Hemophilia A
Conditions
Keywords
Adeno-Associated Virus (AAV), Blood Coagulation Disorders, Blood Coagulation Disorders, Inherited, Coagulation Protein Disorders, Factor VIII (FVIII), Factor VIII (FVIII) Deficiency, Factor VIII (FVIII) Gene, Factor VIII (FVIII) Protein, Genetic Diseases, Inborn, Genetic Diseases, X-Linked, Gene Therapy, Gene Transfer, Hematologic Diseases, Hemorrhagic Disorders, Recombinant, Vector
Brief summary
This clinical research study is being conducted by Spark Therapeutics, Inc. to determine the safety and efficacy of the factor VIII gene transfer treatment with SPK-8011 in individuals with hemophilia A.
Detailed description
Hemophilia A is a condition in which blood is unable to clot effectively. It is caused by a mutation or deletion in the gene that is responsible for producing blood-clotting factor VIII protein. Individuals with hemophilia A suffer from repeated bleeding episodes, often into the joints, which can cause chronic joint disease and sometime results in death due to the inability of the blood to clot efficiently. This chronic joint disease can have significant physical, psychosocial, and quality-of-life effects, including financial burden. The current standard of care includes the use of factor-based therapies which are given either as prophylaxis or to treat bleeding, as well as new non-factor prophylaxis therapies.
Interventions
GENETICSPK-8011
A novel, bio-engineered, recombinant adeno-associated viral vector carrying human factor VIII gene
Sponsors
Spark Therapeutics, Inc.
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Males age 18 years or older * Confirmed diagnosis of hemophilia A as evidenced by their medical history with baseline FVIII activity levels \<=2% * Have received \>150 exposure days (EDs) to FVIII concentrates or cryoprecipitate * Have no prior history of allergic reaction to any FVIII product * Have no measurable inhibitor against FVIII as assessed by the central laboratory and have no prior history of inhibitors to FVIII protein and no clinical signs or symptoms of decreased response to FVIII administration * Agree to use reliable barrier contraception
Exclusion criteria
* Evidence of active hepatitis B or C * Currently on antiviral therapy for hepatitis B or C * Have significant underlying liver disease * Have serological evidence\* of HIV-1 or HIV-2 with CD4 counts ≤200/mm3 and who are on an antiretroviral drug regimen (\* participants who are HIV+ and stable with CD4 count \>200/mm3 and undetectable viral load are eligible to enroll) * Have detectable antibodies reactive with AAV-Spark200 capsid * Participated in a gene transfer trial within the last 52 weeks or in a clinical trial with an investigational product within the last 12 weeks
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Total Annualized FVIII Infusion Rate | Week 5 up to Week 52/EOS Visit | — |
| Peak Factor VIII (FVIII) Activity Levels Assessed by One-Stage Coagulation Assay (OSA) | Up to Week 52/EOS visit | Median peak FVIII activity up to Week 52 |
| Nominal FVIII Level by OSA at Week 52/EOS | Up to Week 52/EOS Visit | Steady-state FVIII activity measured by median FVIII levels at week 52 by OSA. |
| Spontaneous Bleeds Annualized Bleeding Rate | Week 5 up to Week 52/EOS Visit | — |
| Number of Participants With Treatment-emergent Adverse Events (TEAEs) | From date of first dose to Week 52/End of Study (EOS) Visit | An adverse event (AE) was defined as any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. Serious adverse events (SAEs) were defined as adverse events that result in death, are life-threatening, require inpatient hospitalization or prolongation of existing hospitalization, result in persistent or significant disability or incapacity, are a congenital anomaly or birth defect, or are an important medical event that jeopardized participant and required medical intervention to prevent 1 of the outcomes listed in this definition. A TEAE is defined as an AE with an onset date on or following SPK-8011 administration. A summary of other non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section. |
| Number of Participants Who Received Corticosteroids for Presumed Immune Response | Up to Week 52/EOS Visit | — |
Secondary
| Measure | Time frame |
|---|---|
| Number of Participants With Vector-shedding Confirmed Below Quantifiable Limits (BQL) of SPK-8011-101 in Bodily Fluids | Up to Week 52/EOS Visit |
| Incidence of Immune Response to the BDD-hFVIII Transgene | Up to Week 52/EOS Visit |
| Time to Achieve Peak FVIII Activity Level | Up to Week 52/EOS Visit |
Countries
Australia, Canada, Israel, Thailand, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| SPK-8011 5x10^11 vg/kg Participants received a single intravenous infusion of SPK-8011 5x10\^11 vg/kg. | 2 |
| SPK-8011 1x10^12 vg/kg Participants received a single intravenous infusion of SPK-8011 1x10\^12 vg/kg. | 3 |
| SPK-8011 2x10^12 vg/kg Participants received a single intravenous infusion of SPK-8011 2x10\^12 vg/kg. | 9 |
| SPK-8011 1.5x10^12 vg/kg Participants received a single intravenous infusion of SPK-8011 1.5x10\^12 vg/kg. | 11 |
| Total | 25 |
Baseline characteristics
| Characteristic | SPK-8011 5x10^11 vg/kg | SPK-8011 1x10^12 vg/kg | SPK-8011 2x10^12 vg/kg | SPK-8011 1.5x10^12 vg/kg | Total |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 2 Participants | 3 Participants | 9 Participants | 11 Participants | 25 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 2 Participants | 3 Participants | 9 Participants | 11 Participants | 25 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 2 Participants | 2 Participants | 9 Participants | 10 Participants | 23 Participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 2 Participants | 3 Participants | 9 Participants | 11 Participants | 25 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 2 | 0 / 3 | 0 / 9 | 0 / 11 |
| other Total, other adverse events | 2 / 2 | 3 / 3 | 9 / 9 | 11 / 11 |
| serious Total, serious adverse events | 0 / 2 | 1 / 3 | 1 / 9 | 3 / 11 |
Outcome results
Primary
Nominal FVIII Level by OSA at Week 52/EOS
Steady-state FVIII activity measured by median FVIII levels at week 52 by OSA.
Time frame: Up to Week 52/EOS Visit
Population: The Full Analysis Set included all participants who received the infusion of SPK-8011. Here, Overall Number of Participants Analyzed is the number of participants evaluable for this outcome measure.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| SPK-8011 5x10^11 vg/kg | Nominal FVIII Level by OSA at Week 52/EOS | 5.4 percentage of normal activity |
| SPK-8011 1x10^12 vg/kg | Nominal FVIII Level by OSA at Week 52/EOS | 7.8 percentage of normal activity |
| SPK-8011 2x10^12 vg/kg | Nominal FVIII Level by OSA at Week 52/EOS | 8.4 percentage of normal activity |
| SPK-8011 1.5x10^12 vg/kg | Nominal FVIII Level by OSA at Week 52/EOS | 4.1 percentage of normal activity |
Primary
Number of Participants Who Received Corticosteroids for Presumed Immune Response
Time frame: Up to Week 52/EOS Visit
Population: The Full Analysis Set included all participants who received the infusion of SPK-8011.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| SPK-8011 5x10^11 vg/kg | Number of Participants Who Received Corticosteroids for Presumed Immune Response | 0 Participants |
| SPK-8011 1x10^12 vg/kg | Number of Participants Who Received Corticosteroids for Presumed Immune Response | 2 Participants |
| SPK-8011 2x10^12 vg/kg | Number of Participants Who Received Corticosteroids for Presumed Immune Response | 7 Participants |
| SPK-8011 1.5x10^12 vg/kg | Number of Participants Who Received Corticosteroids for Presumed Immune Response | 10 Participants |
Primary
Number of Participants With Treatment-emergent Adverse Events (TEAEs)
An adverse event (AE) was defined as any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. Serious adverse events (SAEs) were defined as adverse events that result in death, are life-threatening, require inpatient hospitalization or prolongation of existing hospitalization, result in persistent or significant disability or incapacity, are a congenital anomaly or birth defect, or are an important medical event that jeopardized participant and required medical intervention to prevent 1 of the outcomes listed in this definition. A TEAE is defined as an AE with an onset date on or following SPK-8011 administration. A summary of other non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section.
Time frame: From date of first dose to Week 52/End of Study (EOS) Visit
Population: The Full Analysis Set included all participants who received the infusion of SPK-8011.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| SPK-8011 5x10^11 vg/kg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | 2 Participants |
| SPK-8011 1x10^12 vg/kg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | 3 Participants |
| SPK-8011 2x10^12 vg/kg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | 9 Participants |
| SPK-8011 1.5x10^12 vg/kg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | 11 Participants |
Primary
Peak Factor VIII (FVIII) Activity Levels Assessed by One-Stage Coagulation Assay (OSA)
Median peak FVIII activity up to Week 52
Time frame: Up to Week 52/EOS visit
Population: The Full Analysis Set included all participants who received the infusion of SPK-8011.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| SPK-8011 5x10^11 vg/kg | Peak Factor VIII (FVIII) Activity Levels Assessed by One-Stage Coagulation Assay (OSA) | 11.5 percentage of normal activity |
| SPK-8011 1x10^12 vg/kg | Peak Factor VIII (FVIII) Activity Levels Assessed by One-Stage Coagulation Assay (OSA) | 20.0 percentage of normal activity |
| SPK-8011 2x10^12 vg/kg | Peak Factor VIII (FVIII) Activity Levels Assessed by One-Stage Coagulation Assay (OSA) | 38.7 percentage of normal activity |
| SPK-8011 1.5x10^12 vg/kg | Peak Factor VIII (FVIII) Activity Levels Assessed by One-Stage Coagulation Assay (OSA) | 55.1 percentage of normal activity |
Primary
Spontaneous Bleeds Annualized Bleeding Rate
Time frame: Week 5 up to Week 52/EOS Visit
Population: The Full Analysis Set included all participants who received the infusion of SPK-8011.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| SPK-8011 5x10^11 vg/kg | Spontaneous Bleeds Annualized Bleeding Rate | NA annualized number of bleeding events |
| SPK-8011 1x10^12 vg/kg | Spontaneous Bleeds Annualized Bleeding Rate | 0.3 annualized number of bleeding events |
| SPK-8011 2x10^12 vg/kg | Spontaneous Bleeds Annualized Bleeding Rate | 0.0 annualized number of bleeding events |
| SPK-8011 1.5x10^12 vg/kg | Spontaneous Bleeds Annualized Bleeding Rate | 0.0 annualized number of bleeding events |
Primary
Total Annualized FVIII Infusion Rate
Time frame: Week 5 up to Week 52/EOS Visit
Population: The Full Analysis Set included all participants who received the infusion of SPK-8011.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| SPK-8011 5x10^11 vg/kg | Total Annualized FVIII Infusion Rate | 0.3 total annualized FVIII infusions | Standard Deviation 0.4 |
| SPK-8011 1x10^12 vg/kg | Total Annualized FVIII Infusion Rate | 3.6 total annualized FVIII infusions | Standard Deviation 3.18 |
| SPK-8011 2x10^12 vg/kg | Total Annualized FVIII Infusion Rate | 7.4 total annualized FVIII infusions | Standard Deviation 7.93 |
| SPK-8011 1.5x10^12 vg/kg | Total Annualized FVIII Infusion Rate | 1.6 total annualized FVIII infusions | Standard Deviation 1.81 |
Secondary
Incidence of Immune Response to the BDD-hFVIII Transgene
Time frame: Up to Week 52/EOS Visit
Population: The Full Analysis Set included all participants who received the infusion of SPK-8011.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| SPK-8011 5x10^11 vg/kg | Incidence of Immune Response to the BDD-hFVIII Transgene | 0 Participants |
| SPK-8011 1x10^12 vg/kg | Incidence of Immune Response to the BDD-hFVIII Transgene | 0 Participants |
| SPK-8011 2x10^12 vg/kg | Incidence of Immune Response to the BDD-hFVIII Transgene | 0 Participants |
| SPK-8011 1.5x10^12 vg/kg | Incidence of Immune Response to the BDD-hFVIII Transgene | 0 Participants |
Secondary
Number of Participants With Vector-shedding Confirmed Below Quantifiable Limits (BQL) of SPK-8011-101 in Bodily Fluids
Time frame: Up to Week 52/EOS Visit
Population: The Full Analysis Set included all participants who received the infusion of SPK-8011.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| SPK-8011 5x10^11 vg/kg | Number of Participants With Vector-shedding Confirmed Below Quantifiable Limits (BQL) of SPK-8011-101 in Bodily Fluids | Saliva | 2 Participants |
| SPK-8011 5x10^11 vg/kg | Number of Participants With Vector-shedding Confirmed Below Quantifiable Limits (BQL) of SPK-8011-101 in Bodily Fluids | Serum | 2 Participants |
| SPK-8011 5x10^11 vg/kg | Number of Participants With Vector-shedding Confirmed Below Quantifiable Limits (BQL) of SPK-8011-101 in Bodily Fluids | Semen | 2 Participants |
| SPK-8011 5x10^11 vg/kg | Number of Participants With Vector-shedding Confirmed Below Quantifiable Limits (BQL) of SPK-8011-101 in Bodily Fluids | Peripheral blood mononuclear cells (PBMCs) | 2 Participants |
| SPK-8011 5x10^11 vg/kg | Number of Participants With Vector-shedding Confirmed Below Quantifiable Limits (BQL) of SPK-8011-101 in Bodily Fluids | Urine | 2 Participants |
| SPK-8011 1x10^12 vg/kg | Number of Participants With Vector-shedding Confirmed Below Quantifiable Limits (BQL) of SPK-8011-101 in Bodily Fluids | Semen | 2 Participants |
| SPK-8011 1x10^12 vg/kg | Number of Participants With Vector-shedding Confirmed Below Quantifiable Limits (BQL) of SPK-8011-101 in Bodily Fluids | Serum | 3 Participants |
| SPK-8011 1x10^12 vg/kg | Number of Participants With Vector-shedding Confirmed Below Quantifiable Limits (BQL) of SPK-8011-101 in Bodily Fluids | Peripheral blood mononuclear cells (PBMCs) | 3 Participants |
| SPK-8011 1x10^12 vg/kg | Number of Participants With Vector-shedding Confirmed Below Quantifiable Limits (BQL) of SPK-8011-101 in Bodily Fluids | Urine | 3 Participants |
| SPK-8011 1x10^12 vg/kg | Number of Participants With Vector-shedding Confirmed Below Quantifiable Limits (BQL) of SPK-8011-101 in Bodily Fluids | Saliva | 3 Participants |
| SPK-8011 2x10^12 vg/kg | Number of Participants With Vector-shedding Confirmed Below Quantifiable Limits (BQL) of SPK-8011-101 in Bodily Fluids | Semen | 8 Participants |
| SPK-8011 2x10^12 vg/kg | Number of Participants With Vector-shedding Confirmed Below Quantifiable Limits (BQL) of SPK-8011-101 in Bodily Fluids | Saliva | 9 Participants |
| SPK-8011 2x10^12 vg/kg | Number of Participants With Vector-shedding Confirmed Below Quantifiable Limits (BQL) of SPK-8011-101 in Bodily Fluids | Peripheral blood mononuclear cells (PBMCs) | 9 Participants |
| SPK-8011 2x10^12 vg/kg | Number of Participants With Vector-shedding Confirmed Below Quantifiable Limits (BQL) of SPK-8011-101 in Bodily Fluids | Serum | 8 Participants |
| SPK-8011 2x10^12 vg/kg | Number of Participants With Vector-shedding Confirmed Below Quantifiable Limits (BQL) of SPK-8011-101 in Bodily Fluids | Urine | 9 Participants |
| SPK-8011 1.5x10^12 vg/kg | Number of Participants With Vector-shedding Confirmed Below Quantifiable Limits (BQL) of SPK-8011-101 in Bodily Fluids | Serum | 10 Participants |
| SPK-8011 1.5x10^12 vg/kg | Number of Participants With Vector-shedding Confirmed Below Quantifiable Limits (BQL) of SPK-8011-101 in Bodily Fluids | Peripheral blood mononuclear cells (PBMCs) | 11 Participants |
| SPK-8011 1.5x10^12 vg/kg | Number of Participants With Vector-shedding Confirmed Below Quantifiable Limits (BQL) of SPK-8011-101 in Bodily Fluids | Saliva | 10 Participants |
| SPK-8011 1.5x10^12 vg/kg | Number of Participants With Vector-shedding Confirmed Below Quantifiable Limits (BQL) of SPK-8011-101 in Bodily Fluids | Semen | 11 Participants |
| SPK-8011 1.5x10^12 vg/kg | Number of Participants With Vector-shedding Confirmed Below Quantifiable Limits (BQL) of SPK-8011-101 in Bodily Fluids | Urine | 10 Participants |
Secondary
Time to Achieve Peak FVIII Activity Level
Time frame: Up to Week 52/EOS Visit
Population: The Full Analysis Set included all participants who received the infusion of SPK-8011.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| SPK-8011 5x10^11 vg/kg | Time to Achieve Peak FVIII Activity Level | 279.5 days | Standard Deviation 58.69 |
| SPK-8011 1x10^12 vg/kg | Time to Achieve Peak FVIII Activity Level | 141.0 days | Standard Deviation 151.79 |
| SPK-8011 2x10^12 vg/kg | Time to Achieve Peak FVIII Activity Level | 56.4 days | Standard Deviation 19.84 |
| SPK-8011 1.5x10^12 vg/kg | Time to Achieve Peak FVIII Activity Level | 54.6 days | Standard Deviation 33.74 |