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Gene Therapy Trial for Platelet Derived Factor VIII Production in Hemophilia A

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT03818763
Recruitment Status : Recruiting
First Posted : January 28, 2019
Last Update Posted : January 12, 2021
Information provided by (Responsible Party):
Parameswaran Hari, Medical College of Wisconsin

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Hemophilia A Biological: Auto CD34+PBSC, transduced with a lentiviral vector encoding the B domain deleted from of human coagulation factor VIII Phase 1

Detailed Description:
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 inhibitors to FVIII.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 5 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Intervention Model Description: Open-label, nonrandomized, single-center phase I cohort study
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : April 29, 2020
Estimated Primary Completion Date : May 1, 2023
Estimated Study Completion Date : May 1, 2033

Arm Intervention/treatment
Experimental: Autologous CD34+PBSC transduced with a lentiviral vector
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.
Biological: Auto CD34+PBSC, transduced with a lentiviral vector encoding the B domain deleted from of human coagulation factor VIII

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 inhibitors to FVIII

The infusion volume of transduced cells will not exceed 20 ml/kg body weight.

Primary Outcome Measures :
  1. 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 ]
    Assessed by availability of ≥4x106 transduced clinical grade CD34+PBSC per kg meeting release criteria for infusion; undetectable microbiological contamination and cell viability ≥70%.

Secondary Outcome Measures :
  1. Incidence of toxicity from gene therapy [ Time Frame: Within 3 months of gene therapy infusion ]
    Number of events meeting CTCAE criteria grade 3 or 4 toxicity

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   Male
Gender Based Eligibility:   Yes
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • Study population will include: adult males ≥18 years of age with a diagnosis of severe hemophilia A and currently active high titer FVIII inhibitors (>5 BU). Females will be excluded because hemophilia A is an X-linked disorder that is extremely rare in females.

    1. Confirmed diagnosis of severe hemophilia A by undetectable plasma factor VIII:C by a one-stage PTT-based assay and coatest chromogenic factor VIII assay. Only subjects with the presence of a high titer factor VIII inhibitor (>5 BU) will be included for enrollment.
    2. Subject may be prescribed prophylactic therapy with factor VIII bypassing agents or factor VIII mimetics prior to referral for inclusion in the study.
    3. Subjects who are treated on demand using factor VIII bypassing agents must have a history of four or more bleeding episodes requiring treatment in the six-month period prior to referral for inclusion in the study.
    4. Adequate bone marrow reserve as demonstrated by ANC >1.5/; Hemoglobin >9g/dL; Platelets >100,000/microliter.
    5. Adequate renal function, defined as creatinine clearance>60 ml/min (Cockroft-Gault formula)
    6. Adequate liver function, defined as defined as total bilirubin ≤1.5 times the upper limit of normal (ULN) (excluding Gilbert's syndrome), both AST and ALT ≤3 times ULN at the time of screening, and no clinical signs or known laboratory/radiographic evidence consistent with cirrhosis.
    7. Subject must sign an informed consent after explanation of the study and having questions answered.
    8. Subject must be willing and able to document type of bleeding episodes and treatment in a paper or electronic diary during the study.
    9. Subject must be willing to return for regular follow-up visits during the 15-year study.

Exclusion Criteria:

  • A potential subject who meets any of the following exclusion criteria is ineligible to participate in the study.

    1. Therapy with factor VIII with the intent of immune tolerance induction within 30 days prior to inclusion within the study.
    2. Enrollment in another interventional clinical trial within 60 days prior to study inclusion.
    3. Medical contraindication to PBSC cytokine mobilization, use of GCSF, PBSC apheresis procedure or conditioning regimen.
    4. Medically significant organ dysfunction that would prevent compliance with conditioning or would severely limit the probability of survival based on clinical status.
    5. Those with a known co-existing clinically significant thrombophilic disorder, or as determined by the presence of any of the below identified on screening laboratory assessments:

      • FV Leiden
      • Protein S deficiency
      • Protein C deficiency
      • Prothrombin mutation (G20210A)
      • D-dimer >3 x the upper limit of normal (ULN) at Screening All known patients with the above and any patient with a personal or significant family history of thrombotic events (DVT, PE, arterial clots) as deemed by the principal investigator will be screened for the above disorders.
    6. Active invasive malignancy (Non-melanoma skin cancers and carcinoma in situ are not excluded).
    7. Known bone marrow disorders or abnormal bone marrow cytogenetics.
    8. Fertile males who are unwilling to use contraceptive techniques during and for the twelve months following treatment.
    9. Life expectancy severely limited by disease(s) other than hemophilia A.
    10. Patients with HIV, hepatitis B, hepatitis C (with an AST/ALT > 3 times the upper limit of normal).
    11. Other active infectious disease that is a contraindicat ion for immunosuppressive therapy.
    12. Patients who have elective surgery scheduled during the study period.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT03818763

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Contact: Parameswaran Hari, MD 414-805-4600
Contact: Debra Pastorek, RN 414-805-6800

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United States, Wisconsin
Froedtert Hospital and the Medical College of Wisconsin Recruiting
Milwaukee, Wisconsin, United States, 53226
Contact: Parameswaran Hari, MD    414-805-4600   
Contact: Temi Oloyede    414-805-4869   
Sponsors and Collaborators
Parameswaran Hari
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Principal Investigator: Parmeswaran Hari, MD Froedtert Hosptial and Medical College of Wisconsin
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Responsible Party: Parameswaran Hari, Chief of the Division of Hematology and Oncology, Professor, Medical College of Wisconsin Identifier: NCT03818763    
Other Study ID Numbers: PRO00033763
First Posted: January 28, 2019    Key Record Dates
Last Update Posted: January 12, 2021
Last Verified: January 2021

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Keywords provided by Parameswaran Hari, Medical College of Wisconsin:
Gene Therapy
Additional relevant MeSH terms:
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Hemophilia A
Blood Coagulation Disorders, Inherited
Blood Coagulation Disorders
Hematologic Diseases
Coagulation Protein Disorders
Hemorrhagic Disorders
Genetic Diseases, Inborn
Factor VIII