Hemophilia APhase 1NCT05265767
Hematopoietic Stem Cell Transplantation Gene Therapy for Treatment of Severe Hemophilia A
A Phase 1 study testing Auto CD34+PBSC transduced with a lentiviral vector encoding a novel coagulation factor VIII transgene in people with Hemophilia A, run by Christian Medical College, Vellore, India at 1 site in India.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 to 45 years, men only
- Conditions the study is for
- Hemophilia A
- What is being tested?
- Auto CD34+PBSC transduced with a lentiviral vector encoding a novel coagulation factor VIII transgene
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 6 participants
- Where
- 1 siteIndia
- Study dates
- 1 Apr 2022to 28 Jun 2024
- Phase
- Phase 1
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 45 years
- Men only
- No healthy volunteers
- Adult
Who may be able to join
- 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.
Who cannot join
- 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.
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- 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.
Trial locations and contacts
1 site in 1 country.
India1 site
Christian Medical College Vellore Ranipet Campus
Vellore, Tamil Nadu, 632517
About this study
Official title: Gene Therapy for Hemophilia A With a High Expression Factor VIII Transgene in Autologous Hematopoietic Stem Cells
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.
Read the 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
- Being tested
- Auto CD34+PBSC transduced with a lentiviral vector encoding a novel coagulation factor VIII transgene
- Medical subject headings
- Hemophilia A
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Auto CD34+PBSC transduced with a lentiviral vector encoding a novel coagulation factor VIII transgeneBiological
Auto CD34+PBSC transduced with a lentiviral vector encoding a novel coagulation factor VIII transgene administered by IV infusion following conditioning regimen.
| Study group | Role | What they receive |
|---|---|---|
| Autologous HSCT CD68-ET3-LV gene therapy | Experimental | Autologous gene modified peripheral blood stem cell transplantation for patients with severe hemophilia A (FVIII <1%). Receives: Biological: Auto CD34+PBSC transduced with a lentiviral vector encoding a novel coagulation factor VIII transgene |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 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
Measured: 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
Measured: Assessment of duration of SAEs after 12 weeks of treatment
Secondary outcomes (8)
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.
Measured: Measurement of ANC upto 5 years
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.
Measured: Measured of platelet recovery upto 5 years
Anti-human factor VIII inhibitor titer
Assessed via Bethesda assay
Measured: 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
Immune response to ET3
Measured: 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)
Vector copy number determined via real time PCR
Measured: Measured of Vector copy number by PCR upto 5 years
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
Measured: Measurement of FVIII activity (assay) upto 5 years
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
Measured: Measured of frequency of bleeding episodes and CFC usage upto 5 years
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
Measured: Evaluation of relationship between FVIII activity and engraftment upto 5 years
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted4 Mar 2022
- Study start1 Apr 2022
- Primary completion28 Jun 2024
- Study completion28 Jun 2024
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Hemophilia AStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Model description
- Patients with Severe haemophilia A
- Masking
- None (open label)
- Enrolment
- 6 participants (actual)
Sponsor and investigators
- Lead sponsor
- Christian Medical College, Vellore, India
- Sponsor type
- University, hospital or other
- Collaborators
- Dr. H. Trent Spencer, Professor, Emory University of Medicine, Atlanta Ga, 30322
- Responsible party
- Sponsor
- Investigators
- Alok Srivastava, MD, Principal investigator, Christian Medical College, Vellore, India
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT05265767
- Sponsor's protocol ID
- CSCR-CMC/FVIII LVGT/2018
- Status last verified
- Jul 2024
- First submitted
- 16 Feb 2022
- Last updated
- 12 Jul 2024
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
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.
PubMed 39655790
Study at a glance
From the registry record, last updated by the sponsor on 12 Jul 2024. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Gene Therapy for Hemophilia A With a High Expression Factor VIII Transgene in Autologous Hematopoietic Stem Cells
- ClinicalTrials.gov ID
- NCT05265767
- Acronym / sponsor ID
- CSCR-CMC/FVIII LVGT/2018
- Conditions
- Hemophilia A
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 6 participants (actual)
- Lead sponsor
- Christian Medical College, Vellore, IndiaUniversity, hospital or other
- Collaborators
- Dr. H. Trent Spencer, Professor, Emory University of Medicine, Atlanta Ga, 30322
- Study start
- 1 Apr 2022 (actual)
- Primary completion
- 28 Jun 2024 (actual)
- Study completion
- 28 Jun 2024 (actual)
- First posted
- 4 Mar 2022 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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 design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
- Model description
- Patients with Severe haemophilia A
| Arm | Type | Receives |
|---|---|---|
| Autologous HSCT CD68-ET3-LV gene therapy | Experimental | Biological: Auto CD34+PBSC transduced with a lentiviral vector encoding a novel coagulation factor VIII transgeneAutologous gene modified peripheral blood stem cell transplantation for patients with severe hemophilia A (FVIII <1%). |
Who may qualify
- Ages
- 18 to 45 years
- Sex
- Male only
- Healthy volunteers
- Not accepted
- Age groups
- Adult
Key inclusion criteria (7 listed)
- 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.
Key exclusion criteria (17 listed)
- 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,
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Auto CD34+PBSC transduced with a lentiviral vector encoding a novel coagulation factor VIII transgeneAuto CD34+PBSC transduced with a lentiviral vector encoding a novel coagulation factor VIII transgene administered by IV infusion following conditioning regimen. | Biological | Autologous HSCT CD68-ET3-LV gene therapy |
Primary outcome
Number of study participants experiencing serious adverse events (SAEs) following treatment through 12 weeks.
Time frame: Percentage of patients experiencing SAEs following 12 weeks of treatment
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.
Time frame: Assessement of severity of SAE through 12 weeks after treatment
Serious adverse events severity assessment
Duration of the serious adverse events following administration of CD68-ET3-LV CD34+.
Time frame: Assessment of duration of SAEs after 12 weeks of treatment
As assessed by stop and end dates of the SAEs
8 secondary outcomes
Time to absolute neutrophil count (ANC) recovery.
Time frame: Measurement of ANC upto 5 years
Time to platelet recovery
Time frame: Measured of platelet recovery upto 5 years
Anti-human factor VIII inhibitor titer
Time frame: 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
Time frame: 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)
Time frame: Measured of Vector copy number by PCR upto 5 years
To evaluate FVIII activity after Autologous Hematopoietic Stem Cell Transplantation (HSCT) with CD68ET3-LV transduced CD34+ cells through measurement of plasma FVIII activity levels.
Time frame: Measurement of FVIII activity (assay) upto 5 years
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.
Time frame: Measured of frequency of bleeding episodes and CFC usage upto 5 years
To evaluate the relationship between FVIII activity level and engraftment of CD68ET3-LV modified cells.
Time frame: Evaluation of relationship between FVIII activity and engraftment upto 5 years
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 12 Jul 2024.
- Derived from this study: PubMed 39655790Srivastava 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.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Alok Srivastava, MD principal investigator
Christian Medical College, Vellore, India
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing Auto CD34+PBSC transduced with a lentiviral vector encoding a novel coagulation factor VIII transgene in people with Hemophilia A, run by Christian Medical College, Vellore, India at 1 site in India.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 7 inclusion and 17 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 12 Jul 2024. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in India. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Number of study participants experiencing serious adverse events (SAEs) following treatment through 12 weeks. (time frame: Percentage of patients experiencing SAEs following 12 weeks of treatment). The study lists 3 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT05265767, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 12 Jul 2024.