<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/NCT01669122</url>
  </required_header>
  <id_info>
    <org_study_id>RH01333</org_study_id>
    <nct_id>NCT01669122</nct_id>
  </id_info>
  <brief_title>Pharmacokinetic Study of 4 mg Nicotine Lozenge.</brief_title>
  <official_title>A Randomized, Cross-Over, Single Dose Pharmacokinetic Study of 4mg Nicotine Lozenges.</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>GlaxoSmithKline</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>GlaxoSmithKline</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      This is a randomized, single center, open label, single dose, four way crossover study in&#xD;
      fasted healthy male subjects to compare the pharmacokinetics of nicotine following&#xD;
      administration of 3 prototype 4mg nicotine lozenge to an internationally marketed 4mg&#xD;
      nicotine lozenge. Blood samples will be drawn at pre-specified intervals for a total of 12&#xD;
      hours post dose in each treatment session and plasma samples analyzed for nicotine levels.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Completed</overall_status>
  <start_date>June 2012</start_date>
  <completion_date type="Actual">August 2012</completion_date>
  <primary_completion_date type="Actual">August 2012</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Crossover Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Area Under the Curve From Time 0 to t, AUC (0-t)</measure>
    <time_frame>Blood samples were collected pre-dose and at 5, 10, 15, 30 and 45 minutes and 1, 1.5, 2, 3, 4, 6, 8, 10 and 12 hours post dosing</time_frame>
    <description>Area under the plasma concentration time curve from zero and extrapolated to the time of last quantifiable sample was determined from plasma concentration time profile of nicotine. AUC(0 -t) was based on the baseline adjusted nicotine plasma concentration data.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Maximum Plasma Concentration (Cmax)</measure>
    <time_frame>Blood samples were collected pre-dose and at 5, 10, 15, 30 and 45 minutes and 1, 1.5, 2, 3, 4, 6, 8, 10 and 12 hours post dosing</time_frame>
    <description>Maximum plasma nicotine concentration was determined from plasma-concentration time profiles. Cmax was based on the baseline adjusted nicotine plasma concentration data.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>AUC(0-inf)</measure>
    <time_frame>Blood samples were collected pre-dose and at 5, 10, 15, 30 and 45 minutes and 1, 1.5, 2, 3, 4, 6, 8, 10 and 12 hours post dosing</time_frame>
    <description>Area under the plasma nicotine concentration-time curve from zero extrapolated to infinity was determined. AUC(0-inf) was based on the baseline adjusted nicotine plasma concentration data.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Time to Maximum Plasma Concentration (Tmax)</measure>
    <time_frame>Blood samples were collected pre-dose and at 5, 10, 15, 30 and 45 minutes and 1, 1.5, 2, 3, 4, 6, 8, 10 and 12 hours post dosing</time_frame>
    <description>Tmax was determined from plasma concentration time profiles. Tmax was based on the baseline adjusted nicotine plasma concentration data.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Rate of Elimination (Kel)</measure>
    <time_frame>Blood samples were collected pre-dose at 5, 10, 15, 30 and 45 minutes and 1, 1.5, 2, 3, 4, 6, 8, 10 and 12 hours post dosing</time_frame>
    <description>Elimination rate constant for nicotine was calculated. Kel was based on the baseline adjusted nicotine plasma concentration data.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Plasma Half Life (t1/2)</measure>
    <time_frame>Blood samples were collected pre-dose and at 5, 10, 15, 30 and 45 minutes and 1, 1.5, 2, 3, 4, 6, 8, 10 and 12 hours post dosing</time_frame>
    <description>Half-life of elimination of nicotine was determined. t1/2 was based on the baseline adjusted nicotine plasma concentration data.</description>
  </secondary_outcome>
  <number_of_arms>4</number_of_arms>
  <enrollment type="Actual">40</enrollment>
  <condition>Smoking Cessation</condition>
  <arm_group>
    <arm_group_label>Prototype 1</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>4mg nicotine lozenge administered orally as a single dose treatment per subject</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Prototype 2</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>4mg nicotine lozenge administered orally as a single dose treatment per subject</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Prototype 3</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>4mg nicotine lozenge administered orally as a single dose treatment per subject</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Reference Therapy</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>4mg nicotine lozenge (internationally marketed) to be administered orally as a single dose treatment per subject.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>nicotine</intervention_name>
    <description>4 mg nicotine lozenge experimental</description>
    <arm_group_label>Prototype 1</arm_group_label>
    <arm_group_label>Prototype 2</arm_group_label>
    <arm_group_label>Prototype 3</arm_group_label>
    <arm_group_label>Reference Therapy</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
        - smoked commercially-manufactured cigarettes daily for the preceding 12 months and&#xD;
        routinely smokes first cigarette within 30mins of awakening.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  inability to refrain from smoking during confinement period, smoking tobacco in any&#xD;
             other form other than commercially manufactured cigarettes, subject has used chewing&#xD;
             tobacco or other tobacco products other than commercially manufactured cigarettes&#xD;
             within 7 days of dosing&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>45 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>GSK Clinical Trials</last_name>
    <role>Study Director</role>
    <affiliation>GlaxoSmithKline</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Lambda Therapeutic Research Ltd</name>
      <address>
        <city>Ahmedabad</city>
        <state>Gujarat</state>
        <zip>380 061</zip>
        <country>India</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>India</country>
  </location_countries>
  <verification_date>October 2014</verification_date>
  <study_first_submitted>August 16, 2012</study_first_submitted>
  <study_first_submitted_qc>August 16, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">August 20, 2012</study_first_posted>
  <results_first_submitted>July 18, 2013</results_first_submitted>
  <results_first_submitted_qc>January 12, 2015</results_first_submitted_qc>
  <results_first_posted type="Estimate">January 22, 2015</results_first_posted>
  <last_update_submitted>January 12, 2015</last_update_submitted>
  <last_update_submitted_qc>January 12, 2015</last_update_submitted_qc>
  <last_update_posted type="Estimate">January 22, 2015</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Nicotine</mesh_term>
  </intervention_browse>

  <clinical_results>

    <participant_flow>
      <recruitment_details>Participants were recruited at the clinical site.</recruitment_details>
      <pre_assignment_details>A total of 102 participants were screened, of which only 40 were randomized into the study. Fourteen participants did not meet the study criteria, 32 were lost to follow up, 2 withdrew consent while remaining 14 were not randomized due to other reasons.</pre_assignment_details>
      <group_list>
        <group group_id="P1">
          <title>Total Participants</title>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Period I</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="40">Participants who received Lozenge A=10, Lozenge B=10, Lozenge C=10, Reference Lozenge=10</participants>
              </participants_list>
            </milestone>
            <milestone>
              <title>Safety Population</title>
              <participants_list>
                <participants group_id="P1" count="39"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="39"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Lost to Follow-up</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
        <period>
          <title>Washout Period I</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="39"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="39"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
        <period>
          <title>Period II</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="39">Participants who received Lozenge A=9, Lozenge B=10, Lozenge C=10, Reference Lozenge=10</participants>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="39"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
        <period>
          <title>Washout Period II</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="39"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="37"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="2"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Protocol Violation</title>
              <participants_list>
                <participants group_id="P1" count="2"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
        <period>
          <title>Washout Period III</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="37"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="37"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
        <period>
          <title>Period III</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="37">Participants who received Lozenge A=10, Lozenge B=8, Lozenge C=10, Reference Lozenge=9</participants>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="37"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
        <period>
          <title>Period IV</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="37">Participants who received Lozenge A=9, Lozenge B=10, Lozenge C=9, Reference Lozenge=9</participants>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="37"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>Safety Population</title>
          <description>Baseline measurements were performed for safety population which included all participants in the study who were dispensed at least one of the study treatment. Out of 40 randomized participants, one participant did not receive any treatment and was lost to follow-up.</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="39"/>
          </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="28.7" spread="6.4"/>
                  </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="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="39"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Area Under the Curve From Time 0 to t, AUC (0-t)</title>
        <description>Area under the plasma concentration time curve from zero and extrapolated to the time of last quantifiable sample was determined from plasma concentration time profile of nicotine. AUC(0 -t) was based on the baseline adjusted nicotine plasma concentration data.</description>
        <time_frame>Blood samples were collected pre-dose and at 5, 10, 15, 30 and 45 minutes and 1, 1.5, 2, 3, 4, 6, 8, 10 and 12 hours post dosing</time_frame>
        <population>Per protocol (PP) population: all randomized participants profiles, without a protocol deviation that would have lead to the data exclusion.</population>
        <group_list>
          <group group_id="O1">
            <title>Test Lozenge (A)</title>
            <description>4 mg nicotine lozenge with excipient A, was administered orally as a single dose treatment.</description>
          </group>
          <group group_id="O2">
            <title>Test Lozenge (B)</title>
            <description>4 mg nicotine lozenge with excipient B, was administered orally as a single dose treatment.</description>
          </group>
          <group group_id="O3">
            <title>Test Lozenge (C)</title>
            <description>4 mg nicotine lozenge with excipient C, was administered orally as a single dose treatment.</description>
          </group>
          <group group_id="O4">
            <title>Reference Lozenge</title>
            <description>Reference 4 mg nicotine lozenge, was administered orally as a single dose treatment.</description>
          </group>
        </group_list>
        <measure>
          <title>Area Under the Curve From Time 0 to t, AUC (0-t)</title>
          <description>Area under the plasma concentration time curve from zero and extrapolated to the time of last quantifiable sample was determined from plasma concentration time profile of nicotine. AUC(0 -t) was based on the baseline adjusted nicotine plasma concentration data.</description>
          <population>Per protocol (PP) population: all randomized participants profiles, without a protocol deviation that would have lead to the data exclusion.</population>
          <units>nanograms (ng)*hours (h)/milliliter (mL)</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="38"/>
                <count group_id="O2" value="37"/>
                <count group_id="O3" value="39"/>
                <count group_id="O4" value="38"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="89.14" spread="44.777"/>
                    <measurement group_id="O2" value="87.38" spread="42.816"/>
                    <measurement group_id="O3" value="86.60" spread="36.191"/>
                    <measurement group_id="O4" value="91.97" spread="45.601"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O4</group_id>
            </group_id_list>
            <groups_desc>Null hypothesis considered no difference in the treatments being compared.</groups_desc>
            <non_inferiority_type>Non-Inferiority or Equivalence</non_inferiority_type>
            <non_inferiority_desc>Testing Bioequivalence</non_inferiority_desc>
            <param_type>Treatment Ratio</param_type>
            <param_value>0.96</param_value>
            <ci_percent>90</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>0.93</ci_lower_limit>
            <ci_upper_limit>0.99</ci_upper_limit>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O2</group_id>
              <group_id>O4</group_id>
            </group_id_list>
            <groups_desc>Null hypothesis considered no difference in the treatments being compared.</groups_desc>
            <non_inferiority_type>Non-Inferiority or Equivalence</non_inferiority_type>
            <non_inferiority_desc>Testing Bioequivalence</non_inferiority_desc>
            <param_type>Treatment Ratio</param_type>
            <param_value>0.96</param_value>
            <ci_percent>90</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>0.93</ci_lower_limit>
            <ci_upper_limit>0.99</ci_upper_limit>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O3</group_id>
              <group_id>O4</group_id>
            </group_id_list>
            <groups_desc>Null hypothesis considered no difference in the treatments being compared.</groups_desc>
            <non_inferiority_type>Non-Inferiority or Equivalence</non_inferiority_type>
            <non_inferiority_desc>Testing Bioequivalence</non_inferiority_desc>
            <param_type>Treatment Ratio</param_type>
            <param_value>0.94</param_value>
            <ci_percent>90</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>0.91</ci_lower_limit>
            <ci_upper_limit>0.97</ci_upper_limit>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Maximum Plasma Concentration (Cmax)</title>
        <description>Maximum plasma nicotine concentration was determined from plasma-concentration time profiles. Cmax was based on the baseline adjusted nicotine plasma concentration data.</description>
        <time_frame>Blood samples were collected pre-dose and at 5, 10, 15, 30 and 45 minutes and 1, 1.5, 2, 3, 4, 6, 8, 10 and 12 hours post dosing</time_frame>
        <population>PP population: all randomized participants profiles, without a protocol deviation that would have lead to the data exclusion.</population>
        <group_list>
          <group group_id="O1">
            <title>Test Lozenge (A)</title>
            <description>4 mg nicotine lozenge with excipient A was administered orally as a single dose treatment.</description>
          </group>
          <group group_id="O2">
            <title>Test Lozenge (B)</title>
            <description>4 mg nicotine lozenge with excipient B, was administered orally as a single dose treatment.</description>
          </group>
          <group group_id="O3">
            <title>Test Lozenge (C)</title>
            <description>4 mg nicotine lozenge with excipient C, was administered orally as a single dose treatment.</description>
          </group>
          <group group_id="O4">
            <title>Reference Lozenge</title>
            <description>Reference 4 mg nicotine lozenge, was administered orally as a single dose treatment.</description>
          </group>
        </group_list>
        <measure>
          <title>Maximum Plasma Concentration (Cmax)</title>
          <description>Maximum plasma nicotine concentration was determined from plasma-concentration time profiles. Cmax was based on the baseline adjusted nicotine plasma concentration data.</description>
          <population>PP population: all randomized participants profiles, without a protocol deviation that would have lead to the data exclusion.</population>
          <units>ng/mL</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="38"/>
                <count group_id="O2" value="37"/>
                <count group_id="O3" value="39"/>
                <count group_id="O4" value="38"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="18.50" spread="5.626"/>
                    <measurement group_id="O2" value="18.39" spread="5.099"/>
                    <measurement group_id="O3" value="17.41" spread="4.796"/>
                    <measurement group_id="O4" value="18.97" spread="6.001"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O4</group_id>
            </group_id_list>
            <groups_desc>Null hypothesis considered no difference in the treatments being compared.</groups_desc>
            <non_inferiority_type>Non-Inferiority or Equivalence</non_inferiority_type>
            <non_inferiority_desc>Testing bioequivalence</non_inferiority_desc>
            <param_type>Treatment Ratio</param_type>
            <param_value>0.97</param_value>
            <ci_percent>90</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>0.93</ci_lower_limit>
            <ci_upper_limit>1.02</ci_upper_limit>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O2</group_id>
              <group_id>O4</group_id>
            </group_id_list>
            <groups_desc>Null hypothesis considered no difference in the treatments being compared.</groups_desc>
            <non_inferiority_type>Non-Inferiority or Equivalence</non_inferiority_type>
            <non_inferiority_desc>Testing Bioequivalence</non_inferiority_desc>
            <param_type>Treatment Ratio</param_type>
            <param_value>0.99</param_value>
            <ci_percent>90</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>0.94</ci_lower_limit>
            <ci_upper_limit>1.03</ci_upper_limit>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O3</group_id>
              <group_id>O4</group_id>
            </group_id_list>
            <groups_desc>Null hypothesis considered no difference in the treatments being compared.</groups_desc>
            <non_inferiority_type>Non-Inferiority or Equivalence</non_inferiority_type>
            <non_inferiority_desc>Testing Bioequivalence</non_inferiority_desc>
            <param_type>Treatment Ratio</param_type>
            <param_value>0.92</param_value>
            <ci_percent>90</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>0.88</ci_lower_limit>
            <ci_upper_limit>0.96</ci_upper_limit>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>AUC(0-inf)</title>
        <description>Area under the plasma nicotine concentration-time curve from zero extrapolated to infinity was determined. AUC(0-inf) was based on the baseline adjusted nicotine plasma concentration data.</description>
        <time_frame>Blood samples were collected pre-dose and at 5, 10, 15, 30 and 45 minutes and 1, 1.5, 2, 3, 4, 6, 8, 10 and 12 hours post dosing</time_frame>
        <population>PP population: all randomized participants profiles, without a protocol deviation that would have lead to the data exclusion.</population>
        <group_list>
          <group group_id="O1">
            <title>Test Lozenge (A)</title>
            <description>4 mg nicotine lozenge with excipient A, was administered orally as a single dose treatment.</description>
          </group>
          <group group_id="O2">
            <title>Test Lozenge (B)</title>
            <description>4 mg nicotine lozenge with excipient B, was administered orally as a single dose treatment.</description>
          </group>
          <group group_id="O3">
            <title>Test Lozenge (C)</title>
            <description>4 mg nicotine lozenge with excipient C, was administered orally as a single dose treatment.</description>
          </group>
          <group group_id="O4">
            <title>Reference Lozenge</title>
            <description>Reference 4 mg nicotine lozenge, was administered orally as a single dose treatment.</description>
          </group>
        </group_list>
        <measure>
          <title>AUC(0-inf)</title>
          <description>Area under the plasma nicotine concentration-time curve from zero extrapolated to infinity was determined. AUC(0-inf) was based on the baseline adjusted nicotine plasma concentration data.</description>
          <population>PP population: all randomized participants profiles, without a protocol deviation that would have lead to the data exclusion.</population>
          <units>ng*hr/mL</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="38"/>
                <count group_id="O2" value="37"/>
                <count group_id="O3" value="39"/>
                <count group_id="O4" value="38"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="100.33" spread="60.132"/>
                    <measurement group_id="O2" value="98.90" spread="61.958"/>
                    <measurement group_id="O3" value="97.83" spread="52.324"/>
                    <measurement group_id="O4" value="104.53" spread="65.525"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O4</group_id>
            </group_id_list>
            <groups_desc>Null hypothesis considered no difference in the treatments being compared.</groups_desc>
            <non_inferiority_type>Non-Inferiority or Equivalence</non_inferiority_type>
            <non_inferiority_desc>Testing bioequivalence</non_inferiority_desc>
            <param_type>Treatment Ratio</param_type>
            <param_value>0.96</param_value>
            <ci_percent>90</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>0.93</ci_lower_limit>
            <ci_upper_limit>0.99</ci_upper_limit>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O2</group_id>
              <group_id>O4</group_id>
            </group_id_list>
            <groups_desc>Null hypothesis considered no difference in the treatments being compared.</groups_desc>
            <non_inferiority_type>Non-Inferiority or Equivalence</non_inferiority_type>
            <non_inferiority_desc>Testing bioequivalence</non_inferiority_desc>
            <param_type>Treatment Ratio</param_type>
            <param_value>0.96</param_value>
            <ci_percent>90</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>0.93</ci_lower_limit>
            <ci_upper_limit>0.99</ci_upper_limit>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O3</group_id>
              <group_id>O4</group_id>
            </group_id_list>
            <groups_desc>Null hypothesis considered no difference in the treatments being compared.</groups_desc>
            <non_inferiority_type>Non-Inferiority or Equivalence</non_inferiority_type>
            <non_inferiority_desc>Testing bioequivalence</non_inferiority_desc>
            <param_type>Treatment Ratio</param_type>
            <param_value>0.93</param_value>
            <ci_percent>90</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>0.90</ci_lower_limit>
            <ci_upper_limit>0.96</ci_upper_limit>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Time to Maximum Plasma Concentration (Tmax)</title>
        <description>Tmax was determined from plasma concentration time profiles. Tmax was based on the baseline adjusted nicotine plasma concentration data.</description>
        <time_frame>Blood samples were collected pre-dose and at 5, 10, 15, 30 and 45 minutes and 1, 1.5, 2, 3, 4, 6, 8, 10 and 12 hours post dosing</time_frame>
        <population>PP population: all randomized participants profiles, without a protocol deviation that would have lead to the data exclusion.</population>
        <group_list>
          <group group_id="O1">
            <title>Test Lozenge (A)</title>
            <description>4 mg nicotine lozenge with excipient A, was administered orally as a single dose treatment.</description>
          </group>
          <group group_id="O2">
            <title>Test Lozenge (B)</title>
            <description>4 mg nicotine lozenge with excipient B, was administered orally as a single dose treatment.</description>
          </group>
          <group group_id="O3">
            <title>Test Lozenge (C)</title>
            <description>4 mg nicotine lozenge with excipient C, was administered orally as a single dose treatment.</description>
          </group>
          <group group_id="O4">
            <title>Reference Lozenge</title>
            <description>Reference 4 mg nicotine lozenge, was administered orally as a single dose treatment.</description>
          </group>
        </group_list>
        <measure>
          <title>Time to Maximum Plasma Concentration (Tmax)</title>
          <description>Tmax was determined from plasma concentration time profiles. Tmax was based on the baseline adjusted nicotine plasma concentration data.</description>
          <population>PP population: all randomized participants profiles, without a protocol deviation that would have lead to the data exclusion.</population>
          <units>hours</units>
          <param>Median</param>
          <dispersion>Full Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="38"/>
                <count group_id="O2" value="37"/>
                <count group_id="O3" value="39"/>
                <count group_id="O4" value="38"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1.50" lower_limit="0.50" upper_limit="4.00"/>
                    <measurement group_id="O2" value="1.50" lower_limit="0.25" upper_limit="6.00"/>
                    <measurement group_id="O3" value="1.50" lower_limit="0.75" upper_limit="6.00"/>
                    <measurement group_id="O4" value="1.50" lower_limit="0.25" upper_limit="3.00"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O4</group_id>
            </group_id_list>
            <groups_desc>Null hypothesis considered no difference in the treatments being compared.</groups_desc>
            <non_inferiority_type>Superiority or Other</non_inferiority_type>
            <p_value>0.2208</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
            <param_type>Median Difference (Final Values)</param_type>
            <param_value>0.00</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>0.00</ci_lower_limit>
            <ci_upper_limit>0.50</ci_upper_limit>
            <estimate_desc>Based on Hodges Lehmann estimate</estimate_desc>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O2</group_id>
              <group_id>O4</group_id>
            </group_id_list>
            <groups_desc>Null hypothesis considered no difference in the treatments being compared.</groups_desc>
            <non_inferiority_type>Superiority or Other</non_inferiority_type>
            <p_value>0.5695</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
            <param_type>Median Difference (Final Values)</param_type>
            <param_value>0.00</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-0.25</ci_lower_limit>
            <ci_upper_limit>0.25</ci_upper_limit>
            <estimate_desc>Based on Hodges Lehmann estimate</estimate_desc>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O3</group_id>
              <group_id>O4</group_id>
            </group_id_list>
            <groups_desc>Null hypothesis considered no difference in the treatments being compared.</groups_desc>
            <non_inferiority_type>Superiority or Other</non_inferiority_type>
            <p_value>0.0063</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
            <param_type>Median Difference (Final Values)</param_type>
            <param_value>0.00</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>0.00</ci_lower_limit>
            <ci_upper_limit>0.50</ci_upper_limit>
            <estimate_desc>Based on Hodges Lehmann estimate</estimate_desc>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Rate of Elimination (Kel)</title>
        <description>Elimination rate constant for nicotine was calculated. Kel was based on the baseline adjusted nicotine plasma concentration data.</description>
        <time_frame>Blood samples were collected pre-dose at 5, 10, 15, 30 and 45 minutes and 1, 1.5, 2, 3, 4, 6, 8, 10 and 12 hours post dosing</time_frame>
        <population>PP population: all randomized participants profiles, without a protocol deviation that would have lead to the data exclusion.</population>
        <group_list>
          <group group_id="O1">
            <title>Test Lozenge (A)</title>
            <description>4 mg nicotine lozenge with excipient A, was administered orally as a single dose treatment.</description>
          </group>
          <group group_id="O2">
            <title>Test Lozenge (B)</title>
            <description>4 mg nicotine lozenge with excipient B, was administered orally as a single dose treatment.</description>
          </group>
          <group group_id="O3">
            <title>Test Lozenge (C)</title>
            <description>4 mg nicotine lozenge with excipient C, was administered orally as a single dose treatment.</description>
          </group>
          <group group_id="O4">
            <title>Reference Lozenge</title>
            <description>Reference 4 mg nicotine lozenge, was administered orally as a single dose treatment.</description>
          </group>
        </group_list>
        <measure>
          <title>Rate of Elimination (Kel)</title>
          <description>Elimination rate constant for nicotine was calculated. Kel was based on the baseline adjusted nicotine plasma concentration data.</description>
          <population>PP population: all randomized participants profiles, without a protocol deviation that would have lead to the data exclusion.</population>
          <units>1/ hour</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="38"/>
                <count group_id="O2" value="37"/>
                <count group_id="O3" value="39"/>
                <count group_id="O4" value="38"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.26" spread="0.06"/>
                    <measurement group_id="O2" value="0.26" spread="0.07"/>
                    <measurement group_id="O3" value="0.27" spread="0.11"/>
                    <measurement group_id="O4" value="0.26" spread="0.07"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Plasma Half Life (t1/2)</title>
        <description>Half-life of elimination of nicotine was determined. t1/2 was based on the baseline adjusted nicotine plasma concentration data.</description>
        <time_frame>Blood samples were collected pre-dose and at 5, 10, 15, 30 and 45 minutes and 1, 1.5, 2, 3, 4, 6, 8, 10 and 12 hours post dosing</time_frame>
        <population>PP population: all randomized participants profiles, without a protocol deviation that would have lead to the data exclusion.</population>
        <group_list>
          <group group_id="O1">
            <title>Test Lozenge (A)</title>
            <description>4 mg nicotine lozenge with excipient A, was administered orally as a single dose treatment.</description>
          </group>
          <group group_id="O2">
            <title>Test Lozenge (B)</title>
            <description>4 mg nicotine lozenge with excipient B, was administered orally as a single dose treatment.</description>
          </group>
          <group group_id="O3">
            <title>Test Lozenge (C)</title>
            <description>4 mg nicotine lozenge with excipient C, was administered orally as a single dose treatment.</description>
          </group>
          <group group_id="O4">
            <title>Reference Lozenge</title>
            <description>Reference 4 mg nicotine lozenge, was administered orally as a single dose treatment.</description>
          </group>
        </group_list>
        <measure>
          <title>Plasma Half Life (t1/2)</title>
          <description>Half-life of elimination of nicotine was determined. t1/2 was based on the baseline adjusted nicotine plasma concentration data.</description>
          <population>PP population: all randomized participants profiles, without a protocol deviation that would have lead to the data exclusion.</population>
          <units>hours</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="38"/>
                <count group_id="O2" value="37"/>
                <count group_id="O3" value="39"/>
                <count group_id="O4" value="38"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2.86" spread="0.80"/>
                    <measurement group_id="O2" value="2.91" spread="0.99"/>
                    <measurement group_id="O3" value="2.86" spread="1.07"/>
                    <measurement group_id="O4" value="2.94" spread="0.99"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>Adverse events were collected from the start of the treatment, and until 7 days following administration of the last dose of investigational product.</time_frame>
      <group_list>
        <group group_id="E1">
          <title>Test Lozenge (A)</title>
          <description>4 mg nicotine lozenge with excipient A, was administered orally as a single dose treatment.</description>
        </group>
        <group group_id="E2">
          <title>Test Lozenge (B)</title>
          <description>4 mg nicotine lozenge with excipient B, was administered orally as a single dose treatment.</description>
        </group>
        <group group_id="E3">
          <title>Test Lozenge (C)</title>
          <description>4 mg nicotine lozenge with excipient C, was administered orally as a single dose treatment.</description>
        </group>
        <group group_id="E4">
          <title>Reference Lozenge</title>
          <description>Reference 4 mg nicotine lozenge, was administered orally as a single dose treatment.</description>
        </group>
      </group_list>
      <serious_events>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="38"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="37"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="39"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="38"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>1</frequency_threshold>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="38"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="37"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="39"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="38"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>Principal Investigators are NOT employed by the organization sponsoring the study.</pi_employee>
      <restrictive_agreement>GSK agreements may vary with individual investigators, but will not prohibit any investigator from publishing. GSK supports the publication of results from all centers of a multi-center trial but requests that reports based on single-site data not precede the primary publication of the entire clinical trial.</restrictive_agreement>
    </certain_agreements>
    <point_of_contact>
      <name_or_title>GSK Response Center</name_or_title>
      <organization>GlaxoSmithKline</organization>
      <phone>866-435-7343</phone>
    </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/NCT01669122
org study id: RH01333
nct id: NCT01669122
lead sponsor: 
has dmc: No
This is a randomized, single center, open label, single dose, four way crossover study in
      fasted healthy male subjects to compare the pharmacokinetics of nicotine following
      administration of 3 prototype 4mg nicotine lozenge to an internationally marketed 4mg
      nicotine lozenge. Blood samples will be drawn at pre-specified intervals for a total of 12
      hours post dose in each treatment session and plasma samples analyzed for nicotine levels.
allocation: Randomized
intervention model: Crossover Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Area Under the Curve From Time 0 to t, AUC (0-t)
time frame: Blood samples were collected pre-dose and at 5, 10, 15, 30 and 45 minutes and 1, 1.5, 2, 3, 4, 6, 8, 10 and 12 hours post dosing
description: Area under the plasma concentration time curve from zero and extrapolated to the time of last quantifiable sample was determined from plasma concentration time profile of nicotine. AUC(0 -t) was based on the baseline adjusted nicotine plasma concentration data.
measure: Maximum Plasma Concentration (Cmax)
time frame: Blood samples were collected pre-dose and at 5, 10, 15, 30 and 45 minutes and 1, 1.5, 2, 3, 4, 6, 8, 10 and 12 hours post dosing
description: Maximum plasma nicotine concentration was determined from plasma-concentration time profiles. Cmax was based on the baseline adjusted nicotine plasma concentration data.
measure: AUC(0-inf)
time frame: Blood samples were collected pre-dose and at 5, 10, 15, 30 and 45 minutes and 1, 1.5, 2, 3, 4, 6, 8, 10 and 12 hours post dosing
description: Area under the plasma nicotine concentration-time curve from zero extrapolated to infinity was determined. AUC(0-inf) was based on the baseline adjusted nicotine plasma concentration data.
measure: Time to Maximum Plasma Concentration (Tmax)
time frame: Blood samples were collected pre-dose and at 5, 10, 15, 30 and 45 minutes and 1, 1.5, 2, 3, 4, 6, 8, 10 and 12 hours post dosing
description: Tmax was determined from plasma concentration time profiles. Tmax was based on the baseline adjusted nicotine plasma concentration data.
measure: Rate of Elimination (Kel)
time frame: Blood samples were collected pre-dose at 5, 10, 15, 30 and 45 minutes and 1, 1.5, 2, 3, 4, 6, 8, 10 and 12 hours post dosing
description: Elimination rate constant for nicotine was calculated. Kel was based on the baseline adjusted nicotine plasma concentration data.
measure: Plasma Half Life (t1/2)
time frame: Blood samples were collected pre-dose and at 5, 10, 15, 30 and 45 minutes and 1, 1.5, 2, 3, 4, 6, 8, 10 and 12 hours post dosing
description: Half-life of elimination of nicotine was determined. t1/2 was based on the baseline adjusted nicotine plasma concentration data.
arm group label: Prototype 1
arm group type: Experimental
description: 4mg nicotine lozenge administered orally as a single dose treatment per subject
arm group label: Prototype 2
arm group type: Experimental
description: 4mg nicotine lozenge administered orally as a single dose treatment per subject
arm group label: Prototype 3
arm group type: Experimental
description: 4mg nicotine lozenge administered orally as a single dose treatment per subject
arm group label: Reference Therapy
arm group type: Active Comparator
description: 4mg nicotine lozenge (internationally marketed) to be administered orally as a single dose treatment per subject.
intervention type: Drug
intervention name: nicotine
description: 4 mg nicotine lozenge experimental
arm group label: Prototype 1
arm group label: Prototype 2
arm group label: Prototype 3
arm group label: Reference Therapy
criteria: 
gender: All
minimum age: 18 Years
maximum age: 45 Years
healthy volunteers: Accepts Healthy Volunteers
last name: GSK Clinical Trials
role: Study Director
affiliation: GlaxoSmithKline
facility: 
country: India
responsible party type: Sponsor
mesh term: Nicotine
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 