<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/NCT02216084</url>
  </required_header>
  <id_info>
    <org_study_id>281101</org_study_id>
    <secondary_id>2012-003221-19</secondary_id>
    <nct_id>NCT02216084</nct_id>
  </id_info>
  <brief_title>Phase 1 Dose Escalation, Single Dose Study to Assess Safety and Pharmacokinetics of BAX930 in Hereditary Thrombotic Thrombocytopenic Purpura (TTP)</brief_title>
  <official_title>BAX930 (rADAMTS13): A Phase 1 Prospective, Uncontrolled, Open-Label, Multicenter, Dose-Escalation Study Evaluating the Safety and Pharmacokinetics in Hereditary Thrombotic Thrombocytopenic Purpura (TTP)</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Baxalta now part of Shire</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Takeda</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      The purpose of this Phase 1, prospective, uncontrolled, open-label, multicenter,&#xD;
      dose-escalation study is to evaluate the safety, including immunogenicity, and&#xD;
      pharmacokinetics of BAX930 (rADAMTS13) in a total of 14 evaluable subjects diagnosed with&#xD;
      severe hereditary thrombotic thrombocytopenic purpura (TTP) (plasma ADAMTS13 activity &lt;6%)&#xD;
      who are assigned to one of three dose cohorts.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">September 30, 2014</start_date>
  <completion_date type="Actual">February 22, 2016</completion_date>
  <primary_completion_date type="Actual">February 22, 2016</primary_completion_date>
  <phase>Phase 1</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>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Occurrence of adverse events (serious and non-serious), including the incidence of binding and inhibitory antibody formation</measure>
    <time_frame>Up to 28 (± 3) days after investigational product infusion</time_frame>
  </primary_outcome>
  <secondary_outcome>
    <measure>Pharmacokinetic [PK] parameter 'incremental recovery [IR]'</measure>
    <time_frame>Within 1 hour pre-infusion and up to 288 (± 4) hours post-infusion</time_frame>
    <description>Will be evaluated after single infusions of rADAMTS13 in Dose Cohorts 1, 2 and 3</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>PK parameter 'maximum concentration following infusion [Cmax]'</measure>
    <time_frame>Within 1 hour pre-infusion and up to 288 (± 4) hours post-infusion</time_frame>
    <description>Will be evaluated after single infusions of rADAMTS13 in Dose Cohorts 1, 2 and 3</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>PK parameter 'minimum time to reach Cmax [T max]'</measure>
    <time_frame>Within 1 hour pre-infusion and up to 288 (± 4) hours post-infusion</time_frame>
    <description>Will be evaluated after single infusions of rADAMTS13 in Dose Cohorts 1, 2 and 3</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>PK parameter 'terminal or disposition half-life [T1/2]'</measure>
    <time_frame>Within 1 hour pre-infusion and up to 288 (± 4) hours post-infusion</time_frame>
    <description>Will be evaluated after single infusions of rADAMTS13 in Dose Cohorts 1, 2 and 3</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>PK parameter 'mean residence time [MRT]'</measure>
    <time_frame>Within 1 hour pre-infusion and up to 288 (± 4) hours post-infusion</time_frame>
    <description>Will be evaluated after single infusions of rADAMTS13 in Dose Cohorts 1, 2 and 3</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>PK parameter 'systemic clearance [Cl]'</measure>
    <time_frame>Within 1 hour pre-infusion and up to 288 (± 4) hours post-infusion</time_frame>
    <description>Will be evaluated after single infusions of rADAMTS13 in Dose Cohorts 1, 2 and 3</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>PK parameter 'area under the plasma/time curve [AUC]'</measure>
    <time_frame>Within 1 hour pre-infusion and up to 288 (± 4) hours post-infusion</time_frame>
    <description>Will be evaluated after single infusions of rADAMTS13 in Dose Cohorts 1, 2 and 3</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>PK parameter 'steady state volume of distribution [Vss]'</measure>
    <time_frame>Within 1 hour pre-infusion and up to 288 (± 4) hours post-infusion</time_frame>
    <description>Will be evaluated after single infusions of rADAMTS13 in Dose Cohorts 1, 2 and 3</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Plasma von Willebrand factor: Ristocetin cofactor activity [VWF:RCo], von Willebrand factor antigen [VWF:Ag] and VWF structure analysis</measure>
    <time_frame>Within 1 hour pre-infusion and up to 288 (± 4) hours post-infusion</time_frame>
    <description>Will be evaluated after single infusions of rADAMTS13 in Dose Cohorts 1, 2 and 3</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">16</enrollment>
  <condition>Hereditary Thrombotic Thrombocytopenic Purpura (TTP)</condition>
  <arm_group>
    <arm_group_label>Recombinant ADAMTS13</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>The study is comprised of 3 dose cohorts and two dose escalation steps [Cohort 1: 3 subjects; Cohort 2: 3 subjects; Cohort 3: 8 subjects]. Subjects will be enrolled and dosed sequentially. Subjects will be recruited to the next dose level only after short-term safety has been demonstrated and reviewed by an independent Data Monitoring Committee (DMC) at the preceding dose level. The first 2 subjects in any cohort will be ≥ 18 years of age. The effects of the investigational product on vital signs, hematology, and clinical chemistry parameters (up to 96 ± 2 hrs blood sampling timepoint) will determine short-term safety. The DMC will recommend whether to proceed with the study or in case of a safety concern recommend remedial actions and/or to discontinue the study. Subject participation will continue until 28 ± 3 days after infusion of the investigational product. Subject participation in one Dose Cohort (1-3) is expected to be approximately 6-8 weeks.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Recombinant ADAMTS13</intervention_name>
    <description>rADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) is a lyophilized formulation for intravenous injection. The lyophilized rADAMTS13 is reconstituted with sterile water for injection.&#xD;
Subjects will receive an intravenous injection with rADAMTS13 at a dose of either 5 U/kg bodyweight (Cohort 1), or 20 U/kg bodyweight (Cohort 2), or 40 U/kg bodyweight (Cohort 3).</description>
    <arm_group_label>Recombinant ADAMTS13</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Subject is between 12 and 65 years of age, inclusive. (The first 2 subjects in any&#xD;
             cohort will be ≥ 18 years of age.)&#xD;
&#xD;
          -  Subject and/or legally authorized representative has provided written informed&#xD;
             consent.&#xD;
&#xD;
          -  Subject has a documented diagnosis of severe hereditary ADAMTS13 deficiency, defined&#xD;
             as 1) confirmed by genetic testing, documented in patient history or at screening, and&#xD;
             2) ADAMTS13 activity &lt; 6%, documented in patient history or at screening. NOTE: In&#xD;
             patients receiving prophylactic therapy with fresh frozen plasma (FFP) or other&#xD;
             ADAMTS13 containing products, the levels of plasma ADAMTS13 activity may exceed 6% at&#xD;
             screening.&#xD;
&#xD;
          -  Cryoprecipitate, FFP, or other ADAMTS13 containing products interfering with ADAMTS13&#xD;
             PK have to be paused at least 10 days prior to infusion of the investigational&#xD;
             product.&#xD;
&#xD;
          -  The subject is not displaying any severe TTP symptoms at screening. Patients&#xD;
             presenting with minor, but stable laboratory abnormalities (LDH not higher than 3&#xD;
             times the upper limit of normal; platelet count not lower than 100,000 per μl) at&#xD;
             screening may be enrolled.&#xD;
&#xD;
          -  Subjects ≥18 years of age have a Karnofsky score ≥ 60%, and subjects &lt; 18 years of age&#xD;
             have a Lansky score ≥ 70%.&#xD;
&#xD;
          -  Subject is hepatitis C virus negative (HCV-) as confirmed by antibody or polymerase&#xD;
             chain reaction (PCR) testing; HCV positive (HCV+) subjects are eligible for inclusion&#xD;
             if their disease is chronic but stable.&#xD;
&#xD;
          -  If female of childbearing potential, subject presents with a negative serum pregnancy&#xD;
             test and agrees to employ adequate birth control measures for the duration of the&#xD;
             study.&#xD;
&#xD;
          -  Subject is willing and able to comply with the requirements of the protocol.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Subject has been diagnosed with any other TTP-like disorder (for example,&#xD;
             microangiopathic hemolytic anemia), including acquired TTP.&#xD;
&#xD;
          -  Subject has known hypersensitivity to hamster proteins or other components of the&#xD;
             investigational product.&#xD;
&#xD;
          -  Subject has a medical history or presence of a functional neutralizing ADAMTS13&#xD;
             inhibitor at screening.&#xD;
&#xD;
          -  Subject has a medical history of immunological disorders, excluding seasonal allergic&#xD;
             rhinitis/conjunctivitis/mild asthma, food allergies or animal allergies.&#xD;
&#xD;
          -  Subject has a medical history of hematological disorders, in particular systemic lupus&#xD;
             erythematosus, amyloidosis, antiphospholipid antibody syndrome, vasculitis, other&#xD;
             hemolytic anemia, disseminated intravascular coagulation, and systemic scleroderma.&#xD;
&#xD;
          -  Subject has a history of significant neurological events, such as major stroke,&#xD;
             indicating that a relapse might have severe consequences, as judged by the&#xD;
             investigator.&#xD;
&#xD;
          -  Subject is HIV positive with an absolute CD4 count &lt; 200/mm3.&#xD;
&#xD;
          -  Subject has been diagnosed with a cardiovascular disease [New York Heart Association&#xD;
             (NYHA) classes 3-4].&#xD;
&#xD;
          -  Subject is scheduled to undergo elective surgery during study participation.&#xD;
&#xD;
          -  Subject has been diagnosed with severe liver disease, as evidenced by, but not limited&#xD;
             to, any of the following: serum ALT 3 times the upper limit of normal, international&#xD;
             normalized ratio (INR) &gt; 1.5, hypoalbuminemia, portal vein hypertension (e.g. presence&#xD;
             of otherwise unexplained splenomegaly, history of esophageal varices).&#xD;
&#xD;
          -  Subject has been diagnosed with severe glomerular disease, with gross proteinuria and&#xD;
             a serum creatinine level ≥ 2.5 mg/dL.&#xD;
&#xD;
          -  Subject has been treated with an immunomodulatory drug, in case of corticoids with an&#xD;
             equivalent to hydrocortisone greater than 10 mg /day, excluding topical treatment&#xD;
             (e.g. ointments, nasal spray), within 30 days prior to enrollment.&#xD;
&#xD;
          -  Subject has a history of drug and/or alcohol abuse within the last 6 months prior to&#xD;
             study enrollment.&#xD;
&#xD;
          -  Subject has a life expectancy of less than 3 months.&#xD;
&#xD;
          -  Subject is identified by the investigator as being unable or unwilling to cooperate&#xD;
             with study procedures.&#xD;
&#xD;
          -  Subject is a family member or employee of the investigator.&#xD;
&#xD;
          -  Subject suffers from a mental condition rendering him/her unable to understand the&#xD;
             nature, scope and possible consequences of the study and/or evidence of an&#xD;
             uncooperative attitude.&#xD;
&#xD;
          -  If female, subject is pregnant or lactating at the time of study enrollment.&#xD;
&#xD;
          -  Subject has participated in another clinical study involving an investigational&#xD;
             product or device within 30 days prior to study enrollment.&#xD;
&#xD;
          -  Subject is scheduled to participate in another clinical study involving an&#xD;
             investigational product or device during the course of this study.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>12 Years</minimum_age>
    <maximum_age>65 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Study Director</last_name>
    <role>Study Director</role>
    <affiliation>Takeda</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Ohio State University Medical Center</name>
      <address>
        <city>Dublin</city>
        <state>Ohio</state>
        <zip>43017</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Oregon Health &amp; Science University</name>
      <address>
        <city>Portland</city>
        <state>Oregon</state>
        <zip>97239</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>The Methodist Hospital Research Institute</name>
      <address>
        <city>Houston</city>
        <state>Texas</state>
        <zip>77030</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>General Hospital Vienna (Allgemeines Krankenhaus der Stadt Wien)</name>
      <address>
        <city>Vienna</city>
        <zip>1090</zip>
        <country>Austria</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Universitätsklinikum Hamburg-Eppendorf</name>
      <address>
        <city>Hamburg</city>
        <zip>20246</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Universitätsklinikum Jena</name>
      <address>
        <city>Jena</city>
        <zip>07743</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>• Tokyo Medical and Dental University Hospital, Faculty of Medicine</name>
      <address>
        <city>Bunkyo-ku, Tokyo</city>
        <zip>113-8519</zip>
        <country>Japan</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hyogo College of Medicine Hospital, Department of Hematology</name>
      <address>
        <city>Nishinomiya-shi</city>
        <zip>663-8501</zip>
        <country>Japan</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Institute of Hematology and Transfusion Medicine</name>
      <address>
        <city>Warsaw</city>
        <zip>02776</zip>
        <country>Poland</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Inselspital - Universitaetsspital Bern</name>
      <address>
        <city>Bern</city>
        <zip>3010</zip>
        <country>Switzerland</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University College London Hospital NHS Foundation Trust</name>
      <address>
        <city>London</city>
        <zip>NW1 2BU</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Austria</country>
    <country>Germany</country>
    <country>Japan</country>
    <country>Poland</country>
    <country>Switzerland</country>
    <country>United Kingdom</country>
    <country>United States</country>
  </location_countries>
  <verification_date>May 2021</verification_date>
  <study_first_submitted>August 12, 2014</study_first_submitted>
  <study_first_submitted_qc>August 12, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">August 13, 2014</study_first_posted>
  <last_update_submitted>May 3, 2021</last_update_submitted>
  <last_update_submitted_qc>May 3, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">May 5, 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>Purpura</mesh_term>
    <mesh_term>Purpura, Thrombocytopenic</mesh_term>
    <mesh_term>Purpura, Thrombotic Thrombocytopenic</mesh_term>
  </condition_browse>
  <!-- Results have not yet been posted for this study                                          -->
</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/NCT02216084
org study id: 281101
secondary id: 2012-003221-19
nct id: NCT02216084
lead sponsor: 
has dmc: Yes
The purpose of this Phase 1, prospective, uncontrolled, open-label, multicenter,
      dose-escalation study is to evaluate the safety, including immunogenicity, and
      pharmacokinetics of BAX930 (rADAMTS13) in a total of 14 evaluable subjects diagnosed with
      severe hereditary thrombotic thrombocytopenic purpura (TTP) (plasma ADAMTS13 activity <6%)
      who are assigned to one of three dose cohorts.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Occurrence of adverse events (serious and non-serious), including the incidence of binding and inhibitory antibody formation
time frame: Up to 28 (± 3) days after investigational product infusion
measure: Pharmacokinetic [PK] parameter 'incremental recovery [IR]'
time frame: Within 1 hour pre-infusion and up to 288 (± 4) hours post-infusion
description: Will be evaluated after single infusions of rADAMTS13 in Dose Cohorts 1, 2 and 3
measure: PK parameter 'maximum concentration following infusion [Cmax]'
time frame: Within 1 hour pre-infusion and up to 288 (± 4) hours post-infusion
description: Will be evaluated after single infusions of rADAMTS13 in Dose Cohorts 1, 2 and 3
measure: PK parameter 'minimum time to reach Cmax [T max]'
time frame: Within 1 hour pre-infusion and up to 288 (± 4) hours post-infusion
description: Will be evaluated after single infusions of rADAMTS13 in Dose Cohorts 1, 2 and 3
measure: PK parameter 'terminal or disposition half-life [T1/2]'
time frame: Within 1 hour pre-infusion and up to 288 (± 4) hours post-infusion
description: Will be evaluated after single infusions of rADAMTS13 in Dose Cohorts 1, 2 and 3
measure: PK parameter 'mean residence time [MRT]'
time frame: Within 1 hour pre-infusion and up to 288 (± 4) hours post-infusion
description: Will be evaluated after single infusions of rADAMTS13 in Dose Cohorts 1, 2 and 3
measure: PK parameter 'systemic clearance [Cl]'
time frame: Within 1 hour pre-infusion and up to 288 (± 4) hours post-infusion
description: Will be evaluated after single infusions of rADAMTS13 in Dose Cohorts 1, 2 and 3
measure: PK parameter 'area under the plasma/time curve [AUC]'
time frame: Within 1 hour pre-infusion and up to 288 (± 4) hours post-infusion
description: Will be evaluated after single infusions of rADAMTS13 in Dose Cohorts 1, 2 and 3
measure: PK parameter 'steady state volume of distribution [Vss]'
time frame: Within 1 hour pre-infusion and up to 288 (± 4) hours post-infusion
description: Will be evaluated after single infusions of rADAMTS13 in Dose Cohorts 1, 2 and 3
measure: Plasma von Willebrand factor: Ristocetin cofactor activity [VWF:RCo], von Willebrand factor antigen [VWF:Ag] and VWF structure analysis
time frame: Within 1 hour pre-infusion and up to 288 (± 4) hours post-infusion
description: Will be evaluated after single infusions of rADAMTS13 in Dose Cohorts 1, 2 and 3
arm group label: Recombinant ADAMTS13
arm group type: Experimental
description: The study is comprised of 3 dose cohorts and two dose escalation steps [Cohort 1: 3 subjects; Cohort 2: 3 subjects; Cohort 3: 8 subjects]. Subjects will be enrolled and dosed sequentially. Subjects will be recruited to the next dose level only after short-term safety has been demonstrated and reviewed by an independent Data Monitoring Committee (DMC) at the preceding dose level. The first 2 subjects in any cohort will be ≥ 18 years of age. The effects of the investigational product on vital signs, hematology, and clinical chemistry parameters (up to 96 ± 2 hrs blood sampling timepoint) will determine short-term safety. The DMC will recommend whether to proceed with the study or in case of a safety concern recommend remedial actions and/or to discontinue the study. Subject participation will continue until 28 ± 3 days after infusion of the investigational product. Subject participation in one Dose Cohort (1-3) is expected to be approximately 6-8 weeks.
intervention type: Drug
intervention name: Recombinant ADAMTS13
description: rADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) is a lyophilized formulation for intravenous injection. The lyophilized rADAMTS13 is reconstituted with sterile water for injection.
Subjects will receive an intravenous injection with rADAMTS13 at a dose of either 5 U/kg bodyweight (Cohort 1), or 20 U/kg bodyweight (Cohort 2), or 40 U/kg bodyweight (Cohort 3).
arm group label: Recombinant ADAMTS13
criteria: 
gender: All
minimum age: 12 Years
maximum age: 65 Years
healthy volunteers: No
last name: Study Director
role: Study Director
affiliation: Takeda
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
country: Austria
country: Germany
country: Japan
country: Poland
country: Switzerland
country: United Kingdom
country: United States
responsible party type: Sponsor
mesh term: Purpura
mesh term: Purpura, Thrombocytopenic
mesh term: Purpura, Thrombotic Thrombocytopenic