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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.
 
ClinicalTrials.gov Identifier: NCT03818763
Recruitment Status : Recruiting
First Posted : January 28, 2019
Last Update Posted : January 12, 2021
Sponsor:
Information provided by (Responsible Party):
Parameswaran Hari, Medical College of Wisconsin

Tracking Information
First Submitted Date  ICMJE January 15, 2019
First Posted Date  ICMJE January 28, 2019
Last Update Posted Date January 12, 2021
Actual Study Start Date  ICMJE April 29, 2020
Estimated Primary Completion Date May 1, 2023   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: January 24, 2019)
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%.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: January 24, 2019)
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
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Gene Therapy Trial for Platelet Derived Factor VIII Production in Hemophilia A
Official Title  ICMJE 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
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.
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.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE 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
Condition  ICMJE Hemophilia A
Intervention  ICMJE 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.

Study Arms  ICMJE 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.
Intervention: Biological: Auto CD34+PBSC, transduced with a lentiviral vector encoding the B domain deleted from of human coagulation factor VIII
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: January 24, 2019)
5
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE May 1, 2033
Estimated Primary Completion Date May 1, 2023   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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/cu.mm; 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.
Sex/Gender  ICMJE
Sexes Eligible for Study: Male
Gender Based Eligibility: Yes
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Parameswaran Hari, MD 414-805-4600 phari@mcw.edu
Contact: Debra Pastorek, RN 414-805-6800 dpastore@mcw.edu
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03818763
Other Study ID Numbers  ICMJE PRO00033763
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
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
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Parameswaran Hari, Medical College of Wisconsin
Study Sponsor  ICMJE Parameswaran Hari
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Parmeswaran Hari, MD Froedtert Hosptial and Medical College of Wisconsin
PRS Account Medical College of Wisconsin
Verification Date January 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP