<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/NCT03268343</url>
  </required_header>
  <id_info>
    <org_study_id>ACH-CYT-01</org_study_id>
    <secondary_id>2017-001562-19</secondary_id>
    <nct_id>NCT03268343</nct_id>
  </id_info>
  <brief_title>A Study in Healthy Volunteers to Investigate the Effect of Food on the Bioavailability of Cytisine</brief_title>
  <official_title>A Phase 1 Open Label, Randomized, Two-Way Crossover Study in Healthy Volunteers to Investigate the Effect of Food on the Bioavailability of Cytisine</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Achieve Life Sciences</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Achieve Life Sciences</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      This will be an open-label, randomised, 2-period, single-dose crossover study to determine&#xD;
      the comparative bioavailability of cytisine following single-dose administration in healthy&#xD;
      male and female subjects under fed and fasted conditions.&#xD;
&#xD;
      The study will be comprised of a pre-study screen, followed by 2 treatment periods (1 and 2)&#xD;
      and a post-study follow-up.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">August 8, 2017</start_date>
  <completion_date type="Actual">September 1, 2017</completion_date>
  <primary_completion_date type="Actual">August 26, 2017</primary_completion_date>
  <phase>Phase 1</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>Plasma Cytisine Pharmacokinetics (PK): Maximum Observed Plasma Concentration (Cmax)</measure>
    <time_frame>Pre-dose (within 60 minutes of dosing); 15 minutes, 20 minutes, 30 minutes, 45 minutes, 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 4 hours, 6 hours, 8 hours, 12 hours, 14 hours, 16 hours and 24 hours post-dose (+/- 1 minute)</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>Plasma Cytisine PK: Total Area Under the Curve From Time Zero to Infinity (AUC0-∞)</measure>
    <time_frame>Pre-dose (within 60 minutes of dosing); 15 minutes, 20 minutes, 30 minutes, 45 minutes, 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 4 hours, 6 hours, 8 hours, 12 hours, 14 hours, 16 hours and 24 hours post-dose (+/- 1 minute)</time_frame>
  </primary_outcome>
  <secondary_outcome>
    <measure>Plasma Cytisine PK: Time of Occurrence of Cmax (Tmax)</measure>
    <time_frame>Pre-dose (within 60 minutes of dosing); 15 minutes, 20 minutes, 30 minutes, 45 minutes, 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 4 hours, 6 hours, 8 hours, 12 hours, 14 hours, 16 hours and 24 hours post-dose (+/- 1 minute)</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Plasma Cytisine PK: AUC From Time Zero to the Last Sampling Time (AUC0-t)</measure>
    <time_frame>Pre-dose (within 60 minutes of dosing); 15 minutes, 20 minutes, 30 minutes, 45 minutes, 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 4 hours, 6 hours, 8 hours, 12 hours, 14 hours, 16 hours and 24 hours post-dose (+/- 1 minute)</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Plasma Cytisine PK: Residual Area, or Percentage of Extrapolated Part for the Calculation of AUC0-∞ (AUC%)</measure>
    <time_frame>Pre-dose (within 60 minutes of dosing); 15 minutes, 20 minutes, 30 minutes, 45 minutes, 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 4 hours, 6 hours, 8 hours, 12 hours, 14 hours, 16 hours and 24 hours post-dose (+/- 1 minute)</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Plasma Cytisine PK: Apparent Terminal Elimination Rate Constant (Lambda z)</measure>
    <time_frame>Pre-dose (within 60 minutes of dosing); 15 minutes, 20 minutes, 30 minutes, 45 minutes, 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 4 hours, 6 hours, 8 hours, 12 hours, 14 hours, 16 hours and 24 hours post-dose (+/- 1 minute)</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Plasma Cytisine PK: Apparent Terminal Elimination Half-Life (t1/2)</measure>
    <time_frame>Pre-dose (within 60 minutes of dosing); 15 minutes, 20 minutes, 30 minutes, 45 minutes, 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 4 hours, 6 hours, 8 hours, 12 hours, 14 hours, 16 hours and 24 hours post-dose (+/- 1 minute)</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Urine Cytisine PK: Amount Excreted in Urine Over Time (Ae)</measure>
    <time_frame>Pre-dose (within 30 minutes prior to first dose); 0-2 hours, 2-4 hours, 4-8 hours, 8-12 hours and 12-24 hours post-dose</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Urine Cytisine PK: Percentage of Drug Excreted in Urine (Ae%)</measure>
    <time_frame>Pre-dose (within 30 minutes prior to first dose); 0-2 hours, 2-4 hours, 4-8 hours, 8-12 hours and 12-24 hours post-dose</time_frame>
    <description>To assess the renal elimination of cytisine via measurement of urinary concentrations of cytisine.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs, and Discontinuation of Study Drug Due to AEs, by Severity and Relationship</measure>
    <time_frame>Day -1 to Day 7 plus 6-8 days (post-study follow-up)</time_frame>
    <description>An adverse event (AE) is defined as any untoward medical occurrence which does not necessarily have a causal relationship with the treatment. TEAEs are defined as AEs not present prior to first administration of investigational product, or AEs present before first administration of study drug that worsen after the subject receives the first dose of study drug. A serious adverse event (SAE) is defined as an AE that: results in death; is life-threatening; requires hospitalization or prolongs existing inpatient's hospitalization; results in persistent or significant disability or incapacity; results in a congenital abnormality or birth defect; is an important medical event which requires medical intervention to prevent any of the above outcomes. Event severity was categorized as mild, moderate, or severe. Relationship of event to study drug was categorized as definite, probably, possible, unlikely, not related, or not applicable (N/A).</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">24</enrollment>
  <condition>Smoking Cessation</condition>
  <arm_group>
    <arm_group_label>Schedule A: Fed Then Fasted</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Schedule A (12 subjects):&#xD;
Period 1: Cytisine (2 x 1.5 mg tablets) will be administered 30 minutes after the start of a high fat breakfast (fed state).&#xD;
Period 2: Cytisine (2 x 1.5 mg tablets) will be administered after an overnight fast of at least 10 hours (fasting state).</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Schedule B: Fasted Then Fed</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Schedule B (12 subjects):&#xD;
Period 1: Cytisine (2 x 1.5 mg tablets) will be administered after an overnight fast of at least 10 hours (fasting state).&#xD;
Period 2: Cytisine (2 x 1.5 mg tablets) will be administered 30 minutes after the start of a high fat breakfast (fed state).</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Cytisine</intervention_name>
    <description>Cytisine 1.5 mg Film-Coated Tablets</description>
    <arm_group_label>Schedule A: Fed Then Fasted</arm_group_label>
    <arm_group_label>Schedule B: Fasted Then Fed</arm_group_label>
    <other_name>Tabex</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Healthy males and females between 18 and 55 years of age.&#xD;
&#xD;
               1. If a female subject of child bearing potential, a negative pregnancy test at&#xD;
                  screening and admission and willing to use an effective method of contraception&#xD;
                  (unless of non-childbearing potential or where abstaining from sexual intercourse&#xD;
                  is in line with the preferred and usual lifestyle of the subject) from first dose&#xD;
                  until 3 months after last dose of investigational medicinal product (IMP).&#xD;
&#xD;
               2. If a female subject of non-child bearing potential, a negative pregnancy test at&#xD;
                  screening and admission. For the purposes of this study, this is defined as the&#xD;
                  subject being amenorrheic for at least 12 consecutive months or at least 4 months&#xD;
                  post-surgical sterilisation (including bilateral fallopian tube ligation or&#xD;
                  bilateral oophorectomy with or without hysterectomy). Menopausal status will be&#xD;
                  confirmed by demonstrating at screening that levels of follicle stimulating&#xD;
                  hormone (FSH) fall within the respective pathology reference range. In the event&#xD;
                  a subject's menopause status has been clearly established (for example, the&#xD;
                  subject indicates she has been amenorrheic for 10 years), but FSH levels are not&#xD;
                  consistent with a post-menopausal condition, determination of subject eligibility&#xD;
                  will be at Investigator's discretion following consultation with the Sponsor.&#xD;
&#xD;
               3. If a male subject, willing to use an effective method of contraception (unless&#xD;
                  anatomically sterile or where abstaining from sexual intercourse is in line with&#xD;
                  the preferred and usual lifestyle of the subject) from first dose until 3 months&#xD;
                  after last dose of IMP.&#xD;
&#xD;
          2. Subject with a body mass index (BMI) of 18-32 kg/m^2. BMI = body weight in kg /&#xD;
             [height in m]^2.&#xD;
&#xD;
          3. Subject with no clinically significant abnormal serum biochemistry, haematology and&#xD;
             urine examination values within 28 days before the first dose of IMP.&#xD;
&#xD;
          4. Subject with negative urinary drugs of abuse screen, determined within 28 days before&#xD;
             the first dose of IMP (a positive alcohol or cotinine result may be repeated at&#xD;
             Investigator's discretion).&#xD;
&#xD;
          5. Subject with negative human immunodeficiency virus (HIV), hepatitis B surface antigen&#xD;
             (Hep B) and hepatitis C virus antibody (Hep C) results.&#xD;
&#xD;
          6. Subject with no clinically significant abnormalities in 12-lead ECG determined after&#xD;
             minimum of 5 minutes in supine position within 28 days before the first dose of IMP.&#xD;
&#xD;
          7. Subject with no clinically significant abnormalities in vital signs (systolic blood&#xD;
             pressure between 90-150 mmHg, diastolic blood pressure (DBP) between 50 and 90 mmHg,&#xD;
             and pulse rate (PR) between 40-110 bpm, measured on the dominant arm after minimum of&#xD;
             5 minutes in supine position) determined within 28 days before first dose of IMP.&#xD;
&#xD;
          8. Subject must be available to complete the study (including post study follow-up) and&#xD;
             comply with study restrictions.&#xD;
&#xD;
          9. Subject must provide written informed consent to participate in the study.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Known hypersensitivity/allergy reaction to varenicline, other cytisine-derivatives or&#xD;
             any of the excipients in the Tabex formulation (lactose, cellulose, talc, magnesium).&#xD;
&#xD;
          2. History of severe hypersensitivity reactions to any other drugs.&#xD;
&#xD;
          3. History of any medical condition (e.g. gastrointestinal, renal or hepatic) or surgical&#xD;
             condition (e.g. cholecystectomy, gastrectomy) that may affect drug pharmacokinetics&#xD;
             (absorption, distribution, metabolism or excretion).&#xD;
&#xD;
          4. Difficulty in donating blood on either arm or known history.&#xD;
&#xD;
          5. History of alcoholism or drug abuse within last 2 years.&#xD;
&#xD;
          6. Regular nicotine intake (e.g., smoking, nicotine patch, nicotine chewing gum or&#xD;
             electronic cigarettes) within previous 3 months and inability to refrain from nicotine&#xD;
             intake from Screening until end of study.&#xD;
&#xD;
          7. Use of prescription or non-prescription drugs, including vitamins, herbal and dietary&#xD;
             supplements within 14 days (or 5 half-lives, whichever is longer) prior to the first&#xD;
             dose of IMP, unless in the opinion of the Investigator the medication will not&#xD;
             interfere with the study procedures or compromise subject safety.&#xD;
&#xD;
          8. Participated in any investigational drug clinical trial within the previous 3 months&#xD;
             or a marketed drug trial within the previous 30 days prior to randomization on Day 1&#xD;
             of Period 1.&#xD;
&#xD;
          9. Donation of 450 mL or more blood or had history of significant blood loss due to any&#xD;
             reason or had plasmapheresis within 3 months before the first dose of IMP.&#xD;
&#xD;
         10. Any special food restrictions that may hinder ability to consume the high fat&#xD;
             breakfast provided during the study; such as lactose intolerance, vegan, low-fat, low&#xD;
             sodium, etc.&#xD;
&#xD;
         11. Any inability or difficulty in fasting.&#xD;
&#xD;
         12. Inability to communicate well with Investigators (i.e., language problem, poor mental&#xD;
             development or impaired cerebral function).&#xD;
&#xD;
         13. Any other condition that the Principal Investigator considers making the subject&#xD;
             unsuitable for this study.&#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>Annelize Koch, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Simbec Research Ltd (Simbec)</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Simbec Research Ltd</name>
      <address>
        <city>Merthyr Tydfil</city>
        <zip>CF11 9AB</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United Kingdom</country>
  </location_countries>
  <verification_date>February 2019</verification_date>
  <study_first_submitted>August 25, 2017</study_first_submitted>
  <study_first_submitted_qc>August 29, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">August 31, 2017</study_first_posted>
  <results_first_submitted>August 27, 2018</results_first_submitted>
  <results_first_submitted_qc>August 27, 2018</results_first_submitted_qc>
  <results_first_posted type="Actual">February 7, 2019</results_first_posted>
  <last_update_submitted>February 6, 2019</last_update_submitted>
  <last_update_submitted_qc>February 6, 2019</last_update_submitted_qc>
  <last_update_posted type="Actual">February 26, 2019</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <patient_data>
    <sharing_ipd>Undecided</sharing_ipd>
  </patient_data>
  <provided_document_section>
    <provided_document>
      <document_type>Study Protocol</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>No</document_has_sap>
      <document_date>May 19, 2017</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/43/NCT03268343/Prot_000.pdf</document_url>
    </provided_document>
    <provided_document>
      <document_type>Statistical Analysis Plan</document_type>
      <document_has_protocol>No</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>October 23, 2017</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/43/NCT03268343/SAP_001.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <group_list>
        <group group_id="P1">
          <title>3 mg Cytisine, Schedule A: Fed Then Fasted</title>
          <description>Period 1: Cytisine (2 x 1.5 mg tablets) administered 30 minutes after the start of a high fat breakfast (fed state).&#xD;
Period 2: Cytisine (2 x 1.5 mg tablets) administered after an overnight fast of at least 10 hours (fasting state).</description>
        </group>
        <group group_id="P2">
          <title>3 mg Cytisine, Schedule B: Fasted Then Fed</title>
          <description>Period 1: Cytisine (2 x 1.5 mg tablets) administered after an overnight fast of at least 10 hours (fasting state).&#xD;
Period 2: Cytisine (2 x 1.5 mg tablets) administered 30 minutes after the start of a high fat breakfast (fed state).</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="12"/>
                <participants group_id="P2" count="12"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="12"/>
                <participants group_id="P2" count="12"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>3 mg Cytisine</title>
          <description>3 mg Cytisine, Schedule A: Fed Then Fasted&#xD;
Period 1: Cytisine (2 x 1.5 mg tablets) administered 30 minutes after the start of a high fat breakfast (fed state).&#xD;
Period 2: Cytisine (2 x 1.5 mg tablets) administered after an overnight fast of at least 10 hours (fasting state).&#xD;
3 mg Cytisine, Schedule B: Fasted Then Fed&#xD;
Period 1: Cytisine (2 x 1.5 mg tablets) administered after an overnight fast of at least 10 hours (fasting state).&#xD;
Period 2: Cytisine (2 x 1.5 mg tablets) administered 30 minutes after the start of a high fat breakfast (fed state).</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" 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="35.1" spread="10.25"/>
                  </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="13"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="11"/>
                  </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>Caucasian</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="23"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Other, Not Specified</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Plasma Cytisine Pharmacokinetics (PK): Maximum Observed Plasma Concentration (Cmax)</title>
        <time_frame>Pre-dose (within 60 minutes of dosing); 15 minutes, 20 minutes, 30 minutes, 45 minutes, 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 4 hours, 6 hours, 8 hours, 12 hours, 14 hours, 16 hours and 24 hours post-dose (+/- 1 minute)</time_frame>
        <population>PK Set: All participants who received doses under both fed and fasted conditions and did not have an occurrence of vomiting which rendered the concentration profile unreliable. (Two participants were excluded for vomiting before twice the median Tmax had been reached following 3 mg cytisine administered in a fed state.)</population>
        <group_list>
          <group group_id="O1">
            <title>3 mg Cytisine, Fed</title>
            <description>Cytisine (2 x 1.5 mg tablets) administered 30 minutes after the start of a high fat breakfast (fed state).</description>
          </group>
          <group group_id="O2">
            <title>3 mg Cytisine, Fasted</title>
            <description>Cytisine (2 x 1.5 mg tablets) administered after an overnight fast of at least 10 hours (fasting state).</description>
          </group>
        </group_list>
        <measure>
          <title>Plasma Cytisine Pharmacokinetics (PK): Maximum Observed Plasma Concentration (Cmax)</title>
          <population>PK Set: All participants who received doses under both fed and fasted conditions and did not have an occurrence of vomiting which rendered the concentration profile unreliable. (Two participants were excluded for vomiting before twice the median Tmax had been reached following 3 mg cytisine administered in a fed state.)</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="22"/>
                <count group_id="O2" value="22"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="22.9" spread="5.44"/>
                    <measurement group_id="O2" value="30.8" spread="7.91"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <param_type>Geometric LS Mean Ratio (%)</param_type>
            <param_value>74.71</param_value>
            <ci_percent>90</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>66.39</ci_lower_limit>
            <ci_upper_limit>84.08</ci_upper_limit>
            <estimate_desc>fed / fasted; results obtained using an ANOVA with fixed effects of treatment, period, sequence and participant (sequence).</estimate_desc>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Plasma Cytisine PK: Total Area Under the Curve From Time Zero to Infinity (AUC0-∞)</title>
        <time_frame>Pre-dose (within 60 minutes of dosing); 15 minutes, 20 minutes, 30 minutes, 45 minutes, 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 4 hours, 6 hours, 8 hours, 12 hours, 14 hours, 16 hours and 24 hours post-dose (+/- 1 minute)</time_frame>
        <population>PK Set: All participants who received doses under both fed and fasted conditions and did not have an occurrence of vomiting which rendered the concentration profile unreliable. (Two participants were excluded for vomiting before twice the median Tmax had been reached following 3 mg cytisine administered in a fed state.)</population>
        <group_list>
          <group group_id="O1">
            <title>3 mg Cytisine, Fed</title>
            <description>Cytisine (2 x 1.5 mg tablets) administered 30 minutes after the start of a high fat breakfast (fed state).</description>
          </group>
          <group group_id="O2">
            <title>3 mg Cytisine, Fasted</title>
            <description>Cytisine (2 x 1.5 mg tablets) administered after an overnight fast of at least 10 hours (fasting state).</description>
          </group>
        </group_list>
        <measure>
          <title>Plasma Cytisine PK: Total Area Under the Curve From Time Zero to Infinity (AUC0-∞)</title>
          <population>PK Set: All participants who received doses under both fed and fasted conditions and did not have an occurrence of vomiting which rendered the concentration profile unreliable. (Two participants were excluded for vomiting before twice the median Tmax had been reached following 3 mg cytisine administered in a fed state.)</population>
          <units>h*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="22"/>
                <count group_id="O2" value="22"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="170" spread="30.3"/>
                    <measurement group_id="O2" value="176" spread="33.1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <param_type>Geometric LS Mean Ratio (%)</param_type>
            <param_value>97.04</param_value>
            <ci_percent>90</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>94.20</ci_lower_limit>
            <ci_upper_limit>99.98</ci_upper_limit>
            <estimate_desc>fed / fasted; results obtained using an ANOVA with fixed effects of treatment, period, sequence and participant (sequence).</estimate_desc>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Plasma Cytisine PK: Time of Occurrence of Cmax (Tmax)</title>
        <time_frame>Pre-dose (within 60 minutes of dosing); 15 minutes, 20 minutes, 30 minutes, 45 minutes, 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 4 hours, 6 hours, 8 hours, 12 hours, 14 hours, 16 hours and 24 hours post-dose (+/- 1 minute)</time_frame>
        <population>PK Set: All participants who received doses under both fed and fasted conditions and did not have an occurrence of vomiting which rendered the concentration profile unreliable. (Two participants were excluded for vomiting before twice the median Tmax had been reached following 3 mg cytisine administered in a fed state.)</population>
        <group_list>
          <group group_id="O1">
            <title>3 mg Cytisine, Fed</title>
            <description>Cytisine (2 x 1.5 mg tablets) administered 30 minutes after the start of a high fat breakfast (fed state).</description>
          </group>
          <group group_id="O2">
            <title>3 mg Cytisine, Fasted</title>
            <description>Cytisine (2 x 1.5 mg tablets) administered after an overnight fast of at least 10 hours (fasting state).</description>
          </group>
        </group_list>
        <measure>
          <title>Plasma Cytisine PK: Time of Occurrence of Cmax (Tmax)</title>
          <population>PK Set: All participants who received doses under both fed and fasted conditions and did not have an occurrence of vomiting which rendered the concentration profile unreliable. (Two participants were excluded for vomiting before twice the median Tmax had been reached following 3 mg cytisine administered in a fed state.)</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="22"/>
                <count group_id="O2" value="22"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2.75" lower_limit="0.500" upper_limit="6.12"/>
                    <measurement group_id="O2" value="0.75" lower_limit="0.333" 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>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>&lt; 0.0001</p_value>
            <method>Wilcoxon Signed-Rank test</method>
            <param_type>Median Difference (Final Values)</param_type>
            <param_value>1.38</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>0.50</ci_lower_limit>
            <ci_upper_limit>2.25</ci_upper_limit>
            <estimate_desc>Hodges-Lehmann method</estimate_desc>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Plasma Cytisine PK: AUC From Time Zero to the Last Sampling Time (AUC0-t)</title>
        <time_frame>Pre-dose (within 60 minutes of dosing); 15 minutes, 20 minutes, 30 minutes, 45 minutes, 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 4 hours, 6 hours, 8 hours, 12 hours, 14 hours, 16 hours and 24 hours post-dose (+/- 1 minute)</time_frame>
        <population>PK Set: All participants who received doses under both fed and fasted conditions and did not have an occurrence of vomiting which rendered the concentration profile unreliable. (Two participants were excluded for vomiting before twice the median Tmax had been reached following 3 mg cytisine administered in a fed state.)</population>
        <group_list>
          <group group_id="O1">
            <title>3 mg Cytisine, Fed</title>
            <description>Cytisine (2 x 1.5 mg tablets) administered 30 minutes after the start of a high fat breakfast (fed state).</description>
          </group>
          <group group_id="O2">
            <title>3 mg Cytisine, Fasted</title>
            <description>Cytisine (2 x 1.5 mg tablets) administered after an overnight fast of at least 10 hours (fasting state).</description>
          </group>
        </group_list>
        <measure>
          <title>Plasma Cytisine PK: AUC From Time Zero to the Last Sampling Time (AUC0-t)</title>
          <population>PK Set: All participants who received doses under both fed and fasted conditions and did not have an occurrence of vomiting which rendered the concentration profile unreliable. (Two participants were excluded for vomiting before twice the median Tmax had been reached following 3 mg cytisine administered in a fed state.)</population>
          <units>h*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="22"/>
                <count group_id="O2" value="22"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="163" spread="29.4"/>
                    <measurement group_id="O2" value="169" spread="33.0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <param_type>Geometric LS Mean Ratio (%)</param_type>
            <param_value>96.52</param_value>
            <ci_percent>90</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>93.30</ci_lower_limit>
            <ci_upper_limit>99.85</ci_upper_limit>
            <estimate_desc>fed / fasted; results obtained using an ANOVA with fixed effects of treatment, period, sequence and participant (sequence).</estimate_desc>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Plasma Cytisine PK: Residual Area, or Percentage of Extrapolated Part for the Calculation of AUC0-∞ (AUC%)</title>
        <time_frame>Pre-dose (within 60 minutes of dosing); 15 minutes, 20 minutes, 30 minutes, 45 minutes, 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 4 hours, 6 hours, 8 hours, 12 hours, 14 hours, 16 hours and 24 hours post-dose (+/- 1 minute)</time_frame>
        <population>PK Set: All participants who received doses under both fed and fasted conditions and did not have an occurrence of vomiting which rendered the concentration profile unreliable. (Two participants were excluded for vomiting before twice the median Tmax had been reached following 3 mg cytisine administered in a fed state.)</population>
        <group_list>
          <group group_id="O1">
            <title>3 mg Cytisine, Fed</title>
            <description>Cytisine (2 x 1.5 mg tablets) administered 30 minutes after the start of a high fat breakfast (fed state).</description>
          </group>
          <group group_id="O2">
            <title>3 mg Cytisine, Fasted</title>
            <description>Cytisine (2 x 1.5 mg tablets) administered after an overnight fast of at least 10 hours (fasting state).</description>
          </group>
        </group_list>
        <measure>
          <title>Plasma Cytisine PK: Residual Area, or Percentage of Extrapolated Part for the Calculation of AUC0-∞ (AUC%)</title>
          <population>PK Set: All participants who received doses under both fed and fasted conditions and did not have an occurrence of vomiting which rendered the concentration profile unreliable. (Two participants were excluded for vomiting before twice the median Tmax had been reached following 3 mg cytisine administered in a fed state.)</population>
          <units>percentage of extrapolated part</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="22"/>
                <count group_id="O2" value="22"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="4.37" spread="1.40"/>
                    <measurement group_id="O2" value="3.85" spread="1.46"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Plasma Cytisine PK: Apparent Terminal Elimination Rate Constant (Lambda z)</title>
        <time_frame>Pre-dose (within 60 minutes of dosing); 15 minutes, 20 minutes, 30 minutes, 45 minutes, 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 4 hours, 6 hours, 8 hours, 12 hours, 14 hours, 16 hours and 24 hours post-dose (+/- 1 minute)</time_frame>
        <population>PK Set: All participants who received doses under both fed and fasted conditions and did not have an occurrence of vomiting which rendered the concentration profile unreliable. (Two participants were excluded for vomiting before twice the median Tmax had been reached following 3 mg cytisine administered in a fed state.)</population>
        <group_list>
          <group group_id="O1">
            <title>3 mg Cytisine, Fed</title>
            <description>Cytisine (2 x 1.5 mg tablets) administered 30 minutes after the start of a high fat breakfast (fed state).</description>
          </group>
          <group group_id="O2">
            <title>3 mg Cytisine, Fasted</title>
            <description>Cytisine (2 x 1.5 mg tablets) administered after an overnight fast of at least 10 hours (fasting state).</description>
          </group>
        </group_list>
        <measure>
          <title>Plasma Cytisine PK: Apparent Terminal Elimination Rate Constant (Lambda z)</title>
          <population>PK Set: All participants who received doses under both fed and fasted conditions and did not have an occurrence of vomiting which rendered the concentration profile unreliable. (Two participants were excluded for vomiting before twice the median Tmax had been reached following 3 mg cytisine administered in a fed state.)</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="22"/>
                <count group_id="O2" value="22"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.154" spread="0.0391"/>
                    <measurement group_id="O2" value="0.156" spread="0.0314"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Plasma Cytisine PK: Apparent Terminal Elimination Half-Life (t1/2)</title>
        <time_frame>Pre-dose (within 60 minutes of dosing); 15 minutes, 20 minutes, 30 minutes, 45 minutes, 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 4 hours, 6 hours, 8 hours, 12 hours, 14 hours, 16 hours and 24 hours post-dose (+/- 1 minute)</time_frame>
        <population>PK Set: All participants who received doses under both fed and fasted conditions and did not have an occurrence of vomiting which rendered the concentration profile unreliable. (Two participants were excluded for vomiting before twice the median Tmax had been reached following 3 mg cytisine administered in a fed state.)</population>
        <group_list>
          <group group_id="O1">
            <title>3 mg Cytisine, Fed</title>
            <description>Cytisine (2 x 1.5 mg tablets) administered 30 minutes after the start of a high fat breakfast (fed state).</description>
          </group>
          <group group_id="O2">
            <title>3 mg Cytisine, Fasted</title>
            <description>Cytisine (2 x 1.5 mg tablets) administered after an overnight fast of at least 10 hours (fasting state).</description>
          </group>
        </group_list>
        <measure>
          <title>Plasma Cytisine PK: Apparent Terminal Elimination Half-Life (t1/2)</title>
          <population>PK Set: All participants who received doses under both fed and fasted conditions and did not have an occurrence of vomiting which rendered the concentration profile unreliable. (Two participants were excluded for vomiting before twice the median Tmax had been reached following 3 mg cytisine administered in a fed state.)</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="22"/>
                <count group_id="O2" value="22"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="4.77" spread="1.16"/>
                    <measurement group_id="O2" value="4.59" spread="0.832"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Urine Cytisine PK: Amount Excreted in Urine Over Time (Ae)</title>
        <time_frame>Pre-dose (within 30 minutes prior to first dose); 0-2 hours, 2-4 hours, 4-8 hours, 8-12 hours and 12-24 hours post-dose</time_frame>
        <population>PK Set: All participants who received doses under both fed and fasted conditions and did not have an occurrence of vomiting which rendered the concentration profile unreliable. (Two participants were excluded for vomiting before twice the median Tmax had been reached following 3 mg cytisine administered in a fed state.)</population>
        <group_list>
          <group group_id="O1">
            <title>3 mg Cytisine, Fed</title>
            <description>Cytisine (2 x 1.5 mg tablets) administered 30 minutes after the start of a high fat breakfast (fed state).</description>
          </group>
          <group group_id="O2">
            <title>3 mg Cytisine, Fasted</title>
            <description>Cytisine (2 x 1.5 mg tablets) administered after an overnight fast of at least 10 hours (fasting state).</description>
          </group>
        </group_list>
        <measure>
          <title>Urine Cytisine PK: Amount Excreted in Urine Over Time (Ae)</title>
          <population>PK Set: All participants who received doses under both fed and fasted conditions and did not have an occurrence of vomiting which rendered the concentration profile unreliable. (Two participants were excluded for vomiting before twice the median Tmax had been reached following 3 mg cytisine administered in a fed state.)</population>
          <units>mg</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="22"/>
                <count group_id="O2" value="22"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2.59" spread="0.407"/>
                    <measurement group_id="O2" value="2.47" spread="0.357"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <param_type>Geometric LS Mean Ratio (%)</param_type>
            <param_value>104.75</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>98.97</ci_lower_limit>
            <ci_upper_limit>110.87</ci_upper_limit>
            <estimate_desc>fed / fasted; results obtained using an ANOVA with fixed effects of treatment, period, sequence and participant (sequence).</estimate_desc>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Urine Cytisine PK: Percentage of Drug Excreted in Urine (Ae%)</title>
        <description>To assess the renal elimination of cytisine via measurement of urinary concentrations of cytisine.</description>
        <time_frame>Pre-dose (within 30 minutes prior to first dose); 0-2 hours, 2-4 hours, 4-8 hours, 8-12 hours and 12-24 hours post-dose</time_frame>
        <population>PK Set: All participants who received doses under both fed and fasted conditions and did not have an occurrence of vomiting which rendered the concentration profile unreliable. (Two participants were excluded for vomiting before twice the median Tmax had been reached following 3 mg cytisine administered in a fed state.)</population>
        <group_list>
          <group group_id="O1">
            <title>3 mg Cytisine, Fed</title>
            <description>Cytisine (2 x 1.5 mg tablets) administered 30 minutes after the start of a high fat breakfast (fed state).</description>
          </group>
          <group group_id="O2">
            <title>3 mg Cytisine, Fasted</title>
            <description>Cytisine (2 x 1.5 mg tablets) administered after an overnight fast of at least 10 hours (fasting state).</description>
          </group>
        </group_list>
        <measure>
          <title>Urine Cytisine PK: Percentage of Drug Excreted in Urine (Ae%)</title>
          <description>To assess the renal elimination of cytisine via measurement of urinary concentrations of cytisine.</description>
          <population>PK Set: All participants who received doses under both fed and fasted conditions and did not have an occurrence of vomiting which rendered the concentration profile unreliable. (Two participants were excluded for vomiting before twice the median Tmax had been reached following 3 mg cytisine administered in a fed state.)</population>
          <units>percentage of drug excreted</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="22"/>
                <count group_id="O2" value="22"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="86.5" spread="13.6"/>
                    <measurement group_id="O2" value="82.4" spread="11.9"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs, and Discontinuation of Study Drug Due to AEs, by Severity and Relationship</title>
        <description>An adverse event (AE) is defined as any untoward medical occurrence which does not necessarily have a causal relationship with the treatment. TEAEs are defined as AEs not present prior to first administration of investigational product, or AEs present before first administration of study drug that worsen after the subject receives the first dose of study drug. A serious adverse event (SAE) is defined as an AE that: results in death; is life-threatening; requires hospitalization or prolongs existing inpatient's hospitalization; results in persistent or significant disability or incapacity; results in a congenital abnormality or birth defect; is an important medical event which requires medical intervention to prevent any of the above outcomes. Event severity was categorized as mild, moderate, or severe. Relationship of event to study drug was categorized as definite, probably, possible, unlikely, not related, or not applicable (N/A).</description>
        <time_frame>Day -1 to Day 7 plus 6-8 days (post-study follow-up)</time_frame>
        <population>Safety Analysis Set: all participants who received at least one dose of cytisine.</population>
        <group_list>
          <group group_id="O1">
            <title>3 mg Cytisine, Fed</title>
            <description>Cytisine (2 x 1.5 mg tablets) administered 30 minutes after the start of a high fat breakfast (fed state).</description>
          </group>
          <group group_id="O2">
            <title>3 mg Cytisine, Fasted</title>
            <description>Cytisine (2 x 1.5 mg tablets) administered after an overnight fast of at least 10 hours (fasting state).</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs, and Discontinuation of Study Drug Due to AEs, by Severity and Relationship</title>
          <description>An adverse event (AE) is defined as any untoward medical occurrence which does not necessarily have a causal relationship with the treatment. TEAEs are defined as AEs not present prior to first administration of investigational product, or AEs present before first administration of study drug that worsen after the subject receives the first dose of study drug. A serious adverse event (SAE) is defined as an AE that: results in death; is life-threatening; requires hospitalization or prolongs existing inpatient's hospitalization; results in persistent or significant disability or incapacity; results in a congenital abnormality or birth defect; is an important medical event which requires medical intervention to prevent any of the above outcomes. Event severity was categorized as mild, moderate, or severe. Relationship of event to study drug was categorized as definite, probably, possible, unlikely, not related, or not applicable (N/A).</description>
          <population>Safety Analysis Set: all participants who received at least one dose of cytisine.</population>
          <units>participants</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="24"/>
                <count group_id="O2" value="24"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>≥ 1 TEAE</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="6"/>
                    <measurement group_id="O2" value="7"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>≥ 1 Serious TEAE</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>≥ 1 TEAE Leading to Withdrawal of Study Drug</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>≥ 1 Mild TEAE</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="6"/>
                    <measurement group_id="O2" value="7"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>≥ 1 Moderate TEAE</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>≥ 1 Severe TEAE</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>≥ 1 TEAE Definitely Related to Study Drug</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>≥ 1 TEAE Probably Related to Study Drug</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1"/>
                    <measurement group_id="O2" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>≥ 1 TEAE Possibly Related to Study Drug</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="3"/>
                    <measurement group_id="O2" value="5"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>≥ 1 TEAE Unlikely Related to Study Drug</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1"/>
                    <measurement group_id="O2" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>≥ 1 TEAE Not Related to Study Drug</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>≥ 1 TEAE Relationship to Study Drug = N/A</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1"/>
                    <measurement group_id="O2" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>Day -1 to Day 7 plus 6-8 days (post-study follow-up)</time_frame>
      <desc>For each reporting group, a participant was counted only once per system organ class and preferred term. Consequently, if the same preferred term was observed for a participant in both fed and fasted states, the participant was counted only once in the &quot;3 mg Cytisine, Overall&quot; reporting group for that preferred term.</desc>
      <group_list>
        <group group_id="E1">
          <title>3 mg Cytisine, Fed</title>
          <description>Cytisine (2 x 1.5 mg tablets) administered 30 minutes after the start of a high fat breakfast (fed state).</description>
        </group>
        <group group_id="E2">
          <title>3 mg Cytisine, Fasted</title>
          <description>Cytisine (2 x 1.5 mg tablets) administered after an overnight fast of at least 10 hours (fasting state).</description>
        </group>
        <group group_id="E3">
          <title>3 mg Cytisine, Overall</title>
          <description>Cytisine (2 x 1.5 mg tablets) administered 30 minutes after the start of a high fat breakfast (fed state).&#xD;
Cytisine (2 x 1.5 mg tablets) administered after an overnight fast of at least 10 hours (fasting state).</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="24"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="24"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="24"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>0</frequency_threshold>
        <default_vocab>MedDRA 20.0</default_vocab>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="6" subjects_at_risk="24"/>
                <counts group_id="E2" subjects_affected="7" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="10" subjects_at_risk="24"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Abdominal pain lower</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="24"/>
              </event>
              <event>
                <sub_title>Nausea</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="24"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="24"/>
              </event>
              <event>
                <sub_title>Vomiting</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="24"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="3" subjects_at_risk="24"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Feeling hot</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="24"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Rhinitis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="24"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="24"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Dizziness</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="24"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="4" subjects_at_risk="24"/>
              </event>
              <event>
                <sub_title>Headache</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="24"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="3" subjects_at_risk="24"/>
              </event>
              <event>
                <sub_title>Hypoaesthesia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="24"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="24"/>
              </event>
              <event>
                <sub_title>Somnolence</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="24"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Skin and subcutaneous tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Cold sweat</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="24"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="24"/>
              </event>
              <event>
                <sub_title>Erythema</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="24"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Surgical and medical procedures</title>
            <event_list>
              <event>
                <sub_title>Tooth repair</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="24"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="24"/>
              </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>Principal Investigators are bound by requirements outlined in their individual clinical trial agreements with regard to publication of trial results.</restrictive_agreement>
    </certain_agreements>
    <point_of_contact>
      <name_or_title>Daniel Cain, Senior Director Clinical Research</name_or_title>
      <organization>Achieve Life Sciences</organization>
      <phone>425.686.1546</phone>
      <email>dcain@achievelifesciences.com</email>
    </point_of_contact>
  </clinical_results>
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03268343
org study id: ACH-CYT-01
secondary id: 2017-001562-19
nct id: NCT03268343
lead sponsor: 
has dmc: No
is fda regulated drug: Yes
is fda regulated device: No
This will be an open-label, randomised, 2-period, single-dose crossover study to determine
      the comparative bioavailability of cytisine following single-dose administration in healthy
      male and female subjects under fed and fasted conditions.

      The study will be comprised of a pre-study screen, followed by 2 treatment periods (1 and 2)
      and a post-study follow-up.
allocation: Randomized
intervention model: Crossover Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Plasma Cytisine Pharmacokinetics (PK): Maximum Observed Plasma Concentration (Cmax)
time frame: Pre-dose (within 60 minutes of dosing); 15 minutes, 20 minutes, 30 minutes, 45 minutes, 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 4 hours, 6 hours, 8 hours, 12 hours, 14 hours, 16 hours and 24 hours post-dose (+/- 1 minute)
measure: Plasma Cytisine PK: Total Area Under the Curve From Time Zero to Infinity (AUC0-∞)
time frame: Pre-dose (within 60 minutes of dosing); 15 minutes, 20 minutes, 30 minutes, 45 minutes, 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 4 hours, 6 hours, 8 hours, 12 hours, 14 hours, 16 hours and 24 hours post-dose (+/- 1 minute)
measure: Plasma Cytisine PK: Time of Occurrence of Cmax (Tmax)
time frame: Pre-dose (within 60 minutes of dosing); 15 minutes, 20 minutes, 30 minutes, 45 minutes, 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 4 hours, 6 hours, 8 hours, 12 hours, 14 hours, 16 hours and 24 hours post-dose (+/- 1 minute)
measure: Plasma Cytisine PK: AUC From Time Zero to the Last Sampling Time (AUC0-t)
time frame: Pre-dose (within 60 minutes of dosing); 15 minutes, 20 minutes, 30 minutes, 45 minutes, 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 4 hours, 6 hours, 8 hours, 12 hours, 14 hours, 16 hours and 24 hours post-dose (+/- 1 minute)
measure: Plasma Cytisine PK: Residual Area, or Percentage of Extrapolated Part for the Calculation of AUC0-∞ (AUC%)
time frame: Pre-dose (within 60 minutes of dosing); 15 minutes, 20 minutes, 30 minutes, 45 minutes, 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 4 hours, 6 hours, 8 hours, 12 hours, 14 hours, 16 hours and 24 hours post-dose (+/- 1 minute)
measure: Plasma Cytisine PK: Apparent Terminal Elimination Rate Constant (Lambda z)
time frame: Pre-dose (within 60 minutes of dosing); 15 minutes, 20 minutes, 30 minutes, 45 minutes, 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 4 hours, 6 hours, 8 hours, 12 hours, 14 hours, 16 hours and 24 hours post-dose (+/- 1 minute)
measure: Plasma Cytisine PK: Apparent Terminal Elimination Half-Life (t1/2)
time frame: Pre-dose (within 60 minutes of dosing); 15 minutes, 20 minutes, 30 minutes, 45 minutes, 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 4 hours, 6 hours, 8 hours, 12 hours, 14 hours, 16 hours and 24 hours post-dose (+/- 1 minute)
measure: Urine Cytisine PK: Amount Excreted in Urine Over Time (Ae)
time frame: Pre-dose (within 30 minutes prior to first dose); 0-2 hours, 2-4 hours, 4-8 hours, 8-12 hours and 12-24 hours post-dose
measure: Urine Cytisine PK: Percentage of Drug Excreted in Urine (Ae%)
time frame: Pre-dose (within 30 minutes prior to first dose); 0-2 hours, 2-4 hours, 4-8 hours, 8-12 hours and 12-24 hours post-dose
description: To assess the renal elimination of cytisine via measurement of urinary concentrations of cytisine.
measure: Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs, and Discontinuation of Study Drug Due to AEs, by Severity and Relationship
time frame: Day -1 to Day 7 plus 6-8 days (post-study follow-up)
description: An adverse event (AE) is defined as any untoward medical occurrence which does not necessarily have a causal relationship with the treatment. TEAEs are defined as AEs not present prior to first administration of investigational product, or AEs present before first administration of study drug that worsen after the subject receives the first dose of study drug. A serious adverse event (SAE) is defined as an AE that: results in death; is life-threatening; requires hospitalization or prolongs existing inpatient's hospitalization; results in persistent or significant disability or incapacity; results in a congenital abnormality or birth defect; is an important medical event which requires medical intervention to prevent any of the above outcomes. Event severity was categorized as mild, moderate, or severe. Relationship of event to study drug was categorized as definite, probably, possible, unlikely, not related, or not applicable (N/A).
arm group label: Schedule A: Fed Then Fasted
arm group type: Experimental
description: Schedule A (12 subjects):
Period 1: Cytisine (2 x 1.5 mg tablets) will be administered 30 minutes after the start of a high fat breakfast (fed state).
Period 2: Cytisine (2 x 1.5 mg tablets) will be administered after an overnight fast of at least 10 hours (fasting state).
arm group label: Schedule B: Fasted Then Fed
arm group type: Experimental
description: Schedule B (12 subjects):
Period 1: Cytisine (2 x 1.5 mg tablets) will be administered after an overnight fast of at least 10 hours (fasting state).
Period 2: Cytisine (2 x 1.5 mg tablets) will be administered 30 minutes after the start of a high fat breakfast (fed state).
intervention type: Drug
intervention name: Cytisine
description: Cytisine 1.5 mg Film-Coated Tablets
arm group label: Schedule A: Fed Then Fasted
arm group label: Schedule B: Fasted Then Fed
other name: Tabex
criteria: 
gender: All
minimum age: 18 Years
maximum age: 55 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Annelize Koch, MD
role: Principal Investigator
affiliation: Simbec Research Ltd (Simbec)
facility: 
country: United Kingdom
responsible party type: Sponsor
sharing ipd: Undecided
provided document: 
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 