medicine</organization>
      <phone>717-531-5772</phone>
      <email>psg6@psu.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/NCT02239770
org study id: 00000873
nct id: NCT02239770
lead sponsor: 
has dmc: No
The objective of this study is to test the effect of a range of doses of a novel nicotine
      film on plasma nicotine levels, expired carbon monoxide and, via a questionnaire, subjective
      ratings of the film and side effects. The nicotine film is not part of standard of care and
      is not available in a non-investigational setting. The investigators hypothesize that plasma
      nicotine levels will be in keeping with those induced by other oral nicotine replacement
      therapies (NRTs) and by the smoking of a cigarette. Thus, the investigators predict that
      random delivery of nicotine via the oral film will be safe and well-tolerated by the human
      subjects.
Briefly, this will be a two-part pharmacokinetic study, each part involving 12 participants.

      In Part 1, 4 volunteer smokers (both male, and female) each will each abstain from all
      tobacco/nicotine products for 16 hours before attending the Penn State Clinical Research
      Center for the measurement of the blood nicotine pharmacokinetic response to a randomly
      allocated dose of either (a) 0mg, (b) 2mg or (c) 4mg oral nicotine film. A trained nurse will
      implant an intravenous indwelling catheter in each participant, through which they will
      provide a baseline blood sample after 16 hours of abstinence, confirmed by an exhaled
      carbon-monoxide < 6 ppm, and then will place a nicotine film in their mouth and have blood
      drawn every 10 minutes for the next 60 minutes, and then every 30 minutes for the next 2
      hours plus one blood draw one minute after the film dissolves (11 blood draws in all over 3
      hours after using the nicotine film). Subjective measures of (a) nicotine withdrawal and
      craving and (b) potential nicotine effects, including symptoms of nicotine intoxication, will
      be recorded at scheduled intervals through the study visit, and blood pressure and heart rate
      will be measured every 30 minutes. The investigators expect to find peak blood nicotine
      concentrations of around 3-4 ng/ml and 5-6 ng/ml from each of the two active doses of
      nicotine film, with the peak occurring approximately 30 minutes after film administration,
      and the level having dropped by at least half by 2 hours later. These peak blood nicotine
      levels are all within the range that a smoker might obtain after smoking a single cigarette.
      Upon completion of all blood draws, a trained nurse will remove the catheter and treat the
      puncture wound. The participant will receive $120 for this visit.

      In Part 2, 12 participants will again attend the Penn State Clinical Research Center after 16
      hours of abstinence, confirmed by an exhaled carbon monoxide < 12 ppm. On this visit
      participants will consume repeated doses of nicotine films intended to mimic the patterns of
      delivery that will be used in smoking cessation study 2 and fMRI study 3. The primary issue
      here is to determine peak blood nicotine concentrations and safety resulting from (a) the
      highest dose schedule that could be used in study 2 and 3, (b) the steady state levels
      produced by repeated administration of the 2mg nicotine film, and (c) to compare the
      subjective effects to placebo. In order to mimic the most aggressive dosing schedule possible
      in the "random nicotine" arm of study 2 and 3, the investigators will assess blood nicotine,
      subjective and basic cardiovascular responses to consuming nicotine film every 3 hours
      beginning at 8:00 a.m. on the following schedule: 4mg, 4mg, 0mg, 4mg.

      All 12 participants will attend after 16 hours nicotine abstinence. 4 subjects each will be
      randomly allocated to consume 4 films over 12 hours in each of the following orders (a)
      0,0,0,0 mg (b) 2,2,2,2 or (c) 4,4,0,4. A blood sample will be drawn at baseline prior to each
      film administration, and then at 30, 60 and 120 minutes after each film administration as
      well as one minute after film dissolution (20 blood draws in total), with heart rate and BP
      being assessed every 30 minutes. Nicotine has a half-life of approximately 2 hours, so the
      investigators expect that with 3-hourly administration there will not be much build-up of
      nicotine levels and these levels will be on the low end of the typical levels experienced by
      smokers every day. The participants will each receive $240 for this visit.

      At clinic visits, in addition to providing blood samples for measurement of plasma nicotine
      concentration, participants will be asked to complete a battery of survey instruments
      assessing subjective effects (e.g. withdrawal and craving) and physical symptoms (e.g.
      dizziness and nausea) that could be caused by either nicotine withdrawal or nicotine
      exposure.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Basic Science
masking: Double (Participant, Investigator)
measure: Peak Plasma Nicotine Concentrations Following Ingestion of a Single (Phase 1) or Repeated (Phase 2) Doses of Nicotine Film
time frame: 10 min - 12 hours
description: In Phase 1, a trained nurse will implant an intravenous (IV) indwelling catheter in each participant. Participants will place a film containing zero, 2, or 4 mg of nicotine in their mouths and blood will be drawn every 10 minutes thereafter for the next 60 minutes, and then every 30 minutes for the next 2 hours (11 blood draws in all over 3 hours after using the nicotine film).
In Phase 2, all 12 participants will receive an IV catheter and randomly allocated to consume 4 films over 12 hours in each of the following orders (a) 0,0,0,0 mg (b) 2,2,2,2 or (c) 4,4,0,4. A blood sample will be drawn at baseline prior to each film administration, and then at 30, 45, 60 and 120 minutes after each film administration and when the film is reported dissolved (20 blood draws in total).
measure: Questionnaire of Smoking Urges-Brief Mean Total Score by Dose Group
time frame: Part 1: The QSU-Brief was measured at baseline and at 15, 35, 55, 80, 140, and 200 minutes post film administration. Part 2: The QSU-Brief was measured at baseline and at 50, 110, 230, 290, 410, 470, 590, and 690 minutes post FIRST film administration.
description: The Questionnaire of Smoking Urges-Brief (QSU-Brief) with a possible total score range of 10 to 70 was used to measure cigarette craving at baseline and at several points throughout the study visit for each participant. A score of 10 on this scale indicates very low cigarette craving, while a score of 70 indicates very high cigarette craving.
Part 1: The QSU-Brief was measured at baseline and at 15, 35, 55, 80, 140, and 200 minutes post film administration.
Part 2: The QSU-Brief was measured at baseline and at 50, 110, 230, 290, 410, 470, 590, and 690 minutes post FIRST film administration.
measure: Mean Systolic Blood Pressure
time frame: Part 1: Systolic blood pressure was measured at baseline and at every 30 minutes, up to 180 minutes post film administration. Part 2: Systolic blood pressure was measured at baseline and at every 30 minutes, up to 660 minutes post film administration.
description: Systolic blood pressure was measured using an electronic sphygmomanometer just prior to film administration and at every 30 minutes after film administration for the duration of each study visit.
arm group label: 0 mg Nicotine Film
arm group type: Placebo Comparator
description: In Part 1, 4 participants will be allocated to this arm and receive one placebo nicotine film.
arm group label: 2 mg Nicotine Film
arm group type: Experimental
description: In Part 1, 4 participants will be allocated to this arm and receive one 2 mg nicotine film.
arm group label: 4 mg Nicotine Film
arm group type: Experimental
description: In Part 1, 4 participants will be allocated to this arm and receive one 4 mg nicotine film.
arm group label: 0, 0, 0, 0mg Nicotine Film Regimen
arm group type: Placebo Comparator
description: In Part 2, 4 participants will be allocated to this arm and receive one nicotine film every 3 hours (for a total of 4 films over 12 hours) in the following order: 0, 0, 0, 0 mg.
arm group label: 2, 2, 2, 2mg Nicotine Film Regimen
arm group type: Experimental
description: In Part 2, 4 participants will be allocated to this arm and receive one nicotine film every 3 hours (for a total of 4 films over 12 hours) in the following order: 2, 2, 2, 2 mg.
arm group label: 4, 4, 0, 4mg Nicotine Film Regimen
arm group type: Experimental
description: In Part 2, 4 participants will be allocated to this arm and receive one nicotine film every 3 hours (for a total of 4 films over 12 hours) in the following order: 4, 4, 0, 4 mg.
intervention type: Drug
intervention name: Nicotine Film
description: Nicotine orally dissolving films (ODF) are films containing nicotine (0, 2, or 4 mg). The active pharmaceutical ingredient in Nicotine ODF is nicotine polacrilex (20%, USP). The film used in Nicotine ODF has a muco-adhesive property, i.e. it can adhere to the oral mucosa and allow the drug to be absorbed through oral mucosa. After placement in the oral cavity, nicotine ODF dissolves over a 5-10 minute period.The unit-dose dosage is in the form of 1 in x 1 in square and weighs about 100 mg. Nicotine films are not available in the United States in a non-investigational setting.
arm group label: 2 mg Nicotine Film
arm group label: 2, 2, 2, 2mg Nicotine Film Regimen
arm group label: 4 mg Nicotine Film
arm group label: 4, 4, 0, 4mg Nicotine Film Regimen
intervention type: Drug
intervention name: Placebo Nicotine Film
description: Nicotine orally dissolving films (ODF) are films containing nicotine (0, 2, or 4 mg). The active pharmaceutical ingredient in Nicotine ODF is nicotine polacrilex (20%, USP). The film used in Nicotine ODF has a muco-adhesive property, i.e. it can adhere to the oral mucosa and allow the drug to be absorbed through oral mucosa. After placement in the oral cavity, nicotine ODF dissolves over a 5-10 minute period.The unit-dose dosage is in the form of 1 in x 1 in square and weighs about 100 mg. Nicotine films are not available in the United States in a non-investigational setting.
arm group label: 0 mg Nicotine Film
arm group label: 0, 0, 0, 0mg Nicotine Film Regimen
criteria: 
gender: All
minimum age: 18 Years
maximum age: 55 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Patricia S. Grigson, Ph.D.
role: Principal Investigator
affiliation: Penn State College of Medicine
last name: Jonathan A Foulds, Ph.D.
role: Principal Investigator
affiliation: Penn State College of Medicine
last name: Christopher N Sciamanna, MD, MPH
role: Study Director
affiliation: Penn State College of Medicine
facility: 
country: United States
responsible party type: Principal Investigator
investigator affiliation: Milton S. Hershey Medical Center
investigator full name: Patricia Sue Grigson
investigator title: Professor
mesh term: Nicotine
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 