<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/NCT03003533</url>
  </required_header>
  <id_info>
    <org_study_id>SPK-8011-101</org_study_id>
    <nct_id>NCT03003533</nct_id>
  </id_info>
  <brief_title>A Gene Transfer Study for Hemophilia A</brief_title>
  <official_title>Gene-transfer, Open-label, Dose-escalation Study of SPK-8011 [Adeno-associated Viral Vector With B-domain Deleted Human Factor VIII Gene] in Individuals With Hemophilia A</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Spark Therapeutics</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Spark Therapeutics</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      This clinical research study is being conducted by Spark Therapeutics, Inc. to determine the&#xD;
      safety and efficacy of the factor VIII gene transfer treatment with SPK-8011 in individuals&#xD;
      with hemophilia A.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Hemophilia A is a condition in which blood is unable to clot effectively. It is caused by a&#xD;
      mutation or deletion in the gene that is responsible for producing blood-clotting factor VIII&#xD;
      protein. Individuals with hemophilia A suffer from repeated bleeding episodes, often into the&#xD;
      joints, which can cause chronic joint disease and sometime results in death due to the&#xD;
      inability of the blood to clot efficiently. This chronic joint disease can have significant&#xD;
      physical, psychosocial, and quality-of-life effects, including financial burden. The current&#xD;
      treatment is intravenous (i.v.) injections of factor VIII protein products, either 2-3 times&#xD;
      weekly or in response to bleeding.&#xD;
&#xD;
      Recent preliminary clinical data of a hemophilia B gene transfer study (which is also being&#xD;
      conducted by Spark Therapeutics) shows all study participants achieving therapeutic factor IX&#xD;
      activity levels (average of maintaining factor IX activity levels around 30% of normal with&#xD;
      no confirmed bleeds, after receiving Spark gene transfer, with the approach of using the&#xD;
      novel bio-engineered recombinant adeno-associated viral (rAAV) vector carrying a high&#xD;
      specific activity of a factor IX gene. The approach being tested in this clinical research&#xD;
      study uses a further modified novel AAV vector (with a stronger attraction to the human&#xD;
      liver) to deliver the human factor VIII (hFVIII) gene into liver cells so that they can&#xD;
      produce factor VIII protein.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">January 26, 2017</start_date>
  <completion_date type="Anticipated">December 2023</completion_date>
  <primary_completion_date type="Anticipated">December 2023</primary_completion_date>
  <phase>Phase 1/Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Sequential Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Number of study-related adverse events, including clinically significant abnormal laboratory values</measure>
    <time_frame>52 weeks</time_frame>
    <description>adverse events</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Changes from baseline in FVIII activity levels after a single outpatient administration of SPK-8011</measure>
    <time_frame>52 weeks</time_frame>
    <description>changes in FVIII activity levels</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Kinetic assessment of SPK-8011 including shedding of vector DNA in bodily fluids</measure>
    <time_frame>52 weeks</time_frame>
    <description>vector shedding</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of participants requiring a course of steroid therapy for the elevations in liver enzymes</measure>
    <time_frame>52 weeks</time_frame>
    <description>number of participants requiring steroids</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Anticipated">50</enrollment>
  <condition>Hemophilia A</condition>
  <arm_group>
    <arm_group_label>SPK-8011</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>All participants who meet the eligibility criteria will receive an outpatient single intravenous (i.v.) administration of SPK-8011.</description>
  </arm_group>
  <intervention>
    <intervention_type>Genetic</intervention_type>
    <intervention_name>SPK-8011</intervention_name>
    <description>A novel, bio-engineered, recombinant adeno-associated viral vector carrying human factor VIII gene</description>
    <arm_group_label>SPK-8011</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Males age18 years or older&#xD;
&#xD;
          -  Confirmed diagnosis of hemophilia A as evidenced by their medical history with plasma&#xD;
             FVIII activity levels ≤ 2% of normal&#xD;
&#xD;
          -  Have received &gt;150 exposure days (EDs) to FVIII concentrates or cryoprecipitate&#xD;
&#xD;
          -  Have experienced &gt;10 bleeding events over the previous 12 months only if receiving&#xD;
             on-demand therapy and having FVIII baseline level 1-2% of normal&#xD;
&#xD;
          -  Have no prior history of allergic reaction to any FVIII product&#xD;
&#xD;
          -  Have no measurable inhibitor against Factor VIII as assessed by the central laboratory&#xD;
             and have no prior history of inhibitors to FVIII protein&#xD;
&#xD;
          -  Agree to use reliable barrier contraception&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Evidence of active hepatitis B or C&#xD;
&#xD;
          -  Currently on antiviral therapy for hepatitis B or C&#xD;
&#xD;
          -  Have significant underlying liver disease&#xD;
&#xD;
          -  Have serological evidence* of HIV-1 or HIV-2 with CD4 counts ≤200/mm3 (* participants&#xD;
             who are HIV+ and stable with CD4 count &gt;200/mm3 and undetectable viral load are&#xD;
             eligible to enroll)&#xD;
&#xD;
          -  Have detectable antibodies reactive with AAV-Spark200 capsid&#xD;
&#xD;
          -  Participated in a gene transfer trial within the last 52 weeks or in a clinical trial&#xD;
             with an investigational product within the last 12 weeks&#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>Clinical Trial Director</last_name>
    <role>Study Director</role>
    <affiliation>Spark Therapeutics, Inc.</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>University of California Davis - Hemostasis and Thrombosis Center</name>
      <address>
        <city>Sacramento</city>
        <state>California</state>
        <zip>94817</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Florida Health</name>
      <address>
        <city>Gainesville</city>
        <state>Florida</state>
        <zip>32610</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Boston Children's Hospital</name>
      <address>
        <city>Boston</city>
        <state>Massachusetts</state>
        <zip>02115</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Mississippi Center for Advanced Medicine</name>
      <address>
        <city>Madison</city>
        <state>Mississippi</state>
        <zip>39110</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Weill Cornell Medicine-Comprehensive Center for Hemophilia and Coagulation Disorders</name>
      <address>
        <city>New York</city>
        <state>New York</state>
        <zip>10065</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>Pennsylvania State University Milton S. Hershey Medical Center</name>
      <address>
        <city>Hershey</city>
        <state>Pennsylvania</state>
        <zip>10733</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Children's Hospital of Philadelphia</name>
      <address>
        <city>Philadelphia</city>
        <state>Pennsylvania</state>
        <zip>19104</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Jefferson University Hospitals</name>
      <address>
        <city>Philadelphia</city>
        <state>Pennsylvania</state>
        <zip>19107</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hemophilia Center of Western Pennsylvania</name>
      <address>
        <city>Pittsburgh</city>
        <state>Pennsylvania</state>
        <zip>15213</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Virginia Commonwealth University School of Medicine</name>
      <address>
        <city>Richmond</city>
        <state>Virginia</state>
        <zip>23219</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Royal Prince Alfred Hosptial</name>
      <address>
        <city>Camperdown</city>
        <state>New South Wales</state>
        <zip>2050</zip>
        <country>Australia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>The Alfred Hospital</name>
      <address>
        <city>Melbourne</city>
        <zip>3004</zip>
        <country>Australia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>McMaster University Medical Centre and Juravinski Hospital</name>
      <address>
        <city>Hamilton</city>
        <state>Ontario</state>
        <zip>L8N 3Z5</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Chaim Sheba Center</name>
      <address>
        <city>Ramat Gan</city>
        <state>Tel Hashomer</state>
        <zip>526000</zip>
        <country>Israel</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Mahidol University - Ramathibody Hospital</name>
      <address>
        <city>Bangkok</city>
        <zip>10400</zip>
        <country>Thailand</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Australia</country>
    <country>Canada</country>
    <country>Israel</country>
    <country>Thailand</country>
    <country>United States</country>
  </location_countries>
  <verification_date>July 2023</verification_date>
  <study_first_submitted>December 16, 2016</study_first_submitted>
  <study_first_submitted_qc>December 21, 2016</study_first_submitted_qc>
  <study_first_posted type="Estimate">December 28, 2016</study_first_posted>
  <last_update_submitted>July 6, 2023</last_update_submitted>
  <last_update_submitted_qc>July 6, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">July 10, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Adeno-Associated Virus (AAV)</keyword>
  <keyword>Blood Coagulation Disorders</keyword>
  <keyword>Blood Coagulation Disorders, Inherited</keyword>
  <keyword>Coagulation Protein Disorders</keyword>
  <keyword>Factor VIII (FVIII)</keyword>
  <keyword>Factor VIII (FVIII) Deficiency</keyword>
  <keyword>Factor VIII (FVIII) Gene</keyword>
  <keyword>Factor VIII (FVIII) Protein</keyword>
  <keyword>Genetic Diseases, Inborn</keyword>
  <keyword>Genetic Diseases, X-Linked</keyword>
  <keyword>Gene Therapy</keyword>
  <keyword>Gene Transfer</keyword>
  <keyword>Hematologic Diseases</keyword>
  <keyword>Hemorrhagic Disorders</keyword>
  <keyword>Recombinant</keyword>
  <keyword>Vector</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Hemophilia A</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>Undecided</sharing_ipd>
  </patient_data>
  <!-- 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/NCT03003533
org study id: SPK-8011-101
nct id: NCT03003533
lead sponsor: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
This clinical research study is being conducted by Spark Therapeutics, Inc. to determine the
      safety and efficacy of the factor VIII gene transfer treatment with SPK-8011 in individuals
      with hemophilia A.
Hemophilia A is a condition in which blood is unable to clot effectively. It is caused by a
      mutation or deletion in the gene that is responsible for producing blood-clotting factor VIII
      protein. Individuals with hemophilia A suffer from repeated bleeding episodes, often into the
      joints, which can cause chronic joint disease and sometime results in death due to the
      inability of the blood to clot efficiently. This chronic joint disease can have significant
      physical, psychosocial, and quality-of-life effects, including financial burden. The current
      treatment is intravenous (i.v.) injections of factor VIII protein products, either 2-3 times
      weekly or in response to bleeding.

      Recent preliminary clinical data of a hemophilia B gene transfer study (which is also being
      conducted by Spark Therapeutics) shows all study participants achieving therapeutic factor IX
      activity levels (average of maintaining factor IX activity levels around 30% of normal with
      no confirmed bleeds, after receiving Spark gene transfer, with the approach of using the
      novel bio-engineered recombinant adeno-associated viral (rAAV) vector carrying a high
      specific activity of a factor IX gene. The approach being tested in this clinical research
      study uses a further modified novel AAV vector (with a stronger attraction to the human
      liver) to deliver the human factor VIII (hFVIII) gene into liver cells so that they can
      produce factor VIII protein.
allocation: N/A
intervention model: Sequential Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Number of study-related adverse events, including clinically significant abnormal laboratory values
time frame: 52 weeks
description: adverse events
measure: Changes from baseline in FVIII activity levels after a single outpatient administration of SPK-8011
time frame: 52 weeks
description: changes in FVIII activity levels
measure: Kinetic assessment of SPK-8011 including shedding of vector DNA in bodily fluids
time frame: 52 weeks
description: vector shedding
measure: Number of participants requiring a course of steroid therapy for the elevations in liver enzymes
time frame: 52 weeks
description: number of participants requiring steroids
arm group label: SPK-8011
arm group type: Experimental
description: All participants who meet the eligibility criteria will receive an outpatient single intravenous (i.v.) administration of SPK-8011.
intervention type: Genetic
intervention name: SPK-8011
description: A novel, bio-engineered, recombinant adeno-associated viral vector carrying human factor VIII gene
arm group label: SPK-8011
criteria: 
gender: Male
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Clinical Trial Director
role: Study Director
affiliation: Spark Therapeutics, Inc.
facility: 
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country: Australia
country: Canada
country: Israel
country: Thailand
country: United States
responsible party type: Sponsor
mesh term: Hemophilia A
sharing ipd: Undecided