<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/NCT03818763</url>
  </required_header>
  <id_info>
    <org_study_id>PRO00033763</org_study_id>
    <nct_id>NCT03818763</nct_id>
  </id_info>
  <brief_title>Gene Therapy Trial for Platelet Derived Factor VIII Production in Hemophilia A</brief_title>
  <official_title>Phase I Study Evaluating Safety and Feasibility of Hematopoietic Stem Cell Gene Transfer That Targets Factor VIII Delivery From Platelets for Patients With Hemophilia A</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Medical College of Wisconsin</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Medical College of Wisconsin</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>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      This is a Phase I study. This research study is being conducted to find new ways to treat&#xD;
      severe hemophilia A. This study is a gene therapy study. Gene therapy is an experimental way&#xD;
      to introduce, into a person's cells, specific genetic material. A gene can be&#xD;
      delivered/introduced into a cell using a carrier known as a &quot;vector.&quot; In this study, a virus&#xD;
      (lentivirus), the &quot;vector&quot;, is used to introduce or deliver a gene that creates and stores a&#xD;
      protein Factor VIII (FVIII) in your platelets. These platelets are made from stem cells&#xD;
      (mother cells for your bone marrow) that are removed from your blood by a procedure called&#xD;
      apheresis. This research study will take some of the patient's own stem cells, from the&#xD;
      apheresis procedure, and genetically modify them using the vector in order to make them&#xD;
      produce FVIII in platelets that arise from the stem cells. They will then give the&#xD;
      genetically modified stem cells back to the patient so that they can possibly create&#xD;
      platelets that produce and store Factor VIII on their own.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This is an open label, nonrandomized, single center, phase I cohort study, involving reduced&#xD;
      intensity conditioning, followed by a single infusion of autologous CD34+PBSC, transduced&#xD;
      with a lentiviral vector (-889ITGA2B-BDDFVIII-WPTS (MUT6)(VSVg)) also known as&#xD;
      (Pleightlet(MUT6)) encoding the B domain deleted from of human coagulation factor VIII&#xD;
      (BDDFVIII) in up to five hemophilia A patients with a history of FVIII inhibitors (≥0.6BU) .&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">April 29, 2020</start_date>
  <completion_date type="Anticipated">May 1, 2033</completion_date>
  <primary_completion_date type="Anticipated">May 1, 2023</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>
    <intervention_model_description>Open-label, nonrandomized, single-center phase I cohort study</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Number of enrolled participants with adequate gene transduced hematopoietic stem cells for FVIII gene therapy infusion</measure>
    <time_frame>Through study completion, an average of 4 years</time_frame>
    <description>Assessed by availability of ≥4x106 transduced clinical grade CD34+PBSC per kg meeting release criteria for infusion; undetectable microbiological contamination and cell viability ≥70%.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Incidence of toxicity from gene therapy</measure>
    <time_frame>Within 3 months of gene therapy infusion</time_frame>
    <description>Number of events meeting CTCAE criteria grade 3 or 4 toxicity</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Anticipated">5</enrollment>
  <condition>Hemophilia A</condition>
  <arm_group>
    <arm_group_label>Autologous CD34+PBSC transduced with a lentiviral vector</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patients will receive a patient specific (autologous) cytokine mobilized CD34+Peripheral Blood Stem Cells (PBSC) transduced ex vivo with a lentiviral vector containing cDNA encoding the human B-domain deleted FVIII protein.</description>
  </arm_group>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>Auto CD34+PBSC, transduced with a lentiviral vector encoding the B domain deleted from of human coagulation factor VIII</intervention_name>
    <description>Reduced intensity conditioning with melphalan and fludarabine, followed by a single infusion of autologous CD34+PBSC, transduced with a lentiviral vector (-889ITGA2B-BDDFVIII-WPTS(MUT6)(VSVg)) also known as (Pleightlet(MUT6)) encoding the B domain deleted from of human coagulation factor VIII (BDDFVIII) in up to five hemophilia A patients with a history of FVIII inhibitors (≥0.6BU).&#xD;
The infusion volume of transduced cells will not exceed 20 ml/kg body weight.</description>
    <arm_group_label>Autologous CD34+PBSC transduced with a lentiviral vector</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
        Study population will include: adult males &gt;18 years of age with a diagnosis of severe&#xD;
        hemophilia A and currently active or a history of FVIII inhibitors (≥0.6 BU). Females will&#xD;
        be excluded because hemophilia A is an X-linked disorder that is extremely rare in females.&#xD;
&#xD;
          1. Confirmed diagnosis of severe hemophilia A by undetectable plasma factor VIII:C by a&#xD;
             one-stage PTT-based assay and coatest chromogenic factor VIII assay. Subjects with&#xD;
             currently active or a history of positive FVIII inhibitor titers (≥0.6 BU)&#xD;
             irrespective of their titer or current inhibitor status will be included for&#xD;
             enrollment.&#xD;
&#xD;
          2. Subject may be prescribed prophylactic therapy with factor VIII bypassing agents or&#xD;
             factor VIII mimetics prior to referral for inclusion in the study.&#xD;
&#xD;
          3. Subjects who are treated on demand using factor VIII bypassing agents must have a&#xD;
             history of four or more bleeding episodes requiring treatment in the six-month period&#xD;
             prior to referral for inclusion in the study.&#xD;
&#xD;
          4. Adequate bone marrow reserve as demonstrated by ANC &gt;1.5/cu.mm; Hemoglobin &gt;9g/dL;&#xD;
             Platelets &gt;100,000/microliter.&#xD;
&#xD;
          5. Adequate renal function, defined as creatinine clearance&gt;60 ml/min (Cockroft-Gault&#xD;
             formula)&#xD;
&#xD;
          6. Adequate liver function, defined as defined as total bilirubin ≤1.5 times the upper&#xD;
             limit of normal (ULN) (excluding Gilbert's syndrome), both AST and ALT ≤3 times ULN at&#xD;
             the time of screening, and no clinical signs or known laboratory/radiographic evidence&#xD;
             consistent with cirrhosis.&#xD;
&#xD;
          7. Subject must sign an informed consent after explanation of the study and having&#xD;
             questions answered.&#xD;
&#xD;
          8. Subject must be willing and able to document type of bleeding episodes and treatment&#xD;
             in a paper or electronic diary during the study.&#xD;
&#xD;
          9. Subject must be willing to return for regular follow-up visits during the 15-year&#xD;
             study.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  A potential subject who meets any of the following exclusion criteria is ineligible to&#xD;
             participate in the study.&#xD;
&#xD;
               1. Therapy with factor VIII with the intent of immune tolerance induction within 30&#xD;
                  days prior to inclusion within the study.&#xD;
&#xD;
               2. Enrollment in another interventional clinical trial within 60 days prior to study&#xD;
                  inclusion.&#xD;
&#xD;
               3. Medical contraindication to PBSC cytokine mobilization, use of GCSF, PBSC&#xD;
                  apheresis procedure or conditioning regimen.&#xD;
&#xD;
               4. Medically significant organ dysfunction that would prevent compliance with&#xD;
                  conditioning or would severely limit the probability of survival based on&#xD;
                  clinical status.&#xD;
&#xD;
               5. Those with a known co-existing clinically significant thrombophilic disorder, or&#xD;
                  as determined by the presence of any of the below identified on screening&#xD;
                  laboratory assessments:&#xD;
&#xD;
                    -  FV Leiden&#xD;
&#xD;
                    -  Protein S deficiency&#xD;
&#xD;
                    -  Protein C deficiency&#xD;
&#xD;
                    -  Prothrombin mutation (G20210A)&#xD;
&#xD;
                    -  D-dimer &gt;3 x the upper limit of normal (ULN) at Screening All known patients&#xD;
                       with the above and any patient with a personal or significant family history&#xD;
                       of thrombotic events (DVT, PE, arterial clots) as deemed by the principal&#xD;
                       investigator will be screened for the above disorders.&#xD;
&#xD;
               6. Active invasive malignancy (Non-melanoma skin cancers and carcinoma in situ are&#xD;
                  not excluded).&#xD;
&#xD;
               7. Known bone marrow disorders or abnormal bone marrow cytogenetics.&#xD;
&#xD;
               8. Fertile males who are unwilling to use contraceptive techniques during and for&#xD;
                  the twelve months following treatment.&#xD;
&#xD;
               9. Life expectancy severely limited by disease(s) other than hemophilia A.&#xD;
&#xD;
              10. Patients with HIV, hepatitis B, hepatitis C (with an AST/ALT &gt; 3 times the upper&#xD;
                  limit of normal).&#xD;
&#xD;
              11. Other active infectious disease that is a contraindicat ion for immunosuppressive&#xD;
                  therapy.&#xD;
&#xD;
              12. Patients who have elective surgery scheduled during the study period.&#xD;
      </textblock>
    </criteria>
    <gender>Male</gender>
    <gender_based>Yes</gender_based>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Mary Eapen, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Froedtert Hosptial and Medical College of Wisconsin</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Mary Eapen, MD</last_name>
    <phone>414-805-0700</phone>
    <email>meapen@mcw.edu</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Arielle Baim</last_name>
    <phone>414-805-8745</phone>
    <email>abaim@mcw.edu</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>Froedtert Hospital and the Medical College of Wisconsin</name>
      <address>
        <city>Milwaukee</city>
        <state>Wisconsin</state>
        <zip>53226</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Mary Eapen, MD</last_name>
      <phone>414-805-0700</phone>
      <email>meapen@mcw.edu</email>
    </contact>
    <contact_backup>
      <last_name>Arielle Baim</last_name>
      <phone>414-805-8745</phone>
      <email>abaim@mcw.edu</email>
    </contact_backup>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>December 2022</verification_date>
  <study_first_submitted>January 15, 2019</study_first_submitted>
  <study_first_submitted_qc>January 24, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">January 28, 2019</study_first_posted>
  <last_update_submitted>December 21, 2022</last_update_submitted>
  <last_update_submitted_qc>December 21, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">December 23, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Medical College of Wisconsin</investigator_affiliation>
    <investigator_full_name>Mary Eapen MBBS MS</investigator_full_name>
    <investigator_title>Professor</investigator_title>
  </responsible_party>
  <keyword>Gene Therapy</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Hemophilia A</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Factor VIII</mesh_term>
  </intervention_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/NCT03818763
org study id: PRO00033763
nct id: NCT03818763
lead sponsor: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
is us export: No
This is a Phase I study. This research study is being conducted to find new ways to treat
      severe hemophilia A. This study is a gene therapy study. Gene therapy is an experimental way
      to introduce, into a person's cells, specific genetic material. A gene can be
      delivered/introduced into a cell using a carrier known as a "vector." In this study, a virus
      (lentivirus), the "vector", is used to introduce or deliver a gene that creates and stores a
      protein Factor VIII (FVIII) in your platelets. These platelets are made from stem cells
      (mother cells for your bone marrow) that are removed from your blood by a procedure called
      apheresis. This research study will take some of the patient's own stem cells, from the
      apheresis procedure, and genetically modify them using the vector in order to make them
      produce FVIII in platelets that arise from the stem cells. They will then give the
      genetically modified stem cells back to the patient so that they can possibly create
      platelets that produce and store Factor VIII on their own.
This is an open label, nonrandomized, single center, phase I cohort study, involving reduced
      intensity conditioning, followed by a single infusion of autologous CD34+PBSC, transduced
      with a lentiviral vector (-889ITGA2B-BDDFVIII-WPTS (MUT6)(VSVg)) also known as
      (Pleightlet(MUT6)) encoding the B domain deleted from of human coagulation factor VIII
      (BDDFVIII) in up to five hemophilia A patients with a history of FVIII inhibitors (≥0.6BU) .
allocation: N/A
intervention model: Single Group Assignment
intervention model description: Open-label, nonrandomized, single-center phase I cohort study
primary purpose: Treatment
masking: None (Open Label)
measure: Number of enrolled participants with adequate gene transduced hematopoietic stem cells for FVIII gene therapy infusion
time frame: Through study completion, an average of 4 years
description: Assessed by availability of ≥4x106 transduced clinical grade CD34+PBSC per kg meeting release criteria for infusion; undetectable microbiological contamination and cell viability ≥70%.
measure: Incidence of toxicity from gene therapy
time frame: Within 3 months of gene therapy infusion
description: Number of events meeting CTCAE criteria grade 3 or 4 toxicity
arm group label: Autologous CD34+PBSC transduced with a lentiviral vector
arm group type: Experimental
description: Patients will receive a patient specific (autologous) cytokine mobilized CD34+Peripheral Blood Stem Cells (PBSC) transduced ex vivo with a lentiviral vector containing cDNA encoding the human B-domain deleted FVIII protein.
intervention type: Biological
intervention name: Auto CD34+PBSC, transduced with a lentiviral vector encoding the B domain deleted from of human coagulation factor VIII
description: Reduced intensity conditioning with melphalan and fludarabine, followed by a single infusion of autologous CD34+PBSC, transduced with a lentiviral vector (-889ITGA2B-BDDFVIII-WPTS(MUT6)(VSVg)) also known as (Pleightlet(MUT6)) encoding the B domain deleted from of human coagulation factor VIII (BDDFVIII) in up to five hemophilia A patients with a history of FVIII inhibitors (≥0.6BU).
The infusion volume of transduced cells will not exceed 20 ml/kg body weight.
arm group label: Autologous CD34+PBSC transduced with a lentiviral vector
criteria: 
gender: Male
gender based: Yes
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Mary Eapen, MD
role: Principal Investigator
affiliation: Froedtert Hosptial and Medical College of Wisconsin
last name: Mary Eapen, MD
phone: 414-805-0700
email: meapen@mcw.edu
last name: Arielle Baim
phone: 414-805-8745
email: abaim@mcw.edu
facility: 
status: Recruiting
contact: 
contact backup: 
country: United States
responsible party type: Principal Investigator
investigator affiliation: Medical College of Wisconsin
investigator full name: Mary Eapen MBBS MS
investigator title: Professor
mesh term: Hemophilia A
mesh term: Factor VIII