<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/NCT02256917</url>
  </required_header>
  <id_info>
    <org_study_id>GENA-21B</org_study_id>
    <nct_id>NCT02256917</nct_id>
  </id_info>
  <brief_title>Assess the Efficacy and Safety of Personalized Prophylaxis Human-cl rhFVIII in Patients With Severe Haemophilia A</brief_title>
  <official_title>Prospective, Open-label, Multi-centre Phase 3b Study to Assess the Efficacy and Safety of Personalized Prophylaxis With Human-cl rhFVIII in Previously Treated Adult Patients With Severe Haemophilia A</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Octapharma</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Octapharma</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      The rationale of this study is to further fine-tune and individualize prophylactic treatment&#xD;
      of patients with severe Haemophilia A with the goal of keeping the trough FVIII level above&#xD;
      1% between doses. Because trough FVIII levels are likely to be important predictors of the&#xD;
      efficacy of prophylaxis, the focus of this study is on pharmacokinetic (PK) data.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">May 2015</start_date>
  <completion_date type="Actual">September 2018</completion_date>
  <primary_completion_date type="Actual">September 2018</primary_completion_date>
  <phase>Phase 3</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Prevention</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Annualized Total Bleeding Rate of Individually Tailored Prophylaxis</measure>
    <time_frame>6 months</time_frame>
    <description>Total annualized bleeding rate (ABR) of individually tailored prophylaxis (GENA-21b) compared to historical bleeding rate in patients having received on-demand treatment (GENA-01) with Human-cl rhFVIII</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Annualized Spontaneous Bleeding Rate of Individually Tailored Prophylaxis</measure>
    <time_frame>6 months</time_frame>
    <description>Spontaneous annualized bleeding rate (ABR) of individually tailored prophylaxis (GENA-21b) compared to historical bleeding rate in patients having received on-demand treatment (GENA-01) with Human-cl rhFVIII</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Annualized Total Bleeding Rate in Patients With 2x/Week (or Less) Prophylaxis</measure>
    <time_frame>6 months</time_frame>
    <description>Total annualized bleeding rate (ABR) in patients with 2x/week (or less) prophylaxis (GENA-21b) compared to historical bleeding rate in patients having received on-demand treatment (GENA-01) with Human-cl rhFVIII</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Median Prophylactic Dosing Interval</measure>
    <time_frame>6 months</time_frame>
    <description>Median over median actual dosing intervals between two prophylactic treatments per patient. The median time (hours) between two prophylactic doses of Human-cl rhFVIII in the prophylactic treatment Phase II per patient</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Mean Prophylactic Dosing Interval</measure>
    <time_frame>6 months</time_frame>
    <description>Mean over mean actual dosing intervals between two prophylactic treatments per patient. The mean time (hours) between two prophylactic doses of Human-cl rhFVIII in the prophylactic treatment Phase II per patient</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>AUC Divided by the Dose (AUCnorm) of Human-cl rhFVIII</measure>
    <time_frame>Before injection (within 1 h before injection) and up to 72 h (± 2 h) after the end of injection</time_frame>
    <description>AUCnorm of Human-cl rhFVIII measured using the one-stage (OS) assay</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>In-vivo Recovery (IVR) of Human-cl rhFVIII</measure>
    <time_frame>Before injection (within 1 h before injection) and up to 72 h (± 2 h) after the end of injection</time_frame>
    <description>IVR of Human-cl rhFVIII measured using the one-stage (OS) assay and will be determined from the FVIII level before the infusion and the peak level after the infusion of Human-cl rhFVIII</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Half Life (t1/2) of Human-cl rhFVIII</measure>
    <time_frame>Before injection (within 1 h before injection) and up to 72 h (± 2 h) after the end of injection</time_frame>
    <description>T1/2 of Human-cl rhFVIII measured using the one-stage (OS) assay</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Mean Residence Time (MRT) of Human-cl rhFVIII</measure>
    <time_frame>Before injection (within 1 h before injection) and up to 72 h (± 2 h) after the end of injection</time_frame>
    <description>MRT of Human-cl rhFVIII measured using the one-stage (OS) assay</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Clearance (CL) of Human-cl rhFVIII</measure>
    <time_frame>Before injection (within 1 h before injection) and up to 72 h (± 2 h) after the end of injection</time_frame>
    <description>CL of Human-cl rhFVIII measured using the one-stage (OS) assay</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Volume of Distribution at Steady State (Vss) of Human-cl rhFVIII</measure>
    <time_frame>Before injection (within 1 h before injection) and up to 72 h (± 2 h) after the end of injection</time_frame>
    <description>Vss of Human-cl rhFVIII measured using the one-stage (OS) assay</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Usage of Human-cl rhFVIII (FVIII IU/kg BW Per Week Per Patient)</measure>
    <time_frame>6 months</time_frame>
    <description>Average weekly consumption of Human-cl rhFVIII reported as IU/kg BW per week per patient was determined during individualized prophylactic treatment</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of Patients With Adverse Events (AEs)</measure>
    <time_frame>At each study visit over the study duration (7-9 months)</time_frame>
    <description>AEs were documented at each (scheduled or unscheduled) study visit. Severity and seriousness of all AEs were documented by the investigator according to pre-defined criteria</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">58</enrollment>
  <condition>Severe Haemophilia A</condition>
  <arm_group>
    <arm_group_label>Human-cl rhFVIII</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
  </arm_group>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>Human cl rhFVIII</intervention_name>
    <arm_group_label>Human-cl rhFVIII</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Severe Haemophilia A (FVIII:C &lt; 1%)&#xD;
&#xD;
          -  Male patients &gt;= 18 years of age&#xD;
&#xD;
          -  Previous treatment with a FVIII concentrate for at least 150 EDs&#xD;
&#xD;
          -  Good documentation regarding dosing and bleeding frequency in the 6 months preceding&#xD;
             study start&#xD;
&#xD;
          -  Immunocompetence (CD4+ count &gt; 200/uL)&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Any coagulation disorder other than Haemophilia A&#xD;
&#xD;
          -  Present of past FVIII inhibitor activity&#xD;
&#xD;
          -  Severe liver or kidney disease&#xD;
      </textblock>
    </criteria>
    <gender>Male</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Craig M Kessler, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Georgetown University</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Octapharma Research Site</name>
      <address>
        <city>Sacramento</city>
        <state>California</state>
        <zip>95817</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Octapharma Research Site</name>
      <address>
        <city>Aurora</city>
        <state>Colorado</state>
        <zip>80045</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Octapharma Research Site</name>
      <address>
        <city>Washington</city>
        <state>District of Columbia</state>
        <zip>20057</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Octapharma Research Site</name>
      <address>
        <city>Miami</city>
        <state>Florida</state>
        <zip>33136</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Octapharma Research Site</name>
      <address>
        <city>Chicago</city>
        <state>Illinois</state>
        <zip>60612</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Octapharma Research Site</name>
      <address>
        <city>Indianapolis</city>
        <state>Indiana</state>
        <zip>46260</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Octapharma Research Site</name>
      <address>
        <city>Memphis</city>
        <state>Tennessee</state>
        <zip>38163</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Octapharma Research Site</name>
      <address>
        <city>Houston</city>
        <state>Texas</state>
        <zip>77030</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Octapharma Research Site</name>
      <address>
        <city>Salt Lake City</city>
        <state>Utah</state>
        <zip>84112</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Octapharma Research Site</name>
      <address>
        <city>Edmonton</city>
        <state>Alberta</state>
        <zip>T6G1C9</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Octapharma Research Site</name>
      <address>
        <city>St. John's</city>
        <state>Newfoundland and Labrador</state>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>McMaster University</name>
      <address>
        <city>Hamilton</city>
        <state>Ontario</state>
        <zip>L8N 4K1</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University Hospital Centre Zagreb</name>
      <address>
        <city>Zagreb</city>
        <country>Croatia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Helsinki University Hospital</name>
      <address>
        <city>Helsinki</city>
        <zip>00290</zip>
        <country>Finland</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Centre Régional de Traitement de l'Hémophilie</name>
      <address>
        <city>Bron</city>
        <zip>69677</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>CHU Estaing</name>
      <address>
        <city>Clermont-Ferrand</city>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Centre Hospitalier Universitaire Félix Guyon</name>
      <address>
        <city>La Réunion</city>
        <zip>97400</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Centre Régional de Traitement de l'hémophilie</name>
      <address>
        <city>Nantes</city>
        <zip>44093</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hôpital Purpan - Centre de Traitment Regional de l'Hemophilie Pole</name>
      <address>
        <city>Toulouse</city>
        <zip>31059</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Nagoya University Hospital</name>
      <address>
        <city>Nagoya</city>
        <state>Aichi</state>
        <country>Japan</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital of the Univ of Occupational and Environmental Health</name>
      <address>
        <city>Kitakyushu</city>
        <state>Fukuoka</state>
        <country>Japan</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>St. Marianna Univ School of Medicine Hospital</name>
      <address>
        <city>Kawasaki</city>
        <state>Kanagawa</state>
        <country>Japan</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Nara Medical University Hospital</name>
      <address>
        <city>Kashihara</city>
        <state>Nara</state>
        <country>Japan</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Gunma University Hospital</name>
      <address>
        <city>Maebashi</city>
        <country>Japan</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Osaka National Hospital</name>
      <address>
        <city>Osaka</city>
        <country>Japan</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Ogikubo Hospital</name>
      <address>
        <city>Tokyo</city>
        <country>Japan</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Teikyo University Hospital</name>
      <address>
        <city>Tokyo</city>
        <country>Japan</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University Medical Center Groningen</name>
      <address>
        <city>Groningen</city>
        <zip>9713</zip>
        <country>Netherlands</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>PHI Institute of Transfusion Medicine of Republic of Macedonia</name>
      <address>
        <city>Skopje</city>
        <country>North Macedonia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University Medical Centre Ljubljana</name>
      <address>
        <city>Ljubljana</city>
        <country>Slovenia</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Canada</country>
    <country>Croatia</country>
    <country>Finland</country>
    <country>France</country>
    <country>Japan</country>
    <country>Netherlands</country>
    <country>North Macedonia</country>
    <country>Slovenia</country>
    <country>United States</country>
  </location_countries>
  <removed_countries>
    <country>Macedonia, The Former Yugoslav Republic of</country>
  </removed_countries>
  <verification_date>December 2020</verification_date>
  <study_first_submitted>September 30, 2014</study_first_submitted>
  <study_first_submitted_qc>October 1, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">October 6, 2014</study_first_posted>
  <results_first_submitted>August 28, 2019</results_first_submitted>
  <results_first_submitted_qc>November 13, 2019</results_first_submitted_qc>
  <results_first_posted type="Actual">December 3, 2019</results_first_posted>
  <last_update_submitted>December 21, 2020</last_update_submitted>
  <last_update_submitted_qc>December 21, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">January 19, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Hemophilia A</mesh_term>
  </condition_browse>
  <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>July 24, 2019</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/17/NCT02256917/Prot_002.pdf</document_url>
    </provided_document>
    <provided_document>
      <document_type>Statistical Analysis Plan</document_type>
      <document_has_protocol>No</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>October 30, 2018</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/17/NCT02256917/SAP_003.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <group_list>
        <group group_id="P1">
          <title>Human-cl rhFVIII</title>
          <description>The study consisted of 3 phases:&#xD;
Pharmacokinetic (PK) Phase: 58 previously treated (≥150 exposure days) immunocompetent adults with severe hemophilia A without inhibitors patients started and completed the PK phase (PK population). Patients were treated with single dose of FVIII (60±5 IU/kg). One patient discontinued after single PK administration.&#xD;
Prophylactic Treatment Phase I: 57 patients started and 56 completed Phase I; Patients were treated prophylactically every other day or 3x/week with a dose of 30-40 IU/kg BW for 1-3 months until PK data had been analysed.&#xD;
Prophylactic Treatment Phase II: 56 patients started and 52 completed Phase II. Patients were treated prophylactically for 6 months using the dose and dosing interval based on individual PK data.&#xD;
All 58 patients were included in the safety (SAF) and the intention-to-treat (ITT) populations.</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Pharmacokinetic (PK) Evaluation Phase</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="58"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="58"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
        <period>
          <title>Prophylactic Treatment Phase I</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="57"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="56"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Lost to Follow-up</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
        <period>
          <title>Prophylactic Treatment Phase II</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="56"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="52"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="4"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Lost to Follow-up</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Withdrawn Consent</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Did not attend completion visit</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Discontinued medication</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>SAF/ITT Population</title>
          <description>All patients who received at least one infusion of Human-cI rhFVIII</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="58"/>
          </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="40.1" spread="13.5"/>
                  </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="58"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Race (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>American Indian or Alaska Native</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Asian</title>
                  <measurement_list>
                    <measurement group_id="B1" value="14"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Native Hawaiian or Other Pacific Islander</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Black or African American</title>
                  <measurement_list>
                    <measurement group_id="B1" value="3"/>
                  </measurement_list>
                </category>
                <category>
                  <title>White</title>
                  <measurement_list>
                    <measurement group_id="B1" value="39"/>
                  </measurement_list>
                </category>
                <category>
                  <title>More than one race</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                  </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>Canada</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="4"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Netherlands</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>United States</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="23"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Japan</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="11"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Finland</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="4"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>North Macedonia</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="4"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Slovenia</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>France</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="6"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Croatia</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Weight</title>
          <units>kg</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="77.0" spread="17.0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Body mass index (BMI)</title>
          <units>kg/m^2</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="25.7" spread="5.0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Hemophilia Joint Health Score</title>
          <description>Joint health status will be assessed using the Hemophilia Joint Health Score (HJHS), which evaluates six index joints to produce a score between 0-124. Higher scores indicate worse joint health.</description>
          <units>units on a scale</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="32.3" spread="20.2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Blood group</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <title>O</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="20"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>A</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="26"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>AB</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>B</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="7"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Unknown/missing</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="4"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Annualized Total Bleeding Rate of Individually Tailored Prophylaxis</title>
        <description>Total annualized bleeding rate (ABR) of individually tailored prophylaxis (GENA-21b) compared to historical bleeding rate in patients having received on-demand treatment (GENA-01) with Human-cl rhFVIII</description>
        <time_frame>6 months</time_frame>
        <population>The analysis population comprised 56 patients who received at least one infusion of Human-cI rhFVIII for individualized prophylaxis in the GENA-21b trial. Their annualized bleeding rate was compared with those in patients from the completed GENA-01 trial who received only on-demand treatment.</population>
        <group_list>
          <group group_id="O1">
            <title>Individualized Prophylaxis in GENA-21b</title>
            <description>Patients who received at least one infusion of Human-cI rhFVIII for individualized prophylaxis</description>
          </group>
          <group group_id="O2">
            <title>GENA-01</title>
            <description>All patients receiving on-demand treatment with Human-cl rhFVIII in GENA-01</description>
          </group>
        </group_list>
        <measure>
          <title>Annualized Total Bleeding Rate of Individually Tailored Prophylaxis</title>
          <description>Total annualized bleeding rate (ABR) of individually tailored prophylaxis (GENA-21b) compared to historical bleeding rate in patients having received on-demand treatment (GENA-01) with Human-cl rhFVIII</description>
          <population>The analysis population comprised 56 patients who received at least one infusion of Human-cI rhFVIII for individualized prophylaxis in the GENA-21b trial. Their annualized bleeding rate was compared with those in patients from the completed GENA-01 trial who received only on-demand treatment.</population>
          <units>Bleeding events per year (ABR)</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="56"/>
                <count group_id="O2" value="22"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="4.67" spread="6.46"/>
                    <measurement group_id="O2" value="58.08" spread="30.78"/>
                  </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>Other</non_inferiority_type>
            <non_inferiority_desc>Confirmative one-sided one-sample Poisson-test.</non_inferiority_desc>
            <param_type>ABR</param_type>
            <param_value>4.87</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>4.06</ci_lower_limit>
            <ci_upper_limit>5.79</ci_upper_limit>
            <estimate_desc>A confidence interval of 97.5% for confirmative analysis was also used - the respective upper and lower limit CIs were 3.96-5.93</estimate_desc>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Other</non_inferiority_type>
            <non_inferiority_desc>Reduction of the annualized total bleeding rate (ABR) observed in the GENA-01 study vs. GENA-21B analyzed with a Negative Binomial regression model including a correction for overdispersion.</non_inferiority_desc>
            <p_value>&lt;0.0001</p_value>
            <method>Negative binomial regression model</method>
            <param_type>Rate ratio</param_type>
            <param_value>11.89</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>7.50</ci_lower_limit>
            <ci_upper_limit>18.86</ci_upper_limit>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Other</non_inferiority_type>
            <non_inferiority_desc>Reduction of the annualized total bleeding rate (ABR) observed in the GENA-01 study vs. GENA-21B analyzed with a Poisson regression model including a correction for overdispersion.</non_inferiority_desc>
            <p_value>&lt;0.0001</p_value>
            <method>Poisson regression model</method>
            <param_type>Rate ratio</param_type>
            <param_value>10.14</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>6.12</ci_lower_limit>
            <ci_upper_limit>16.80</ci_upper_limit>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Annualized Spontaneous Bleeding Rate of Individually Tailored Prophylaxis</title>
        <description>Spontaneous annualized bleeding rate (ABR) of individually tailored prophylaxis (GENA-21b) compared to historical bleeding rate in patients having received on-demand treatment (GENA-01) with Human-cl rhFVIII</description>
        <time_frame>6 months</time_frame>
        <population>The analysis population comprised 56 patients who received at least one infusion of Human-cI rhFVIII for individualized prophylaxis in the GENA-21b trial. Their annualized spontaneous bleeding rate was compared with those in patients from the completed GENA-01 trial who received only on-demand treatment.</population>
        <group_list>
          <group group_id="O1">
            <title>Individualised Prophylaxis in GENA-21b</title>
            <description>Patients who received at least one infusion of Human-cI rhFVIII for prophylaxis</description>
          </group>
          <group group_id="O2">
            <title>GENA-01</title>
            <description>All patients receiving on-demand treatment with Human-cl rhFVIII in GENA-01</description>
          </group>
        </group_list>
        <measure>
          <title>Annualized Spontaneous Bleeding Rate of Individually Tailored Prophylaxis</title>
          <description>Spontaneous annualized bleeding rate (ABR) of individually tailored prophylaxis (GENA-21b) compared to historical bleeding rate in patients having received on-demand treatment (GENA-01) with Human-cl rhFVIII</description>
          <population>The analysis population comprised 56 patients who received at least one infusion of Human-cI rhFVIII for individualized prophylaxis in the GENA-21b trial. Their annualized spontaneous bleeding rate was compared with those in patients from the completed GENA-01 trial who received only on-demand treatment.</population>
          <units>Bleeding events per year (ABR)</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="56"/>
                <count group_id="O2" value="22"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2.98" spread="5.76"/>
                    <measurement group_id="O2" value="38.46" spread="28.07"/>
                  </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>Other</non_inferiority_type>
            <non_inferiority_desc>A respective confirmative one-sided one-sample Poisson-test was used to demonstrate if the mean spontaneous ABR in patients with individually tailored prophylaxis is at least 50% below the mean ABR rate in the GENA-01 trial.</non_inferiority_desc>
            <param_type>ABR</param_type>
            <param_value>3.12</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>2.48</ci_lower_limit>
            <ci_upper_limit>3.87</ci_upper_limit>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Annualized Total Bleeding Rate in Patients With 2x/Week (or Less) Prophylaxis</title>
        <description>Total annualized bleeding rate (ABR) in patients with 2x/week (or less) prophylaxis (GENA-21b) compared to historical bleeding rate in patients having received on-demand treatment (GENA-01) with Human-cl rhFVIII</description>
        <time_frame>6 months</time_frame>
        <population>The analysis population comprised 29 patients who received at least one infusion of Human-cI rhFVIII for individualized prophylaxis in the GENA-21b trial at intervals of 2x/week or less. Their annualized spontaneous bleeding rate was compared with those in patients from the completed GENA-01 trial who received only on-demand treatment.</population>
        <group_list>
          <group group_id="O1">
            <title>Prophylaxis 2x/Week or Less</title>
            <description>Patients who received at least one infusion of Human-cI rhFVIII for prophylaxis and were treated with a prophylaxis infusion frequency of 2x/week or less</description>
          </group>
          <group group_id="O2">
            <title>GENA-01</title>
            <description>All patients receiving on-demand treatment with Human-cl rhFVIII in GENA-01</description>
          </group>
        </group_list>
        <measure>
          <title>Annualized Total Bleeding Rate in Patients With 2x/Week (or Less) Prophylaxis</title>
          <description>Total annualized bleeding rate (ABR) in patients with 2x/week (or less) prophylaxis (GENA-21b) compared to historical bleeding rate in patients having received on-demand treatment (GENA-01) with Human-cl rhFVIII</description>
          <population>The analysis population comprised 29 patients who received at least one infusion of Human-cI rhFVIII for individualized prophylaxis in the GENA-21b trial at intervals of 2x/week or less. Their annualized spontaneous bleeding rate was compared with those in patients from the completed GENA-01 trial who received only on-demand treatment.</population>
          <units>Bleeding events per year (ABR)</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="29"/>
                <count group_id="O2" value="22"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="4.82" spread="6.98"/>
                    <measurement group_id="O2" value="58.08" spread="30.78"/>
                  </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>Other</non_inferiority_type>
            <non_inferiority_desc>A respective confirmative one-sided one-sample Poisson-test was used to demonstrate if the mean ABR in patients with 2x/week prophylaxis or less with individually tailored prophylaxis is at least 50% below the mean ABR rate in the GENA-01 trial.</non_inferiority_desc>
            <param_type>ABR</param_type>
            <param_value>5.03</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>3.90</ci_lower_limit>
            <ci_upper_limit>6.39</ci_upper_limit>
            <estimate_desc>A confidence interval of 97.5% for confirmative analysis was also used - the respective upper and lower limit CIs were 3.76-6.60</estimate_desc>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Median Prophylactic Dosing Interval</title>
        <description>Median over median actual dosing intervals between two prophylactic treatments per patient. The median time (hours) between two prophylactic doses of Human-cl rhFVIII in the prophylactic treatment Phase II per patient</description>
        <time_frame>6 months</time_frame>
        <population>The analysis population comprised 56 patients who received at least one infusion of Human-cI rhFVIII for individualized prophylaxis in the GENA-21b trial.</population>
        <group_list>
          <group group_id="O1">
            <title>Prophylaxis</title>
            <description>Patients who received at least one infusion of Human-cI rhFVIII for prophylaxis</description>
          </group>
        </group_list>
        <measure>
          <title>Median Prophylactic Dosing Interval</title>
          <description>Median over median actual dosing intervals between two prophylactic treatments per patient. The median time (hours) between two prophylactic doses of Human-cl rhFVIII in the prophylactic treatment Phase II per patient</description>
          <population>The analysis population comprised 56 patients who received at least one infusion of Human-cI rhFVIII for individualized prophylaxis in the GENA-21b trial.</population>
          <units>hours</units>
          <param>Median</param>
          <dispersion>Inter-Quartile Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="56"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="83.9" lower_limit="53.5" upper_limit="96.1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Mean Prophylactic Dosing Interval</title>
        <description>Mean over mean actual dosing intervals between two prophylactic treatments per patient. The mean time (hours) between two prophylactic doses of Human-cl rhFVIII in the prophylactic treatment Phase II per patient</description>
        <time_frame>6 months</time_frame>
        <population>The analysis population comprised 56 patients who received at least one infusion of Human-cI rhFVIII for individualized prophylaxis in the GENA-21b trial.</population>
        <group_list>
          <group group_id="O1">
            <title>Prophylaxis</title>
            <description>Patients who received at least one infusion of Human-cI rhFVIII for prophylaxis</description>
          </group>
        </group_list>
        <measure>
          <title>Mean Prophylactic Dosing Interval</title>
          <description>Mean over mean actual dosing intervals between two prophylactic treatments per patient. The mean time (hours) between two prophylactic doses of Human-cl rhFVIII in the prophylactic treatment Phase II per patient</description>
          <population>The analysis population comprised 56 patients who received at least one infusion of Human-cI rhFVIII for individualized prophylaxis in the GENA-21b trial.</population>
          <units>hours</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="56"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="83.0" spread="22.37"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>AUC Divided by the Dose (AUCnorm) of Human-cl rhFVIII</title>
        <description>AUCnorm of Human-cl rhFVIII measured using the one-stage (OS) assay</description>
        <time_frame>Before injection (within 1 h before injection) and up to 72 h (± 2 h) after the end of injection</time_frame>
        <population>The PK-PP population contained all patients in the PK analysis population who completed the initial PK sampling phase of the trial without significantly violating the inclusion/exclusion criteria or other aspects of the protocol considered to potentially affect the PK results.</population>
        <group_list>
          <group group_id="O1">
            <title>PK Evaluation</title>
            <description>PK-PP population</description>
          </group>
        </group_list>
        <measure>
          <title>AUC Divided by the Dose (AUCnorm) of Human-cl rhFVIII</title>
          <description>AUCnorm of Human-cl rhFVIII measured using the one-stage (OS) assay</description>
          <population>The PK-PP population contained all patients in the PK analysis population who completed the initial PK sampling phase of the trial without significantly violating the inclusion/exclusion criteria or other aspects of the protocol considered to potentially affect the PK results.</population>
          <units>hr*IU/mL/(IU/kg)</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="47"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.302" spread="0.116"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>In-vivo Recovery (IVR) of Human-cl rhFVIII</title>
        <description>IVR of Human-cl rhFVIII measured using the one-stage (OS) assay and will be determined from the FVIII level before the infusion and the peak level after the infusion of Human-cl rhFVIII</description>
        <time_frame>Before injection (within 1 h before injection) and up to 72 h (± 2 h) after the end of injection</time_frame>
        <population>The PK-PP population contained all patients in the PK analysis population who completed the initial PK sampling phase of the trial without significantly violating the inclusion/exclusion criteria or other aspects of the protocol considered to potentially affect the PK results.</population>
        <group_list>
          <group group_id="O1">
            <title>PK Evaluation</title>
            <description>PK-PP population</description>
          </group>
        </group_list>
        <measure>
          <title>In-vivo Recovery (IVR) of Human-cl rhFVIII</title>
          <description>IVR of Human-cl rhFVIII measured using the one-stage (OS) assay and will be determined from the FVIII level before the infusion and the peak level after the infusion of Human-cl rhFVIII</description>
          <population>The PK-PP population contained all patients in the PK analysis population who completed the initial PK sampling phase of the trial without significantly violating the inclusion/exclusion criteria or other aspects of the protocol considered to potentially affect the PK results.</population>
          <units>% per IU/kg</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="47"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1.775" spread="0.421"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Half Life (t1/2) of Human-cl rhFVIII</title>
        <description>T1/2 of Human-cl rhFVIII measured using the one-stage (OS) assay</description>
        <time_frame>Before injection (within 1 h before injection) and up to 72 h (± 2 h) after the end of injection</time_frame>
        <population>The PK-PP population contained all patients in the PK analysis population who completed the initial PK sampling phase of the trial without significantly violating the inclusion/exclusion criteria or other aspects of the protocol considered to potentially affect the PK results.</population>
        <group_list>
          <group group_id="O1">
            <title>PK Evaluation</title>
            <description>PK-PP population</description>
          </group>
        </group_list>
        <measure>
          <title>Half Life (t1/2) of Human-cl rhFVIII</title>
          <description>T1/2 of Human-cl rhFVIII measured using the one-stage (OS) assay</description>
          <population>The PK-PP population contained all patients in the PK analysis population who completed the initial PK sampling phase of the trial without significantly violating the inclusion/exclusion criteria or other aspects of the protocol considered to potentially affect the PK results.</population>
          <units>hours</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="47"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="15.725" spread="4.029"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Mean Residence Time (MRT) of Human-cl rhFVIII</title>
        <description>MRT of Human-cl rhFVIII measured using the one-stage (OS) assay</description>
        <time_frame>Before injection (within 1 h before injection) and up to 72 h (± 2 h) after the end of injection</time_frame>
        <population>The PK-PP population contained all patients in the PK analysis population who completed the initial PK sampling phase of the trial without significantly violating the inclusion/exclusion criteria or other aspects of the protocol considered to potentially affect the PK results.</population>
        <group_list>
          <group group_id="O1">
            <title>PK Evaluation</title>
            <description>PK-PP population</description>
          </group>
        </group_list>
        <measure>
          <title>Mean Residence Time (MRT) of Human-cl rhFVIII</title>
          <description>MRT of Human-cl rhFVIII measured using the one-stage (OS) assay</description>
          <population>The PK-PP population contained all patients in the PK analysis population who completed the initial PK sampling phase of the trial without significantly violating the inclusion/exclusion criteria or other aspects of the protocol considered to potentially affect the PK results.</population>
          <units>hours</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="47"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="20.762" spread="5.997"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Clearance (CL) of Human-cl rhFVIII</title>
        <description>CL of Human-cl rhFVIII measured using the one-stage (OS) assay</description>
        <time_frame>Before injection (within 1 h before injection) and up to 72 h (± 2 h) after the end of injection</time_frame>
        <population>The PK-PP population contained all patients in the PK analysis population who completed the initial PK sampling phase of the trial without significantly violating the inclusion/exclusion criteria or other aspects of the protocol considered to potentially affect the PK results.</population>
        <group_list>
          <group group_id="O1">
            <title>PK Evaluation</title>
            <description>PK-PP population</description>
          </group>
        </group_list>
        <measure>
          <title>Clearance (CL) of Human-cl rhFVIII</title>
          <description>CL of Human-cl rhFVIII measured using the one-stage (OS) assay</description>
          <population>The PK-PP population contained all patients in the PK analysis population who completed the initial PK sampling phase of the trial without significantly violating the inclusion/exclusion criteria or other aspects of the protocol considered to potentially affect the PK results.</population>
          <units>mL/hr/kg</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="47"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="3.859" spread="1.670"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Volume of Distribution at Steady State (Vss) of Human-cl rhFVIII</title>
        <description>Vss of Human-cl rhFVIII measured using the one-stage (OS) assay</description>
        <time_frame>Before injection (within 1 h before injection) and up to 72 h (± 2 h) after the end of injection</time_frame>
        <population>The PK-PP population contained all patients in the PK analysis population who completed the initial PK sampling phase of the trial without significantly violating the inclusion/exclusion criteria or other aspects of the protocol considered to potentially affect the PK results.</population>
        <group_list>
          <group group_id="O1">
            <title>PK Evaluation</title>
            <description>PK-PP population</description>
          </group>
        </group_list>
        <measure>
          <title>Volume of Distribution at Steady State (Vss) of Human-cl rhFVIII</title>
          <description>Vss of Human-cl rhFVIII measured using the one-stage (OS) assay</description>
          <population>The PK-PP population contained all patients in the PK analysis population who completed the initial PK sampling phase of the trial without significantly violating the inclusion/exclusion criteria or other aspects of the protocol considered to potentially affect the PK results.</population>
          <units>mL/kg</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="47"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="72.901" spread="16.454"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Usage of Human-cl rhFVIII (FVIII IU/kg BW Per Week Per Patient)</title>
        <description>Average weekly consumption of Human-cl rhFVIII reported as IU/kg BW per week per patient was determined during individualized prophylactic treatment</description>
        <time_frame>6 months</time_frame>
        <population>The analysis population comprised 56 patients who received at least one infusion of Human-cI rhFVIII for individualized prophylaxis in the GENA-21b trial.</population>
        <group_list>
          <group group_id="O1">
            <title>Prophylaxis</title>
            <description>Patients who received at least one infusion of Human-cI rhFVIII for prophylaxis in Phase III</description>
          </group>
        </group_list>
        <measure>
          <title>Usage of Human-cl rhFVIII (FVIII IU/kg BW Per Week Per Patient)</title>
          <description>Average weekly consumption of Human-cl rhFVIII reported as IU/kg BW per week per patient was determined during individualized prophylactic treatment</description>
          <population>The analysis population comprised 56 patients who received at least one infusion of Human-cI rhFVIII for individualized prophylaxis in the GENA-21b trial.</population>
          <units>IU/kg per week</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="56"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="83.7" spread="25.7"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Number of Patients With Adverse Events (AEs)</title>
        <description>AEs were documented at each (scheduled or unscheduled) study visit. Severity and seriousness of all AEs were documented by the investigator according to pre-defined criteria</description>
        <time_frame>At each study visit over the study duration (7-9 months)</time_frame>
        <population>The SAF population included 58 patients who received at least one infusion of Human-c1 rhFVIII in the GENA-21b trial</population>
        <group_list>
          <group group_id="O1">
            <title>SAF/ITT Population</title>
            <description>All patients who received at least one infusion of Human-cI rhFVIII</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Patients With Adverse Events (AEs)</title>
          <description>AEs were documented at each (scheduled or unscheduled) study visit. Severity and seriousness of all AEs were documented by the investigator according to pre-defined criteria</description>
          <population>The SAF population included 58 patients who received at least one infusion of Human-c1 rhFVIII in the GENA-21b trial</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="58"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>AE</title>
                  <measurement_list>
                    <measurement group_id="O1" value="34"/>
                  </measurement_list>
                </category>
                <category>
                  <title>No AE</title>
                  <measurement_list>
                    <measurement group_id="O1" value="24"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>At each study visit over the study duration (7-9 months)</time_frame>
      <group_list>
        <group group_id="E1">
          <title>SAF/ITT Population</title>
          <description>All patients who received at least one infusion of Human-cI rhFVIII</description>
        </group>
      </group_list>
      <serious_events>
        <default_assessment>Systematic Assessment</default_assessment>
        <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="58"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="58"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Blood and lymphatic system disorders</title>
            <event_list>
              <event>
                <sub_title>Subdural haematoma</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="58"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Pyrexia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="58"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Metabolism and nutrition disorders</title>
            <event_list>
              <event>
                <sub_title>Hypokalemia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="58"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Back pain</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="58"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Neoplasms benign, malignant and unspecified (incl cysts and polyps)</title>
            <event_list>
              <event>
                <sub_title>Basosquamous carcinoma</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="58"/>
              </event>
              <event>
                <sub_title>Large B-cell lymphoma</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="58"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>3</frequency_threshold>
        <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="34" subjects_at_risk="58"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Blood and lymphatic system disorders</title>
            <event_list>
              <event>
                <sub_title>Anemia</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="58"/>
              </event>
              <event>
                <sub_title>Lymphadenopathy</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="58"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Diarrhea</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="58"/>
              </event>
              <event>
                <sub_title>Dyspepsia</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="58"/>
              </event>
              <event>
                <sub_title>Gastritis</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="58"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Pyrexia</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="58"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Nasopharyngitis</sub_title>
                <counts group_id="E1" subjects_affected="12" subjects_at_risk="58"/>
              </event>
              <event>
                <sub_title>Influenza</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="58"/>
              </event>
              <event>
                <sub_title>Urinary tract infection</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="58"/>
              </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="4" subjects_at_risk="58"/>
              </event>
              <event>
                <sub_title>Bone pain</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="58"/>
              </event>
              <event>
                <sub_title>Pain in extremity</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="58"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Headache</sub_title>
                <counts group_id="E1" subjects_affected="5" subjects_at_risk="58"/>
              </event>
              <event>
                <sub_title>Dizziness</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="58"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Psychiatric disorders</title>
            <event_list>
              <event>
                <sub_title>Depression</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="58"/>
              </event>
              <event>
                <sub_title>Insomnia</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="58"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Oropharyngeal pain</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="58"/>
              </event>
              <event>
                <sub_title>Nasal congestion</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="58"/>
              </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>Octapharma agreements may vary with individual investigators, but will not prohibit any investigator from publishing. Octapharma supports the publication of results from all centers of a multi-center trial but requests that reports based on single-site data not precede the primary publication of the entire clinical trial. Octapharma also reserves the right to review data prior to publishing and provide comments/changes within a certain time period.</restrictive_agreement>
    </certain_agreements>
    <point_of_contact>
      <name_or_title>Sylvia Werner</name_or_title>
      <organization>Octapharma</organization>
      <phone>415 260-9577</phone>
      <email>sylvia.werner@octapharma.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/NCT02256917
org study id: GENA-21B
nct id: NCT02256917
lead sponsor: 
has dmc: No
The rationale of this study is to further fine-tune and individualize prophylactic treatment
      of patients with severe Haemophilia A with the goal of keeping the trough FVIII level above
      1% between doses. Because trough FVIII levels are likely to be important predictors of the
      efficacy of prophylaxis, the focus of this study is on pharmacokinetic (PK) data.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Prevention
masking: None (Open Label)
measure: Annualized Total Bleeding Rate of Individually Tailored Prophylaxis
time frame: 6 months
description: Total annualized bleeding rate (ABR) of individually tailored prophylaxis (GENA-21b) compared to historical bleeding rate in patients having received on-demand treatment (GENA-01) with Human-cl rhFVIII
measure: Annualized Spontaneous Bleeding Rate of Individually Tailored Prophylaxis
time frame: 6 months
description: Spontaneous annualized bleeding rate (ABR) of individually tailored prophylaxis (GENA-21b) compared to historical bleeding rate in patients having received on-demand treatment (GENA-01) with Human-cl rhFVIII
measure: Annualized Total Bleeding Rate in Patients With 2x/Week (or Less) Prophylaxis
time frame: 6 months
description: Total annualized bleeding rate (ABR) in patients with 2x/week (or less) prophylaxis (GENA-21b) compared to historical bleeding rate in patients having received on-demand treatment (GENA-01) with Human-cl rhFVIII
measure: Median Prophylactic Dosing Interval
time frame: 6 months
description: Median over median actual dosing intervals between two prophylactic treatments per patient. The median time (hours) between two prophylactic doses of Human-cl rhFVIII in the prophylactic treatment Phase II per patient
measure: Mean Prophylactic Dosing Interval
time frame: 6 months
description: Mean over mean actual dosing intervals between two prophylactic treatments per patient. The mean time (hours) between two prophylactic doses of Human-cl rhFVIII in the prophylactic treatment Phase II per patient
measure: AUC Divided by the Dose (AUCnorm) of Human-cl rhFVIII
time frame: Before injection (within 1 h before injection) and up to 72 h (± 2 h) after the end of injection
description: AUCnorm of Human-cl rhFVIII measured using the one-stage (OS) assay
measure: In-vivo Recovery (IVR) of Human-cl rhFVIII
time frame: Before injection (within 1 h before injection) and up to 72 h (± 2 h) after the end of injection
description: IVR of Human-cl rhFVIII measured using the one-stage (OS) assay and will be determined from the FVIII level before the infusion and the peak level after the infusion of Human-cl rhFVIII
measure: Half Life (t1/2) of Human-cl rhFVIII
time frame: Before injection (within 1 h before injection) and up to 72 h (± 2 h) after the end of injection
description: T1/2 of Human-cl rhFVIII measured using the one-stage (OS) assay
measure: Mean Residence Time (MRT) of Human-cl rhFVIII
time frame: Before injection (within 1 h before injection) and up to 72 h (± 2 h) after the end of injection
description: MRT of Human-cl rhFVIII measured using the one-stage (OS) assay
measure: Clearance (CL) of Human-cl rhFVIII
time frame: Before injection (within 1 h before injection) and up to 72 h (± 2 h) after the end of injection
description: CL of Human-cl rhFVIII measured using the one-stage (OS) assay
measure: Volume of Distribution at Steady State (Vss) of Human-cl rhFVIII
time frame: Before injection (within 1 h before injection) and up to 72 h (± 2 h) after the end of injection
description: Vss of Human-cl rhFVIII measured using the one-stage (OS) assay
measure: Usage of Human-cl rhFVIII (FVIII IU/kg BW Per Week Per Patient)
time frame: 6 months
description: Average weekly consumption of Human-cl rhFVIII reported as IU/kg BW per week per patient was determined during individualized prophylactic treatment
measure: Number of Patients With Adverse Events (AEs)
time frame: At each study visit over the study duration (7-9 months)
description: AEs were documented at each (scheduled or unscheduled) study visit. Severity and seriousness of all AEs were documented by the investigator according to pre-defined criteria
arm group label: Human-cl rhFVIII
arm group type: Experimental
intervention type: Biological
intervention name: Human cl rhFVIII
arm group label: Human-cl rhFVIII
criteria: 
gender: Male
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Craig M Kessler, MD
role: Principal Investigator
affiliation: Georgetown University
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country: Canada
country: Croatia
country: Finland
country: France
country: Japan
country: Netherlands
country: North Macedonia
country: Slovenia
country: United States
country: Macedonia, The Former Yugoslav Republic of
responsible party type: Sponsor
mesh term: Hemophilia A
provided document: 
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 