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

NCT05265767 | Completed Phase 1 DMC FDA Drug

• 1 other identifier: CSCR-CMC/FVIII LVGT/2018
• Study Type: interventional
• Target: 6
• Locations: 1 country
• Sites: 1

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.

Conditions

Hemophilia A

Outcome Measures

Primary Outcomes (3)

• Number of study participants experiencing serious adverse events (SAEs) following treatment through 12 weeks.

  As assessed by physical examination, vital signs, clinical labs, and FVIII inhibitor levels (Bethesda assay). Serious adverse event (SAE) is an AE resulting in any of the following outcomes: death; Life-threatening event; Required or prolonged inpatient hospitalization; persistent or significant disability/incapacity; congenital anomaly.

  Percentage of patients experiencing SAEs following 12 weeks of treatment

• Severity of serious adverse events following administration of CD68-ET3-LV CD34+ as assessed by NCI Common Toxicity Criteria for Adverse Events (CTCAE) Version 5.0.

  Serious adverse events severity assessment

  Assessement of severity of SAE through 12 weeks after treatment

• Duration of the serious adverse events following administration of CD68-ET3-LV CD34+.

  As assessed by stop and end dates of the SAEs

  Assessment of duration of SAEs after 12 weeks of treatment

Secondary Outcomes (8)

• Time to absolute neutrophil count (ANC) recovery.

  Measurement of ANC upto 5 years

• Time to platelet recovery

  Measured of platelet recovery upto 5 years

• Anti-human factor VIII inhibitor titer

  Measured of FVIII inhibitor titer upto 5 years

• Immune response to ET3 as measured by modified Bethesda assay incorporating ET3i spiked into FVIII-deficient plasma

  Measured of Immune response to ET3 for up to 5 years

• Vector copy number of circulating genetically modified cells as determined by real time Polymerase Chain Reaction (PCR)

  Measured of Vector copy number by PCR upto 5 years

Other Outcomes (1)

• Annualized bleed rate (ABR) assessed by number of bleeding episodes and in comparison to before gene therapy.

  Assessement of Annualized bleeding rate (ABR) through long term follow-up for up to 15 years

Study Arms (1)

Autologous HSCT CD68-ET3-LV gene therapy

EXPERIMENTAL

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

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

Interventions

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

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

Autologous HSCT CD68-ET3-LV gene therapy

Eligibility Criteria

• Age: 18 Years - 45 Years
• Gender Eligibility Details: Hemophilia A is an inherited X-linked recessive genetic pattern, so males are commonly affected
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• 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.

You may not qualify if:

• 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

Sponsors & Collaborators

• Christian Medical College, Vellore, India: lead
• Dr. H. Trent Spencer, Professor, Emory University of Medicine, Atlanta Ga, 30322: collaborator

Study Sites (1)

Christian Medical College Vellore Ranipet Campus

Vellore, Tamil Nadu, 632517, India

Location

Related Publications (1)

• 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.

  PMID: 39655790 DERIVED

MeSH Terms

Conditions

Hemophilia A

Condition Hierarchy (Ancestors)

Blood Coagulation Disorders, Inherited; Blood Coagulation Disorders; Hematologic Diseases; Hemic and Lymphatic Diseases; Coagulation Protein Disorders; Hemorrhagic Disorders; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities

Study Officials

• Alok Srivastava, MD

  Christian Medical College, Vellore, India

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Patients with Severe haemophilia A

Study Record Dates

• First Submitted: February 16, 2022
• First Posted: March 4, 2022
• Study Start: April 1, 2022
• Primary Completion: June 28, 2024
• Study Completion: June 28, 2024
• Last Updated: July 12, 2024

Record last verified: 2024-07

Data Sharing

• IPD Sharing: Will not share

Locations

IN (1)