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

Primary Purpose

Hemophilia A

Status

Recruiting

Phase

Phase 1

Locations

India

Study Type

Interventional

Intervention

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

About this trial

This is an interventional treatment trial for Hemophilia A

Eligibility Criteria

18 Years - 45 Years (Adult)MaleDoes not accept healthy volunteers

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.

Sites / Locations

Christian Medical College Vellore Ranipet CampusRecruiting

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Autologous HSCT CD68-ET3-LV gene therapy

Arm Description

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

Outcomes

Primary Outcome Measures

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.

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

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

As assessed by stop and end dates of the SAEs

Secondary Outcome Measures

Time to absolute neutrophil count (ANC) recovery.

Time to ANC recovery (the first day a neutrophil count is >0.5 x 109/L (>500/µL) on three consecutive days) following busulfan/ anti-thymocyte globulin conditioning and infusion of autologous CD34+ hematopoietic stem and progenitor cells (HSPC) transduced with CD68-ET3-LV.

Time to platelet recovery

Time to platelet recovery (the first day a platelet count is > 50,000/µL on three consecutive days without platelet transfusions during the prior 7 days) following infusion of autologous CD34+ cells transduced with CD68-ET3-LV.

Anti-human factor VIII inhibitor titer

Assessed via Bethesda assay

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

Immune response to ET3

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

Vector copy number determined via real time PCR

To evaluate FVIII activity after Autologous Hematopoietic Stem Cell Transplantation (HSCT) with CD68ET3-LV transduced CD34+ cells through measurement of plasma FVIII activity levels.

Evaluate FVIII activity

To evaluate the impact of autologous HSCT with CD68ET3-LV transduced CD34+ cells on bleeding phenotype as measured by frequency of bleeding episodes and clotting factor concentrate (CFC) usage.

Evaluate the impact of autologous HSCT with CD68ET3-LV transduced CD34+ cells

To evaluate the relationship between FVIII activity level and engraftment of CD68ET3-LV modified cells.

Evaluate correlation between FVIII activity in % level and engraftment of ANC measured in per cubic milliliter (cumm) Platelets values in per cumm

Full Information

NCT ID

NCT05265767

First Posted

February 16, 2022

Last Updated

April 5, 2023

Sponsor

Christian Medical College, Vellore, India

Collaborators

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

1. Study Identification

Unique Protocol Identification Number

NCT05265767

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

Study Type

Interventional

2. Study Status

Record Verification Date

March 2023

Overall Recruitment Status

Recruiting

Study Start Date

April 1, 2022 (Actual)

Primary Completion Date

January 1, 2025 (Anticipated)

Study Completion Date

January 1, 2039 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Christian Medical College, Vellore, India

Collaborators

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

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Product Manufactured in and Exported from the U.S.

Yes

Data Monitoring Committee

Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Hemophilia A

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1

Interventional Study Model

Single Group Assignment

Model Description

Patients with Severe haemophilia A

Masking

None (Open Label)

Allocation

N/A

Enrollment

9 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Autologous HSCT CD68-ET3-LV gene therapy

Arm Type

Experimental

Arm Description

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

Intervention Type

Biological

Intervention Name(s)

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

Intervention Description

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

Primary Outcome Measure Information:

Title

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

Description

Time Frame

Percentage of patients experiencing SAEs following 12 weeks of treatment

Title

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.

Description

Serious adverse events severity assessment

Time Frame

Assessement of severity of SAE through 12 weeks after treatment

Title

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

Description

As assessed by stop and end dates of the SAEs

Time Frame

Assessment of duration of SAEs after 12 weeks of treatment

Secondary Outcome Measure Information:

Title

Time to absolute neutrophil count (ANC) recovery.

Description

Time Frame

Measurement of ANC upto 5 years

Title

Time to platelet recovery

Description

Time Frame

Measured of platelet recovery upto 5 years

Title

Anti-human factor VIII inhibitor titer

Description

Assessed via Bethesda assay

Time Frame

Measured of FVIII inhibitor titer upto 5 years

Title

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

Description

Immune response to ET3

Time Frame

Measured of Immune response to ET3 for up to 5 years

Title

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

Description

Vector copy number determined via real time PCR

Time Frame

Measured of Vector copy number by PCR upto 5 years

Title

To evaluate FVIII activity after Autologous Hematopoietic Stem Cell Transplantation (HSCT) with CD68ET3-LV transduced CD34+ cells through measurement of plasma FVIII activity levels.

Description

Evaluate FVIII activity

Time Frame

Measurement of FVIII activity (assay) upto 5 years

Title

To evaluate the impact of autologous HSCT with CD68ET3-LV transduced CD34+ cells on bleeding phenotype as measured by frequency of bleeding episodes and clotting factor concentrate (CFC) usage.

Description

Evaluate the impact of autologous HSCT with CD68ET3-LV transduced CD34+ cells

Time Frame

Measured of frequency of bleeding episodes and CFC usage upto 5 years

Title

To evaluate the relationship between FVIII activity level and engraftment of CD68ET3-LV modified cells.

Description

Evaluate correlation between FVIII activity in % level and engraftment of ANC measured in per cubic milliliter (cumm) Platelets values in per cumm

Time Frame

Evaluation of relationship between FVIII activity and engraftment upto 5 years

Other Pre-specified Outcome Measures:

Title

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

Description

To evaluate the impact of autologous HSCT with CD68-ET3-LV CD34+ on annualized bleed rate.

Time Frame

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

10. Eligibility

Sex

Male

Gender Based

Yes

Gender Eligibility Description

Hemophilia A is an inherited X-linked recessive genetic pattern, so males are commonly affected

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

45 Years

Accepts Healthy Volunteers

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.

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

Christopher Benjamin, BPharm

Phone

+914172224480

haemres@cmcvellore.ac.in

First Name & Middle Initial & Last Name or Official Title & Degree

Abraham Sundersingh, BScN

Phone

+914172224464

haembleed@cmcvellore.ac.in

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Alok Srivastava, MD

Organizational Affiliation

Christian Medical College, Vellore, India

Official's Role

Principal Investigator

Facility Information:

Facility Name

Christian Medical College Vellore Ranipet Campus

City

Vellore

State/Province

Tamil Nadu

ZIP/Postal Code

632517

Country

India

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Christopher Benjamin, BPharm

Phone

+914172224480

haemres@cmcvellore.ac.in

First Name & Middle Initial & Last Name & Degree

Abraham Sundersingh, BScN

Phone

+914172224464

haembleed@cmcvellore.ac.in

First Name & Middle Initial & Last Name & Degree

Alok Srivastava, MD

First Name & Middle Initial & Last Name & Degree

Aby Abraham, DM

12. IPD Sharing Statement

Plan to Share IPD

Learn more about this trial

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

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