<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/NCT03276455</url>
  </required_header>
  <id_info>
    <org_study_id>NanFangHospital</org_study_id>
    <nct_id>NCT03276455</nct_id>
  </id_info>
  <brief_title>Gene Therapy for Beta-Thalassemia Major Using Autologous Hematopoietic Stem Cell Genetically Modified</brief_title>
  <official_title>Evaluation of Safety and Efficacy of Transplantation of Autologous Hematopoietic Stem Cell Genetically Modified in Beta-Thalassemia Major</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Nanfang Hospital, Southern Medical University</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Guangdong Yike Gene Science and Technology CO.,Ltd</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>Nanfang Hospital, Southern Medical University</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      This is a single group, open label study in 10 subjects who are 8 years of age or older with&#xD;
      beta-thalassemia major. The objective of this study is to evaluate the safety and efficacy of&#xD;
      autologous hematopoietic stem cell transduced with lentiviral vector for the treatment of&#xD;
      beta-thalassemia major.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Beta-thalassemia major is a life-threatening genetic disease of red cell malfunction. It is&#xD;
      caused by mutations in the beta-globin gene which encodes the beta-globin protein, leading to&#xD;
      the ineffective erythropoiesis, hemolysis and anemia. Transplantation of allogeneic&#xD;
      hematopoietic stem cells (HSCT) is the only available cure which is, however, has the&#xD;
      significant risk of transplant related mortality, graft versus host disease and limited&#xD;
      source. Therefore, transplantation of autologous hematopoietic stem cells will be an&#xD;
      attractive therapeutic treatment for beta-thalassemia major patients. 10 patients will be&#xD;
      treated with genetically modified autologous hematopoietic stem cells which transduced with&#xD;
      lentiviral vector encoding for beta-globin gene.&#xD;
&#xD;
      Patients will participate for this study for 3 years.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Not yet recruiting</last_known_status>
  <start_date type="Anticipated">September 15, 2017</start_date>
  <completion_date type="Anticipated">September 15, 2021</completion_date>
  <primary_completion_date type="Anticipated">September 15, 2020</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>Single Group Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>incidence of adverse events</measure>
    <time_frame>0-36 months after transplantation</time_frame>
    <description>Evaluate the safety of treatment with transplantation of autologous hematopoietic stem cell transduced with lentiviral vector encoding the therapeutic beta-globin gene as measured by the incidence of adverse events.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>hemoglobin conten</measure>
    <time_frame>3-36 months after transplantation</time_frame>
    <description>Evaluate the efficacy of treatment with transplantation of autologous hematopoietic stem cell transduced with lentiviral vector encoding the therapeutic beta-globin gene by the detection hemoglobin content of peripheral blood cells.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Hematopoietic stem cell engraftment</measure>
    <time_frame>42 days after transplantation</time_frame>
    <description>Success and kinetics of hematopoietic stem cell engraftment.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>RCL</measure>
    <time_frame>1-36 months after transplantation</time_frame>
    <description>The generation of a replication-competent lentivirus (RCL).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>VCN</measure>
    <time_frame>1-36 months after transplantation</time_frame>
    <description>Quantify gene transfer efficiency and expression by evaluation of average vector copy number(VCN) in blood or bone marrow cells.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>bete-globin content</measure>
    <time_frame>1-36 months after transplantation</time_frame>
    <description>Evaluate the efficacy of treatment by detection of bete-globin content of HGB of peripheral blood cells.</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Anticipated">10</enrollment>
  <condition>Beta Thalassemia Major</condition>
  <arm_group>
    <arm_group_label>Experimental</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Beta-thalassemia major subjects who are 8 years age or older are transplated by autologous CD34+ cells genetically modified(autologous hematopoietic stem cell transduced with lentiviral vector encoding the therapeutic beta-globin gene).</description>
  </arm_group>
  <intervention>
    <intervention_type>Genetic</intervention_type>
    <intervention_name>Autologous CD34+ cells genetically modified</intervention_name>
    <description>Autologous hematopoietic stem cell transduced with lentiviral vector encoding the therapeutic beta-globin gene. The target dose in the transduced product is 3x10^6 cells/Kg CD34+ cells, with a minimum dose of 2 x 10^6/Kg and a maximum dose of 20 x 10^6/Kg, depending on the yield of cells. The product will be injected intraosseously following intravenous BU ±Flu ±Cy.</description>
    <arm_group_label>Experimental</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Subjects must be 8 years of age or older.&#xD;
&#xD;
          -  Subjects or their parents/legal guardians must be able to understand and voluntarily&#xD;
             sign an informed consent form.&#xD;
&#xD;
          -  Subjects must have a confirmed diagnosis of ß-thalassemia major and&#xD;
&#xD;
             ≥100 mL/kg/year of pRBCs or ≥ 8 transfusions of pRBCs per year over a minimum of two&#xD;
             years prior to entry onto the study.&#xD;
&#xD;
          -  Subjects must be in clinically stable condition and eligible for hematopoietic stem&#xD;
             cell transplantation.&#xD;
&#xD;
          -  Subjects must satisfy Karnofsky index ≥80% for adults or Lansky index&#xD;
&#xD;
             ≥70% for children.&#xD;
&#xD;
          -  Subjects must have survival expectancy of greater than 6 months.&#xD;
&#xD;
          -  Subjects must have been treated and followed up for at least the past 2 years in&#xD;
             specialized institutions where they have comprehensive assessment of the&#xD;
             disease（including psychiatric assessment），and detailed medical materials at least the&#xD;
             past 2years so as to self-contrast before and after treatment.&#xD;
&#xD;
          -  Subjects must discontinue treatment of hydroxyurea, 5-azoside or cytarabine at least&#xD;
             three months prior to entry onto the study.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Having an HLA-matched donor(sibling or of a suitable 10/10 matched unrelated donor).&#xD;
&#xD;
          -  Positivity for HIV (serology or RNA), and/or HbsAg and/or HBV DNA and/or HCV RNA (or&#xD;
             negative HCV RNA but on antiviral treatment).&#xD;
&#xD;
          -  Contraindication to anesthesia for bone marrow collection.&#xD;
&#xD;
          -  Severe, bacterial, active viral, or fungal infection, etc.&#xD;
&#xD;
          -  The history of malignant tumor.&#xD;
&#xD;
          -  The white blood cell (WBC) count &lt;3000/uL and/or platelet count &lt;100,000/uL exclude&#xD;
             hypersplenism factor.&#xD;
&#xD;
          -  Family history of familial cancer syndromes (including but not limited to Hereditary&#xD;
             breast and ovarian syndrome, hereditary non-polyp colorectal cancer syndrome, familial&#xD;
             adenomatous polyposis).&#xD;
&#xD;
          -  Previous allogeneic bone marrow transplantation.&#xD;
&#xD;
          -  The history of psychosis and any psychiatric disorder.&#xD;
&#xD;
          -  Active substance abuse, drug or alcohol abuse recently.&#xD;
&#xD;
          -  The history of complex allo-immunization which could cause difficulty administering&#xD;
             transfusions.&#xD;
&#xD;
          -  Female adults who are pregnant , breast feeding or lack of effective contraception.&#xD;
&#xD;
          -  History of major organ damage including:&#xD;
&#xD;
        Severe cerebrovascular disease or cognitive sequelae, including hemiplegia. Severe liver&#xD;
        disease with alanine transaminase (ALT) &gt;3 upper limit of normal. Severe liver cirrhosis or&#xD;
        fibrosis on liver biopsy. Heart disease with ejection fraction&lt;25% or T2* &lt;10 ms by&#xD;
        magnetic resonance imaging (MRI). Kidney disease with creatinine clearance &lt;30% normal&#xD;
        value. Lung disease, including pulmonary fibrosis, pulmonary arterial hypertension or&#xD;
        pulmonary function tests below standard (i.e., pO2&lt;90 mmHg and/or carbon dioxide diffusion&#xD;
        coefficient&lt;50%). Endocrine disorder including insulin dependent diabetes mellitus,&#xD;
        Hyperthyroidism or deficiency, Hyperparathyroidism or deficiency.&#xD;
&#xD;
          -  Participation in another clinical study within 30 days of screening.&#xD;
&#xD;
          -  Subjects with severe iron overload determined by the researchers.&#xD;
&#xD;
          -  Any other situation that unsuitably undergoing hematopoietic stem cell transplantation&#xD;
             determined by the physicians or researchers.&#xD;
&#xD;
          -  Presence of chromosomal abnormalities by bone marrow detected.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>8 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_contact>
    <last_name>Chunfu Li, PhD</last_name>
    <phone>86-020-61641921</phone>
    <email>chunfugzcn@126.com</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Zhiyong Peng</last_name>
    <phone>86-020-61641925</phone>
    <email>pengzhiyong8@163.com</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>Nanfang Hospial</name>
      <address>
        <city>Guangzhou</city>
        <state>Guangdong</state>
        <zip>510515</zip>
        <country>China</country>
      </address>
    </facility>
    <contact>
      <last_name>ChunFu Li, PhD</last_name>
      <phone>86-020-61641921</phone>
      <email>chunfugzcn@126.com</email>
    </contact>
    <investigator>
      <last_name>ChunFu Li, PhD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location_countries>
    <country>China</country>
  </location_countries>
  <verification_date>September 2017</verification_date>
  <study_first_submitted>September 6, 2017</study_first_submitted>
  <study_first_submitted_qc>September 6, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">September 8, 2017</study_first_posted>
  <last_update_submitted>September 6, 2017</last_update_submitted>
  <last_update_submitted_qc>September 6, 2017</last_update_submitted_qc>
  <last_update_posted type="Actual">September 8, 2017</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Nanfang Hospital, Southern Medical University</investigator_affiliation>
    <investigator_full_name>Chunfu Li</investigator_full_name>
    <investigator_title>Director and professor</investigator_title>
  </responsible_party>
  <keyword>Beta thalassemia</keyword>
  <keyword>Gene therapy</keyword>
  <keyword>Beta-globin</keyword>
  <keyword>Hematopoietic stem cells</keyword>
  <keyword>Lentiviral vector</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Thalassemia</mesh_term>
    <mesh_term>beta-Thalassemia</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>No</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/NCT03276455
org study id: NanFangHospital
nct id: NCT03276455
lead sponsor: 
collaborator: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
This is a single group, open label study in 10 subjects who are 8 years of age or older with
      beta-thalassemia major. The objective of this study is to evaluate the safety and efficacy of
      autologous hematopoietic stem cell transduced with lentiviral vector for the treatment of
      beta-thalassemia major.
Beta-thalassemia major is a life-threatening genetic disease of red cell malfunction. It is
      caused by mutations in the beta-globin gene which encodes the beta-globin protein, leading to
      the ineffective erythropoiesis, hemolysis and anemia. Transplantation of allogeneic
      hematopoietic stem cells (HSCT) is the only available cure which is, however, has the
      significant risk of transplant related mortality, graft versus host disease and limited
      source. Therefore, transplantation of autologous hematopoietic stem cells will be an
      attractive therapeutic treatment for beta-thalassemia major patients. 10 patients will be
      treated with genetically modified autologous hematopoietic stem cells which transduced with
      lentiviral vector encoding for beta-globin gene.

      Patients will participate for this study for 3 years.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: incidence of adverse events
time frame: 0-36 months after transplantation
description: Evaluate the safety of treatment with transplantation of autologous hematopoietic stem cell transduced with lentiviral vector encoding the therapeutic beta-globin gene as measured by the incidence of adverse events.
measure: hemoglobin conten
time frame: 3-36 months after transplantation
description: Evaluate the efficacy of treatment with transplantation of autologous hematopoietic stem cell transduced with lentiviral vector encoding the therapeutic beta-globin gene by the detection hemoglobin content of peripheral blood cells.
measure: Hematopoietic stem cell engraftment
time frame: 42 days after transplantation
description: Success and kinetics of hematopoietic stem cell engraftment.
measure: RCL
time frame: 1-36 months after transplantation
description: The generation of a replication-competent lentivirus (RCL).
measure: VCN
time frame: 1-36 months after transplantation
description: Quantify gene transfer efficiency and expression by evaluation of average vector copy number(VCN) in blood or bone marrow cells.
measure: bete-globin content
time frame: 1-36 months after transplantation
description: Evaluate the efficacy of treatment by detection of bete-globin content of HGB of peripheral blood cells.
arm group label: Experimental
arm group type: Experimental
description: Beta-thalassemia major subjects who are 8 years age or older are transplated by autologous CD34+ cells genetically modified(autologous hematopoietic stem cell transduced with lentiviral vector encoding the therapeutic beta-globin gene).
intervention type: Genetic
intervention name: Autologous CD34+ cells genetically modified
description: Autologous hematopoietic stem cell transduced with lentiviral vector encoding the therapeutic beta-globin gene. The target dose in the transduced product is 3x10^6 cells/Kg CD34+ cells, with a minimum dose of 2 x 10^6/Kg and a maximum dose of 20 x 10^6/Kg, depending on the yield of cells. The product will be injected intraosseously following intravenous BU ±Flu ±Cy.
arm group label: Experimental
criteria: 
gender: All
minimum age: 8 Years
maximum age: N/A
healthy volunteers: No
last name: Chunfu Li, PhD
phone: 86-020-61641921
email: chunfugzcn@126.com
last name: Zhiyong Peng
phone: 86-020-61641925
email: pengzhiyong8@163.com
facility: 
contact: 
investigator: 
country: China
responsible party type: Principal Investigator
investigator affiliation: Nanfang Hospital, Southern Medical University
investigator full name: Chunfu Li
investigator title: Director and professor
mesh term: Thalassemia
mesh term: beta-Thalassemia
sharing ipd: No