Hematopoietic Stem Cell Transplantation Gene Therapy for Treatment of Severe Hemophilia A

NCT ID: NCT05265767

Last Updated: 2024-07-12

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1
• Total Enrollment: 6 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2022-04-01
• Study Completion Date: 2024-06-28

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.

Conditions

Hemophilia A

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Autologous HSCT CD68-ET3-LV gene therapy

Autologous gene modified peripheral blood stem cell transplantation for patients with severe hemophilia A (FVIII \<1%).

Group Type: EXPERIMENTAL

Auto CD34+PBSC transduced with a lentiviral vector encoding a novel coagulation factor VIII transgene

Intervention Type: BIOLOGICAL

Auto CD34+PBSC transduced with a lentiviral vector encoding a novel coagulation factor VIII transgene administered by IV infusion following conditioning regimen.

Interventions

Auto CD34+PBSC transduced with a lentiviral vector encoding a novel coagulation factor VIII transgene

Auto CD34+PBSC transduced with a lentiviral vector encoding a novel coagulation factor VIII transgene administered by IV infusion following conditioning regimen.

Intervention Type: BIOLOGICAL

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.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 45 Years
• Eligible Sex: MALE
• Accepts Healthy Volunteers: No

Sponsors

Dr. H. Trent Spencer, Professor, Emory University of Medicine, Atlanta Ga, 30322

UNKNOWN

Sponsor Role: collaborator

Christian Medical College, Vellore, India

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Alok Srivastava, MD

Role: PRINCIPAL_INVESTIGATOR

Christian Medical College, Vellore, India

Locations

Christian Medical College Vellore Ranipet Campus

Vellore, Tamil Nadu, India

Countries

India

References

Srivastava A, Abraham A, Aboobacker F, Singh G, Geevar T, Kulkarni U, Selvarajan S, Korula A, Dave RG, Shankar M, Singh AS, Jeba A, Kumaar N, Benjamin C, Lakshmi KM, Srivastava VM, Shaji RV, Nair SC, Brown HC, Denning G, Lollar P, Doering CB, Spencer T. Lentiviral Gene Therapy with CD34+ Hematopoietic Cells for Hemophilia A. N Engl J Med. 2025 Jan 30;392(5):450-457. doi: 10.1056/NEJMoa2410597. Epub 2024 Dec 9.

Reference Type: DERIVED

PMID: 39655790 (View on PubMed)

Other Identifiers

CSCR-CMC/FVIII LVGT/2018

Identifier Type: -

Identifier Source: org_study_id