Brief Title
Hematopoietic Stem Cell Transplantation Gene Therapy for Treatment of Severe Hemophilia A
Official Title
Gene Therapy for Hemophilia A With a High Expression Factor VIII Transgene in Autologous Hematopoietic Stem Cells
Brief Summary
Factor VIII (FVIII) is a large plasma glycoprotein that participates in blood coagulation.
Loss of circulating FVIII activity due to mutations within the F8 gene results in the
X-linked, recessive bleeding disorder hemophilia A. The clinical presentation ranges from a
mild to severe bleeding phenotype that correlates with the patient's residual plasma FVIII
activity level.
Current state of the art treatment entails frequent infusion of FVIII protein. However,
several limitations remain to treating hemophilia A, which are 1) access to FVIII-replacement
products (currently <30% of the world population is treated adequately, access is highly
restricted in India), 2) high burden of compliance with treatment protocols particularly in
children 3) the expense of FVIII-replacement products, 4) the development of humoral
anti-FVIII immune responses that block FVIII activity and limit treatment efficacy and 5)
morbidity due to crippling musculoskeletal disease when inadequately treated. Several newer
hemostasis agents are being developed but like the recombinant Clotting Factor Concentrate
(CFC) from the 1990s, these are also not likely to be made available in India for many years.
Currently, the only cure for hemophilia A is orthotopic liver transplantation.
Detailed Description
Eligible subjects will undergo (Cluster of Differentiation) CD34+ hematopoietic stem cell
collection. These cells will be transduced ex vivo with (Cluster of Differentiation) CD68-ET3
lentiviral vector and subsequently, following a conditioning regimen, the transduced cells
will be infused to patients. After completion of study treatment, patients are followed up
periodically for up to 15 years.
Study Phase
Phase 1
Study Type
Interventional
Primary Outcome
Number of study participants experiencing serious adverse events (SAEs) following treatment through 12 weeks.
Secondary Outcome
Time to absolute neutrophil count (ANC) recovery.
Condition
Hemophilia A
Intervention
Gene therapy
Study Arms / Comparison Groups
Autologous HSCT CD68-ET3-LV gene therapy
Description: Autologous gene modified peripheral blood stem cell transplantation for patients with severe hemophilia A (FVIII <1%).
Publications
* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.
Recruitment Information
Recruitment Status
Drug
Estimated Enrollment
9
Start Date
April 1, 2022
Completion Date
January 1, 2039
Primary Completion Date
January 1, 2025
Eligibility Criteria
Inclusion Criteria:
- Able to provide informed consent for the protocol approved by the Institutional Review
Board.
- Male subjects who are ≥18 years of age and < 45 years of age.
- Diagnosis of severe hemophilia A (<1 IU/dl factor VIII activity).
- Documented history of more than 100 exposures of factor VIII treatment.
- Average of at least 3 bleeds requiring treatment per year over the prior three years,
at least 3 bleeds per year during the 3 years preceding the initiation of prophylaxis,
or evidence of joint damage (knee, elbow or ankle) on physical or radiographic
examination thought to be related to hemophilia.
- Performance status (Karnofsky score) of at least 70.
- Willing and able to comply with the requirements of the protocol.
Exclusion Criteria:
- History of spontaneous central nervous system bleeding within the last 5 years.
- Significant organ dysfunction which could interfere with outcome of therapy such as: -
- Cardiac: There should be no evidence of significant cardiac dysfunction (resting left
ventricular ejection fraction of < 50%) and no cardiomegaly. There should not be
uncontrollable hypertension.
- Renal: Glomerular Filtration Rate (GFR) < 60 ml/min/1.73m2 as calculated using the
Cockcroft-Gault equation.
- Hepatic: There should be no evidence of hepatic dysfunction which is defined as a
serum bilirubin of > 1.5 mg/dl and Aspartate Amino Transferase (AST) / Alanine Amino
Transferase (ALT) > 3X the upper limit of normal,
- Hematologic: Absolute neutrophil counts (ANC) < 1000/mm3 and platelets counts <
150,000/μL.
- Pulmonary function with a corrected Diffusing Capacity of lung for Carbon Monoxide
(DLCO) of < 50% predicted
- History of a FVIII inhibitor (>0.6 Bethesda Units/ml) including at least 2
measurements over the preceding 5 years or any single titer >5 Bethesda Units (BU)
/ml.
- Previous stem cell transplant.
- HIV positive.
- Evidence of hepatitis B active infection or chronic carrier
- Evidence of chronic hepatitis C infection. Absence of chronic infection will be
documented with at least 2 negative viral loads at least 6 months apart.
- Diagnosis of a bleeding disorder other than hemophilia A
- Use of medication(s) that can affect hemostasis (e.g. aspirin and non- cyclooxygenase
(COX-2) selective non-steroid anti-inflammatory drugs).
- History of cancer or familial cancer syndromes
- Any condition in the opinion of the principle investigator that will negatively impact
the subject's ability to safely undergo an autologous stem cell transplant.
- Any reason in the opinion of the principle investigator that will negatively impact
the subject's ability to complete the clinical trial per the trial protocol.
Gender
Male
Ages
18 Years - 45 Years
Accepts Healthy Volunteers
No
Contacts
Alok Srivastava, MD, +914172224480, [email protected]
Location Countries
India
Location Countries
India
Administrative Informations
NCT ID
NCT05265767
Organization ID
CSCR-CMC/FVIII LVGT/2018
Responsible Party
Sponsor
Study Sponsor
Christian Medical College, Vellore, India
Collaborators
Dr. H. Trent Spencer, Professor, Emory University of Medicine, Atlanta Ga, 30322
Study Sponsor
Alok Srivastava, MD, Principal Investigator, Christian Medical College, Vellore, India
Verification Date
March 2023