<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/NCT04419493</url>
  </required_header>
  <id_info>
    <org_study_id>0135-0340</org_study_id>
    <secondary_id>2019-004932-40</secondary_id>
    <nct_id>NCT04419493</nct_id>
  </id_info>
  <brief_title>A Study in Healthy Men to Compare 2 Different Formulations of Alteplase</brief_title>
  <official_title>Bioequivalence of Alteplase Derived From Two Different Manufacturing Processes Following Intravenous Administration in Healthy Male Volunteers</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Boehringer Ingelheim</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Boehringer Ingelheim</source>
  <oversight_info>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      To establish the bioequivalence of alteplase derived from two different manufacturing&#xD;
      processes.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">June 23, 2020</start_date>
  <completion_date type="Actual">June 21, 2021</completion_date>
  <primary_completion_date type="Actual">June 21, 2021</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>
    <intervention_model_description>Part A: Open label Part B: Adaptive two-stage group-sequential design</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Part A: Area Under the Concentration-time Curve of Alteplase in Plasma Over the Time Interval From 0 up to the Last Quantifiable Data Point (AUC0-tz)</measure>
    <time_frame>Within 3 hours (h) before and 5 minutes (min), 10min, 15min, 20min, 25min, 30min, 32min, 34min, 36min, 40min, 45min, 50min, 1h, 1.33h, 1.67h, 2h, 3h, 4h and 6h after start of alteplase infusion.</time_frame>
    <description>The area under the concentration-time curve of alteplase in plasma over the time interval from 0 to the last quantifiable data point (AUC0-tz) is reported.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Part B: Area Under the Concentration-time Curve of Alteplase in Plasma Over the Time Interval From 0 up to the Last Quantifiable Data Point (AUC0-tz)</measure>
    <time_frame>Within 3 hours (h) before and 5 minutes (min), 10min, 15min, 20min, 25min, 30min, 32min, 34min, 36min, 40min, 45min, 50min, 1h, 1.33h, 1.67h, 2h, 3h, 4h and 6h after start of alteplase infusion.</time_frame>
    <description>The area under the concentration-time curve of Alteplase in plasma over the time interval from 0 to the last quantifiable data point (AUC0-tz) is reported.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Part A: Maximum Measured Concentration of Alteplase in Plasma (Cmax)</measure>
    <time_frame>Within 3 hours (h) before and 5 minutes (min), 10min, 15min, 20min, 25min, 30min, 32min, 34min, 36min, 40min, 45min, 50min, 1h, 1.33h, 1.67h, 2h, 3h, 4h and 6h after start of alteplase infusion.</time_frame>
    <description>Maximum measured concentration of alteplase in plasma is reported.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Part B: Maximum Measured Concentration of Alteplase in Plasma (Cmax)</measure>
    <time_frame>Within 3 hours (h) before and 5 minutes (min), 10min, 15min, 20min, 25min, 30min, 32min, 34min, 36min, 40min, 45min, 50min, 1h, 1.33h, 1.67h, 2h, 3h, 4h and 6h after start of alteplase infusion.</time_frame>
    <description>Maximum measured concentration of Alteplase in plasma (Cmax) is reported.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Part A: Area Under the Concentration-time Curve of Alteplase in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞)</measure>
    <time_frame>Within 3 hours (h) before and 5 minutes (min), 10min, 15min, 20min, 25min, 30min, 32min, 34min, 36min, 40min, 45min, 50min, 1h, 1.33h, 1.67h, 2h, 3h, 4h and 6h after start of alteplase infusion.</time_frame>
    <description>Area under the concentration-time curve of alteplase in plasma over interval from 0 extrapolated to infinity is reported.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Part B: Area Under the Concentration-time Curve of Alteplase in Plasma Over the Interval From 0 Extrapolated to Infinity (AUC0-∞)</measure>
    <time_frame>Within 3 hours (h) before and 5 minutes (min), 10min, 15min, 20min, 25min, 30min, 32min, 34min, 36min, 40min, 45min, 50min, 1h, 1.33h, 1.67h, 2h, 3h, 4h and 6h after start of alteplase infusion.</time_frame>
    <description>Area under the concentration-time curve of alteplase in plasma over the interval from 0 extrapolated to infinity is reported.</description>
  </secondary_outcome>
  <number_of_arms>4</number_of_arms>
  <enrollment type="Actual">30</enrollment>
  <condition>Healthy</condition>
  <arm_group>
    <arm_group_label>Part B: Alteplase, TPA-02 then Alteplase, TPA-05</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
  </arm_group>
  <arm_group>
    <arm_group_label>Part B: Alteplase, TPA-05 then Alteplase, TPA-02</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
  </arm_group>
  <arm_group>
    <arm_group_label>Part A: Alteplase, TPA-05 then Alteplase, TPA-02</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Open-label</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Part A: Alteplase, TPA-02 then Alteplase, TPA-05</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Alteplase (from modified manufacturing process)</intervention_name>
    <description>Alteplase, TPA-05</description>
    <arm_group_label>Part A: Alteplase, TPA-05 then Alteplase, TPA-02</arm_group_label>
    <arm_group_label>Part B: Alteplase, TPA-02 then Alteplase, TPA-05</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Alteplase (from current manufacturing process)</intervention_name>
    <description>Alteplase, TPA-02</description>
    <arm_group_label>Part A: Alteplase, TPA-02 then Alteplase, TPA-05</arm_group_label>
    <arm_group_label>Part B: Alteplase, TPA-05 then Alteplase, TPA-02</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Heparin-Natrium-5000-ratiopharm (unfractionated heparin)</intervention_name>
    <description>Heparin-Natrium-5000-ratiopharm (unfractionated heparin)</description>
    <arm_group_label>Part A: Alteplase, TPA-02 then Alteplase, TPA-05</arm_group_label>
    <arm_group_label>Part A: Alteplase, TPA-05 then Alteplase, TPA-02</arm_group_label>
    <arm_group_label>Part B: Alteplase, TPA-02 then Alteplase, TPA-05</arm_group_label>
    <arm_group_label>Part B: Alteplase, TPA-05 then Alteplase, TPA-02</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Healthy male subjects according to the assessment of the investigator, as based on a&#xD;
             complete medical history including a physical examination, vital signs (blood pressure&#xD;
             (BP), pulse rate (PR)), 12-lead electrocardiogram (ECG), and clinical laboratory tests&#xD;
&#xD;
          -  Age of 18 to 45 years (inclusive)&#xD;
&#xD;
          -  Body mass index (weight divided by height squared) (BMI) of 18.5 to 29.9 kg/m2&#xD;
             (inclusive)&#xD;
&#xD;
          -  Body weight of 65 - 100 kg (inclusive) at screening&#xD;
&#xD;
          -  Signed and dated written informed consent prior to admission to the study, in&#xD;
             accordance with Good Clinical Practice (GCP) and local legislation&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Any finding in the medical examination (including BP, PR or ECG) deviating from normal&#xD;
             and assessed as clinically relevant by the investigator&#xD;
&#xD;
          -  Repeated measurement of systolic blood pressure outside the range of 90 to 140 mmHg,&#xD;
             diastolic blood pressure outside the range of 50 to 90 mmHg, or pulse rate outside the&#xD;
             range of 45 to 90 bpm&#xD;
&#xD;
          -  Any laboratory value outside the reference range that the investigator considers to be&#xD;
             of clinical relevance, e.g. thrombotic predisposition according to thrombophilic&#xD;
             testing&#xD;
&#xD;
          -  Any evidence of a concomitant disease assessed as clinically relevant by the&#xD;
             investigator&#xD;
&#xD;
          -  Gastrointestinal, hepatic, renal, respiratory, cardiovascular, metabolic,&#xD;
             immunological or hormonal disorders&#xD;
&#xD;
          -  Diseases of the central nervous system (including but not limited to any kind of&#xD;
             seizures or stroke), and other relevant neurological or psychiatric disorders&#xD;
&#xD;
          -  History of relevant orthostatic hypotension, fainting spells, or blackouts&#xD;
&#xD;
          -  Chronic or relevant acute infections&#xD;
&#xD;
          -  History of relevant allergy or hypersensitivity&#xD;
&#xD;
          -  During COVID-19 pandemic: laboratory test indicative of an ongoing SARS-CoV-2&#xD;
             infection Further exclusion criteria apply.&#xD;
      </textblock>
    </criteria>
    <gender>Male</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>45 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <location>
    <facility>
      <name>Humanpharmakologisches Zentrum Biberach</name>
      <address>
        <city>Biberach</city>
        <zip>88397</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Germany</country>
  </location_countries>
  <link>
    <url>http://www.mystudywindow.com</url>
    <description>Related Info</description>
  </link>
  <verification_date>April 2023</verification_date>
  <study_first_submitted>June 4, 2020</study_first_submitted>
  <study_first_submitted_qc>June 4, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">June 5, 2020</study_first_posted>
  <results_first_submitted>June 20, 2022</results_first_submitted>
  <results_first_submitted_qc>April 25, 2023</results_first_submitted_qc>
  <results_first_posted type="Actual">April 26, 2023</results_first_posted>
  <last_update_submitted>April 25, 2023</last_update_submitted>
  <last_update_submitted_qc>April 25, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">April 26, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Heparin</mesh_term>
    <mesh_term>Calcium heparin</mesh_term>
    <mesh_term>Tissue Plasminogen Activator</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
    <ipd_description>Clinical studies sponsored by Boehringer Ingelheim, phases I to IV, interventional and non-interventional, are in scope for sharing of the raw clinical study data and clinical study documents, except for the following exclusions:&#xD;
studies in products where Boehringer Ingelheim is not the license holder;&#xD;
studies regarding pharmaceutical formulations and associated analytical methods, and studies pertinent to pharmacokinetics using human biomaterials;&#xD;
studies conducted in a single center or targeting rare diseases (because of limitations with anonymization).&#xD;
For more details refer to: https://www.mystudywindow.com/msw/datasharing</ipd_description>
  </patient_data>
  <provided_document_section>
    <provided_document>
      <document_type>Study Protocol</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>No</document_has_sap>
      <document_date>April 14, 2021</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/93/NCT04419493/Prot_000.pdf</document_url>
    </provided_document>
    <provided_document>
      <document_type>Statistical Analysis Plan</document_type>
      <document_has_protocol>No</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>April 19, 2021</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/93/NCT04419493/SAP_001.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <recruitment_details>This was a randomised, open-label, 2 -way cross-over design with at least 24 h wash-out, to establish the bioequivalence of alteplase derived from two different manufacturing processes (new process, tissue plasminogen activator (TPA)-05, vs. current process, TPA-02) in healthy male volunteers.</recruitment_details>
      <pre_assignment_details>All subjects were screened for eligibility prior to participation in the trial. Subjects attended a specialist site which ensured that they (the subjects) strictly met all inclusion and none of the exclusion criteria.&#xD;
Subjects were not to be allocated to a treatment group if any of the entry criteria were violated. In this cross-over trial 2 single doses of alteplase were infused on 2 consecutive days keeping a wash-out period of at least 24 h.</pre_assignment_details>
      <group_list>
        <group group_id="P1">
          <title>Part A: Alteplase, TPA-02 Then Alteplase, TPA-05</title>
          <description>Participants were administered on Day 1 of Period 1 a single dose of 0.2 milligram (mg)/kilogram (kg) body weight of alteplase from current manufacturing process (alteplase, TPA-02) intravenously (i.v.) over a 30 minutes (min) infusion.&#xD;
On Day 1 of Period 2 participants were administered a single dose of 0.2 mg/kg body weight of alteplase from modified manufacturing process (alteplase, TPA-05) intravenously (i.v.) over a 30 min infusion.&#xD;
The 2 treatment periods were separated by a washout period of at least 24 hours (h).</description>
        </group>
        <group group_id="P2">
          <title>Part A: Alteplase, TPA-05 Then Alteplase, TPA-02</title>
          <description>Participants were administered on Day 1 of Period 1 a single dose of 0.2 milligram (mg)/kilogram (kg) body weight of alteplase from modified manufacturing process (alteplase, TPA-05) intravenously (i.v.) over a 30 minutes (min) infusion.&#xD;
On Day 1 of Period 2 participants were administered a single dose of 0.2 mg/kg body weight of alteplase from current manufacturing process (alteplase, TPA-02) intravenously (i.v.) over a 30 min infusion.&#xD;
The 2 treatment periods were separated by a washout period of at least 24 hours (h).</description>
        </group>
        <group group_id="P3">
          <title>Part B: Alteplase, TPA-02 Then Alteplase, TPA-05</title>
          <description>Participants were administered on Day 1 of Period 1 a single dose of 0.2 milligram (mg)/kilogram (kg) body weight of alteplase from current manufacturing process (alteplase, TPA-02) intravenously (i.v.) over a 30 minutes (min) infusion. 5 min prior to the infusion of alteplase, TPA-02, participants were administered 5000 international units (IU) of the auxiliary medicinal product (AMP) unfractionated heparin (Heparin-Natrium-ratiopharm®) as an intravenous bolus.&#xD;
On Day 1 of Period 2 participants were administered a single dose of 0.2 mg/kg body weight of alteplase from modified manufacturing process (alteplase, TPA-05) intravenously (i.v.) over a 30 min infusion. 5 min prior to the infusion of alteplase, TPA-05, participants were administered 5000 international units (IU) of the auxiliary medicinal product (AMP) unfractionated heparin (Heparin-Natrium-ratiopharm®) as an intravenous bolus.&#xD;
The 2 treatment periods were separated by a washout period of at least 24 hours (h).</description>
        </group>
        <group group_id="P4">
          <title>Part B: Alteplase, TPA-05 Then Alteplase, TPA-02</title>
          <description>Participants were administered on Day 1 of Period 1 a single dose of 0.2 milligram (mg)/kilogram (kg) body weight of alteplase from modified manufacturing process (alteplase, TPA-05) intravenously (i.v.) over a 30 minutes (min) infusion. 5 min prior to the infusion of alteplase, TPA-05, participants were administered 5000 international units (IU) of the auxiliary medicinal product (AMP) unfractionated heparin (Heparin-Natrium-ratiopharm®) as an intravenous bolus.&#xD;
On Day 1 of Period 2 participants were administered a single dose of 0.2 mg/kg body weight of alteplase from current manufacturing process (alteplase, TPA-02) intravenously (i.v.) over a 30 min infusion. 5 min prior to the infusion of alteplase, TPA-02, participants were administered 5000 international units (IU) of the auxiliary medicinal product (AMP) unfractionated heparin (Heparin-Natrium-ratiopharm®) as an intravenous bolus.&#xD;
The 2 treatment periods were separated by a washout period of at least 24 hours (h).</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Period 1</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="6"/>
                <participants group_id="P2" count="6"/>
                <participants group_id="P3" count="9"/>
                <participants group_id="P4" count="9"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="6"/>
                <participants group_id="P2" count="6"/>
                <participants group_id="P3" count="9"/>
                <participants group_id="P4" count="9"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="0"/>
                <participants group_id="P4" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
        <period>
          <title>Wash-out After Period 1</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="6"/>
                <participants group_id="P2" count="6"/>
                <participants group_id="P3" count="9"/>
                <participants group_id="P4" count="9"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="5"/>
                <participants group_id="P2" count="4"/>
                <participants group_id="P3" count="8"/>
                <participants group_id="P4" count="9"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="2"/>
                <participants group_id="P3" count="1"/>
                <participants group_id="P4" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Adverse Event</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="2"/>
                <participants group_id="P3" count="1"/>
                <participants group_id="P4" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
        <period>
          <title>Period 2</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="5"/>
                <participants group_id="P2" count="4"/>
                <participants group_id="P3" count="8"/>
                <participants group_id="P4" count="9"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="5"/>
                <participants group_id="P2" count="4"/>
                <participants group_id="P3" count="8"/>
                <participants group_id="P4" count="9"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="0"/>
                <participants group_id="P4" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <population>Treated set - part A (TS-A) included all subjects who were randomised and treated with at least 1 dose of the investigational medicinal product.&#xD;
Treated set - part B (TS-B) included all subjects who had been randomised and treated with at least 1 dose of the investigational medicinal product.</population>
      <group_list>
        <group group_id="B1">
          <title>Part A: Alteplase, TPA-02 Then Alteplase, TPA-05</title>
          <description>Participants were administered on Day 1 of Period 1 a single dose of 0.2 milligram (mg)/kilogram (kg) body weight of alteplase from current manufacturing process (alteplase, TPA-02) intravenously (i.v.) over a 30 minutes (min) infusion.&#xD;
On Day 1 of Period 2 participants were administered a single dose of 0.2 mg/kg body weight of alteplase from modified manufacturing process (alteplase, TPA-05) intravenously (i.v.) over a 30 min infusion.&#xD;
The 2 treatment periods were separated by a washout period of at least 24 hours (h).</description>
        </group>
        <group group_id="B2">
          <title>Part A: Alteplase, TPA-05 Then Alteplase, TPA-02</title>
          <description>Participants were administered on Day 1 of Period 1 a single dose of 0.2 milligram (mg)/kilogram (kg) body weight of alteplase from modified manufacturing process (alteplase, TPA-05) intravenously (i.v.) over a 30 minutes (min) infusion.&#xD;
On Day 1 of Period 2 participants were administered a single dose of 0.2 mg/kg body weight of alteplase from current manufacturing process (alteplase, TPA-02) intravenously (i.v.) over a 30 min infusion.&#xD;
The 2 treatment periods were separated by a washout period of at least 24 hours (h).</description>
        </group>
        <group group_id="B3">
          <title>Part B: Alteplase, TPA-02 Then Alteplase, TPA-05</title>
          <description>Participants were administered on Day 1 of Period 1 a single dose of 0.2 milligram (mg)/kilogram (kg) body weight of alteplase from current manufacturing process (alteplase, TPA-02) intravenously (i.v.) over a 30 minutes (min) infusion. 5 min prior to the infusion of alteplase, TPA-02, participants were administered 5000 international units (IU) of the auxiliary medicinal product (AMP) unfractionated heparin (Heparin-Natrium-ratiopharm®) as an intravenous bolus.&#xD;
On Day 1 of Period 2 participants were administered a single dose of 0.2 mg/kg body weight of alteplase from modified manufacturing process (alteplase, TPA-05) intravenously (i.v.) over a 30 min infusion. 5 min prior to the infusion of alteplase, TPA-05, participants were administered 5000 international units (IU) of the auxiliary medicinal product (AMP) unfractionated heparin (Heparin-Natrium-ratiopharm®) as an intravenous bolus.&#xD;
The 2 treatment periods were separated by a washout period of at least 24 hours (h).</description>
        </group>
        <group group_id="B4">
          <title>Part B: Alteplase, TPA-05 Then Alteplase, TPA-02</title>
          <description>Participants were administered on Day 1 of Period 1 a single dose of 0.2 milligram (mg)/kilogram (kg) body weight of alteplase from modified manufacturing process (alteplase, TPA-05) intravenously (i.v.) over a 30 minutes (min) infusion. 5 min prior to the infusion of alteplase, TPA-05, participants were administered 5000 international units (IU) of the auxiliary medicinal product (AMP) unfractionated heparin (Heparin-Natrium-ratiopharm®) as an intravenous bolus.&#xD;
On Day 1 of Period 2 participants were administered a single dose of 0.2 mg/kg body weight of alteplase from current manufacturing process (alteplase, TPA-02) intravenously (i.v.) over a 30 min infusion. 5 min prior to the infusion of alteplase, TPA-02, participants were administered 5000 international units (IU) of the auxiliary medicinal product (AMP) unfractionated heparin (Heparin-Natrium-ratiopharm®) as an intravenous bolus.&#xD;
The 2 treatment periods were separated by a washout period of at least 24 hours (h).</description>
        </group>
        <group group_id="B5">
          <title>Total</title>
          <description>Total of all reporting groups</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="6"/>
            <count group_id="B2" value="6"/>
            <count group_id="B3" value="9"/>
            <count group_id="B4" value="9"/>
            <count group_id="B5" value="30"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>Years</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="34.3" spread="5.8"/>
                    <measurement group_id="B2" value="32.2" spread="6.2"/>
                    <measurement group_id="B3" value="31.7" spread="5.8"/>
                    <measurement group_id="B4" value="35.8" spread="5.8"/>
                    <measurement group_id="B5" value="33.5" spread="5.8"/>
                  </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 group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="0"/>
                    <measurement group_id="B5" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="6"/>
                    <measurement group_id="B2" value="6"/>
                    <measurement group_id="B3" value="9"/>
                    <measurement group_id="B4" value="9"/>
                    <measurement group_id="B5" value="30"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Ethnicity (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="1"/>
                    <measurement group_id="B5" value="1"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Not Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="6"/>
                    <measurement group_id="B2" value="6"/>
                    <measurement group_id="B3" value="9"/>
                    <measurement group_id="B4" value="8"/>
                    <measurement group_id="B5" value="29"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="0"/>
                    <measurement group_id="B5" value="0"/>
                  </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 group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="0"/>
                    <measurement group_id="B5" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Asian</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="0"/>
                    <measurement group_id="B5" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Native Hawaiian or Other Pacific Islander</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="0"/>
                    <measurement group_id="B5" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Black or African American</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="1"/>
                    <measurement group_id="B5" value="1"/>
                  </measurement_list>
                </category>
                <category>
                  <title>White</title>
                  <measurement_list>
                    <measurement group_id="B1" value="6"/>
                    <measurement group_id="B2" value="6"/>
                    <measurement group_id="B3" value="9"/>
                    <measurement group_id="B4" value="8"/>
                    <measurement group_id="B5" value="29"/>
                  </measurement_list>
                </category>
                <category>
                  <title>More than one race</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="0"/>
                    <measurement group_id="B5" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="0"/>
                    <measurement group_id="B5" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Part A: Area Under the Concentration-time Curve of Alteplase in Plasma Over the Time Interval From 0 up to the Last Quantifiable Data Point (AUC0-tz)</title>
        <description>The area under the concentration-time curve of alteplase in plasma over the time interval from 0 to the last quantifiable data point (AUC0-tz) is reported.</description>
        <time_frame>Within 3 hours (h) before and 5 minutes (min), 10min, 15min, 20min, 25min, 30min, 32min, 34min, 36min, 40min, 45min, 50min, 1h, 1.33h, 1.67h, 2h, 3h, 4h and 6h after start of alteplase infusion.</time_frame>
        <population>Pharmacokinetic parameter analysis set - part A (PKS-A): Includes all subjects in the treated set - part A (TS-A) who provide at least one PK endpoint that was defined as primary or secondary and was not excluded due to a protocol violation to the evaluation of PK or due to PK non-evaluability. PK data for Part A were not used for the final assessment of bioequivalence according to protocol amendment after obtaining unreliable PK results.</population>
        <group_list>
          <group group_id="O1">
            <title>Part A: Alteplase, TPA -02</title>
            <description>Participants were administered during trial Part A a single dose of 0.2 milligram (mg)/kilogram (kg) body weight of alteplase from current manufacturing process (alteplase, TPA-02) intravenously (i.v.) over a 30 minutes (min) infusion.</description>
          </group>
          <group group_id="O2">
            <title>Part A: Alteplase, TPA-05</title>
            <description>Participants were administered during trial Part B a single dose of 0.2 milligram (mg)/kilogram (kg) body weight of alteplase from modified manufacturing process (alteplase, TPA-05) intravenously (i.v.) over a 30 minutes (min) infusion.</description>
          </group>
        </group_list>
        <measure>
          <title>Part A: Area Under the Concentration-time Curve of Alteplase in Plasma Over the Time Interval From 0 up to the Last Quantifiable Data Point (AUC0-tz)</title>
          <description>The area under the concentration-time curve of alteplase in plasma over the time interval from 0 to the last quantifiable data point (AUC0-tz) is reported.</description>
          <population>Pharmacokinetic parameter analysis set - part A (PKS-A): Includes all subjects in the treated set - part A (TS-A) who provide at least one PK endpoint that was defined as primary or secondary and was not excluded due to a protocol violation to the evaluation of PK or due to PK non-evaluability. PK data for Part A were not used for the final assessment of bioequivalence according to protocol amendment after obtaining unreliable PK results.</population>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="0"/>
                <count group_id="O2" value="0"/>
              </count_list>
            </analyzed>
          </analyzed_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Part B: Area Under the Concentration-time Curve of Alteplase in Plasma Over the Time Interval From 0 up to the Last Quantifiable Data Point (AUC0-tz)</title>
        <description>The area under the concentration-time curve of Alteplase in plasma over the time interval from 0 to the last quantifiable data point (AUC0-tz) is reported.</description>
        <time_frame>Within 3 hours (h) before and 5 minutes (min), 10min, 15min, 20min, 25min, 30min, 32min, 34min, 36min, 40min, 45min, 50min, 1h, 1.33h, 1.67h, 2h, 3h, 4h and 6h after start of alteplase infusion.</time_frame>
        <population>Pharmacokinetic parameter analysis set - part B(PKS-B): This set includes all subjects in the treated set - part B (TS-B) who provide at least one Pharmacokinetic (PK) endpoint that was defined as primary or secondary and was not excluded due to a protocol violation relevant to the evaluation of PK or due to PK non-evaluability.</population>
        <group_list>
          <group group_id="O1">
            <title>Part B: Alteplase, TPA -02</title>
            <description>Participants were administered during trial Part B a single dose of 0.2 milligram (mg)/kilogram (kg) body weight of alteplase from current manufacturing process (alteplase, TPA-02) intravenously (i.v.) over a 30 minutes (min) infusion. 5 min prior to the infusion of alteplase, TPA-02, participants were administered 5000 international units (IU) of the auxiliary medicinal product (AMP) unfractionated heparin (Heparin-Natrium-ratiopharm®) as an intravenous bolus.</description>
          </group>
          <group group_id="O2">
            <title>Part B: Alteplase, TPA-05</title>
            <description>Participants were administered during trial Part B a single dose of 0.2 milligram (mg)/kilogram (kg) body weight of alteplase from modified manufacturing process (alteplase, TPA-05) intravenously (i.v.) over a 30 minutes (min) infusion. 5 min prior to the infusion of alteplase, TPA-05, participants were administered 5000 international units (IU) of the auxiliary medicinal product (AMP) unfractionated heparin (Heparin-Natrium-ratiopharm®) as an intravenous bolus.</description>
          </group>
        </group_list>
        <measure>
          <title>Part B: Area Under the Concentration-time Curve of Alteplase in Plasma Over the Time Interval From 0 up to the Last Quantifiable Data Point (AUC0-tz)</title>
          <description>The area under the concentration-time curve of Alteplase in plasma over the time interval from 0 to the last quantifiable data point (AUC0-tz) is reported.</description>
          <population>Pharmacokinetic parameter analysis set - part B(PKS-B): This set includes all subjects in the treated set - part B (TS-B) who provide at least one Pharmacokinetic (PK) endpoint that was defined as primary or secondary and was not excluded due to a protocol violation relevant to the evaluation of PK or due to PK non-evaluability.</population>
          <units>hour * nanogram / milliliter (h*ng/mL)</units>
          <param>Geometric Least Squares Mean</param>
          <dispersion>Standard Error</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="16"/>
                <count group_id="O2" value="16"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="369.21" spread="NA">The standard error is actually adjusted standard error and is equal to 1.03.</measurement>
                    <measurement group_id="O2" value="377.35" spread="NA">The standard error is actually adjusted standard error and is equal to 1.03.</measurement>
                  </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>
            <groups_desc>The null hypothesis was that the ratio of expected geometric least squares means Alteplase, TPA-02 vs. Alteplase, TPA-05 is less than 80.00% or more than 125.00%.&#xD;
The statistical model used for the analysis of this endpoints was an analysis of variance (ANOVA) model on the logarithmic scale.&#xD;
This model included effects accounting for the following sources of variation: sequence, subjects within sequences, period and treatment. All effects were considered as fixed.</groups_desc>
            <non_inferiority_type>Equivalence</non_inferiority_type>
            <non_inferiority_desc>Bioequivalence was concluded, if the confidence interval (CI) for the comparison of geometric least squares means ratio was included in the pre-defined equivalence range of 80.00% to 125.00%</non_inferiority_desc>
            <param_type>Geometric Least Squares Mean ratio (%)</param_type>
            <param_value>102.20</param_value>
            <dispersion_type>Standard Error of the Mean</dispersion_type>
            <dispersion_value>10.8</dispersion_value>
            <ci_percent>92.83</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>94.87</ci_lower_limit>
            <ci_upper_limit>110.10</ci_upper_limit>
            <estimate_desc>Geometric Least Squares Mean ratio is: Alteplase, TPA-02/Alteplase, TPA-05. Standard Error of the mean is actually the intra-individual geometric coefficient variation.</estimate_desc>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Part A: Maximum Measured Concentration of Alteplase in Plasma (Cmax)</title>
        <description>Maximum measured concentration of alteplase in plasma is reported.</description>
        <time_frame>Within 3 hours (h) before and 5 minutes (min), 10min, 15min, 20min, 25min, 30min, 32min, 34min, 36min, 40min, 45min, 50min, 1h, 1.33h, 1.67h, 2h, 3h, 4h and 6h after start of alteplase infusion.</time_frame>
        <population>Pharmacokinetic parameter analysis set - part A (PKS-A): Includes all subjects in the treated set - part A (TS-A) who provide at least one PK endpoint that was defined as primary or secondary and was not excluded due to a protocol violation to the evaluation of PK or due to PK non-evaluability. PK data for Part A were not used for the final assessment of bioequivalence according to protocol amendment after obtaining unreliable PK results.</population>
        <group_list>
          <group group_id="O1">
            <title>Part A: Alteplase, TPA -02</title>
            <description>Participants were administered during trial Part A a single dose of 0.2 milligram (mg)/kilogram (kg) body weight of alteplase from current manufacturing process (alteplase, TPA-02) intravenously (i.v.) over a 30 minutes (min) infusion.</description>
          </group>
          <group group_id="O2">
            <title>Part A: Alteplase, TPA-05</title>
            <description>Participants were administered during trial Part A a single dose of 0.2 milligram (mg)/kilogram (kg) body weight of alteplase from modified manufacturing process (alteplase, TPA-05) intravenously (i.v.) over a 30 minutes (min) infusion.</description>
          </group>
        </group_list>
        <measure>
          <title>Part A: Maximum Measured Concentration of Alteplase in Plasma (Cmax)</title>
          <description>Maximum measured concentration of alteplase in plasma is reported.</description>
          <population>Pharmacokinetic parameter analysis set - part A (PKS-A): Includes all subjects in the treated set - part A (TS-A) who provide at least one PK endpoint that was defined as primary or secondary and was not excluded due to a protocol violation to the evaluation of PK or due to PK non-evaluability. PK data for Part A were not used for the final assessment of bioequivalence according to protocol amendment after obtaining unreliable PK results.</population>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="0"/>
                <count group_id="O2" value="0"/>
              </count_list>
            </analyzed>
          </analyzed_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Part B: Maximum Measured Concentration of Alteplase in Plasma (Cmax)</title>
        <description>Maximum measured concentration of Alteplase in plasma (Cmax) is reported.</description>
        <time_frame>Within 3 hours (h) before and 5 minutes (min), 10min, 15min, 20min, 25min, 30min, 32min, 34min, 36min, 40min, 45min, 50min, 1h, 1.33h, 1.67h, 2h, 3h, 4h and 6h after start of alteplase infusion.</time_frame>
        <population>Pharmacokinetic parameter analysis set - part B(PKS-B): This set includes all subjects in the treated set - part B (TS-B) who provide at least one Pharmacokinetic (PK) endpoint that was defined as primary or secondary and was not excluded due to a protocol violation relevant to the evaluation of PK or due to PK non-evaluability.</population>
        <group_list>
          <group group_id="O1">
            <title>Part B: Alteplase, TPA -02</title>
            <description>Participants were administered during trial Part B a single dose of 0.2 milligram (mg)/kilogram (kg) body weight of alteplase from current manufacturing process (alteplase, TPA-02) intravenously (i.v.) over a 30 minutes (min) infusion. 5 min prior to the infusion of alteplase, TPA-02, participants were administered 5000 international units (IU) of the auxiliary medicinal product (AMP) unfractionated heparin (Heparin-Natrium-ratiopharm®) as an intravenous bolus.</description>
          </group>
          <group group_id="O2">
            <title>Part B: Alteplase, TPA-05</title>
            <description>Participants were administered during trial Part B a single dose of 0.2 milligram (mg)/kilogram (kg) body weight of alteplase from modified manufacturing process (alteplase, TPA-05) intravenously (i.v.) over a 30 minutes (min) infusion. 5 min prior to the infusion of alteplase, TPA-05, participants were administered 5000 international units (IU) of the auxiliary medicinal product (AMP) unfractionated heparin (Heparin-Natrium-ratiopharm®) as an intravenous bolus.</description>
          </group>
        </group_list>
        <measure>
          <title>Part B: Maximum Measured Concentration of Alteplase in Plasma (Cmax)</title>
          <description>Maximum measured concentration of Alteplase in plasma (Cmax) is reported.</description>
          <population>Pharmacokinetic parameter analysis set - part B(PKS-B): This set includes all subjects in the treated set - part B (TS-B) who provide at least one Pharmacokinetic (PK) endpoint that was defined as primary or secondary and was not excluded due to a protocol violation relevant to the evaluation of PK or due to PK non-evaluability.</population>
          <units>nanogram / milliliter (ng/mL)</units>
          <param>Geometric Least Squares Mean</param>
          <dispersion>Standard Error</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="16"/>
                <count group_id="O2" value="16"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="738.35" spread="NA">The standard error is actually adjusted standard error and is equal to 1.02.</measurement>
                    <measurement group_id="O2" value="781.24" spread="NA">The standard error is actually adjusted standard error and is equal to 1.02.</measurement>
                  </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>
            <groups_desc>The null hypothesis was that the ratio of expected geometric least squares means Alteplase, TPA-02 vs. Alteplase, TPA-05 is less than 80.00% or more than 125.00%.&#xD;
The statistical model used for the analysis of this endpoints was an analysis of variance (ANOVA) model on the logarithmic scale.&#xD;
This model included effects accounting for the following sources of variation: sequence, subjects within sequences, period and treatment. All effects were considered as fixed.</groups_desc>
            <non_inferiority_type>Equivalence</non_inferiority_type>
            <non_inferiority_desc>Bioequivalence was concluded, if the confidence interval (CI) for the comparison of geometric least squares means ratio was included in the pre-defined equivalence range of 80.00% to 125.00%</non_inferiority_desc>
            <param_type>Geometric Least Squares Mean ratio (%)</param_type>
            <param_value>105.81</param_value>
            <dispersion_type>Standard Error of the Mean</dispersion_type>
            <dispersion_value>9.3</dispersion_value>
            <ci_percent>92.83</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>99.18</ci_lower_limit>
            <ci_upper_limit>112.88</ci_upper_limit>
            <estimate_desc>Geometric Least Squares Mean ratio is: Alteplase, TPA-02/Alteplase, TPA-05. Standard Error of the mean is actually the intra-individual geometric coefficient variation.</estimate_desc>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Part A: Area Under the Concentration-time Curve of Alteplase in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞)</title>
        <description>Area under the concentration-time curve of alteplase in plasma over interval from 0 extrapolated to infinity is reported.</description>
        <time_frame>Within 3 hours (h) before and 5 minutes (min), 10min, 15min, 20min, 25min, 30min, 32min, 34min, 36min, 40min, 45min, 50min, 1h, 1.33h, 1.67h, 2h, 3h, 4h and 6h after start of alteplase infusion.</time_frame>
        <population>Pharmacokinetic parameter analysis set - part A (PKS-A): Includes all subjects in the treated set - part A (TS-A) who provide at least one PK endpoint that was defined as primary or secondary and was not excluded due to a protocol violation to the evaluation of PK or due to PK non-evaluability. PK data for Part A were not used for the final assessment of bioequivalence according to protocol amendment after obtaining unreliable PK results.</population>
        <group_list>
          <group group_id="O1">
            <title>Part A: Alteplase, TPA -02</title>
            <description>Participants were administered during trial Part A a single dose of 0.2 milligram (mg)/kilogram (kg) body weight of alteplase from current manufacturing process (alteplase, TPA-02) intravenously (i.v.) over a 30 minutes (min) infusion.</description>
          </group>
          <group group_id="O2">
            <title>Part A: Alteplase, TPA-05</title>
            <description>Participants were administered during trial Part A a single dose of 0.2 milligram (mg)/kilogram (kg) body weight of alteplase from modified manufacturing process (alteplase, TPA-05) intravenously (i.v.) over a 30 minutes (min) infusion.</description>
          </group>
        </group_list>
        <measure>
          <title>Part A: Area Under the Concentration-time Curve of Alteplase in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞)</title>
          <description>Area under the concentration-time curve of alteplase in plasma over interval from 0 extrapolated to infinity is reported.</description>
          <population>Pharmacokinetic parameter analysis set - part A (PKS-A): Includes all subjects in the treated set - part A (TS-A) who provide at least one PK endpoint that was defined as primary or secondary and was not excluded due to a protocol violation to the evaluation of PK or due to PK non-evaluability. PK data for Part A were not used for the final assessment of bioequivalence according to protocol amendment after obtaining unreliable PK results.</population>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="0"/>
                <count group_id="O2" value="0"/>
              </count_list>
            </analyzed>
          </analyzed_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Part B: Area Under the Concentration-time Curve of Alteplase in Plasma Over the Interval From 0 Extrapolated to Infinity (AUC0-∞)</title>
        <description>Area under the concentration-time curve of alteplase in plasma over the interval from 0 extrapolated to infinity is reported.</description>
        <time_frame>Within 3 hours (h) before and 5 minutes (min), 10min, 15min, 20min, 25min, 30min, 32min, 34min, 36min, 40min, 45min, 50min, 1h, 1.33h, 1.67h, 2h, 3h, 4h and 6h after start of alteplase infusion.</time_frame>
        <population>Pharmacokinetic parameter analysis set - part B(PKS-B): This set includes all subjects in the treated set - part B (TS-B) who provide at least one Pharmacokinetic (PK) endpoint that was defined as primary or secondary and was not excluded due to a protocol violation relevant to the evaluation of PK or due to PK non-evaluability.</population>
        <group_list>
          <group group_id="O1">
            <title>Part B: Alteplase, TPA -02</title>
            <description>Participants were administered during trial Part B a single dose of 0.2 milligram (mg)/kilogram (kg) body weight of alteplase from current manufacturing process (alteplase, TPA-02) intravenously (i.v.) over a 30 minutes (min) infusion. 5 min prior to the infusion of alteplase, TPA-02, participants were administered 5000 international units (IU) of the auxiliary medicinal product (AMP) unfractionated heparin (Heparin-Natrium-ratiopharm®) as an intravenous bolus.</description>
          </group>
          <group group_id="O2">
            <title>Part B: Alteplase, TPA-05</title>
            <description>Participants were administered during trial Part B a single dose of 0.2 milligram (mg)/kilogram (kg) body weight of alteplase from modified manufacturing process (alteplase, TPA-05) intravenously (i.v.) over a 30 minutes (min) infusion. 5 min prior to the infusion of alteplase, TPA-05, participants were administered 5000 international units (IU) of the auxiliary medicinal product (AMP) unfractionated heparin (Heparin-Natrium-ratiopharm®) as an intravenous bolus.</description>
          </group>
        </group_list>
        <measure>
          <title>Part B: Area Under the Concentration-time Curve of Alteplase in Plasma Over the Interval From 0 Extrapolated to Infinity (AUC0-∞)</title>
          <description>Area under the concentration-time curve of alteplase in plasma over the interval from 0 extrapolated to infinity is reported.</description>
          <population>Pharmacokinetic parameter analysis set - part B(PKS-B): This set includes all subjects in the treated set - part B (TS-B) who provide at least one Pharmacokinetic (PK) endpoint that was defined as primary or secondary and was not excluded due to a protocol violation relevant to the evaluation of PK or due to PK non-evaluability.</population>
          <units>hour*nanogram/milliliter (h*ng/mL)</units>
          <param>Geometric Least Squares Mean</param>
          <dispersion>Standard Error</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="16"/>
                <count group_id="O2" value="16"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="371.85" spread="NA">The standard error is actually adjusted standard error and is equal to 1.03.</measurement>
                    <measurement group_id="O2" value="379.90" spread="NA">The standard error is actually adjusted standard error and is equal to 1.03.</measurement>
                  </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>
            <groups_desc>The null hypothesis was that the ratio of expected geometric least squares means Alteplase, TPA-02 vs. Alteplase, TPA-05 is less than 80.00% or more than 125.00%.&#xD;
The statistical model used for the analysis of this endpoints was an analysis of variance (ANOVA) model on the logarithmic scale.&#xD;
This model included effects accounting for the following sources of variation: sequence, subjects within sequences, period and treatment. All effects were considered as fixed.</groups_desc>
            <non_inferiority_type>Equivalence</non_inferiority_type>
            <non_inferiority_desc>Bioequivalence was concluded, if the confidence interval (CI) for the comparison of geometric least squares means ratio was included in the pre-defined equivalence range of 80.00% to 125.00% .</non_inferiority_desc>
            <param_type>Geometric Least Squares Mean ratio (%)</param_type>
            <param_value>102.17</param_value>
            <dispersion_type>Standard Error of the Mean</dispersion_type>
            <dispersion_value>10.8</dispersion_value>
            <ci_percent>92.83</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>94.79</ci_lower_limit>
            <ci_upper_limit>110.12</ci_upper_limit>
            <estimate_desc>Geometric Least Squares Mean ratio is: Alteplase, TPA-02/Alteplase, TPA-05. Standard Error of the mean is actually the intra-individual geometric coefficient variation.</estimate_desc>
          </analysis>
        </analysis_list>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>Up to 22 days after the last administration of alteplase.</time_frame>
      <desc>Treated set - part A (TS-A) and Treated set - part B (TS-B): The treated sets includes all subjects who were randomized and treated with at least one dose of study drug.</desc>
      <group_list>
        <group group_id="E1">
          <title>Part A: Alteplase, TPA-02</title>
          <description>Participants were administered during trial Part A a single dose of 0.2 milligram (mg)/kilogram (kg) body weight of alteplase from current manufacturing process (alteplase, TPA-02) intravenously (i.v.) over a 30 minutes (min) infusion.</description>
        </group>
        <group group_id="E2">
          <title>Part B: Alteplase, TPA-02</title>
          <description>Participants were administered during trial Part B a single dose of 0.2 milligram (mg)/kilogram (kg) body weight of alteplase from current manufacturing process (alteplase, TPA-02) intravenously (i.v.) over a 30 minutes (min) infusion. 5 min prior to the infusion of alteplase, TPA-02, participants were administered 5000 international units (IU) of the auxiliary medicinal product (AMP) unfractionated heparin (Heparin-Natrium-ratiopharm®) as an intravenous bolus.</description>
        </group>
        <group group_id="E3">
          <title>Part A: Alteplase, TPA-05</title>
          <description>Participants were administered during trial Part A a single dose of 0.2 milligram (mg)/kilogram (kg) body weight of alteplase from modified manufacturing process (alteplase, TPA-05) intravenously (i.v.) over a 30 minutes (min) infusion.</description>
        </group>
        <group group_id="E4">
          <title>Part B: Alteplase, TPA-05</title>
          <description>Participants were administered during trial Part B a single dose of 0.2 milligram (mg)/kilogram (kg) body weight of alteplase from modified manufacturing process (alteplase, TPA-05) intravenously (i.v.) over a 30 minutes (min) infusion. 5 min prior to the infusion of alteplase, TPA-05, participants were administered 5000 international units (IU) of the auxiliary medicinal product (AMP) unfractionated heparin (Heparin-Natrium-ratiopharm®) as an intravenous bolus.</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="10"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="18"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="17"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="18"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="17"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>5</frequency_threshold>
        <default_vocab>MedDRA 24.0</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="10"/>
                <counts group_id="E2" subjects_affected="7" subjects_at_risk="18"/>
                <counts group_id="E3" subjects_affected="4" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="6" subjects_at_risk="17"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Catheter site paraesthesia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="18"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="17"/>
              </event>
              <event>
                <sub_title>Catheter site swelling</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="18"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="17"/>
              </event>
              <event>
                <sub_title>Catheter site haematoma</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="18"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="2" subjects_at_risk="17"/>
              </event>
              <event>
                <sub_title>Catheter site pain</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="18"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="17"/>
              </event>
              <event>
                <sub_title>Infusion site pain</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="18"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="17"/>
              </event>
              <event>
                <sub_title>Vessel puncture site haematoma</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="18"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="17"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Injury, poisoning and procedural complications</title>
            <event_list>
              <event>
                <sub_title>Subcutaneous haematoma</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="18"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="17"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Arthralgia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="18"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="17"/>
              </event>
              <event>
                <sub_title>Muscle discomfort</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="18"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="17"/>
              </event>
              <event>
                <sub_title>Pain in extremity</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="18"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="17"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Headache</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="18"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="17"/>
              </event>
              <event>
                <sub_title>Paraesthesia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="18"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="17"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Product Issues</title>
            <event_list>
              <event>
                <sub_title>Device occlusion</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="18"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="17"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Vascular disorders</title>
            <event_list>
              <event>
                <sub_title>Haematoma</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="18"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="17"/>
              </event>
              <event>
                <sub_title>Hypotension</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="18"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="17"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>All Principal Investigators ARE employed by the organization sponsoring the study.</pi_employee>
      <restrictive_agreement>There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed. </restrictive_agreement>
    </certain_agreements>
    <limitations_and_caveats>For study Part A three subjects underwent only one treatment period, thereafter the trial was put on-hold. Trial Part B was performed as planned. There were no important protocol deviations (IPDs). Each entered subject met all of the inclusion criteria and none of the exclusion criteria.</limitations_and_caveats>
    <point_of_contact>
      <name_or_title>Boehringer Ingelheim, Call Center</name_or_title>
      <organization>Boehringer Ingelheim</organization>
      <phone>1-800-243-0127</phone>
      <email>clintriage.rdg@boehringer-ingelheim.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/NCT04419493
org study id: 0135-0340
secondary id: 2019-004932-40
nct id: NCT04419493
lead sponsor: 
is fda regulated drug: No
is fda regulated device: No
To establish the bioequivalence of alteplase derived from two different manufacturing
      processes.
allocation: Randomized
intervention model: Crossover Assignment
intervention model description: Part A: Open label Part B: Adaptive two-stage group-sequential design
primary purpose: Treatment
masking: None (Open Label)
measure: Part A: Area Under the Concentration-time Curve of Alteplase in Plasma Over the Time Interval From 0 up to the Last Quantifiable Data Point (AUC0-tz)
time frame: Within 3 hours (h) before and 5 minutes (min), 10min, 15min, 20min, 25min, 30min, 32min, 34min, 36min, 40min, 45min, 50min, 1h, 1.33h, 1.67h, 2h, 3h, 4h and 6h after start of alteplase infusion.
description: The area under the concentration-time curve of alteplase in plasma over the time interval from 0 to the last quantifiable data point (AUC0-tz) is reported.
measure: Part B: Area Under the Concentration-time Curve of Alteplase in Plasma Over the Time Interval From 0 up to the Last Quantifiable Data Point (AUC0-tz)
time frame: Within 3 hours (h) before and 5 minutes (min), 10min, 15min, 20min, 25min, 30min, 32min, 34min, 36min, 40min, 45min, 50min, 1h, 1.33h, 1.67h, 2h, 3h, 4h and 6h after start of alteplase infusion.
description: The area under the concentration-time curve of Alteplase in plasma over the time interval from 0 to the last quantifiable data point (AUC0-tz) is reported.
measure: Part A: Maximum Measured Concentration of Alteplase in Plasma (Cmax)
time frame: Within 3 hours (h) before and 5 minutes (min), 10min, 15min, 20min, 25min, 30min, 32min, 34min, 36min, 40min, 45min, 50min, 1h, 1.33h, 1.67h, 2h, 3h, 4h and 6h after start of alteplase infusion.
description: Maximum measured concentration of alteplase in plasma is reported.
measure: Part B: Maximum Measured Concentration of Alteplase in Plasma (Cmax)
time frame: Within 3 hours (h) before and 5 minutes (min), 10min, 15min, 20min, 25min, 30min, 32min, 34min, 36min, 40min, 45min, 50min, 1h, 1.33h, 1.67h, 2h, 3h, 4h and 6h after start of alteplase infusion.
description: Maximum measured concentration of Alteplase in plasma (Cmax) is reported.
measure: Part A: Area Under the Concentration-time Curve of Alteplase in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞)
time frame: Within 3 hours (h) before and 5 minutes (min), 10min, 15min, 20min, 25min, 30min, 32min, 34min, 36min, 40min, 45min, 50min, 1h, 1.33h, 1.67h, 2h, 3h, 4h and 6h after start of alteplase infusion.
description: Area under the concentration-time curve of alteplase in plasma over interval from 0 extrapolated to infinity is reported.
measure: Part B: Area Under the Concentration-time Curve of Alteplase in Plasma Over the Interval From 0 Extrapolated to Infinity (AUC0-∞)
time frame: Within 3 hours (h) before and 5 minutes (min), 10min, 15min, 20min, 25min, 30min, 32min, 34min, 36min, 40min, 45min, 50min, 1h, 1.33h, 1.67h, 2h, 3h, 4h and 6h after start of alteplase infusion.
description: Area under the concentration-time curve of alteplase in plasma over the interval from 0 extrapolated to infinity is reported.
arm group label: Part B: Alteplase, TPA-02 then Alteplase, TPA-05
arm group type: Experimental
arm group label: Part B: Alteplase, TPA-05 then Alteplase, TPA-02
arm group type: Active Comparator
arm group label: Part A: Alteplase, TPA-05 then Alteplase, TPA-02
arm group type: Experimental
description: Open-label
arm group label: Part A: Alteplase, TPA-02 then Alteplase, TPA-05
arm group type: Active Comparator
intervention type: Drug
intervention name: Alteplase (from modified manufacturing process)
description: Alteplase, TPA-05
arm group label: Part A: Alteplase, TPA-05 then Alteplase, TPA-02
arm group label: Part B: Alteplase, TPA-02 then Alteplase, TPA-05
intervention type: Drug
intervention name: Alteplase (from current manufacturing process)
description: Alteplase, TPA-02
arm group label: Part A: Alteplase, TPA-02 then Alteplase, TPA-05
arm group label: Part B: Alteplase, TPA-05 then Alteplase, TPA-02
intervention type: Drug
intervention name: Heparin-Natrium-5000-ratiopharm (unfractionated heparin)
description: Heparin-Natrium-5000-ratiopharm (unfractionated heparin)
arm group label: Part A: Alteplase, TPA-02 then Alteplase, TPA-05
arm group label: Part A: Alteplase, TPA-05 then Alteplase, TPA-02
arm group label: Part B: Alteplase, TPA-02 then Alteplase, TPA-05
arm group label: Part B: Alteplase, TPA-05 then Alteplase, TPA-02
criteria: 
gender: Male
minimum age: 18 Years
maximum age: 45 Years
healthy volunteers: Accepts Healthy Volunteers
facility: 
country: Germany
url: http://www.mystudywindow.com
description: Related Info
responsible party type: Sponsor
mesh term: Heparin
mesh term: Calcium heparin
mesh term: Tissue Plasminogen Activator
sharing ipd: No
ipd description: Clinical studies sponsored by Boehringer Ingelheim, phases I to IV, interventional and non-interventional, are in scope for sharing of the raw clinical study data and clinical study documents, except for the following exclusions:
studies in products where Boehringer Ingelheim is not the license holder;
studies regarding pharmaceutical formulations and associated analytical methods, and studies pertinent to pharmacokinetics using human biomaterials;
studies conducted in a single center or targeting rare diseases (because of limitations with anonymization).
For more details refer to: https://www.mystudywindow.com/msw/datasharing
provided document: 
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
limitations and caveats: For study Part A three subjects underwent only one treatment period, thereafter the trial was put on-hold. Trial Part B was performed as planned. There were no important protocol deviations (IPDs). Each entered subject met all of the inclusion criteria and none of the exclusion criteria.
point of contact: 