Hemophilia B
Conditions
Keywords
Hemophilia B, BeneFIX
Brief summary
This study is designed to evaluate BeneFIX infused as prophylaxis regimens, compared with BeneFIX administered as an on-demand regimen only. In the trial, subjects will participate in 4 study periods. The first period is a 16-week on-demand treatment, during which subjects will utilize BeneFIX to treat bleeding events episodically only as they occur (i.e., on-demand treatment). At the end of this period, subjects will be randomly assigned to 1 of 2 BeneFIX prophylaxis regimens: either 100 IU/kg once weekly or 50 IU/kg twice weekly, and followed for 16 weeks. At the end of this period, subjects will use on-demand treatment for 8 weeks. The purpose of this 8-week period is to mitigate the potential carry-over effect of the prior prophylaxis regimen on bleeding frequency. Following this 8-week on-demand treatment, subjects will cross-over and receive the alternate study prophylactic regimen for 16 weeks. The primary endpoint is annualized number of bleeding episodes, compared between the first on-demand period and each of the prophylaxis regimens. A comparison of annualized bleeding episodes between the two prophylaxis regimens will also be performed. Subject-reported outcomes will also be collected using a patient diary. At 24 and 48 hours following the onset of each joint bleeding episode, information on pain, sleep, and work will be collected. Additional data on physical functioning will be recorded on the diary at the end of the 16-week on-demand period, and at the end of each prophylaxis period. Information on safety will also be collected. Each subject will participate in this study for approximately 59 weeks (15 months), including a screening period of up to 3 weeks, an initial 16-week on-demand period, two prophylaxis treatment periods of 16 weeks each, separated by an 8-week on-demand treatment period. A modified FIX recovery study will be performed once during each prophylaxis period. The study diary will also be used by subjects to collect secondary endpoints. These endpoints, which are subject-reported outcomes, will be recorded in the diary at 24 and 48 hours following the onset of each joint bleeding episode. Additional data on physical functioning will be recorded on the diary at the end of the 16-week on-demand period, and at the end of each prophylaxis period. Patients will be recruited in the United States, Canada, Europe and Russia.
Interventions
DRUGRecombinant Coagulation Factor IX (BeneFIX)
100 IU/kg once weekly then crossover to 50 IU/kg twice weekly
Sponsors
Pfizer
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
PREVENTION
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
6 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* Documented history of moderately severe or severe hemophilia B (FIX:C less than or equal to 2%) * Male subjects, aged 6 years to 65 years. * Subjects with a minimum of 12 bleeding episodes, 6 of which must be joint bleeds, in the 12 months before screening.
Exclusion criteria
* Subjects currently utilizing FIX primary prophylaxis. * Subjects with HIV+ who have a CD4 count less than 200 * Subjects with hepatic or renal impairment. * Prothrombin time or International Normalized Ration more than 1.5 times the upper limit of normal. * Major surgery or an orthopedic surgical procedure within the past 3 months or is planned within the duration of participation in this study. * Past history of, or current FIX inhibitor. * Hypersensitivity to any FIX product or hamster protein. * Exposure to any investigational drug, except for rFIX-R, or device within 30 days of providing consent/assent (as appropriate) for this study. * Bleeding disorders other than hemophilia B. * Concurrent inflammatory disease that in the investigator's judgment could confound the study results.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Annualized Number of Bleeding Episodes | Baseline up to Week 56 | Annualized bleed rate (ABR) or number of bleeds per year derived for each participant for each treatment regimen by using the following formula: ABR = number of bleeds / (days on treatment regimen / 365.25) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Quality of Sleep Measured by Sleep Diary After Hemarthrosis | 24 and 48 hours post-bleed | For each bleeding event, a diary was filled out that night and the subsequent night. Questions included: How would you describe the quality of your sleep last night? 1=Very Good, 2=Good, 3=Fair, 4=Poor, 5=Very Poor. Reported as quality of sleep during study. |
| Acute Pain After Hemarthrosis | 24 and 48 hours post-bleed | For each bleeding event, a diary was filled out that night and the subsequent night and included a Brief Pain Inventory (BPI): self-reported scale that measured severity of pain experienced over the past 24 hours. Questions included How much pain right now? 0 (no pain) to 10 (pain as severe as you can imagine). |
| Amount of Sleep Measured by Sleep Diary After Hemarthrosis | 24 and 48 hours post-bleed | For each bleeding event, a diary was filled out that night and the subsequent night. Questions included: How long do you think you slept last night? Reported as average duration of sleep during study. |
| HRPQ Score: Hours Lost From Work or School at 48 Hours Post-bleed | 48 hours post-bleed | HRPQ: self-reported scale that measured for each bleed event, hours lost from work, school and housework because of hemophilia and its treatments. Mean and standard deviations calculated from measured values. |
| 36-Item Short-Form Health Survey (SF-36): Physical Functioning Domain | Weeks 16, 32, and 56 | SF-36: standardized survey evaluating 8 aspects of functional health and well being: physical and social functioning, physical and emotional role limitations, bodily pain, general health, vitality, and mental health. The physical functioning domain score was an average of the individual physical functioning question scores across all time points, which was scaled 0-100 (100=highest level of functioning). |
| Health-Related Productivity Questionnaire (HRPQ) Score: Hours Lost From Work or School at 24 Hours Post-bleed | 24 hours post-bleed | HRPQ: self-reported scale that measured for each bleed event, hours lost from work, school and housework because of hemophilia and its treatments. Mean and standard deviations calculated from measured values. |
Countries
Canada, Croatia, Hungary, Italy, Romania, Russia, Serbia, Spain, United States
Participant flow
Pre-assignment details
3 participants who enrolled in the study were not randomized to either prophylaxis treatment regimen, but participated in the study during the first on demand treatment period
Participants by arm
| Arm | Count |
|---|---|
| Pre-Randomization Participants were enrolled and received BeneFix (recombinant coagulation factor IX) as intravenous (IV) bolus infusion in the first on-demand (OD1) period but were never randomized. | 3 |
| BeneFIX OD1, Then 100 IU/kg, Then OD2, Then 50 IU/kg BeneFIX (recombinant coagulation factor IX) on-demand for 16 weeks (OD1), followed by 100 international units per kilogram (IU/kg) once per week (QW) for 16 weeks prophylactically, followed by 8 weeks BeneFIX on-demand (OD2), followed by 50 IU/kg twice weekly (BW) for 16 weeks prophylactically. Dosage form: IV bolus infusion. | 22 |
| BeneFIX OD1 Then 50 IU/kg, Then OD2, Then 100 IU/kg BeneFIX (recombinant coagulation factor IX) on-demand for 16 weeks (OD1), followed by 50 IU/kg BW for 16 weeks prophylactically, followed by 8 weeks BeneFIX on-demand (OD2), followed by 100 IU/kg QW for 16 weeks prophylactically. Dosage form: IV bolus infusion. | 25 |
| Total | 50 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| First Intervention | Secondary prophylaxis | 1 | 0 | 0 |
| First Intervention | Withdrawal by Subject | 2 | 0 | 0 |
| Second Intervention | Adverse Event | 0 | 0 | 1 |
| Second Intervention | non-compliance | 0 | 1 | 1 |
| Second Intervention | Protocol Violation | 0 | 1 | 0 |
| Third Intervention | Lost to Follow-up | 0 | 0 | 1 |
| Third Intervention | non-compliance | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | Pre-Randomization | BeneFIX OD1, Then 100 IU/kg, Then OD2, Then 50 IU/kg | BeneFIX OD1 Then 50 IU/kg, Then OD2, Then 100 IU/kg | Total |
|---|---|---|---|---|
| Age Continuous | 19.3 years STANDARD_DEVIATION 4.5 | 31.7 years STANDARD_DEVIATION 13.4 | 25.1 years STANDARD_DEVIATION 14.4 | 27.7 years STANDARD_DEVIATION 13.9 |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 3 Participants | 22 Participants | 25 Participants | 50 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 | 8 / 50 | 8 / 44 | 4 / 44 | 4 / 43 |
| serious Total, serious adverse events | 1 / 50 | 2 / 44 | 2 / 44 | 0 / 43 |
Outcome results
Primary
Annualized Number of Bleeding Episodes
Annualized bleed rate (ABR) or number of bleeds per year derived for each participant for each treatment regimen by using the following formula: ABR = number of bleeds / (days on treatment regimen / 365.25)
Time frame: Baseline up to Week 56
Population: Intention-to-treat (ITT) population: all enrolled participants
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| BeneFIX OD1 | Annualized Number of Bleeding Episodes | 35.1 episodes |
| BeneFIX 100 IU/kg | Annualized Number of Bleeding Episodes | 4.6 episodes |
| BeneFIX 50 IU/kg | Annualized Number of Bleeding Episodes | 2.6 episodes |
p-value: <0.000195% CI: [-36.5, -24.5]ANOVA
p-value: <0.000195% CI: [-38.5, -26.6]ANOVA
p-value: 0.216795% CI: [-1.2, 5.2]ANOVA
Secondary
36-Item Short-Form Health Survey (SF-36): Physical Functioning Domain
SF-36: standardized survey evaluating 8 aspects of functional health and well being: physical and social functioning, physical and emotional role limitations, bodily pain, general health, vitality, and mental health. The physical functioning domain score was an average of the individual physical functioning question scores across all time points, which was scaled 0-100 (100=highest level of functioning).
Time frame: Weeks 16, 32, and 56
Population: ITT; N=number of participants with evaluable data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| BeneFIX OD1 | 36-Item Short-Form Health Survey (SF-36): Physical Functioning Domain | 64 units on a scale | Standard Deviation 26 |
| BeneFIX 100 IU/kg | 36-Item Short-Form Health Survey (SF-36): Physical Functioning Domain | 66 units on a scale | Standard Deviation 25 |
| BeneFIX 50 IU/kg | 36-Item Short-Form Health Survey (SF-36): Physical Functioning Domain | 63 units on a scale | Standard Deviation 28 |
p-value: 0.54495% CI: [-9.2, 4.9]ANOVA
p-value: 0.59295% CI: [-7.5, 4.3]ANOVA
p-value: 0.13195% CI: [-1.1, 8.4]ANOVA
Secondary
Acute Pain After Hemarthrosis
For each bleeding event, a diary was filled out that night and the subsequent night and included a Brief Pain Inventory (BPI): self-reported scale that measured severity of pain experienced over the past 24 hours. Questions included How much pain right now? 0 (no pain) to 10 (pain as severe as you can imagine).
Time frame: 24 and 48 hours post-bleed
Population: ITT
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| BeneFIX OD1 | Acute Pain After Hemarthrosis | 24 hours post-bleed | 2.8 units on a scale | Standard Deviation 2.1 |
| BeneFIX OD1 | Acute Pain After Hemarthrosis | 48 hours post-bleed | 2.3 units on a scale | Standard Deviation 1.6 |
| BeneFIX 100 IU/kg | Acute Pain After Hemarthrosis | 48 hours post-bleed | 1.8 units on a scale | Standard Deviation 1.2 |
| BeneFIX 100 IU/kg | Acute Pain After Hemarthrosis | 24 hours post-bleed | 2.8 units on a scale | Standard Deviation 2 |
| BeneFIX 50 IU/kg | Acute Pain After Hemarthrosis | 24 hours post-bleed | 3.1 units on a scale | Standard Deviation 2.2 |
| BeneFIX 50 IU/kg | Acute Pain After Hemarthrosis | 48 hours post-bleed | 2.7 units on a scale | Standard Deviation 1.5 |
| BeneFIX OD2 | Acute Pain After Hemarthrosis | 24 hours post-bleed | 3.0 units on a scale | Standard Deviation 2.1 |
| BeneFIX OD2 | Acute Pain After Hemarthrosis | 48 hours post-bleed | 4.1 units on a scale | Standard Deviation 2.4 |
Secondary
Amount of Sleep Measured by Sleep Diary After Hemarthrosis
For each bleeding event, a diary was filled out that night and the subsequent night. Questions included: How long do you think you slept last night? Reported as average duration of sleep during study.
Time frame: 24 and 48 hours post-bleed
Population: ITT
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| BeneFIX OD1 | Amount of Sleep Measured by Sleep Diary After Hemarthrosis | 24 hours post-bleed | 7.5 hours | Standard Deviation 2 |
| BeneFIX OD1 | Amount of Sleep Measured by Sleep Diary After Hemarthrosis | 48 hours post-bleed | 7.9 hours | Standard Deviation 1.7 |
| BeneFIX 100 IU/kg | Amount of Sleep Measured by Sleep Diary After Hemarthrosis | 48 hours post-bleed | 7.8 hours | Standard Deviation 1.6 |
| BeneFIX 100 IU/kg | Amount of Sleep Measured by Sleep Diary After Hemarthrosis | 24 hours post-bleed | 7.3 hours | Standard Deviation 1.8 |
| BeneFIX 50 IU/kg | Amount of Sleep Measured by Sleep Diary After Hemarthrosis | 24 hours post-bleed | 7.1 hours | Standard Deviation 1.6 |
| BeneFIX 50 IU/kg | Amount of Sleep Measured by Sleep Diary After Hemarthrosis | 48 hours post-bleed | 7.5 hours | Standard Deviation 1.4 |
| BeneFIX OD2 | Amount of Sleep Measured by Sleep Diary After Hemarthrosis | 24 hours post-bleed | 7.4 hours | Standard Deviation 1.9 |
| BeneFIX OD2 | Amount of Sleep Measured by Sleep Diary After Hemarthrosis | 48 hours post-bleed | 8.0 hours | Standard Deviation 1.7 |
Comparison: Mean difference in duration of sleep on the first night (24 hours post-bleed) and the second night (48 hours post-bleed).p-value: 0.00295% CI: [0.1, 0.6]ANOVA
Comparison: Mean difference in duration of sleep on the first night (24 hours post-bleed) and the second night (48 hours post-bleed).p-value: 0.02195% CI: [0.1, 0.8]ANOVA
Comparison: Mean difference in duration of sleep on the first night (24 hours post-bleed) and the second night (48 hours post-bleed).p-value: 0.00495% CI: [0.2, 0.9]ANOVA
Comparison: Mean difference in duration of sleep on the first night (24 hours post-bleed) and the second night (48 hours post-bleed).p-value: 0.09395% CI: [-0.1, 0.8]ANOVA
Secondary
Health-Related Productivity Questionnaire (HRPQ) Score: Hours Lost From Work or School at 24 Hours Post-bleed
HRPQ: self-reported scale that measured for each bleed event, hours lost from work, school and housework because of hemophilia and its treatments. Mean and standard deviations calculated from measured values.
Time frame: 24 hours post-bleed
Population: ITT
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| BeneFIX OD1 | Health-Related Productivity Questionnaire (HRPQ) Score: Hours Lost From Work or School at 24 Hours Post-bleed | Work missed | 0.4 hours | Standard Deviation 1.6 |
| BeneFIX OD1 | Health-Related Productivity Questionnaire (HRPQ) Score: Hours Lost From Work or School at 24 Hours Post-bleed | Classwork couldn't do | 0.8 hours | Standard Deviation 1.7 |
| BeneFIX OD1 | Health-Related Productivity Questionnaire (HRPQ) Score: Hours Lost From Work or School at 24 Hours Post-bleed | Housework couldn't do | 0.7 hours | Standard Deviation 2.4 |
| BeneFIX 100 IU/kg | Health-Related Productivity Questionnaire (HRPQ) Score: Hours Lost From Work or School at 24 Hours Post-bleed | Work missed | 1.2 hours | Standard Deviation 2.6 |
| BeneFIX 100 IU/kg | Health-Related Productivity Questionnaire (HRPQ) Score: Hours Lost From Work or School at 24 Hours Post-bleed | Classwork couldn't do | 0.7 hours | Standard Deviation 2.2 |
| BeneFIX 100 IU/kg | Health-Related Productivity Questionnaire (HRPQ) Score: Hours Lost From Work or School at 24 Hours Post-bleed | Housework couldn't do | 0.3 hours | Standard Deviation 0.8 |
| BeneFIX 50 IU/kg | Health-Related Productivity Questionnaire (HRPQ) Score: Hours Lost From Work or School at 24 Hours Post-bleed | Housework couldn't do | 0.4 hours | Standard Deviation 0.7 |
| BeneFIX 50 IU/kg | Health-Related Productivity Questionnaire (HRPQ) Score: Hours Lost From Work or School at 24 Hours Post-bleed | Work missed | 0.6 hours | Standard Deviation 1.9 |
| BeneFIX 50 IU/kg | Health-Related Productivity Questionnaire (HRPQ) Score: Hours Lost From Work or School at 24 Hours Post-bleed | Classwork couldn't do | 0.4 hours | Standard Deviation 1.1 |
| BeneFIX OD2 | Health-Related Productivity Questionnaire (HRPQ) Score: Hours Lost From Work or School at 24 Hours Post-bleed | Work missed | 0.6 hours | Standard Deviation 1.3 |
| BeneFIX OD2 | Health-Related Productivity Questionnaire (HRPQ) Score: Hours Lost From Work or School at 24 Hours Post-bleed | Classwork couldn't do | 0.0 hours | Standard Deviation 0 |
| BeneFIX OD2 | Health-Related Productivity Questionnaire (HRPQ) Score: Hours Lost From Work or School at 24 Hours Post-bleed | Housework couldn't do | 0.2 hours | Standard Deviation 0.5 |
Secondary
HRPQ Score: Hours Lost From Work or School at 48 Hours Post-bleed
HRPQ: self-reported scale that measured for each bleed event, hours lost from work, school and housework because of hemophilia and its treatments. Mean and standard deviations calculated from measured values.
Time frame: 48 hours post-bleed
Population: ITT
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| BeneFIX OD1 | HRPQ Score: Hours Lost From Work or School at 48 Hours Post-bleed | Work missed | 0.2 hours | Standard Deviation 1 |
| BeneFIX OD1 | HRPQ Score: Hours Lost From Work or School at 48 Hours Post-bleed | Classwork couldn't do | 0.4 hours | Standard Deviation 1.2 |
| BeneFIX OD1 | HRPQ Score: Hours Lost From Work or School at 48 Hours Post-bleed | Housework couldn't do | 0.5 hours | Standard Deviation 1.4 |
| BeneFIX 100 IU/kg | HRPQ Score: Hours Lost From Work or School at 48 Hours Post-bleed | Work missed | 0.7 hours | Standard Deviation 2.1 |
| BeneFIX 100 IU/kg | HRPQ Score: Hours Lost From Work or School at 48 Hours Post-bleed | Classwork couldn't do | 0.7 hours | Standard Deviation 2.4 |
| BeneFIX 100 IU/kg | HRPQ Score: Hours Lost From Work or School at 48 Hours Post-bleed | Housework couldn't do | 0.3 hours | Standard Deviation 0.7 |
| BeneFIX 50 IU/kg | HRPQ Score: Hours Lost From Work or School at 48 Hours Post-bleed | Housework couldn't do | 0.0 hours | Standard Deviation 0.2 |
| BeneFIX 50 IU/kg | HRPQ Score: Hours Lost From Work or School at 48 Hours Post-bleed | Work missed | 0.1 hours | Standard Deviation 0.4 |
| BeneFIX 50 IU/kg | HRPQ Score: Hours Lost From Work or School at 48 Hours Post-bleed | Classwork couldn't do | 0.0 hours | Standard Deviation 0 |
| BeneFIX OD2 | HRPQ Score: Hours Lost From Work or School at 48 Hours Post-bleed | Work missed | 0.2 hours | Standard Deviation 0.5 |
| BeneFIX OD2 | HRPQ Score: Hours Lost From Work or School at 48 Hours Post-bleed | Classwork couldn't do | 1.7 hours | Standard Deviation 2.6 |
| BeneFIX OD2 | HRPQ Score: Hours Lost From Work or School at 48 Hours Post-bleed | Housework couldn't do | 0.0 hours | Standard Deviation 0 |
Secondary
Quality of Sleep Measured by Sleep Diary After Hemarthrosis
For each bleeding event, a diary was filled out that night and the subsequent night. Questions included: How would you describe the quality of your sleep last night? 1=Very Good, 2=Good, 3=Fair, 4=Poor, 5=Very Poor. Reported as quality of sleep during study.
Time frame: 24 and 48 hours post-bleed
Population: ITT
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| BeneFIX OD1 | Quality of Sleep Measured by Sleep Diary After Hemarthrosis | 24 hours post-bleed | 2.4 Units on a scale | Standard Deviation 0.9 |
| BeneFIX OD1 | Quality of Sleep Measured by Sleep Diary After Hemarthrosis | 48 hours post-bleed | 2.1 Units on a scale | Standard Deviation 0.7 |
| BeneFIX 100 IU/kg | Quality of Sleep Measured by Sleep Diary After Hemarthrosis | 48 hours post-bleed | 2.1 Units on a scale | Standard Deviation 0.8 |
| BeneFIX 100 IU/kg | Quality of Sleep Measured by Sleep Diary After Hemarthrosis | 24 hours post-bleed | 2.5 Units on a scale | Standard Deviation 0.9 |
| BeneFIX 50 IU/kg | Quality of Sleep Measured by Sleep Diary After Hemarthrosis | 24 hours post-bleed | 2.3 Units on a scale | Standard Deviation 0.9 |
| BeneFIX 50 IU/kg | Quality of Sleep Measured by Sleep Diary After Hemarthrosis | 48 hours post-bleed | 2.1 Units on a scale | Standard Deviation 0.7 |
| BeneFIX OD2 | Quality of Sleep Measured by Sleep Diary After Hemarthrosis | 24 hours post-bleed | 2.4 Units on a scale | Standard Deviation 0.9 |
| BeneFIX OD2 | Quality of Sleep Measured by Sleep Diary After Hemarthrosis | 48 hours post-bleed | 2.1 Units on a scale | Standard Deviation 0.9 |
Comparison: Mean difference in quality of sleep on the first night (24 hours post-bleed) and the second night (48 hours post-bleed).p-value: 095% CI: [-0.4, -0.1]ANOVA
Comparison: Mean difference in quality of sleep on the first night (24 hours post-bleed) and the second night (48 hours post-bleed).p-value: 095% CI: [-0.5, -0.2]ANOVA
Comparison: Mean difference in quality of sleep on the first night (24 hours post-bleed) and the second night (48 hours post-bleed).p-value: 0.00295% CI: [-0.5, -0.1]ANOVA
Comparison: Mean difference in quality of sleep on the first night (24 hours post-bleed) and the second night (48 hours post-bleed).p-value: 0.03195% CI: [-0.5, 0]ANOVA