Hemophilia APhase 1NCT04418414
Hematopoietic Stem Cell Transplantation Gene Therapy for Treatment of Severe Hemophilia A
A Phase 1 study testing Gene therapy and Biological in people with Hemophilia A, run by Expression Therapeutics, LLC.
Trial summary
This is a first-in-human, non-randomized, open label, single treatment, Phase 1 study in approximately 7 patients with severe hemophilia A. The study will evaluate gene therapy by transplantation of autologous CD34+ hematopoietic stem cells transduced ex vivo with the CD68-ET3 lentiviral vector. Read more about this study
- Who is it for?
- Ages 18 years and older, men only
- Conditions the study is for
- Hemophilia A
- What is being tested?
- Gene therapy and Biological
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 7 participants
- Where
- No sites listed yet
- Study dates
- 1 Sep 2024to Aug 2039
- Phase
- Phase 1
- Are there results?
- Not yet: the study is under way
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 years and older
- Men only
- No healthy volunteers
- Adult, Older 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.
- Diagnosis of severe hemophilia A (<1 IU/dL factor VIII activity) based on one-stage coagulation assay.
- Documented history of more than 150 days of factor VIII treatment.
- Average of at least 4 bleeds requiring treatment per year over the prior three years, or at least 4 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.
- Willingness to use effective barrier contraception or limit sexual intercourse to postmenopausal, surgically sterilized, or contraception-practicing partners, for 12 weeks (3 months) after transplantation.
- 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 functional deficits in major organs which would interfere with successful outcome following autologous stem cell transplant, the following guidelines will be utilized:
- Cardiac: There should be no evidence of significant cardiac dysfunction (resting left ventricular ejection fraction of < 50%) and no marked cardiomegaly. There should not be uncontrollable hypertension.
- Renal: GFR < 60 mL/min/1.73m2 per local institutional standard such as CKD-EPI creatinine equation or equivalent.
- Hepatic: There should be no evidence of hepatic dysfunction which is defined as a serum total bilirubin of > 1.5 mg/dL and AST/ALT > 3X the upper limit of normal.
- Hematologic: Absolute neutrophil counts (ANC) <1000/ µL or platelets counts < 150,000/µL.
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- Pulmonary function with a corrected carbon monoxide diffusing capacity (cDLCO) < 50% predicted.
- History of a fVIII inhibitor (> 0.4 Bethesda Units/mL) including at least 2 measurements done at least a week apart or any single titer > 5 BU/mL.
- Subjects who have had prior cellular based therapy or gene editing/ gene therapy including a previous stem cell transplant.
- Subjects with any evidence of active infection or any immunosuppressive disorder, including currently detectable HIV viral load
- Subjects who are RPR, anti-HTLV-1 and II antibody, CMV PCR, VZV antibody and HSV PCR positive at screening.
- Subjects who have allergic reactions or hypersensitivity to any of the drugs used in the study (i.e., anti-thymocyte globulin, plerixafor, G-CSF, busulfan, levetiracetam) or to the constituents of the investigational product formulation.
- Evidence of hepatitis B active infection or chronic carrier based on a positive Hepatitis B DNA testing at screening.
- Positive (detectable viral load per local institutional standard) for the presence of Hepatitis C virus (HCV). Subjects who are positive for anti-HCV antibody are eligible as long as they have a negative undetectable HCV viral load at screening.
- Subjects diagnosed with any history of clinically relevant coagulation or bleeding disorder other than hemophilia A.
- Use of medication(s) that can affect hemostasis (e.g. aspirin, ibuprofen and non-COX-2 selective non-steroid anti-inflammatory drugs).
- Subjects with a history of a malignancy (except surgically resected non-melanoma skin cancer) or subjects with a family history of a known cancer syndrome in a first degree relative.
- Planned surgery within 6 months of enrollment (other than study procedures).
- Treatment with any live vaccines or systemic immunosuppressive agents, not including corticosteroids within 30 days before CD68-ET3-LV CD34+ infusion.
- Treatment with any investigational product within 30 days or 5 half-lives of the investigational product (whichever is longer) prior to enrollment.
- History of autoimmune disease (e.g., inflammatory bowel disease, systemic lupus erythematosus, vasculitis).
- Concurrent enrollment in another clinical study, which might interfere with the requirements of this study or have the potential to impact the evaluation of safety and efficacy of CD68-ET3-LV CD34+- unless it is a non-interventional observational study.
- Any condition in the opinion of the Study Investigators that will negatively impact the subject's ability to safely undergo an autologous stem cell transplant.
- Any reason in the opinion of the Study Investigators that will negatively impact the subject's ability to complete the clinical trial per the trial protocol.
Trial locations and contacts
No sites are listed yet. Contact the study team or a site near you to ask about taking part.
About this study
Official title: ET3-201: Phase 1 Study of Hematopoietic Stem Cell Transplantation (HSCT) Gene Therapy Incorporating a Lentiviral Vector (LV) Encoding a High Expressing Factor VIII Transgene for Treatment of Severe Hemophilia A
This is a first-in-human, non-randomized, open label, single treatment, Phase 1 study in approximately 7 patients with severe hemophilia A. The study will evaluate gene therapy by transplantation of autologous CD34+ hematopoietic stem cells transduced ex vivo with the CD68-ET3 lentiviral vector.
Read the detailed description
Eligible subjects will undergo CD34+ hematopoietic stem cell collection. These cells will be transduced ex vivo with CD68-ET3 lentiviral vector and subsequently, following a conditioning regimen of busulfan and anti-thymocyte globulin, 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
- Gene therapy, Biological
- Keywords
- Hematopoietic stem cell transplant, Gene therapy
- Medical subject headings
- Hemophilia A
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Gene therapyDrug
Also called CD68-ET3-LV CD34+
CD34+ hematopoietic stem cells transduced with CD68-ET3 lentiviral vector (encoding human factor VIII gene) is administered by IV infusion following conditioning regimen with busulfan and anti-thymocyte globulin.
BiologicalOther
G-CSF and Plerixafor are administered by subcutaneous injection prior to apheresis.
| Study group | Role | What they receive |
|---|---|---|
| Autologous HSCT CD68-ET3-LV gene therapy | Experimental | G-CSF/Plerixafor mobilization and apheresis will be used for collection of hematopoietic stem cells and subjects will receive transplantation of autologous CD34+ hematopoietic stem cells transduced with CD68-ET3 lentiviral vector encoding the human factor VIII gene. Receives: Drug: Gene therapy; Other: Biological |
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: 12 weeks
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
Measured: 12 weeks
Duration of the serious adverse events following administration of CD68-ET3-LV CD34+.
As assessed by stop and end dates of the SAEs
Measured: 12 weeks
Secondary outcomes (7)
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: Measured up to 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 up to 5 years.
Anti-human factor VIII inhibitor titer
Assessed via Bethesda assay
Measured: Measured up to 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 up to 5 years.
Vector copy number of circulating genetically modified cells as determined by real time PCR
Vector copy number determined via real time PCR
Measured: Measured up to 5 years.
Clonality of circulating genetically modified cells as determined by LAM-PCR and insertion site analysis using DNA sequencing of LAM-PCR products
Clonality assessment via LAM-PCR
Measured: Measured up to 5 years.
Survival of autologous HSCT CD68-ET3-LV gene therapy.
Survival among subjects who were treated with autologous HSCT with CD68-ET3-LV CD34+.
Measured: Up to 12 weeks following treatment
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted5 Jun 2020
- Study start1 Sep 2024 (estimated)
- Primary completionAug 2029 (estimated)
- Study completionAug 2039 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- 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
- Masking
- None (open label)
- Enrolment
- 7 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Expression Therapeutics, LLC
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04418414
- Sponsor's protocol ID
- ET3-201
- Status last verified
- Feb 2024
- First submitted
- 28 May 2020
- Last updated
- 20 Feb 2024
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 20 Feb 2024. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- ET3-201: Phase 1 Study of Hematopoietic Stem Cell Transplantation (HSCT) Gene Therapy Incorporating a Lentiviral Vector (LV) Encoding a High Expressing Factor VIII Transgene for Treatment of Severe Hemophilia A
- ClinicalTrials.gov ID
- NCT04418414
- Acronym / sponsor ID
- ET3-201
- Conditions
- Hemophilia A
- Keywords
- Hematopoietic stem cell transplant, Gene therapy
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Not yet recruiting
- Enrolment
- 7 participants (estimated)
- Lead sponsor
- Expression Therapeutics, LLCIndustry (pharma, biotech, devices)
- Study start
- 1 Sep 2024 (estimated)
- Primary completion
- Aug 2029 (estimated)
- Study completion
- Aug 2039 (estimated)
- First posted
- 5 Jun 2020 (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.
This is a first-in-human, non-randomized, open label, single treatment, Phase 1 study in approximately 7 patients with severe hemophilia A. The study will evaluate gene therapy by transplantation of autologous CD34+ hematopoietic stem cells transduced ex vivo with the CD68-ET3 lentiviral vector.
Detailed description
Eligible subjects will undergo CD34+ hematopoietic stem cell collection. These cells will be transduced ex vivo with CD68-ET3 lentiviral vector and subsequently, following a conditioning regimen of busulfan and anti-thymocyte globulin, 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
| Arm | Type | Receives |
|---|---|---|
| Autologous HSCT CD68-ET3-LV gene therapy | Experimental | Drug: Gene therapy, Other: BiologicalG-CSF/Plerixafor mobilization and apheresis will be used for collection of hematopoietic stem cells and subjects will receive transplantation of autologous CD34+ hematopoietic stem cells transduced with CD68-ET3 lentiviral vector encoding the human factor VIII gene. |
Who may qualify
- Ages
- 18 years and older
- Sex
- Male only
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (8 listed)
- Able to provide informed consent for the protocol approved by the Institutional Review Board.
- Male subjects who are >= 18 years of age.
- Diagnosis of severe hemophilia A (<1 IU/dL factor VIII activity) based on one-stage coagulation assay.
- Documented history of more than 150 days of factor VIII treatment.
- Average of at least 4 bleeds requiring treatment per year over the prior three years, or at least 4 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 (24 listed)
- History of spontaneous central nervous system bleeding within the last 5 years.
- Significant functional deficits in major organs which would interfere with successful outcome following autologous stem cell transplant, the following guidelines will be utilized:
- History of a fVIII inhibitor (> 0.4 Bethesda Units/mL) including at least 2 measurements done at least a week apart or any single titer > 5 BU/mL.
- Subjects who have had prior cellular based therapy or gene editing/ gene therapy including a previous stem cell transplant.
- Subjects with any evidence of active infection or any immunosuppressive disorder, including currently detectable HIV viral load
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 |
|---|---|---|
| Gene therapyAlso: CD68-ET3-LV CD34+CD34+ hematopoietic stem cells transduced with CD68-ET3 lentiviral vector (encoding human factor VIII gene) is administered by IV infusion following conditioning regimen with busulfan and anti-thymocyte globulin. | Drug | Autologous HSCT CD68-ET3-LV gene therapy |
| BiologicalG-CSF and Plerixafor are administered by subcutaneous injection prior to apheresis. | Other | 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: 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.
Time frame: 12 weeks
Serious adverse events
Duration of the serious adverse events following administration of CD68-ET3-LV CD34+.
Time frame: 12 weeks
As assessed by stop and end dates of the SAEs
7 secondary outcomes
Time to absolute neutrophil count (ANC) recovery.
Time frame: Measured up to 5 years.
Time to platelet recovery.
Time frame: Measured up to 5 years.
Anti-human factor VIII inhibitor titer
Time frame: Measured up to 5 years.
Immune response to ET3 as measured by modified Bethesda assay incorporating ET3i spiked into fVIII-deficient plasma
Time frame: Measured up to 5 years.
Vector copy number of circulating genetically modified cells as determined by real time PCR
Time frame: Measured up to 5 years.
Clonality of circulating genetically modified cells as determined by LAM-PCR and insertion site analysis using DNA sequencing of LAM-PCR products
Time frame: Measured up to 5 years.
Survival of autologous HSCT CD68-ET3-LV gene therapy.
Time frame: Up to 12 weeks following treatment
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 20 Feb 2024.
- 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.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing Gene therapy and Biological in people with Hemophilia A, run by Expression Therapeutics, LLC.
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 8 inclusion and 24 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: opening soon, as of the sponsor's last update on 20 Feb 2024. Status can change between updates, so confirm with the study contact before making plans.
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?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Contact Study Coordinator (404-850-0123, clinicaltrials@expressiontherapeutics.com), or a site near the patient. 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: 12 weeks). 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?
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 20 Feb 2024.