<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/NCT02265224</url>
  </required_header>
  <id_info>
    <org_study_id>Z7169J02</org_study_id>
    <secondary_id>CRO-PK-14-286</secondary_id>
    <nct_id>NCT02265224</nct_id>
  </id_info>
  <brief_title>Bioequivalence Study of Two Different Formulations of N-acetyl-cysteine (NAC)</brief_title>
  <official_title>Comparative Bioavailability Study of N-acetyl-cysteine (NAC) 600 mg Uncoated Tablets vs. NAC 600 mg Film-coated Tablets in Healthy Male and Female Volunteers</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Zambon SpA</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Zambon SpA</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      Study primary Objective:&#xD;
&#xD;
      - To evaluate the bioequivalent rate (Cmax) and extent (AUC0-t) of absorption of&#xD;
      N-acetyl-cysteine 600 mg uncoated tablets vs. N-acetyl-cysteine 600 mg film-coated tablets&#xD;
      (NAC) in healthy male and female volunteers.&#xD;
&#xD;
      Study secondary objectives:&#xD;
&#xD;
        -  To describe the pharmacokinetic (PK) profile of NAC in plasma after single dose&#xD;
           administration of NAC 600 mg uncoated tablets vs. NAC 600 mg film-coated tablets;&#xD;
&#xD;
        -  to collect safety and tolerability data after single dose administration of NAC 600 mg&#xD;
           uncoated tablets vs. NAC 600 mg film-coated tablets.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This is single centre, single dose, open, randomised, cross-over, two-stage bioequivalence&#xD;
      study to compare two different oral formulations of NAC.&#xD;
&#xD;
      The study has been conducted in healthy volunteers of both genders, in one single dose of&#xD;
      both formulations.&#xD;
&#xD;
      The initial 48 subjects were sufficient to satisfy the study objectives on the basis of the&#xD;
      ad interim preliminary bioequivalence test. The study was then considered as concluded and&#xD;
      the second stage did not take place.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date>September 2014</start_date>
  <completion_date type="Actual">September 2014</completion_date>
  <primary_completion_date type="Actual">September 2014</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>Cmax of NAC After Single Dose Administration of Test and Reference</measure>
    <time_frame>0-24h (5,15, 30, 45, 60, 75, 90 min and 2, 3, 4, 6, 8, 12, 16 and 24 h postdose)</time_frame>
    <description>Cmax is the maximum concentration level of the drug reached in plasma.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>AUC0-t of NAC After Single Dose Administration of Test and Reference</measure>
    <time_frame>0-24h (5,15, 30, 45, 60, 75, 90 min and 2, 3, 4, 6, 8, 12, 16 and 24 h postdose)</time_frame>
    <description>AUC0-t is the Area under the concentration-time curve from time zero to time t, calculated with the linear trapezoidal summation from time 0 to the last measurable data point.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>AUC0-∞ of NAC After Single Dose Administration of Test and Reference</measure>
    <time_frame>0-24h (5,15, 30, 45, 60, 75, 90 min and 2, 3, 4, 6, 8, 12, 16 and 24 h postdose)</time_frame>
    <description>AUC0-∞ is the area under the concentration-time curve extrapolated to infinity, calculated, if feasible, as AUC0-t + Ct/λz, where Ct is the last measurable drug concentration.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Tmax of NAC After Single Dose Administration of Test and Reference</measure>
    <time_frame>0-24h (5,15, 30, 45, 60, 75, 90 min and 2, 3, 4, 6, 8, 12, 16 and 24 h postdose)</time_frame>
    <description>time to achieve the maximum concentration level of the drug in plasma.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>t1/2 of NAC After Single Dose Administration of Test and Reference</measure>
    <time_frame>0-24h (5,15, 30, 45, 60, 75, 90 min and 2, 3, 4, 6, 8, 12, 16 and 24 h postdose)</time_frame>
    <description>Half-life (t1/2) is the time to halve the plasma concentration level of the drug.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Lambda Zeta of NAC After Single Dose Administration of Test and Reference</measure>
    <time_frame>0-24h (5,15, 30, 45, 60, 75, 90 min and 2, 3, 4, 6, 8, 12, 16 and 24 h postdose)</time_frame>
    <description>Lambda zeta is the terminal elimination rate constant. Individual estimate of the terminal elimination rate constant can be calculated using log-linear regression of the terminal portions of the plasma concentration-versus-time curves.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Frel of NAC After Single Dose Administration of Test and Reference</measure>
    <time_frame>0-24h (5,15, 30, 45, 60, 75, 90 min and 2, 3, 4, 6, 8, 12, 16 and 24 h postdose)</time_frame>
    <description>Frel is the relative bioavailability, calculated as ratio AUC0-t (test)/ AUC0-t (reference)</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">48</enrollment>
  <condition>no Condition</condition>
  <arm_group>
    <arm_group_label>Test - Reference</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>N-acetylcysteine (NAC) 600 mg uncoated tablet (single dose) followed by NAC 600 mg film-coated tablet (single dose)</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Reference - Test</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>N-acetylcysteine (NAC) 600 mg film-coated tablet (single dose) followed by NAC 600 mg uncoated tablet (single dose)</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>N-acetylcysteine</intervention_name>
    <description>The product was administered according to the randomisation list and cross-over design, with 150 mL of still mineral water under fasting conditions on study day 1 of periods 1 or 2 at 8:00±1 h.</description>
    <arm_group_label>Reference - Test</arm_group_label>
    <arm_group_label>Test - Reference</arm_group_label>
    <other_name>Fluimucil uncoated tablets</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Informed consent: signed written informed consent before inclusion in the study&#xD;
&#xD;
          2. Sex and age: males and females,18-55 years old, inclusive&#xD;
&#xD;
          3. Body Mass Index (BMI): 18.5-30 kg/m2, inclusive&#xD;
&#xD;
          4. Vital signs: systolic blood pressure (SBP) 100-139 mmHg, diastolic blood pressure&#xD;
             (DBP) 50-89 mmHg, heart rate (HR) 50-90 bpm, measured after 5 min of rest in the&#xD;
             sitting position&#xD;
&#xD;
          5. Full comprehension: ability to comprehend the full nature and purpose of the study,&#xD;
             including possible risks and side effects; ability to co-operate with the investigator&#xD;
             and to comply with the requirements of the entire study&#xD;
&#xD;
          6. Contraception and fertility (females only): females of child-bearing potential and&#xD;
             with an active sexual life must be using at least one of the following reliable&#xD;
             methods of contraception:&#xD;
&#xD;
               -  Hormonal oral, implantable, transdermal, or injectable contraceptives for at&#xD;
                  least 2 months before the screening visit&#xD;
&#xD;
               -  A non-hormonal intrauterine device or female condom with spermicide or&#xD;
                  contraceptive sponge with spermicide or diaphragm with spermicide or cervical cap&#xD;
                  with spermicide for at least 2 months before the screening visit&#xD;
&#xD;
               -  A male sexual partner who agrees to use a male condom with spermicide&#xD;
&#xD;
               -  A sterile sexual partner Female participants of non-child-bearing potential or in&#xD;
                  post-menopausal status for at least 1 year will be admitted.&#xD;
&#xD;
        For all female subjects, pregnancy test result must be negative at screening (serum β-HCG&#xD;
        test) and day -1 (urine test).&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Electrocardiogram (ECG 12-leads, supine position): clinically significant&#xD;
             abnormalities&#xD;
&#xD;
          2. Physical findings: clinically significant abnormal physical findings which could&#xD;
             interfere with the objectives of the study&#xD;
&#xD;
          3. Laboratory analyses: clinically significant abnormal laboratory values indicative of&#xD;
             physical illness&#xD;
&#xD;
          4. Allergy: ascertained or presumptive hypersensitivity to the active principle and/or&#xD;
             formulations' ingredients; history of anaphylaxis to drugs or allergic reactions in&#xD;
             general, which the investigator considers may affect the outcome of the study&#xD;
&#xD;
          5. Diseases: significant history of renal, hepatic, gastrointestinal, cardiovascular,&#xD;
             respiratory, skin, haematological, endocrine or neurological diseases that may&#xD;
             interfere with the aim of the study&#xD;
&#xD;
          6. Medications: medications, including over the counter (OTC) medications and herbal&#xD;
             remedies for 2 weeks before the start of the study. Hormonal contraceptives for&#xD;
             females will be allowed&#xD;
&#xD;
          7. Investigative drug studies: participation in the evaluation of any investigational&#xD;
             product for 3 months before this study. The 3-month interval is calculated as the time&#xD;
             between the first calendar day of the month that follows the last visit of the&#xD;
             previous study and the first day of the present study&#xD;
&#xD;
          8. Blood donation: blood donations for 3 months before this study&#xD;
&#xD;
          9. Drug, alcohol, caffeine, tobacco: history of drug, alcohol [&gt;1 drink/day for females&#xD;
             and &gt;2 drinks/day for males, defined according to the USDA Dietary Guidelines 2010],&#xD;
             caffeine (&gt;5 cups coffee/tea/day) or tobacco abuse (≥6 cigarettes/day)&#xD;
&#xD;
         10. Drug test: positive result at the drug test at screening or day-1&#xD;
&#xD;
         11. Alcohol test: positive alcohol breath test at day -1&#xD;
&#xD;
         12. Diet: abnormal diets (&lt;1600 or &gt;3500 kcal/day) or substantial changes in eating habits&#xD;
             in the 4 weeks before this study; vegetarians&#xD;
&#xD;
         13. Pregnancy (females only): positive or missing pregnancy test at screening or day -1,&#xD;
             pregnant or lactating women&#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>Milko Radicioni, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Cross Research SA</affiliation>
  </overall_official>
  <verification_date>October 2021</verification_date>
  <study_first_submitted>October 3, 2014</study_first_submitted>
  <study_first_submitted_qc>October 9, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">October 15, 2014</study_first_posted>
  <results_first_submitted>October 6, 2021</results_first_submitted>
  <results_first_submitted_qc>October 6, 2021</results_first_submitted_qc>
  <results_first_posted type="Actual">November 5, 2021</results_first_posted>
  <last_update_submitted>October 6, 2021</last_update_submitted>
  <last_update_submitted_qc>October 6, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">November 5, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>healthy volunteers</keyword>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Acetylcysteine</mesh_term>
    <mesh_term>N-monoacetylcystine</mesh_term>
  </intervention_browse>

  <clinical_results>

    <participant_flow>
      <recruitment_details>48 healthy subjects were included in the study, as planned, and received test and reference treatment according to the cross-over design.</recruitment_details>
      <pre_assignment_details>Subjects were assigned to a sequence of treatments (TR or RT) according to the randomisation list. Randomisation number was given to the subjects on study day -1, Period 1, and was used to assign the treatment sequence according to the randomisation list.&#xD;
The randomisation list was computer-generated by the Contract Research Organisation (CRO) Biometry Unit, using the PLAN procedure of SAS® version 9.3 (TS1M1) (24). The randomisation list was supplied to the Phase I Unit before study start.</pre_assignment_details>
      <group_list>
        <group group_id="P1">
          <title>Enrolled Subjects Set</title>
          <description>According to the crossover design, all the enrolled subjects received both NAC formulations based on the randomization schedule.Two single doses of 600 mg of NAC (one with test and one with reference formulation) were administered to each volunteer in two subsequent study periods (morning of day 1), separated by a wash-out interval of at least 5 days.</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="48"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="48"/>
              </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>
      <population>Enrolled set: All subjects included in the interventional phase of the study. The enrolment was performed through randomised allocation to a treatment sequence.</population>
      <group_list>
        <group group_id="B1">
          <title>Enrolled Subjects Set</title>
          <description>According to the crossover design, all the enrolled subjects received both NAC formulations based on the randomization schedule. Two single doses of 600 mg of NAC (one with test and one with reference formulation) were administered to each volunteer in two subsequent study periods (morning of day 1), separated by a wash-out interval of at least 5 days.</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="48"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>&lt;=18 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Between 18 and 65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="48"/>
                  </measurement_list>
                </category>
                <category>
                  <title>&gt;=65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <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="42.6" spread="8.6"/>
                  </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="25"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="23"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Race (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>American Indian or Alaska Native</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Asian</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Native Hawaiian or Other Pacific Islander</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Black or African American</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>White</title>
                  <measurement_list>
                    <measurement group_id="B1" value="47"/>
                  </measurement_list>
                </category>
                <category>
                  <title>More than one race</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Region of Enrollment</title>
          <units>participants</units>
          <param>Number</param>
          <class_list>
            <class>
              <title>Switzerland</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="48"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Cmax of NAC After Single Dose Administration of Test and Reference</title>
        <description>Cmax is the maximum concentration level of the drug reached in plasma.</description>
        <time_frame>0-24h (5,15, 30, 45, 60, 75, 90 min and 2, 3, 4, 6, 8, 12, 16 and 24 h postdose)</time_frame>
        <population>PK set: all randomised subjects who fulfilled the study protocol requirements in terms of investigational medicinal product intake and had evaluable PK data readouts for the planned treatment comparisons, with no major deviations that could affect the PK results.</population>
        <group_list>
          <group group_id="O1">
            <title>Test</title>
            <description>N-acetylcysteine (NAC) 600 mg uncoated tablet (single dose). The product was administered according to the randomisation list and cross-over design, with 150 mL of still mineral water under fasting conditions on study day 1 of periods 1 or 2 at 8:00±1 h.</description>
          </group>
          <group group_id="O2">
            <title>Reference</title>
            <description>N-acetylcysteine (NAC) 600 mg film-coated tablet (single dose). The product was administered according to the randomisation list and cross-over design, with 150 mL of still mineral water under fasting conditions on study day 1 of periods 1 or 2 at 8:00±1 h.</description>
          </group>
        </group_list>
        <measure>
          <title>Cmax of NAC After Single Dose Administration of Test and Reference</title>
          <description>Cmax is the maximum concentration level of the drug reached in plasma.</description>
          <population>PK set: all randomised subjects who fulfilled the study protocol requirements in terms of investigational medicinal product intake and had evaluable PK data readouts for the planned treatment comparisons, with no major deviations that could affect the PK results.</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="48"/>
                <count group_id="O2" value="48"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2804.38" spread="899.47"/>
                    <measurement group_id="O2" value="3215.63" spread="1382.02"/>
                  </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>Equivalence</non_inferiority_type>
            <non_inferiority_desc>The statistical analysis took into account treatment, period, sequence and subject (sequence) as sources of variation. Acceptance criterion for bioequivalence was that the 94.12% confidence interval for the ratio between test and reference of the geometric means of the parameters under consideration fell within the 80.00-125.00% range, according to the current guidelines for bioequivalence studies and to the Pocock α spending function.</non_inferiority_desc>
            <p_value>0.0136</p_value>
            <p_value_desc>p value for treatment effect</p_value_desc>
            <method>ANOVA</method>
            <param_type>Geometric means ratio</param_type>
            <param_value>89.81</param_value>
            <ci_percent>94.12</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>82.82</ci_lower_limit>
            <ci_upper_limit>97.40</ci_upper_limit>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>AUC0-t of NAC After Single Dose Administration of Test and Reference</title>
        <description>AUC0-t is the Area under the concentration-time curve from time zero to time t, calculated with the linear trapezoidal summation from time 0 to the last measurable data point.</description>
        <time_frame>0-24h (5,15, 30, 45, 60, 75, 90 min and 2, 3, 4, 6, 8, 12, 16 and 24 h postdose)</time_frame>
        <population>PK set: all randomised subjects who fulfilled the study protocol requirements in terms of investigational medicinal product intake and had evaluable PK data readouts for the planned treatment comparisons, with no major deviations that could affect the PK results.</population>
        <group_list>
          <group group_id="O1">
            <title>Test</title>
            <description>N-acetylcysteine (NAC) 600 mg uncoated tablet (single dose). The product was administered according to the randomisation list and cross-over design, with 150 mL of still mineral water under fasting conditions on study day 1 of periods 1 or 2 at 8:00±1 h.</description>
          </group>
          <group group_id="O2">
            <title>Reference</title>
            <description>N-acetylcysteine (NAC) 600 mg film-coated tablet (single dose). The product was administered according to the randomisation list and cross-over design, with 150 mL of still mineral water under fasting conditions on study day 1 of periods 1 or 2 at 8:00±1 h.</description>
          </group>
        </group_list>
        <measure>
          <title>AUC0-t of NAC After Single Dose Administration of Test and Reference</title>
          <description>AUC0-t is the Area under the concentration-time curve from time zero to time t, calculated with the linear trapezoidal summation from time 0 to the last measurable data point.</description>
          <population>PK set: all randomised subjects who fulfilled the study protocol requirements in terms of investigational medicinal product intake and had evaluable PK data readouts for the planned treatment comparisons, with no major deviations that could affect the PK results.</population>
          <units>ng/mL*h</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="48"/>
                <count group_id="O2" value="48"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="10637.87" spread="3100.94"/>
                    <measurement group_id="O2" value="11773.11" spread="3775.43"/>
                  </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>Equivalence</non_inferiority_type>
            <non_inferiority_desc>The statistical analysis took into account treatment, period, sequence and subject (sequence) as sources of variation. Acceptance criterion for bioequivalence was that the 94.12% confidence interval for the ratio between test and reference of the geometric means of the parameters under consideration fell within the 80.00-125.00% range, according to the current guidelines for bioequivalence studies and to the Pocock α spending function.</non_inferiority_desc>
            <p_value>0.0047</p_value>
            <method>ANOVA</method>
            <method_desc>p value for treatment effect</method_desc>
            <param_type>Geometric means ratio</param_type>
            <param_value>90.79</param_value>
            <ci_percent>94.12</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>85.25</ci_lower_limit>
            <ci_upper_limit>96.69</ci_upper_limit>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>AUC0-∞ of NAC After Single Dose Administration of Test and Reference</title>
        <description>AUC0-∞ is the area under the concentration-time curve extrapolated to infinity, calculated, if feasible, as AUC0-t + Ct/λz, where Ct is the last measurable drug concentration.</description>
        <time_frame>0-24h (5,15, 30, 45, 60, 75, 90 min and 2, 3, 4, 6, 8, 12, 16 and 24 h postdose)</time_frame>
        <population>PK set: all randomised subjects who fulfilled the study protocol requirements in terms of investigational medicinal product intake and had evaluable PK data readouts for the planned treatment comparisons, with no major deviations that could affect the PK results.</population>
        <group_list>
          <group group_id="O1">
            <title>Test</title>
            <description>N-acetylcysteine (NAC) 600 mg uncoated tablet (single dose). The product was administered according to the randomisation list and cross-over design, with 150 mL of still mineral water under fasting conditions on study day 1 of periods 1 or 2 at 8:00±1 h.</description>
          </group>
          <group group_id="O2">
            <title>Reference</title>
            <description>N-acetylcysteine (NAC) 600 mg film-coated tablet (single dose). The product was administered according to the randomisation list and cross-over design, with 150 mL of still mineral water under fasting conditions on study day 1 of periods 1 or 2 at 8:00±1 h.</description>
          </group>
        </group_list>
        <measure>
          <title>AUC0-∞ of NAC After Single Dose Administration of Test and Reference</title>
          <description>AUC0-∞ is the area under the concentration-time curve extrapolated to infinity, calculated, if feasible, as AUC0-t + Ct/λz, where Ct is the last measurable drug concentration.</description>
          <population>PK set: all randomised subjects who fulfilled the study protocol requirements in terms of investigational medicinal product intake and had evaluable PK data readouts for the planned treatment comparisons, with no major deviations that could affect the PK results.</population>
          <units>ng/mL*h</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="48"/>
                <count group_id="O2" value="48"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="12586.17" spread="3577.24"/>
                    <measurement group_id="O2" value="13739.43" spread="4190.59"/>
                  </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>Equivalence</non_inferiority_type>
            <non_inferiority_desc>The statistical analysis took into account treatment, period, sequence and subject (sequence) as sources of variation. Acceptance criterion for bioequivalence was that the 94.12% confidence interval for the ratio between test and reference of the geometric means of the parameters under consideration fell within the 80.00-125.00% range, according to the current guidelines for bioequivalence studies and to the Pocock α spending function.</non_inferiority_desc>
            <p_value>0.0095</p_value>
            <p_value_desc>p value for treatment effect</p_value_desc>
            <method>ANOVA</method>
            <param_type>Geometric means ratio</param_type>
            <param_value>91.86</param_value>
            <ci_percent>94.12</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>86.45</ci_lower_limit>
            <ci_upper_limit>97.61</ci_upper_limit>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Tmax of NAC After Single Dose Administration of Test and Reference</title>
        <description>time to achieve the maximum concentration level of the drug in plasma.</description>
        <time_frame>0-24h (5,15, 30, 45, 60, 75, 90 min and 2, 3, 4, 6, 8, 12, 16 and 24 h postdose)</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Test</title>
            <description>N-acetylcysteine (NAC) 600 mg uncoated tablet (single dose). The product was administered according to the randomisation list and cross-over design, with 150 mL of still mineral water under fasting conditions on study day 1 of periods 1 or 2 at 8:00±1 h.</description>
          </group>
          <group group_id="O2">
            <title>Reference</title>
            <description>N-acetylcysteine (NAC) 600 mg film-coated tablet (single dose). The product was administered according to the randomisation list and cross-over design, with 150 mL of still mineral water under fasting conditions on study day 1 of periods 1 or 2 at 8:00±1 h.</description>
          </group>
        </group_list>
        <measure>
          <title>Tmax of NAC After Single Dose Administration of Test and Reference</title>
          <description>time to achieve the maximum concentration level of the drug in plasma.</description>
          <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="48"/>
                <count group_id="O2" value="48"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1.00" lower_limit="0.50" upper_limit="3.00"/>
                    <measurement group_id="O2" value="1.00" 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>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Equivalence</non_inferiority_type>
            <non_inferiority_desc>The statistical analysis took into account treatment, period, sequence and subject (sequence) as sources of variation. Acceptance criterion for bioequivalence was that the 94.12% confidence interval for the ratio between test and reference of the geometric means of the parameters under consideration fell within the 80.00-125.00% range, according to the current guidelines for bioequivalence studies and to the Pocock α spending function.</non_inferiority_desc>
            <p_value>0.5050</p_value>
            <method>Friedman test</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>t1/2 of NAC After Single Dose Administration of Test and Reference</title>
        <description>Half-life (t1/2) is the time to halve the plasma concentration level of the drug.</description>
        <time_frame>0-24h (5,15, 30, 45, 60, 75, 90 min and 2, 3, 4, 6, 8, 12, 16 and 24 h postdose)</time_frame>
        <population>PK set: all randomised subjects who fulfilled the study protocol requirements in terms of investigational medicinal product intake and had evaluable PK data readouts for the planned treatment comparisons, with no major deviations that could affect the PK results.</population>
        <group_list>
          <group group_id="O1">
            <title>Test</title>
            <description>N-acetylcysteine (NAC) 600 mg uncoated tablet (single dose). The product was administered according to the randomisation list and cross-over design, with 150 mL of still mineral water under fasting conditions on study day 1 of periods 1 or 2 at 8:00±1 h.</description>
          </group>
          <group group_id="O2">
            <title>Reference</title>
            <description>N-acetylcysteine (NAC) 600 mg film-coated tablet (single dose). The product was administered according to the randomisation list and cross-over design, with 150 mL of still mineral water under fasting conditions on study day 1 of periods 1 or 2 at 8:00±1 h.</description>
          </group>
        </group_list>
        <measure>
          <title>t1/2 of NAC After Single Dose Administration of Test and Reference</title>
          <description>Half-life (t1/2) is the time to halve the plasma concentration level of the drug.</description>
          <population>PK set: all randomised subjects who fulfilled the study protocol requirements in terms of investigational medicinal product intake and had evaluable PK data readouts for the planned treatment comparisons, with no major deviations that could affect the PK results.</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="48"/>
                <count group_id="O2" value="48"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="14.11" spread="4.16"/>
                    <measurement group_id="O2" value="13.59" spread="2.69"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Lambda Zeta of NAC After Single Dose Administration of Test and Reference</title>
        <description>Lambda zeta is the terminal elimination rate constant. Individual estimate of the terminal elimination rate constant can be calculated using log-linear regression of the terminal portions of the plasma concentration-versus-time curves.</description>
        <time_frame>0-24h (5,15, 30, 45, 60, 75, 90 min and 2, 3, 4, 6, 8, 12, 16 and 24 h postdose)</time_frame>
        <population>PK set: all randomised subjects who fulfilled the study protocol requirements in terms of investigational medicinal product intake and had evaluable PK data readouts for the planned treatment comparisons, with no major deviations that could affect the PK results.</population>
        <group_list>
          <group group_id="O1">
            <title>Test</title>
            <description>N-acetylcysteine (NAC) 600 mg uncoated tablet (single dose). The product was administered according to the randomisation list and cross-over design, with 150 mL of still mineral water under fasting conditions on study day 1 of periods 1 or 2 at 8:00±1 h.</description>
          </group>
          <group group_id="O2">
            <title>Reference</title>
            <description>N-acetylcysteine (NAC) 600 mg film-coated tablet (single dose). The product was administered according to the randomisation list and cross-over design, with 150 mL of still mineral water under fasting conditions on study day 1 of periods 1 or 2 at 8:00±1 h.</description>
          </group>
        </group_list>
        <measure>
          <title>Lambda Zeta of NAC After Single Dose Administration of Test and Reference</title>
          <description>Lambda zeta is the terminal elimination rate constant. Individual estimate of the terminal elimination rate constant can be calculated using log-linear regression of the terminal portions of the plasma concentration-versus-time curves.</description>
          <population>PK set: all randomised subjects who fulfilled the study protocol requirements in terms of investigational medicinal product intake and had evaluable PK data readouts for the planned treatment comparisons, with no major deviations that could affect the PK results.</population>
          <units>1/h</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="48"/>
                <count group_id="O2" value="48"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.05" spread="0.01"/>
                    <measurement group_id="O2" value="0.05" spread="0.01"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Frel of NAC After Single Dose Administration of Test and Reference</title>
        <description>Frel is the relative bioavailability, calculated as ratio AUC0-t (test)/ AUC0-t (reference)</description>
        <time_frame>0-24h (5,15, 30, 45, 60, 75, 90 min and 2, 3, 4, 6, 8, 12, 16 and 24 h postdose)</time_frame>
        <population>PK set: all randomised subjects who fulfilled the study protocol requirements in terms of investigational medicinal product intake and had evaluable PK data readouts for the planned treatment comparisons, with no major deviations that could affect the PK results.</population>
        <group_list>
          <group group_id="O1">
            <title>Enrolled Subjects Set</title>
            <description>According to the crossover design, all the enrolled subjects received both NAC formulations based on the randomization schedule.</description>
          </group>
        </group_list>
        <measure>
          <title>Frel of NAC After Single Dose Administration of Test and Reference</title>
          <description>Frel is the relative bioavailability, calculated as ratio AUC0-t (test)/ AUC0-t (reference)</description>
          <population>PK set: all randomised subjects who fulfilled the study protocol requirements in terms of investigational medicinal product intake and had evaluable PK data readouts for the planned treatment comparisons, with no major deviations that could affect the PK results.</population>
          <units>percentage</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="48"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="92.82" spread="18.05"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>From the beginning of screening days ( day -21 ) up to Final Visit (Day 2).</time_frame>
      <group_list>
        <group group_id="E1">
          <title>Test - Reference</title>
          <description>N-acetylcysteine (NAC) 600 mg uncoated tablet (single dose) followed by NAC 600 mg film-coated tablet (single dose)&#xD;
N-acetylcysteine: The product was administered according to the randomisation list and cross-over design, with 150 mL of still mineral water under fasting conditions on study day 1 of periods 1 or 2 at 8:00±1 h.</description>
        </group>
        <group group_id="E2">
          <title>Reference - Test</title>
          <description>N-acetylcysteine (NAC) 600 mg film-coated tablet (single dose) followed by NAC 600 mg uncoated tablet (single dose)&#xD;
N-acetylcysteine: The product was administered according to the randomisation list and cross-over design, with 150 mL of still mineral water under fasting conditions on study day 1 of periods 1 or 2 at 8:00±1 h.</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="48"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="48"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="48"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="48"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>2</frequency_threshold>
        <default_vocab>MedDRA (17.1)</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="4" subjects_at_risk="48"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="48"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Nausea</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="48"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="48"/>
              </event>
              <event>
                <sub_title>Abdominal discomfort</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="48"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="48"/>
              </event>
              <event>
                <sub_title>Vomiting</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="48"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="48"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Dizziness</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="48"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="48"/>
              </event>
              <event>
                <sub_title>Headache</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="48"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="48"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>Principal Investigators are NOT employed by the organization sponsoring the study.</pi_employee>
      <restrictive_agreement>There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed. </restrictive_agreement>
    </certain_agreements>
    <limitations_and_caveats>Limitations and Caveats not specified</limitations_and_caveats>
    <point_of_contact>
      <name_or_title>Isabella Salerio, PhD</name_or_title>
      <organization>Zambon S.p.A.</organization>
      <phone>+3902665241</phone>
      <email>clinicaltrials@zambongroup.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/NCT02265224
org study id: Z7169J02
secondary id: CRO-PK-14-286
nct id: NCT02265224
lead sponsor: 
has dmc: No
is fda regulated device: No
Study primary Objective:

      - To evaluate the bioequivalent rate (Cmax) and extent (AUC0-t) of absorption of
      N-acetyl-cysteine 600 mg uncoated tablets vs. N-acetyl-cysteine 600 mg film-coated tablets
      (NAC) in healthy male and female volunteers.

      Study secondary objectives:

        -  To describe the pharmacokinetic (PK) profile of NAC in plasma after single dose
           administration of NAC 600 mg uncoated tablets vs. NAC 600 mg film-coated tablets;

        -  to collect safety and tolerability data after single dose administration of NAC 600 mg
           uncoated tablets vs. NAC 600 mg film-coated tablets.
This is single centre, single dose, open, randomised, cross-over, two-stage bioequivalence
      study to compare two different oral formulations of NAC.

      The study has been conducted in healthy volunteers of both genders, in one single dose of
      both formulations.

      The initial 48 subjects were sufficient to satisfy the study objectives on the basis of the
      ad interim preliminary bioequivalence test. The study was then considered as concluded and
      the second stage did not take place.
allocation: Randomized
intervention model: Crossover Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Cmax of NAC After Single Dose Administration of Test and Reference
time frame: 0-24h (5,15, 30, 45, 60, 75, 90 min and 2, 3, 4, 6, 8, 12, 16 and 24 h postdose)
description: Cmax is the maximum concentration level of the drug reached in plasma.
measure: AUC0-t of NAC After Single Dose Administration of Test and Reference
time frame: 0-24h (5,15, 30, 45, 60, 75, 90 min and 2, 3, 4, 6, 8, 12, 16 and 24 h postdose)
description: AUC0-t is the Area under the concentration-time curve from time zero to time t, calculated with the linear trapezoidal summation from time 0 to the last measurable data point.
measure: AUC0-∞ of NAC After Single Dose Administration of Test and Reference
time frame: 0-24h (5,15, 30, 45, 60, 75, 90 min and 2, 3, 4, 6, 8, 12, 16 and 24 h postdose)
description: AUC0-∞ is the area under the concentration-time curve extrapolated to infinity, calculated, if feasible, as AUC0-t + Ct/λz, where Ct is the last measurable drug concentration.
measure: Tmax of NAC After Single Dose Administration of Test and Reference
time frame: 0-24h (5,15, 30, 45, 60, 75, 90 min and 2, 3, 4, 6, 8, 12, 16 and 24 h postdose)
description: time to achieve the maximum concentration level of the drug in plasma.
measure: t1/2 of NAC After Single Dose Administration of Test and Reference
time frame: 0-24h (5,15, 30, 45, 60, 75, 90 min and 2, 3, 4, 6, 8, 12, 16 and 24 h postdose)
description: Half-life (t1/2) is the time to halve the plasma concentration level of the drug.
measure: Lambda Zeta of NAC After Single Dose Administration of Test and Reference
time frame: 0-24h (5,15, 30, 45, 60, 75, 90 min and 2, 3, 4, 6, 8, 12, 16 and 24 h postdose)
description: Lambda zeta is the terminal elimination rate constant. Individual estimate of the terminal elimination rate constant can be calculated using log-linear regression of the terminal portions of the plasma concentration-versus-time curves.
measure: Frel of NAC After Single Dose Administration of Test and Reference
time frame: 0-24h (5,15, 30, 45, 60, 75, 90 min and 2, 3, 4, 6, 8, 12, 16 and 24 h postdose)
description: Frel is the relative bioavailability, calculated as ratio AUC0-t (test)/ AUC0-t (reference)
arm group label: Test - Reference
arm group type: Experimental
description: N-acetylcysteine (NAC) 600 mg uncoated tablet (single dose) followed by NAC 600 mg film-coated tablet (single dose)
arm group label: Reference - Test
arm group type: Active Comparator
description: N-acetylcysteine (NAC) 600 mg film-coated tablet (single dose) followed by NAC 600 mg uncoated tablet (single dose)
intervention type: Drug
intervention name: N-acetylcysteine
description: The product was administered according to the randomisation list and cross-over design, with 150 mL of still mineral water under fasting conditions on study day 1 of periods 1 or 2 at 8:00±1 h.
arm group label: Reference - Test
arm group label: Test - Reference
other name: Fluimucil uncoated tablets
criteria: 
gender: All
minimum age: 18 Years
maximum age: 55 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Milko Radicioni, MD
role: Principal Investigator
affiliation: Cross Research SA
responsible party type: Sponsor
mesh term: Acetylcysteine
mesh term: N-monoacetylcystine
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
limitations and caveats: Limitations and Caveats not specified
point of contact: 