Hemophilia A
Conditions
Keywords
Haemophilia treatment, rFVIII
Brief summary
The objective of the trial is to demonstrate that 2-3 times per week prophylaxis therapy with BAY81-8973 is superior to on-demand therapy with BAY81-8973 in patients with severe Hemophilia A. The hypothesis is that prophylaxis will result in fewer bleeds than on-demand treatment.
Interventions
BIOLOGICALrFVIII (BAY81-8973) on demand
Participants received on-demand treatment with rFVIII (BAY81-8973) assayed by CS/EP (Chromogenic Substrate Assay per European Pharmacopoeia) for 6 months and by CS/ADJ (Chromogenic Substrate Assay/label adjusted to one-stage assay) for 6 months, sequence according to randomization
BIOLOGICALrFVIII (BAY81-8973) prophylaxis low-dose
Participants received low dose prophylaxis treatment at 20, 25 or 30 IU/kg twice per week with rFVIII (BAY81-8973) assayed by CS/EP for 6 months and by CS/ADJ for 6 months, sequence according to randomization.
BIOLOGICALrFVIII (BAY81-8973) prophylaxis high-dose
Participants received high dose prophylaxis treatment at 30, 35 or 40 IU/kg 3 times per week with rFVIII (BAY81-8973) assayed by CS/EP for 6 months and by CS/ADJ for 6 months, sequence according to randomization.
Sponsors
Bayer
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
12 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* Male, aged 12 to 65 years * Severe hemophilia A * History of more than 150 exposure days (ED) with clotting factor concentrates * Currently receiving episodic treatment with FVIII; no regular prophylaxis for more than 6 consecutive months in the past 5 years * No current Factor VIII inhibitor or history of inhibitor * Willing to use electronic patient diary
Exclusion criteria
* Presence of another bleeding disease that is different from hemophilia A * Thrombocytopenia * Abnormal renal function * Presence of active liver disease * Known hypersensitivity to FVIII
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Annualized Number of All Bleeds | Up to 12 months (6 months per mode of potency assignment according to the randomized cross-over design) | The annualized number of bleeds experienced by participants |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Annualized Number of All Bleeds During CS/EP Period | Up to 6 months (6 months on CS/EP potency assignment) | The annualized number of bleeds experienced by participants while they were taking rFVIII (BAY81-8973) assayed by CS/EP |
| Annualized Number of All Bleeds During CS/ADJ Period | Up to 6 months (6 months on CS/ADJ potency assignment) | The annualized number of bleeds experienced by participants while they were taking rFVIII (BAY81-8973) assayed by CS/ADJ |
| Percentage of Bleeds Per Participant Controlled With ≤ 2 Injections in Participants Treated on Demand With rFVIII (BAY81-8973) | Up to 12 months (6 months per mode of potency assignment according to the randomized cross-over design) | The percentage of bleeds per participant on on-demand treatment that stopped after two or fewer injections |
Other
| Measure | Time frame | Description |
|---|---|---|
| Number of Bleeds During Treatment | 12 months | The number of bleeds experienced by each participant |
| Number of Participants With Inhibitory Antibody Formation | 3, 6, 9 and 12 months after baseline | A test to ensure that participants have not developed antibodies that will interfere with the action of rFVIII (BAY81-8973) |
Countries
Argentina, China, Colombia, Czechia, India, Indonesia, Japan, Mexico, Romania, Russia, Serbia, Slovakia, South Africa, Taiwan, Thailand, Turkey (Türkiye), Ukraine, United States
Participant flow
Recruitment details
Participants were recruited from specialized hemophilia treatment centers.
Pre-assignment details
83 participants were randomized, but 3 of these terminated the study before their first injection of study drug.
Participants by arm
| Arm | Count |
|---|---|
| rFVIII (BAY81-8973) on Demand Participants received on-demand treatment with rFVIII (BAY81-8973) assayed by CS/EP (Chromogenic Substrate Assay per European Pharmacopoeia) for 6 months and by CS/ADJ (Chromogenic Substrate Assay/label adjusted to one-stage assay) for 6 months, sequence according to randomization. | 21 |
| rFVIII (BAY81-8973) Prophylaxis Low-dose Participants received low dose prophylaxis treatment at 20, 25 or 30 IU/kg twice per week with rFVIII (BAY81-8973) assayed by CS/EP for 6 months and by CS/ADJ for 6 months, sequence according to randomization. | 28 |
| rFVIII (BAY81-8973) Prophylaxis High-dose Participants received high dose prophylaxis treatment at 30, 35 or 40 IU/kg 3 times per week with rFVIII (BAY81-8973) assayed by CS/EP for 6 months and by CS/ADJ for 6 months, sequence according to randomization. | 31 |
| Total | 80 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| First Intervention (6 Months) | Non-compliance with study medication | 1 | 0 | 0 | 0 | 0 | 0 |
| First Intervention (6 Months) | Protocol Violation | 0 | 0 | 1 | 0 | 0 | 0 |
| First Intervention (6 Months) | Withdrawal by Subject | 0 | 0 | 0 | 1 | 0 | 1 |
Baseline characteristics
| Characteristic | rFVIII (BAY81-8973) on Demand | rFVIII (BAY81-8973) Prophylaxis Low-dose | rFVIII (BAY81-8973) Prophylaxis High-dose | Total |
|---|---|---|---|---|
| Age, Continuous | 31.4 years STANDARD_DEVIATION 10.9 | 28.8 years STANDARD_DEVIATION 10.9 | 29.1 years STANDARD_DEVIATION 11.5 | 29.6 years STANDARD_DEVIATION 11 |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 21 Participants | 28 Participants | 31 Participants | 80 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 23 / 80 |
| serious Total, serious adverse events | 2 / 80 |
Outcome results
Primary
Annualized Number of All Bleeds
The annualized number of bleeds experienced by participants
Time frame: Up to 12 months (6 months per mode of potency assignment according to the randomized cross-over design)
Population: ITT (Intent to Treat). Low and high dose prophylaxis arms and both potencies combined as planned for the statistical analysis to achieve intended sample size.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| rFVIII (BAY81-8973) on Demand | Annualized Number of All Bleeds | 57.7 Bleeds per year per participant | Standard Deviation 24.6 |
| rFVIII (BAY81-8973) Prophylaxis Treatment | Annualized Number of All Bleeds | 4.9 Bleeds per year per participant | Standard Deviation 6.8 |
Comparison: Null hypothesis: bleeding rates are equal, alternative hypothesis rates are unequal. Power calculation: Assumption 5 bleeds per year on prophylactic treatment, 15 on on-demand treatment; 2-sided alpha 5% and 90% power.p-value: 0.0001ANOVA
Secondary
Annualized Number of All Bleeds During CS/ADJ Period
The annualized number of bleeds experienced by participants while they were taking rFVIII (BAY81-8973) assayed by CS/ADJ
Time frame: Up to 6 months (6 months on CS/ADJ potency assignment)
Population: ITT. Low and high dose prophylaxis arms combined as planned for the statistical analysis to achieve sufficient sample size.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| rFVIII (BAY81-8973) on Demand | Annualized Number of All Bleeds During CS/ADJ Period | 59.7 Bleeds per year per participant | Standard Deviation 25.1 |
| rFVIII (BAY81-8973) Prophylaxis Treatment | Annualized Number of All Bleeds During CS/ADJ Period | 4.8 Bleeds per year per participant | Standard Deviation 6.8 |
Comparison: Null hypothesis: bleeding rates are equal, alternative hypothesis rates are unequal. Power calculation not done for this comparison as not primary comparison.p-value: 0.0001ANOVA
Secondary
Annualized Number of All Bleeds During CS/EP Period
The annualized number of bleeds experienced by participants while they were taking rFVIII (BAY81-8973) assayed by CS/EP
Time frame: Up to 6 months (6 months on CS/EP potency assignment)
Population: ITT. Low and high dose prophylaxis arms combined as planned for the statistical analysis to achieve sufficient sample size.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| rFVIII (BAY81-8973) on Demand | Annualized Number of All Bleeds During CS/EP Period | 57.6 Bleeds per year per participant | Standard Deviation 24.3 |
| rFVIII (BAY81-8973) Prophylaxis Treatment | Annualized Number of All Bleeds During CS/EP Period | 5.1 Bleeds per year per participant | Standard Deviation 8 |
Comparison: Null hypothesis: bleeding rates are equal, alternative hypothesis rates are unequal. Power calculation not done for this comparison as not primary comparison.p-value: 0.0001ANOVA
Secondary
Percentage of Bleeds Per Participant Controlled With ≤ 2 Injections in Participants Treated on Demand With rFVIII (BAY81-8973)
The percentage of bleeds per participant on on-demand treatment that stopped after two or fewer injections
Time frame: Up to 12 months (6 months per mode of potency assignment according to the randomized cross-over design)
Population: ITT
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| rFVIII (BAY81-8973) on Demand | Percentage of Bleeds Per Participant Controlled With ≤ 2 Injections in Participants Treated on Demand With rFVIII (BAY81-8973) | 96.8 Percentage of bleeds |
| rFVIII (BAY81-8973) Prophylaxis Treatment | Percentage of Bleeds Per Participant Controlled With ≤ 2 Injections in Participants Treated on Demand With rFVIII (BAY81-8973) | 100.0 Percentage of bleeds |
Comparison: Null hypothesis: the proportion of bleeds controlled by no more than 2 infusions in the CS/EP group plus 10% is less than the proportion of bleeds controlled by no more than 2 infusions in the CS/ADJ group. Alternative hypothesis: the proportion of bleeds controlled by no more than 2 infusions in the CS/EP group plus 10% is greater than or equal to the proportion of bleeds controlled by no more than 2 infusions in the CS/ADJ group. No power calculation since this is not the primary comparison.p-value: 0.0001Exact Permutation Test for paired sample
Other Pre-specified
Number of Bleeds During Treatment
The number of bleeds experienced by each participant
Time frame: 12 months
Population: ITT
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| rFVIII (BAY81-8973) on Demand | Number of Bleeds During Treatment | 60.0 Bleeds |
| rFVIII (BAY81-8973) Prophylaxis Treatment | Number of Bleeds During Treatment | 4.0 Bleeds |
| rFVIII (BAY81-8973) Prophylaxis High-dose | Number of Bleeds During Treatment | 2.0 Bleeds |
Other Pre-specified
Number of Participants With Inhibitory Antibody Formation
A test to ensure that participants have not developed antibodies that will interfere with the action of rFVIII (BAY81-8973)
Time frame: 3, 6, 9 and 12 months after baseline
Population: Safety population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| rFVIII (BAY81-8973) on Demand | Number of Participants With Inhibitory Antibody Formation | 12 months after baseline | 0 Participants |
| rFVIII (BAY81-8973) on Demand | Number of Participants With Inhibitory Antibody Formation | 6 months after baseline | 0 Participants |
| rFVIII (BAY81-8973) on Demand | Number of Participants With Inhibitory Antibody Formation | 3 months after baseline | 0 Participants |
| rFVIII (BAY81-8973) on Demand | Number of Participants With Inhibitory Antibody Formation | 9 months after baseline | 0 Participants |
| rFVIII (BAY81-8973) Prophylaxis Treatment | Number of Participants With Inhibitory Antibody Formation | 12 months after baseline | 0 Participants |
| rFVIII (BAY81-8973) Prophylaxis Treatment | Number of Participants With Inhibitory Antibody Formation | 9 months after baseline | 0 Participants |
| rFVIII (BAY81-8973) Prophylaxis Treatment | Number of Participants With Inhibitory Antibody Formation | 6 months after baseline | 0 Participants |
| rFVIII (BAY81-8973) Prophylaxis Treatment | Number of Participants With Inhibitory Antibody Formation | 3 months after baseline | 0 Participants |
| rFVIII (BAY81-8973) Prophylaxis High-dose | Number of Participants With Inhibitory Antibody Formation | 9 months after baseline | 0 Participants |
| rFVIII (BAY81-8973) Prophylaxis High-dose | Number of Participants With Inhibitory Antibody Formation | 6 months after baseline | 0 Participants |
| rFVIII (BAY81-8973) Prophylaxis High-dose | Number of Participants With Inhibitory Antibody Formation | 3 months after baseline | 0 Participants |
| rFVIII (BAY81-8973) Prophylaxis High-dose | Number of Participants With Inhibitory Antibody Formation | 12 months after baseline | 0 Participants |