Hemophilia A
Conditions
Keywords
Hemophilia A
Brief summary
To evaluate the effect of secondary prophylaxis as compared to episodic treatment on bleeding frequency (number of bleeds per year) and on joint damage.
Interventions
Prophylaxis treatment includes three times per week administration of 25 IU/kg of Kogenate FS. Dose escalation steps by 5 IU/kg (to 30 IU/kg or 35 IU/kg maximum) exhibiting a bleeding frequency of 12 bleeding episodes per year or greater.
Sponsors
Bayer
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
12 Years to 50 Years
Healthy volunteers
No
Inclusion criteria
* Males aged 12 to 50 years (US and Argentina) * Males aged 18 to 50 years (other countries) * Subjects with severe hemophilia A (\<1% FVIII:C) as confirmed by the central lab from a sample obtained at least 96 hours after FVIII administration wash-out. Allow for the inclusion of a maximum of 10% (n=8) of patients with 1-2% FVIII:C baseline levels as long as they exhibit clinical severity and comply with all other inclusion criteria. * Subjects with at least 150 prior exposure days with any FVIII * Subjects who have been on episodic treatment and no known regular prophylaxis treatment for more than 12 consecutive months in the previous 5 years * Subjects with 6 to 24 bleeding events and/or treatments in the previous 6 months prior to study entry which are documented and available in the subjects medical records. Documentation can include records from previous physicians, specific home treatment records, emergency room or hospital records, x-ray reports, etc. The investigator can also document with a detailed note the number of bleeds reported by the subject in the last 6 months. * Subjects with inhibitor formation surveillance (inhibitor or recovery testing) over the ten years prior to enrollment documented by the investigator and who do not have a history of any of the following: * A positive inhibitor titer of 5.0 Bethesda Unit (BU) or greater by either BU assay system at any time since first exposure to exogenous factor VIII * A positive inhibitor test result of 1.0 or greater performed by the original BU assay at any time in the past 10 years (A subject can have more than one positive inhibitor test of 0.6 or greater by the original BU assay test but all must be less than 1.0 BU using the original BU assay.) * A positive inhibitor test result of 0.6 or greater performed by the Nijmegen method at any time in the past 10 years * Subjects with no inhibitor activity by Nijmegen-modified Bethesda assay, either positive (\> 0.6 BU is considered positive) or borderline (\> 0.3 and \< 0.6 BU is considered borderline) as measured in the current study reference laboratory
Exclusion criteria
* Subjects with any other bleeding disease besides hemophilia A (i.e. von Willebrand disease) * Subjects with thrombocytopenia (platelets \< 100,000/mm3) * Subjects with abnormal renal function (Cockcroft-Gault Creatinine Clearance value of 60 mL/min or lower) * Subjects with active hepatic disease (Aspartate aminotransferase \[AST\] or Alanine aminotransferase \[ALT\] \> 5xUpper Limit of Normal (ULN)) * Subjects on treatment with immunomodulatory agents within the last 3 months prior to study entry or during the study (the following drugs are however allowed: interferon-a treatment for Hepatitis C virus (HCV), Highly active anti-retroviral therapy (HAART) therapy for human immunodeficiency virus (HIV) and/or a total of two courses of pulse treatment with steroids for a maximum of 7 days at 1mg/kg or less) * Subjects with an absolute CD4 lymphocyte cell count \< 200 cells/mm3 (due to HIV, HCV or another suspected medical condition) * Subjects with known hypersensitivity to rFVIII, mouse or hamster proteins * Subjects who are receiving or had received other experimental drugs within 1 month prior to study entry * Subjects who require any pre-medication to tolerate FVIII injections (e.g. anti-histamines) * Subjects who are unwilling to comply with study visits or either of the possible treatment regimens * Subjects who have a planned orthopedic intervention to be performed during the study that may substantially affect bleeding (e.g. surgical or chemical or radiological synovectomy) * Subjects who are not suitable for participation in this study for any reason, according to the Investigator * Subjects who have poor joint status as defined by routine need for a wheelchair or unable to ambulate without the assistance of a brace, cane or crutches * Three or more joints that are already fused or frozen also called ankylosis
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Bleeding Frequency (Number of Total Bleeds) | After the last enrolled patient has been in the study for 1 year. At the cut-off, the median follow-up duration was 616 days (minimum was 111 days and maximum was 1109 days) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline to 3 Years in the MRI (Magnetic Resonance Imaging) Scale. | Baseline and 3 years | The Extended MRI Scale total score has a range between 0 (normal unaffected joint) to 45 (maximal joint damage) points. It is composed of 2 domains, the soft tissue domain with a maximum of 9 points and the osteochondral domain with a maximum of 36 points. A single score for each subject was to be calculated from the sum of both domains and the average over all joints for the Extended MRI endpoint. Higher MRI score denotes greater joint structure damage thus a positive change from baseline means worsening. |
| Change From Baseline to 3 Years in the Colorado Adult Joint Assessment Scale | Baseline and 3 years | The total joint score is derived for each of six joints: left and right sides for knees (score: 0-25), ankles (score: 0-25), and elbows (score: 0-21). Higher CAJAS (Colorado Adult Joint Assessment Scale) score denotes greater joint structure damage thus a positive change from baseline means worsening. CAJAS total score is the sum of all 6 joints, ranging from 0 (best possible outcome) to 142 (worst possible outcome). |
Other
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline to 3 Years in the Physical Functioning Domain of the Haemo-QoL-A | Baseline and 3 years | The Haemo-QoL-A total score as well as each of its domains have a range between 0 (worst Quality of Life) and 100 (best Quality of Life) points. Therefore, a higher Haemo-QoL-A score denotes greater Quality of Life. |
Countries
Argentina, Bulgaria, Romania, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Recombinant Factor VIII Prophylaxis Treatment Participants received 25 IU/kg of Recombinant Factor VIII (Kogenate FS, BAY14-2222) intravenously (IV), 3 times per week. Dose escalation steps by 5 IU/kg (to 30 IU/kg or 35 IU/kg maximum) for patients exhibiting a bleeding frequency of 12 bleeding episodes per year or greater. | 42 |
| Recombinant Factor VIII On-demand Treatment Participants received Recombinant Factor VIII (Kogenate FS, BAY14-2222) IV for bleeds in accordance with package insert instructions and study physician recommendations. | 42 |
| Total | 84 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lack of Efficacy | 1 | 0 |
| Overall Study | Lost to Follow-up | 0 | 1 |
| Overall Study | Non-compliant with study medication | 4 | 0 |
| Overall Study | Protocol Violation | 0 | 1 |
| Overall Study | Site closed by sponsor | 0 | 1 |
| Overall Study | Withdrawal by Subject | 2 | 4 |
Baseline characteristics
| Characteristic | Recombinant Factor VIII Prophylaxis Treatment | Recombinant Factor VIII On-demand Treatment | Total |
|---|---|---|---|
| Age, Continuous | 30.6 Years STANDARD_DEVIATION 8.8 | 30.7 Years STANDARD_DEVIATION 9.7 | 30.6 Years STANDARD_DEVIATION 9.2 |
| Number of bleeds during last 6 months | 10.0 Bleeds STANDARD_DEVIATION 4.4 | 12.2 Bleeds STANDARD_DEVIATION 5.1 | 11.1 Bleeds STANDARD_DEVIATION 4.8 |
| Number of patients with target joints, Yes/No No | 14 Participants | 11 Participants | 25 Participants |
| Number of patients with target joints, Yes/No Yes | 28 Participants | 31 Participants | 59 Participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 42 Participants | 42 Participants | 84 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 11 / 42 | 28 / 42 |
| serious Total, serious adverse events | 9 / 42 | 11 / 42 |
Outcome results
Primary
Bleeding Frequency (Number of Total Bleeds)
Time frame: After the last enrolled patient has been in the study for 1 year. At the cut-off, the median follow-up duration was 616 days (minimum was 111 days and maximum was 1109 days)
Population: ITT (Intent-to-treat) Population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Recombinant Factor VIII Prophylaxis Treatment | Bleeding Frequency (Number of Total Bleeds) | 0 Bleeds |
| Recombinant Factor VIII On-demand Treatment | Bleeding Frequency (Number of Total Bleeds) | 54.5 Bleeds |
p-value: <0.000195% CI: [8.1, 26.5]Negative Binomial Regression Model
Secondary
Change From Baseline to 3 Years in the Colorado Adult Joint Assessment Scale
The total joint score is derived for each of six joints: left and right sides for knees (score: 0-25), ankles (score: 0-25), and elbows (score: 0-21). Higher CAJAS (Colorado Adult Joint Assessment Scale) score denotes greater joint structure damage thus a positive change from baseline means worsening. CAJAS total score is the sum of all 6 joints, ranging from 0 (best possible outcome) to 142 (worst possible outcome).
Time frame: Baseline and 3 years
Population: Full Analysis Set
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Recombinant Factor VIII Prophylaxis Treatment | Change From Baseline to 3 Years in the Colorado Adult Joint Assessment Scale | -0.31 Scores on a scale |
| Recombinant Factor VIII On-demand Treatment | Change From Baseline to 3 Years in the Colorado Adult Joint Assessment Scale | 0.63 Scores on a scale |
p-value: 0.007295% CI: [-1.61, -0.26]Based on cLDA model
Secondary
Change From Baseline to 3 Years in the MRI (Magnetic Resonance Imaging) Scale.
The Extended MRI Scale total score has a range between 0 (normal unaffected joint) to 45 (maximal joint damage) points. It is composed of 2 domains, the soft tissue domain with a maximum of 9 points and the osteochondral domain with a maximum of 36 points. A single score for each subject was to be calculated from the sum of both domains and the average over all joints for the Extended MRI endpoint. Higher MRI score denotes greater joint structure damage thus a positive change from baseline means worsening.
Time frame: Baseline and 3 years
Population: Full Analysis Set
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Recombinant Factor VIII Prophylaxis Treatment | Change From Baseline to 3 Years in the MRI (Magnetic Resonance Imaging) Scale. | 0.79 Scores on a scale |
| Recombinant Factor VIII On-demand Treatment | Change From Baseline to 3 Years in the MRI (Magnetic Resonance Imaging) Scale. | 0.96 Scores on a scale |
p-value: 0.661495% CI: [-0.92, 0.59]Based on cLDA model
Other Pre-specified
Change From Baseline to 3 Years in the Physical Functioning Domain of the Haemo-QoL-A
The Haemo-QoL-A total score as well as each of its domains have a range between 0 (worst Quality of Life) and 100 (best Quality of Life) points. Therefore, a higher Haemo-QoL-A score denotes greater Quality of Life.
Time frame: Baseline and 3 years
Population: Full Analysis Set
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Recombinant Factor VIII Prophylaxis Treatment | Change From Baseline to 3 Years in the Physical Functioning Domain of the Haemo-QoL-A | 7.86 Scores on a scale |
| Recombinant Factor VIII On-demand Treatment | Change From Baseline to 3 Years in the Physical Functioning Domain of the Haemo-QoL-A | -5.30 Scores on a scale |
95% CI: [5.23, 21.08]Based on cLDA model