Hemophilia A
Conditions
Keywords
Hemophilia A, FVIII disease, rFVIII
Brief summary
A study to assess treatment with a new formulation of recombinant factor VIII reconstituted with liposomes (BAY79-4980) to evaluate whether a once-a-week treatment is safe and can prevent bleeds in subjects with severe haemophilia A.
Interventions
BIOLOGICALrFVIII-FS/pegylated liposomes (BAY79-4980)
35 IU/kg body weight intravenous 1x/week for 52 weeks This arm will be stopped by 30.04.10 the subjects will be offered to change to the active comparator arm
BIOLOGICALrFVIII-FS/WFI (BAY14-2222)
25 IU/kg body weight intravenous 3x/week for 52 weeks
Sponsors
Bayer
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
MALE
Age
12 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
* Males aged 12 to 70 years * Subjects with severe hemophilia A (\< 1% factor VIII \[FVIII\]:C) * Subjects with equal or greater than 150 exposure days (EDs) with any FVIII in total * Subjects who have been on-demand treatment with a minimum of 1 relevant bleed per month or have been on secondary prophylaxis treatment with not more than a 3x/week schedule * Subjects with bleeding events and/or treatments during the last 6 months prior to study entry which are documented in the subjects medical records * Subjects with no measurable inhibitor activity * Subjects with no history of FVIII inhibitor antibody formation * Written informed consent by subject and parent / legal representative, if \< 18 years
Exclusion criteria
* Subjects who are receiving primary prophylaxis * Subjects on prophylaxis with documented requirements of \> 75 IU/kg/week * Subjects with any other bleeding disease beside hemophilia A (i.e., von Willebrand disease) * Subjects with abnormal renal function * Subjects with elevated hepatic transaminases * Subjects on treatment with immunomodulatory agents within the last 3 months prior to study entry or during the study * Subjects with known hypersensitivity to the active substance, mouse or hamster protein, liposomes or polyethyleneglycol (PEG) * Subjects who require any pre-medication for FVIII injections
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Less Than 9 Total Bleeds Per Year | up to one year | Bleeds occurring on the same day were counted as one bleeding event. Bleeds occurring within 72 hours into the same location were also counted as one bleeding event. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Less Than 5 Joint Bleeds Per Year | up to one year | Bleeds occurring on the same day were counted as one bleeding event. Bleeds occurring within 72 hours into the same location were also counted as one bleeding event. |
| Number of Joint Bleeds Per Participant Per Year in Responders | up to one year | Bleeds occurring on the same day were counted as one bleeding event. Bleeds occurring within 72 hours into the same location were also counted as one bleeding event. Responders were the subjects with less than 9 total bleeds per year |
Other
| Measure | Time frame | Description |
|---|---|---|
| Number of Bleeds Per Year | up to one year | Bleeds occurring on the same day were counted as one bleeding event. Bleeds occurring within 72 hours into the same location were also counted as one bleeding event. Number of bleeds 3 weeks after the first infusion per 12 months |
| Percentage of Participants With Less Than 9 Total Bleeds Per Year in the Open Label Extension Period | 6 months after start of open label extension period | Bleeds occurring on the same day were counted as one bleeding event. Bleeds occurring within 72 hours into the same location were also counted as one bleeding event. |
| Percentage of Bleeds Treated by Various Numbers of Injections | up to one year | Bleeds occurring on the same day were counted as one bleeding event. Bleeds occurring within 72 hours into the same location were also counted as one bleeding event. |
| Total rFVIII Consumption Per Year | up to one year | Total number of units per kg of study medication (rFVIII) administered to participant for one year. rFVIII is recombinant factor VIII, factor VIII is functional coagulation factor |
Countries
Argentina, Australia, Austria, Belgium, Canada, Chile, Croatia, Denmark, Estonia, France, Germany, Israel, Italy, Lithuania, Netherlands, New Zealand, Norway, Poland, Romania, South Africa, Spain, Switzerland, Taiwan, Turkey (Türkiye), United Kingdom, United States
Participant flow
Recruitment details
Previously treated participants with severe hemophilia A (\<1% FVIII (Factor VIII)), who were currently on on-demand or secondary prophylaxis treatment with any FVIII for ≥150 exposure days (ED) with documented bleeds/injections during the last 6 months prior to study entry could participate in the study.
Pre-assignment details
Of 168 enrolled participants, 25 failed screening.
Participants by arm
| Arm | Count |
|---|---|
| rFVIII-FS/Pegylated Liposomes (BAY79-4980) 35 IU/kg body weight of BAY79-4980 1x/week plus 2 dummy injections/week (dummy = rFVIII (recombinant factor VIII)-FS (formulated with sucrose) excipient reconstituted in WFI (sterile water for injection)) | 67 |
| rFVIII-FS/WFI (BAY14-2222) 25 IU/kg body weight of rFVIII-FS 3x/week (employing 1 percent POPC (1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine)-alone liposome (rFVIII-FS-POPC) as blinding agent used for first weekly injection and rFVIII-FS in WFI for 2nd and 3rd injection) | 72 |
| Total | 139 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Double Blind (DB) | Adverse Event | 1 | 3 |
| Double Blind (DB) | Lack of Efficacy | 2 | 2 |
| Double Blind (DB) | Lost to Follow-up | 1 | 1 |
| Double Blind (DB) | Physician Decision | 0 | 1 |
| Double Blind (DB) | Protocol Violation | 2 | 2 |
| Double Blind (DB) | Termination of the double-blind period | 22 | 21 |
| Double Blind (DB) | Withdrawal by Subject | 8 | 2 |
| Open Label Follow-up | Participant convenience | 0 | 1 |
| Open Label Follow-up | Study termination | 0 | 6 |
| Open Label Follow-up | Withdrawal by Subject | 0 | 1 |
Baseline characteristics
| Characteristic | rFVIII-FS/WFI (BAY14-2222) | Total | rFVIII-FS/Pegylated Liposomes (BAY79-4980) |
|---|---|---|---|
| Age Continuous | 34.1 years STANDARD_DEVIATION 13 | 33.5 years STANDARD_DEVIATION 12.2 | 33.0 years STANDARD_DEVIATION 11.3 |
| Previous treatment On demand | 44 participants | 79 participants | 35 participants |
| Previous treatment Prophylaxis | 28 participants | 60 participants | 32 participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 72 Participants | 139 Participants | 67 Participants |
| target joint No | 16 participants | 29 participants | 13 participants |
| target joint Yes | 56 participants | 110 participants | 54 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 | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 27 / 67 | 27 / 72 | 2 / 26 | 10 / 20 |
| serious Total, serious adverse events | 7 / 67 | 1 / 72 | 0 / 26 | 1 / 20 |
Outcome results
Primary
Percentage of Participants With Less Than 9 Total Bleeds Per Year
Bleeds occurring on the same day were counted as one bleeding event. Bleeds occurring within 72 hours into the same location were also counted as one bleeding event.
Time frame: up to one year
Population: Per protocol (PP) population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| rFVIII-FS/Pegylated Liposomes (BAY79-4980) | Percentage of Participants With Less Than 9 Total Bleeds Per Year | 38.1 Percentage of participants |
| rFVIII-FS/WFI (BAY14-2222) | Percentage of Participants With Less Than 9 Total Bleeds Per Year | 72.1 Percentage of participants |
Secondary
Number of Joint Bleeds Per Participant Per Year in Responders
Bleeds occurring on the same day were counted as one bleeding event. Bleeds occurring within 72 hours into the same location were also counted as one bleeding event. Responders were the subjects with less than 9 total bleeds per year
Time frame: up to one year
Population: PP population in responders
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| rFVIII-FS/Pegylated Liposomes (BAY79-4980) | Number of Joint Bleeds Per Participant Per Year in Responders | 2.341 Joint bleeds per year |
| rFVIII-FS/WFI (BAY14-2222) | Number of Joint Bleeds Per Participant Per Year in Responders | 0.000 Joint bleeds per year |
Secondary
Percentage of Participants With Less Than 5 Joint Bleeds Per Year
Bleeds occurring on the same day were counted as one bleeding event. Bleeds occurring within 72 hours into the same location were also counted as one bleeding event.
Time frame: up to one year
Population: PP population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| rFVIII-FS/Pegylated Liposomes (BAY79-4980) | Percentage of Participants With Less Than 5 Joint Bleeds Per Year | 38.1 Percentage of participants |
| rFVIII-FS/WFI (BAY14-2222) | Percentage of Participants With Less Than 5 Joint Bleeds Per Year | 63.2 Percentage of participants |
Other Pre-specified
Number of Bleeds Per Year
Bleeds occurring on the same day were counted as one bleeding event. Bleeds occurring within 72 hours into the same location were also counted as one bleeding event. Number of bleeds 3 weeks after the first infusion per 12 months
Time frame: up to one year
Population: PP population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| rFVIII-FS/Pegylated Liposomes (BAY79-4980) | Number of Bleeds Per Year | 9.96 bleeds per year |
| rFVIII-FS/WFI (BAY14-2222) | Number of Bleeds Per Year | 2.20 bleeds per year |
Other Pre-specified
Percentage of Bleeds Treated by Various Numbers of Injections
Bleeds occurring on the same day were counted as one bleeding event. Bleeds occurring within 72 hours into the same location were also counted as one bleeding event.
Time frame: up to one year
Population: PP Population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| rFVIII-FS/Pegylated Liposomes (BAY79-4980) | Percentage of Bleeds Treated by Various Numbers of Injections | 1 injection | 73.2 percentage of bleeds |
| rFVIII-FS/Pegylated Liposomes (BAY79-4980) | Percentage of Bleeds Treated by Various Numbers of Injections | 3 injections | 6.5 percentage of bleeds |
| rFVIII-FS/Pegylated Liposomes (BAY79-4980) | Percentage of Bleeds Treated by Various Numbers of Injections | 2 injections | 15.3 percentage of bleeds |
| rFVIII-FS/Pegylated Liposomes (BAY79-4980) | Percentage of Bleeds Treated by Various Numbers of Injections | >3 injections | 5.0 percentage of bleeds |
| rFVIII-FS/Pegylated Liposomes (BAY79-4980) | Percentage of Bleeds Treated by Various Numbers of Injections | 1-2 injections | 88.5 percentage of bleeds |
| rFVIII-FS/WFI (BAY14-2222) | Percentage of Bleeds Treated by Various Numbers of Injections | >3 injections | 4.7 percentage of bleeds |
| rFVIII-FS/WFI (BAY14-2222) | Percentage of Bleeds Treated by Various Numbers of Injections | 1-2 injections | 93.0 percentage of bleeds |
| rFVIII-FS/WFI (BAY14-2222) | Percentage of Bleeds Treated by Various Numbers of Injections | 1 injection | 81.7 percentage of bleeds |
| rFVIII-FS/WFI (BAY14-2222) | Percentage of Bleeds Treated by Various Numbers of Injections | 2 injections | 11.3 percentage of bleeds |
| rFVIII-FS/WFI (BAY14-2222) | Percentage of Bleeds Treated by Various Numbers of Injections | 3 injections | 2.3 percentage of bleeds |
Other Pre-specified
Percentage of Participants With Less Than 9 Total Bleeds Per Year in the Open Label Extension Period
Bleeds occurring on the same day were counted as one bleeding event. Bleeds occurring within 72 hours into the same location were also counted as one bleeding event.
Time frame: 6 months after start of open label extension period
Population: Participants who completed open label extension period
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| rFVIII-FS/Pegylated Liposomes (BAY79-4980) | Percentage of Participants With Less Than 9 Total Bleeds Per Year in the Open Label Extension Period | 55.0 Percentage of participants |
Other Pre-specified
Total rFVIII Consumption Per Year
Total number of units per kg of study medication (rFVIII) administered to participant for one year. rFVIII is recombinant factor VIII, factor VIII is functional coagulation factor
Time frame: up to one year
Population: ITT population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| rFVIII-FS/Pegylated Liposomes (BAY79-4980) | Total rFVIII Consumption Per Year | 2524 IU per kg |
| rFVIII-FS/WFI (BAY14-2222) | Total rFVIII Consumption Per Year | 4378 IU per kg |