<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/NCT01682538</url>
  </required_header>
  <id_info>
    <org_study_id>Sobi.NTBC-001</org_study_id>
    <nct_id>NCT01682538</nct_id>
  </id_info>
  <brief_title>Bioequivalence of Orfadin Suspension Compared to Orfadin Capsules, and the Effect of Food on the Bioavailability of the Suspension</brief_title>
  <official_title>A Study to Evaluate the Bioequivalence of Orfadin Suspension 4 mg/mL Compared to Orfadin Capsules 10 mg, and the Effect of Food on the Bioavailability of the Suspension. An Open-label, Randomized, Cross-over, Single-dose Study in Healthy Volunteers</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Swedish Orphan Biovitrum</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Swedish Orphan Biovitrum</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      The study is primarily being performed in order to demonstrate bioequivalence between the&#xD;
      Orfadin (nitisinone) suspension and the marketed capsule formulation. The study will also&#xD;
      contain a comparison of the bioavailability of the suspension given with food and on an empty&#xD;
      stomach.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This is an open, randomized 3-way crossover study in 12 healthy volunteers. Subjects will&#xD;
      receive single oral 30-mg doses of nitisinone as a suspension (fasting and with food) and as&#xD;
      hard gelatin capsules (fasting only). There will be a 2-week washout period between the&#xD;
      doses.&#xD;
&#xD;
      There will be a screening visit within 3 weeks prior to the first dose. During each treatment&#xD;
      period, subjects will be admitted to the clinic from the afternoon on the day before drug&#xD;
      administration (i.e., on Day -1) and remain at the clinic until the 48-hour post-dose blood&#xD;
      sample has been collected in the morning of Day 3. They will then return for ambulatory visit&#xD;
      in the morning of Day 4 (72-hour sample). A follow-up visit will take place 7-14 days after&#xD;
      the last dose.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date>August 2012</start_date>
  <completion_date type="Actual">October 2012</completion_date>
  <primary_completion_date type="Actual">October 2012</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>The Area Under the Serum Concentration Curve (AUC) During 72 Hours After Dose (AUC72h) During Fasting Conditions.</measure>
    <time_frame>Day 1 predose and at 15, 30, 45 minutes and 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 24, 36, 48 and 72 hours postdose.</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>The Maximum Serum Concentration (Cmax) During Fasting Conditions.</measure>
    <time_frame>Day 1 predose and at 15, 30, 45 minutes and 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 24, 36, 48 and 72 hours postdose.</time_frame>
  </primary_outcome>
  <secondary_outcome>
    <measure>The Area Under the Serum Concentration Curve (AUC) During 72 Hours After Dose (AUC72h)</measure>
    <time_frame>Day 1 predose and at 15, 30, 45 minutes and 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 24, 36, 48 and 72 hours postdose.</time_frame>
    <description>Measured for the Orfadin suspension treatments arms- both fasting and with food.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>The Maximum Serum Concentration (Cmax)</measure>
    <time_frame>Day 1 predose and at 15, 30, 45 minutes and 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 24, 36, 48 and 72 hours postdose.</time_frame>
    <description>Measured for the Orfadin suspension treatment arms- both fasting and with food.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>AUC From Time Zero to Infinity</measure>
    <time_frame>Day 1 predose and at 15, 30, 45 minutes and 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 24, 36, 48 and 72 hours postdose.</time_frame>
    <description>Measured for the Orfadin capsules and suspension treatments arms - both fasting and with food.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Time to Reach C-Max (t-Max)</measure>
    <time_frame>Day 1 predose and at 15, 30, 45 minutes and 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 24, 36, 48 and 72 hours postdose.</time_frame>
    <description>Measured for the Orfadin capsules and suspension treatments arms - both fasting and with food.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Terminal Half-life</measure>
    <time_frame>Day 1 predose and at 15, 30, 45 minutes and 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 24, 36, 48 and 72 hours postdose.</time_frame>
    <description>Measured for the Orfadin capsules and suspension treatments arms - both fasting and with food.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Oral Clearance (CL/F)</measure>
    <time_frame>Day 1 predose and at 15, 30, 45 minutes and 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 24, 36, 48 and 72 hours postdose.</time_frame>
    <description>Measured for the Orfadin capsules and suspension treatments arms - both fasting and with food.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Apparent Volume of Distribution (Vz/F)</measure>
    <time_frame>Day 1 predose and at 15, 30, 45 minutes and 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 24, 36, 48 and 72 hours postdose.</time_frame>
    <description>Measured for the Orfadin capsules and suspension treatments arms - both fasting and with food.</description>
  </secondary_outcome>
  <number_of_arms>3</number_of_arms>
  <enrollment type="Actual">12</enrollment>
  <condition>Healthy Volunteers</condition>
  <arm_group>
    <arm_group_label>Orfadin capsules, fasting</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Orfadin capsules, single dose, 30 mg</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Orfadin suspension, fasting</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Orfadin suspension 4 mg/mL, single dose 30 mg (7,5 mL)</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Orfadin suspension, with food</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Orfadin suspension 4mg/mL, single dose 30 mg (7,5 mL)</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Nitisinone, capsule</intervention_name>
    <arm_group_label>Orfadin capsules, fasting</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Nitisinone, suspension</intervention_name>
    <arm_group_label>Orfadin suspension, fasting</arm_group_label>
    <arm_group_label>Orfadin suspension, with food</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Healthy male volunteers&#xD;
&#xD;
          -  Age: 18-55 years, inclusive&#xD;
&#xD;
          -  BMI: 18,5-30,0 kg/m2, inclusive&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  heavy smokers&#xD;
&#xD;
          -  Consumption of more than 4 cups of coffee per day.&#xD;
&#xD;
          -  History of drug and/or alcohol abuse.&#xD;
&#xD;
          -  Positive drug screen or alcohol breath test.&#xD;
&#xD;
          -  Positive screens for hepatitis B surface antigen, hepatitis C antibodies and human&#xD;
             immunodeficiency virus (HIV) 1-2 antibodies.&#xD;
&#xD;
          -  Enrollment in another concurrent clinical study&#xD;
&#xD;
          -  Intake of an investigational medicinal product within three months prior to inclusion&#xD;
             in this study.&#xD;
&#xD;
          -  Donation of more than 50 mL of blood within 60 days prior to drug administration&#xD;
&#xD;
          -  Donation of more than 1,5 liters of blood in the 10 months prior to first drug&#xD;
             administration.&#xD;
      </textblock>
    </criteria>
    <gender>Male</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>Erik Brouwer, MD</last_name>
    <role>Study Director</role>
    <affiliation>Swedish Orphan Biovitrum</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Pharmaceutical Research Associates Group B.V (PRA)</name>
      <address>
        <city>Zuidlaren</city>
        <country>Netherlands</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Netherlands</country>
  </location_countries>
  <verification_date>February 2014</verification_date>
  <study_first_submitted>September 7, 2012</study_first_submitted>
  <study_first_submitted_qc>September 10, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">September 11, 2012</study_first_posted>
  <results_first_submitted>October 8, 2013</results_first_submitted>
  <results_first_submitted_qc>January 23, 2014</results_first_submitted_qc>
  <results_first_posted type="Estimate">February 20, 2014</results_first_posted>
  <last_update_submitted>February 20, 2014</last_update_submitted>
  <last_update_submitted_qc>February 20, 2014</last_update_submitted_qc>
  <last_update_posted type="Estimate">March 17, 2014</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Orfadin</keyword>
  <keyword>Nitisinone</keyword>
  <keyword>Bioequivalence</keyword>
  <keyword>Bioavailability</keyword>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Nitisinone</mesh_term>
  </intervention_browse>

  <clinical_results>

    <participant_flow>
      <recruitment_details>First subject screened: 29 August 2012 Last subject last visit: 25 October 2012.</recruitment_details>
      <group_list>
        <group group_id="P1">
          <title>All Treatment Groups</title>
          <description>All participants received all study treatments in a randomized fashion. Subjects were allocated to one of the following treatment sequences (2 subjects to each sequence):&#xD;
A B C; B C A; C A B; C B A; A C B; B A C where A=Orfadin capsules, single dose, 30 mg; B=Orfadin suspension, single dose 30 mg, fasting; C=Orfadin suspension, single dose 30 mg, fed</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_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="12"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>Overall Study</title>
          <description>All treatment arms</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="12"/>
          </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="12"/>
                  </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="35" spread="12"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Sex: Female, Male</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Female</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="12"/>
                  </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>Netherlands</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="12"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>The Area Under the Serum Concentration Curve (AUC) During 72 Hours After Dose (AUC72h) During Fasting Conditions.</title>
        <time_frame>Day 1 predose and at 15, 30, 45 minutes and 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 24, 36, 48 and 72 hours postdose.</time_frame>
        <population>Full analysis set was used; subjects with available PK data for at least one of the treatments.</population>
        <group_list>
          <group group_id="O1">
            <title>Orfadin Capsules, Fasting</title>
            <description>Orfadin capsules, single dose, 30 mg</description>
          </group>
          <group group_id="O2">
            <title>Orfadin Suspension, Fasting</title>
            <description>Orfadin suspension 4 mg/mL, single dose, 30 mg (7,5 mL)</description>
          </group>
        </group_list>
        <measure>
          <title>The Area Under the Serum Concentration Curve (AUC) During 72 Hours After Dose (AUC72h) During Fasting Conditions.</title>
          <population>Full analysis set was used; subjects with available PK data for at least one of the treatments.</population>
          <units>uM*h</units>
          <param>Geometric Mean</param>
          <dispersion>Full Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="12"/>
                <count group_id="O2" value="12"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="403" lower_limit="315" upper_limit="500"/>
                    <measurement group_id="O2" value="346" lower_limit="264" upper_limit="456"/>
                  </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>Non-Inferiority or Equivalence</non_inferiority_type>
            <non_inferiority_desc>Bioequivalence was established if the 90% confidence interval of the ratio was completely within the acceptance range (0.80-1.25)</non_inferiority_desc>
            <param_type>Ratio of geometric means</param_type>
            <param_value>0.858</param_value>
            <ci_percent>90</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>0.81</ci_lower_limit>
            <ci_upper_limit>0.91</ci_upper_limit>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>The Maximum Serum Concentration (Cmax) During Fasting Conditions.</title>
        <time_frame>Day 1 predose and at 15, 30, 45 minutes and 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 24, 36, 48 and 72 hours postdose.</time_frame>
        <population>Full analysis set was used; subjects with available PK data for at least one of the treatments.</population>
        <group_list>
          <group group_id="O1">
            <title>Orfadin Capsules, Fasting</title>
            <description>Orfadin capsules, single dose, 30 mg</description>
          </group>
          <group group_id="O2">
            <title>Orfadin Suspension, Fasting</title>
            <description>Orfadin suspension 4 mg/mL, single dose, 30 mg (7,5 mL)</description>
          </group>
        </group_list>
        <measure>
          <title>The Maximum Serum Concentration (Cmax) During Fasting Conditions.</title>
          <population>Full analysis set was used; subjects with available PK data for at least one of the treatments.</population>
          <units>nM</units>
          <param>Geometric Mean</param>
          <dispersion>Full Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="12"/>
                <count group_id="O2" value="12"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="10213" lower_limit="8030" upper_limit="18000"/>
                    <measurement group_id="O2" value="9741" lower_limit="7780" upper_limit="20300"/>
                  </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>Non-Inferiority or Equivalence</non_inferiority_type>
            <non_inferiority_desc>Bioequivalence was established if the 90% confidence interval of the ratio was completely within the acceptance range (0.80-1.25)</non_inferiority_desc>
            <param_type>Ratio of geometric means</param_type>
            <param_value>0.954</param_value>
            <ci_percent>90</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>0.85</ci_lower_limit>
            <ci_upper_limit>1.07</ci_upper_limit>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>The Area Under the Serum Concentration Curve (AUC) During 72 Hours After Dose (AUC72h)</title>
        <description>Measured for the Orfadin suspension treatments arms- both fasting and with food.</description>
        <time_frame>Day 1 predose and at 15, 30, 45 minutes and 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 24, 36, 48 and 72 hours postdose.</time_frame>
        <population>Full analysis set was used; subjects with available PK data for at least one of the treatments.</population>
        <group_list>
          <group group_id="O1">
            <title>Orfadin Suspension, Fasting</title>
            <description>Orfadin suspension 4 mg/mL, single dose 30 mg (7,5 mL)</description>
          </group>
          <group group_id="O2">
            <title>Orfadin Suspension, With Food</title>
            <description>Orfadin suspension 4 mg/mL, single dose 30 mg (7,5 mL)</description>
          </group>
        </group_list>
        <measure>
          <title>The Area Under the Serum Concentration Curve (AUC) During 72 Hours After Dose (AUC72h)</title>
          <description>Measured for the Orfadin suspension treatments arms- both fasting and with food.</description>
          <population>Full analysis set was used; subjects with available PK data for at least one of the treatments.</population>
          <units>uM*h</units>
          <param>Geometric Mean</param>
          <dispersion>Full Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="12"/>
                <count group_id="O2" value="11"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="346" lower_limit="264" upper_limit="456"/>
                    <measurement group_id="O2" value="350" lower_limit="251" upper_limit="467"/>
                  </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>Non-Inferiority or Equivalence</non_inferiority_type>
            <non_inferiority_desc>Equivalence (no food effect) was established if the 90% confidence interval of the ratio was completely within the acceptance range (0.80 - 1.25).</non_inferiority_desc>
            <param_type>Ratio of geometric means</param_type>
            <param_value>1.013</param_value>
            <ci_percent>90</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>0.96</ci_lower_limit>
            <ci_upper_limit>1.07</ci_upper_limit>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>The Maximum Serum Concentration (Cmax)</title>
        <description>Measured for the Orfadin suspension treatment arms- both fasting and with food.</description>
        <time_frame>Day 1 predose and at 15, 30, 45 minutes and 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 24, 36, 48 and 72 hours postdose.</time_frame>
        <population>Full analysis set was used; subjects with available PK data for at least one of the treatments.</population>
        <group_list>
          <group group_id="O1">
            <title>Orfadin Suspension, Fasting</title>
            <description>Orfadin suspension 4 mg/mL, single dose 30 mg (7,5 mL)</description>
          </group>
          <group group_id="O2">
            <title>Orfadin Suspension, With Food</title>
            <description>Orfadin suspension 4 mg/mL, single dose 30 mg (7,5 mL)</description>
          </group>
        </group_list>
        <measure>
          <title>The Maximum Serum Concentration (Cmax)</title>
          <description>Measured for the Orfadin suspension treatment arms- both fasting and with food.</description>
          <population>Full analysis set was used; subjects with available PK data for at least one of the treatments.</population>
          <units>nM</units>
          <param>Geometric Mean</param>
          <dispersion>Full Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="12"/>
                <count group_id="O2" value="11"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="9741" lower_limit="7780" upper_limit="20300"/>
                    <measurement group_id="O2" value="7808" lower_limit="5300" upper_limit="12500"/>
                  </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>Non-Inferiority or Equivalence</non_inferiority_type>
            <non_inferiority_desc>Equivalence (no food effect) was established if the 90% confidence interval of the ratio was completely within the acceptance range (0.80 - 1.25)</non_inferiority_desc>
            <param_type>Ratio of geometric means</param_type>
            <param_value>0.802</param_value>
            <ci_percent>90</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>0.71</ci_lower_limit>
            <ci_upper_limit>0.90</ci_upper_limit>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>AUC From Time Zero to Infinity</title>
        <description>Measured for the Orfadin capsules and suspension treatments arms - both fasting and with food.</description>
        <time_frame>Day 1 predose and at 15, 30, 45 minutes and 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 24, 36, 48 and 72 hours postdose.</time_frame>
        <population>Per-protocol set (bioequivalence) was used for fasted treatment groups and per-protocol set (food effect) for fed treatment group (all subjects with available PK data)</population>
        <group_list>
          <group group_id="O1">
            <title>Orfadin Capsules, Fasting</title>
            <description>Orfadin capsules, single dose, 30 mg</description>
          </group>
          <group group_id="O2">
            <title>Orfadin Suspension, Fasting</title>
            <description>Orfadin suspension 4 mg/mL, single dose, 30 mg (7,5 mL)</description>
          </group>
          <group group_id="O3">
            <title>Orfadin Suspension, With Food</title>
            <description>Orfadin suspension 4 mg/mL, single dose, 30 mg (7,5 mL)</description>
          </group>
        </group_list>
        <measure>
          <title>AUC From Time Zero to Infinity</title>
          <description>Measured for the Orfadin capsules and suspension treatments arms - both fasting and with food.</description>
          <population>Per-protocol set (bioequivalence) was used for fasted treatment groups and per-protocol set (food effect) for fed treatment group (all subjects with available PK data)</population>
          <units>h*uM</units>
          <param>Geometric Mean</param>
          <dispersion>Full Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="12"/>
                <count group_id="O2" value="12"/>
                <count group_id="O3" value="11"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="633" lower_limit="366" upper_limit="891"/>
                    <measurement group_id="O2" value="559" lower_limit="454" upper_limit="715"/>
                    <measurement group_id="O3" value="577" lower_limit="417" upper_limit="858"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Time to Reach C-Max (t-Max)</title>
        <description>Measured for the Orfadin capsules and suspension treatments arms - both fasting and with food.</description>
        <time_frame>Day 1 predose and at 15, 30, 45 minutes and 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 24, 36, 48 and 72 hours postdose.</time_frame>
        <population>Per protocol set (bioequivalence) was used for fasting treatments and per protocol set (food effect) used for fed treatment (all subjects with available PK data)</population>
        <group_list>
          <group group_id="O1">
            <title>Orfadin Capsules, Fasting</title>
            <description>Orfadin capsules, single dose, 30 mg</description>
          </group>
          <group group_id="O2">
            <title>Orfadin Suspension, Fasting</title>
            <description>Orfadin suspension 4 mg/mL, single dose 30 mg (7,5 mL)</description>
          </group>
          <group group_id="O3">
            <title>Orfadin Suspension, With Food</title>
            <description>Orfadin suspension 4 mg/mL, single dose 30 mg (7,5 mL)</description>
          </group>
        </group_list>
        <measure>
          <title>Time to Reach C-Max (t-Max)</title>
          <description>Measured for the Orfadin capsules and suspension treatments arms - both fasting and with food.</description>
          <population>Per protocol set (bioequivalence) was used for fasting treatments and per protocol set (food effect) used for fed treatment (all subjects with available PK data)</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="12"/>
                <count group_id="O2" value="12"/>
                <count group_id="O3" value="11"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="3.50" lower_limit="0.75" upper_limit="8.00"/>
                    <measurement group_id="O2" value="0.38" lower_limit="0.25" upper_limit="4.00"/>
                    <measurement group_id="O3" value="8.00" lower_limit="3.50" upper_limit="10.00"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Terminal Half-life</title>
        <description>Measured for the Orfadin capsules and suspension treatments arms - both fasting and with food.</description>
        <time_frame>Day 1 predose and at 15, 30, 45 minutes and 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 24, 36, 48 and 72 hours postdose.</time_frame>
        <population>Per protocol set (bioequivalence) was used for fasting treatments and per protocol set (food effect) used for fed treatment (all subjects with available PK data)</population>
        <group_list>
          <group group_id="O1">
            <title>Orfadin Capsules, Fasting</title>
            <description>Orfadin capsules, single dose, 30 mg</description>
          </group>
          <group group_id="O2">
            <title>Orfadin Suspension, Fasting</title>
            <description>Orfadin suspension 4 mg/mL, single dose, 30 mg (7.5 mL)</description>
          </group>
          <group group_id="O3">
            <title>Orfadin Suspension, With Food</title>
            <description>Orfadin suspension 4 mg/mL, single dose, 30 mg (7.5 mL)</description>
          </group>
        </group_list>
        <measure>
          <title>Terminal Half-life</title>
          <description>Measured for the Orfadin capsules and suspension treatments arms - both fasting and with food.</description>
          <population>Per protocol set (bioequivalence) was used for fasting treatments and per protocol set (food effect) used for fed treatment (all subjects with available PK data)</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="12"/>
                <count group_id="O2" value="12"/>
                <count group_id="O3" value="11"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="48.7" lower_limit="20.6" upper_limit="66.4"/>
                    <measurement group_id="O2" value="53.6" lower_limit="39.3" upper_limit="63.7"/>
                    <measurement group_id="O3" value="54.3" lower_limit="37.3" upper_limit="75.6"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Oral Clearance (CL/F)</title>
        <description>Measured for the Orfadin capsules and suspension treatments arms - both fasting and with food.</description>
        <time_frame>Day 1 predose and at 15, 30, 45 minutes and 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 24, 36, 48 and 72 hours postdose.</time_frame>
        <population>Per protocol set (bioequivalence) was used for fasting treatments and per protocol set (food effect) used for fed treatment (all subjects with available PK data)</population>
        <group_list>
          <group group_id="O1">
            <title>Orfadin Capsules, Fasting</title>
            <description>Orfadin capsules, single dose, 30 mg</description>
          </group>
          <group group_id="O2">
            <title>Orfadin Suspension, Fasting</title>
            <description>Orfadin suspension, 4 mg/mL, single dose, 30 mg (7.5 mL)</description>
          </group>
          <group group_id="O3">
            <title>Orfadin Suspension, With Food</title>
            <description>Orfadin suspension 4 mg/mL, single dose, 30 mg (7.5 mL)</description>
          </group>
        </group_list>
        <measure>
          <title>Oral Clearance (CL/F)</title>
          <description>Measured for the Orfadin capsules and suspension treatments arms - both fasting and with food.</description>
          <population>Per protocol set (bioequivalence) was used for fasting treatments and per protocol set (food effect) used for fed treatment (all subjects with available PK data)</population>
          <units>L/h</units>
          <param>Median</param>
          <dispersion>Full Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="12"/>
                <count group_id="O2" value="12"/>
                <count group_id="O3" value="11"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.145" lower_limit="0.102" upper_limit="0.249"/>
                    <measurement group_id="O2" value="0.160" lower_limit="0.127" upper_limit="0.201"/>
                    <measurement group_id="O3" value="0.158" lower_limit="0.106" upper_limit="0.218"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Apparent Volume of Distribution (Vz/F)</title>
        <description>Measured for the Orfadin capsules and suspension treatments arms - both fasting and with food.</description>
        <time_frame>Day 1 predose and at 15, 30, 45 minutes and 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 24, 36, 48 and 72 hours postdose.</time_frame>
        <population>Per protocol set (bioequivalence) was used for fasting treatments and per protocol set (food effect) used for fed treatment (all subjects with available PK data)</population>
        <group_list>
          <group group_id="O1">
            <title>Orfadin Capsules, Fasting</title>
            <description>Orfadin capsules, single dose, 30 mg</description>
          </group>
          <group group_id="O2">
            <title>Orfadin Suspension, Fasting</title>
            <description>Orfadin suspension 4 mg/mL, single dose, 30 mg (7.5 mL)</description>
          </group>
          <group group_id="O3">
            <title>Orfadin Suspension, With Food</title>
            <description>Orfadin suspension 4 mg/mL, single dose, 30 mg (7.5 mL)</description>
          </group>
        </group_list>
        <measure>
          <title>Apparent Volume of Distribution (Vz/F)</title>
          <description>Measured for the Orfadin capsules and suspension treatments arms - both fasting and with food.</description>
          <population>Per protocol set (bioequivalence) was used for fasting treatments and per protocol set (food effect) used for fed treatment (all subjects with available PK data)</population>
          <units>L</units>
          <param>Median</param>
          <dispersion>Full Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="12"/>
                <count group_id="O2" value="12"/>
                <count group_id="O3" value="11"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="9.80" lower_limit="7.42" upper_limit="12.0"/>
                    <measurement group_id="O2" value="12.2" lower_limit="8.59" upper_limit="16.7"/>
                    <measurement group_id="O3" value="12.8" lower_limit="8.48" upper_limit="17.2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <group_list>
        <group group_id="E1">
          <title>Orfadin Capsules, Fasting</title>
          <description>Orfadin capsules, single dose, 30 mg</description>
        </group>
        <group group_id="E2">
          <title>Orfadin Suspension, Fasting</title>
          <description>Orfadin suspension 4 mg/mL, single dose, 30 mg (7.5 mL)</description>
        </group>
        <group group_id="E3">
          <title>Orfadin Suspension, With Food</title>
          <description>Orfadin suspension 4 mg/mL, single dose, 30 mg (7.5 mL)</description>
        </group>
      </group_list>
      <serious_events>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="12"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>0</frequency_threshold>
        <default_vocab>MedDRA 15.0</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="1" subjects_at_risk="12"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="12"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="12"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Dyspepsia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="12"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Catheter site related reaction</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="12"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="12"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Nasopharyngitis</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="12"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="12"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Musculoskeletal pain</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="12"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Dizziness</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="12"/>
              </event>
              <event>
                <sub_title>Headache</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="12"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="12"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Epistaxis</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="12"/>
              </event>
              <event>
                <sub_title>Nasal congestion</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="12"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="12"/>
              </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>The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.</restrictive_agreement>
    </certain_agreements>
    <point_of_contact>
      <name_or_title>Medical Director</name_or_title>
      <organization>Swedish Orphan Biovitrum</organization>
      <phone>+4686972000</phone>
      <email>erik.brouwer@sobi.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/NCT01682538
org study id: Sobi.NTBC-001
nct id: NCT01682538
lead sponsor: 
has dmc: No
The study is primarily being performed in order to demonstrate bioequivalence between the
      Orfadin (nitisinone) suspension and the marketed capsule formulation. The study will also
      contain a comparison of the bioavailability of the suspension given with food and on an empty
      stomach.
This is an open, randomized 3-way crossover study in 12 healthy volunteers. Subjects will
      receive single oral 30-mg doses of nitisinone as a suspension (fasting and with food) and as
      hard gelatin capsules (fasting only). There will be a 2-week washout period between the
      doses.

      There will be a screening visit within 3 weeks prior to the first dose. During each treatment
      period, subjects will be admitted to the clinic from the afternoon on the day before drug
      administration (i.e., on Day -1) and remain at the clinic until the 48-hour post-dose blood
      sample has been collected in the morning of Day 3. They will then return for ambulatory visit
      in the morning of Day 4 (72-hour sample). A follow-up visit will take place 7-14 days after
      the last dose.
allocation: Randomized
intervention model: Crossover Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: The Area Under the Serum Concentration Curve (AUC) During 72 Hours After Dose (AUC72h) During Fasting Conditions.
time frame: Day 1 predose and at 15, 30, 45 minutes and 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 24, 36, 48 and 72 hours postdose.
measure: The Maximum Serum Concentration (Cmax) During Fasting Conditions.
time frame: Day 1 predose and at 15, 30, 45 minutes and 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 24, 36, 48 and 72 hours postdose.
measure: The Area Under the Serum Concentration Curve (AUC) During 72 Hours After Dose (AUC72h)
time frame: Day 1 predose and at 15, 30, 45 minutes and 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 24, 36, 48 and 72 hours postdose.
description: Measured for the Orfadin suspension treatments arms- both fasting and with food.
measure: The Maximum Serum Concentration (Cmax)
time frame: Day 1 predose and at 15, 30, 45 minutes and 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 24, 36, 48 and 72 hours postdose.
description: Measured for the Orfadin suspension treatment arms- both fasting and with food.
measure: AUC From Time Zero to Infinity
time frame: Day 1 predose and at 15, 30, 45 minutes and 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 24, 36, 48 and 72 hours postdose.
description: Measured for the Orfadin capsules and suspension treatments arms - both fasting and with food.
measure: Time to Reach C-Max (t-Max)
time frame: Day 1 predose and at 15, 30, 45 minutes and 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 24, 36, 48 and 72 hours postdose.
description: Measured for the Orfadin capsules and suspension treatments arms - both fasting and with food.
measure: Terminal Half-life
time frame: Day 1 predose and at 15, 30, 45 minutes and 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 24, 36, 48 and 72 hours postdose.
description: Measured for the Orfadin capsules and suspension treatments arms - both fasting and with food.
measure: Oral Clearance (CL/F)
time frame: Day 1 predose and at 15, 30, 45 minutes and 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 24, 36, 48 and 72 hours postdose.
description: Measured for the Orfadin capsules and suspension treatments arms - both fasting and with food.
measure: Apparent Volume of Distribution (Vz/F)
time frame: Day 1 predose and at 15, 30, 45 minutes and 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 24, 36, 48 and 72 hours postdose.
description: Measured for the Orfadin capsules and suspension treatments arms - both fasting and with food.
arm group label: Orfadin capsules, fasting
arm group type: Active Comparator
description: Orfadin capsules, single dose, 30 mg
arm group label: Orfadin suspension, fasting
arm group type: Experimental
description: Orfadin suspension 4 mg/mL, single dose 30 mg (7,5 mL)
arm group label: Orfadin suspension, with food
arm group type: Experimental
description: Orfadin suspension 4mg/mL, single dose 30 mg (7,5 mL)
intervention type: Drug
intervention name: Nitisinone, capsule
arm group label: Orfadin capsules, fasting
intervention type: Drug
intervention name: Nitisinone, suspension
arm group label: Orfadin suspension, fasting
arm group label: Orfadin suspension, with food
criteria: 
gender: Male
minimum age: 18 Years
maximum age: 55 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Erik Brouwer, MD
role: Study Director
affiliation: Swedish Orphan Biovitrum
facility: 
country: Netherlands
responsible party type: Sponsor
mesh term: Nitisinone
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 