- Participant Assessment of Response to Injections to Treat a Bleeding Episode [ Time Frame: up to 52 weeks ± 1 week ]
Participant's assessment of the response to the first rFIXFc injection for each bleeding episode. Percentages were based on the number of bleeding episodes for which a response was provided for the first injection, using the following 4-point scale: excellent=abrupt pain relief and/or improvement in signs of bleeding within approximately 8 hours after the initial injection; good=definite pain relief and/or improvement in signs of bleeding within approximately 8 hours after an injection, but possibly requiring more than one injection after 24 to 48 hours for complete resolution; moderate=probable or slight beneficial effect within 8 hours after the initial injection and requiring more than one injection; no response=no improvement, or condition worsened, within approximately 8 hours after the initial injection.
- Physicians' Global Assessments of Participants' Response to Treatment With rFIXFc [ Time Frame: up to 52 weeks ± 1 week ]
Physicians assessed each participant's response to rFIXFc using a 4-point scale: excellent=bleeding episodes responded to less than or equal to the usual number of injections or less than or equal to the usual dose of rFIXFc, or the rate of breakthrough bleeding during prophylaxis was less than or equal to that usually observed; effective=most bleeding episodes responded to the same number of injections and dose, but some required more injections or higher doses, or there was a minor increase in the rate of breakthrough bleeding; partially effective=bleeding episodes most often required more injections and/or higher doses than expected, or adequate breakthrough bleeding prevention during prophylaxis required more frequent injections and/or higher doses; ineffective=routine failure to control hemostasis or hemostatic control required additional agents. Percentage of the total count of scale responses for all participants is presented. Multiple responses per participant are counted.
- Annualized rFIXFc Consumption Per Participant [ Time Frame: up to 52 weeks ± 1 week (efficacy period as defined in description) ]
Consumption is calculated for the efficacy period (EP). In Arms 1 and 2, the EP started with date and time of first prophylactic dose following a completed PK sampling period and ended with last dose administered (for prophylaxis or a bleeding episode). In Arm 3, the EP started following last PK sampling timepoint and ended with either date of last contact or date of last entry into the eDiary, whichever was later. The EP was interrupted for the repeat PK period in Arm 1 (sequential PK subgroup) and for all surgical/rehabilitation periods (for both major and minor surgeries) in all 3 arms. Overall units (IU/kg) of annualized rFIXFc consumption = [Total rFIXFc IU/kg received during the EP / number of days in EP]*365.25.
- Average Weekly Dose For the Fixed Weekly Interval Prophylaxis Arm [ Time Frame: up to 52 weeks ± 1 week (efficacy period as defined in description) ]
Average weekly dose = (total IU/kg of all eligible prophylactic doses in the included intervals / total number of days in the included intervals)*7. Eligible dose = the first of the 2 doses defining the interval. Participants could have multiple prophylactic dose changes. Prophylactic dosing = from first prophylactic injection received for rFIXFc to the last prophylactic injection on study. Intervals between 2 prophylactic doses separated by a bleed/surgery/PK visit were not included. In Arm 1, the efficacy period (EP) started with date and time of first prophylactic dose following a completed PK sampling period and ended with last dose administered (for prophylaxis or a bleeding episode). The EP was interrupted for the repeat PK period in Arm 1 (sequential PK subgroup) and for all surgical/rehabilitation periods (for both major and minor surgeries).
- Average Dosing Interval For the Individualized Interval Prophylaxis Arm [ Time Frame: up to 52 weeks ± 1 week (efficacy period as defined in description) ]
Average dosing interval = sum of days in the included dosing intervals divided by the number of included intervals. Participants could have multiple prophylactic dose interval changes. Prophylactic dosing = from first prophylactic injection received for rFIXFc to the last prophylactic injection on study. Intervals between 2 prophylactic doses separated by a bleed/surgery/PK visit were not included. In Arm 2, the efficacy period (EP) started with date and time of first prophylactic dose following a completed PK sampling period and ended with last dose administered (for prophylaxis or a bleeding episode). The EP was interrupted for all surgical/rehabilitation periods (for both major and minor surgeries).
- Annualized Bleeding Rate by Type of Bleed (Spontaneous and Traumatic) [ Time Frame: up to 52 weeks ± 1 week (efficacy period as defined in description) ]
Annualized bleeding episodes = (number of bleeding episodes/number of days in efficacy period)*365.25. Please see the definition of the efficacy period (EP) in the Outcome Measure 4 Description. The EP was interrupted for the repeat PK period in Arm 1 (sequential PK subgroup) and for all surgical/rehabilitation periods (for both major and minor surgeries) in all 3 arms. A bleeding episode started from the first sign of a bleed, and ended 72 hours after the last treatment for the bleeding, within which any symptoms of bleeding at the same location, or injections less than or equal to 72 hours apart, were considered the same bleeding episode. Any bleeding at a different location was a separate bleeding episode regardless of time from the last injection.
- Annualized Bleeding Rate by Location of Bleed (Joint, Muscle, Internal, Skin/Mucosa) [ Time Frame: up to 52 weeks ± 1 week (efficacy period as defined in description) ]
Annualized bleeding episodes = (number of bleeding episodes/number of days in efficacy period)*365.25. Please see the definition of the efficacy period (EP) in the Outcome Measure 4 Description. The EP was interrupted for the repeat PK period in Arm 1 (sequential PK subgroup) and for all surgical/rehabilitation periods (for both major and minor surgeries) in all 3 arms. A bleeding episode started from the first sign of a bleed, and ended 72 hours after the last treatment for the bleeding, within which any symptoms of bleeding at the same location, or injections less than or equal to 72 hours apart, were considered the same bleeding episode. Any bleeding at a different location was a separate bleeding episode regardless of time from the last injection.
- Number of Days From Last Injection to Treat a New Bleeding Episode [ Time Frame: up to 52 weeks ± 1 week (efficacy period as defined in description) ]
Please see the definition of the Efficacy Period (EP) in the Outcome Measure 4 Description. The EP was interrupted for the repeat PK period in Arm 1 (sequential PK subgroup) and for all surgical/rehabilitation periods (for both major and minor surgeries) in all 3 arms. A follow-up injection administered >72 hours after the most recent injection given to treat a bleed was considered a new bleed at the same location and was classified as type=Unknown (bleeding episodes of this type were not evaluable). The first bleed for each participant could not be included in this analysis since there was no previous bleed from which to measure time. The number of days from the last injection to treat a bleed to a new bleeding episode was analyzed across all evaluable bleeding episodes per participant.
- Number of Injections Required for Resolution of a Bleeding Episode [ Time Frame: up to 52 weeks ± 1 week (efficacy period as defined in description) ]
In Arms 1 and 2, the efficacy period (EP) started with date and time of first prophylactic dose following a completed PK sampling period and ended with last dose administered (for prophylaxis or a bleeding episode). In Arm 3, the EP started following last PK sampling timepoint and ended with either date of last contact or date of last entry into the eDiary, whichever was later. The EP was interrupted for the repeat PK period in Arm 1 and for all surgical/rehabilitation periods in all 3 arms. A bleeding episode started from the first sign of a bleed, and ended 72 hours after the last treatment for the bleeding, within which any symptoms of bleeding at the same location, or injections less than or equal to 72 hours apart, were considered the same bleeding episode. All injections given from the initial sign of a bleed until the last date/time within the bleed window are counted. The resolution of a bleed is defined as no sign of bleeding following injection for the bleed.
- Number of Injections Required for Resolution of a Bleeding Episode by Location of Bleed [ Time Frame: up to 52 weeks ± 1 week (efficacy period as defined in description) ]
Please see the definition of the efficacy period (EP) in the Outcome Measure 4 Description. The EP was interrupted for the repeat PK period in Arm 1 (sequential PK subgroup) and for all surgical/rehabilitation periods (for both major and minor surgeries) in all 3 arms. A bleeding episode started from the first sign of a bleed, and ended 72 hours after the last treatment for the bleeding, within which any symptoms of bleeding at the same location, or injections less than or equal to 72 hours apart, were considered the same bleeding episode. All injections given from the initial sign of a bleed until the last date/time within the bleed window were counted. The resolution of a bleed was defined as no sign of bleeding following injection for the bleed. Bleeding episodes that presented in multiple locations are included as a single event in the overall summary for the number of injections to resolve that bleeding episode but are included in summaries for each location.
- Total Dose Per Injection Required for Resolution of a Bleeding Episode by Location of Bleed [ Time Frame: up to 52 weeks ± 1 week (efficacy period as defined in description) ]
For each bleeding episode at one location, the total dose is the sum of the doses (IU/kg) administered across all injections given to treat that bleeding episode. Please see the definition of the efficacy period (EP) in the Outcome Measure 4 Description. The EP was interrupted for the repeat PK period in Arm 1 (sequential PK subgroup) and for all surgical/rehabilitation periods (for both major and minor surgeries) in all 3 arms. A bleeding episode started from the first sign of a bleed, and ended 72 hours after the last treatment for the bleeding, within which any symptoms of bleeding at the same location, or injections less than or equal to 72 hours apart, were considered the same bleeding episode. Bleeding episodes that presented in multiple locations are included as a single event in the overall summary for dose administered to resolve that bleeding episode but are included in the individual summaries for each location.
- Hemophilia-Specific Quality of Life Index for Adults (Haem-A-QoL) Questionnaire: Change From Baseline to Week 26 [ Time Frame: Baseline, Week 26 ]
The Haem-A-QoL consists of items pertaining to 10 domains specific to living with hemophilia and was administered to adult participants (> 17 years). The areas covered by this instrument are: physical health, feeling, view of yourself, sports/leisure, school/work, dealing with hemophilia, and treatment (all 7 domains, during the last month) and future, family planning, and outlook for the future (all 3 domains, recently). Changes from baseline for the Haem-A-QoL questionnaire are summarized by prestudy treatment regimen (pooled for Arms 1 and 2). Lower scores represent better QoL; therefore, a negative change from baseline represents improvement during the course of the study. Scores on a scale range between 0 and 100.
- Haem-A-QoL Questionnaire for Adults: Change From Baseline to Week 52 [ Time Frame: Baseline, Week 52 ]
The Haem-A-QoL consists of items pertaining to 10 domains specific to living with hemophilia and was administered to adult participants (> 17 years). The areas covered by this instrument are: physical health, feeling, view of yourself, sports/leisure, school/work, dealing with hemophilia, and treatment (all 7 domains, during the last month) and future, family planning, and outlook for the future (all 3 domains, recently). Changes from baseline for the Haem-A-QoL questionnaire are summarized by prestudy treatment regimen (pooled for Arms 1 and 2). Lower scores represent better QoL; therefore, a negative change from baseline represents improvement during the course of the study. Scores on a scale range between 0 and 100.
- Hemophilia-Specific Quality of Life Index for Children (Haemo-QoL) Questionnaire: Change From Baseline to Week 26 and Week 52 [ Time Frame: Baseline, Week 26, Week 52 ]
The Haemo-QoL, a quality of life (QoL) assessment instrument for children and adolescents with hemophilia, was administered to participants from 13- to 17-years-old. This instrument assesses domains specific to living with hemophilia. For the Haemo-QoL, higher scores indicate a worse quality of life. Scores on a scale range between 0 and 100.
- Investigators'/Surgeons' Assessment of Participants' Response to rFIXFc for Major Surgery [ Time Frame: up to 52 weeks ± 1 week ]
Based on the first assessment of hemostasis by the surgeon/investigator 24 hours or later post-surgery. Scaled responses: Excellent = 1, Good = 2, Fair = 3, Poor/none = 4.
- Number of Injections Required to Maintain Hemostasis During Major Surgery [ Time Frame: up to 52 weeks ± 1 week ]
The number of injections to maintain hemostasis during surgery includes all injections for surgery purposes including the loading dose to the end date/time of surgery.
- Dose Per Injection and Total Dose Required to Maintain Hemostasis During Major Surgery [ Time Frame: up to 52 weeks ± 1 week ]
Mean dose per injection is the average dose for all injections (including loading dose) needed to maintain hemostasis during surgery. Total dose is the sum across all injections (including loading dose) needed to maintain hemostasis during surgery.
- Estimated Total Blood Loss During Major Surgery [ Time Frame: up to 52 weeks ± 1 week ]
- Number of Transfusions Required Per Surgery [ Time Frame: up to 52 weeks ± 1 week ]
Number of blood component transfusions during a single surgery.
- Maximum Concentration (Cmax) [ Time Frame: See Measure Description for complete time frame. Each participant was to complete PK sampling up to, and including, the 96-hour (4-day) timepoint for BeneFIX PK assessment and the 240-hour (10-day) timepoint for rFIXFc PK assessment. ]
Maximum concentration during a dosing interval. Assessment of FIX activity with BeneFIX was conducted following a required 120-hour (5-day) washout period, at these timepoints: predose, 10 (±2) minutes, 1 hour (±15 minutes), 3 hours (±15 minutes), 6 hours (±15 minutes), 24 (±2) hours, 48 (±2) hours, 72 (±3) hours, and 96 (±3) hours (4 days) from the start of the injection. Assessment of FIX activity and rFIXFc concentration was conducted following the initial dose of rFIXFc (after a required 120-hour [5-day] washout period) and at Week 26, at these timepoints: predose, 10 (±2) minutes, 1 hour (±15 minutes), 3 hours (±15 minutes), 6 hours (±15 minutes), 24 (±2) hours, 48 (±2) hours, 96 (±3) hours (4 days), 144 (±3) hours (6 days), 168 (±3) hours (7 days), 192 (±3) hours (8 days), and 240 (±3) hours (10 days) from the start of the injection.
- Area Under the Curve (AUC) Per Dose [ Time Frame: See Measure Description for complete time frame. Each participant was to complete PK sampling up to, and including, the 96-hour (4-day) timepoint for BeneFIX PK assessment and the 240-hour (10-day) timepoint for rFIXFc PK assessment. ]
Dose normalized area under the drug concentration-time curve. Assessment of FIX activity with BeneFIX was conducted following a required 120-hour (5-day) washout period, at these timepoints: predose, 10 (±2) minutes, 1 hour (±15 minutes), 3 hours (±15 minutes), 6 hours (±15 minutes), 24 (±2) hours, 48 (±2) hours, 72 (±3) hours, and 96 (±3) hours (4 days) from the start of the injection. Assessment of FIX activity and rFIXFc concentration was conducted following the initial dose of rFIXFc (after a required 120-hour [5-day] washout period) and at Week 26, at these timepoints: predose, 10 (±2) minutes, 1 hour (±15 minutes), 3 hours (±15 minutes), 6 hours (±15 minutes), 24 (±2) hours, 48 (±2) hours, 96 (±3) hours (4 days), 144 (±3) hours (6 days), 168 (±3) hours (7 days), 192 (±3) hours (8 days), and 240 (±3) hours (10 days) from the start of the injection.
- Half Life (t1/2) Alpha and t1/2 Beta [ Time Frame: See Measure Description for complete time frame. Each participant was to complete PK sampling up to, and including, the 96-hour (4-day) timepoint for BeneFIX PK assessment and the 240-hour (10-day) timepoint for rFIXFc PK assessment. ]
Time required for the concentration of the drug to reach half of its original value. Alpha and beta half-life indicate distribution and elimination half-life in a two-compartment PK model. Assessment of FIX activity with BeneFIX was conducted following a required 120-hour (5-day) washout period, at these timepoints: predose, 10 (±2) minutes, 1 hour (±15 minutes), 3 hours (±15 minutes), 6 hours (±15 minutes), 24 (±2) hours, 48 (±2) hours, 72 (±3) hours, and 96 (±3) hours (4 days) from the start of the injection. Assessment of FIX activity and rFIXFc concentration was conducted following the initial dose of rFIXFc (after a required 120-hour [5-day] washout period) and at Week 26, at these timepoints: predose, 10 (±2) minutes, 1 hour (±15 minutes), 3 hours (±15 minutes), 6 hours (±15 minutes), 24 (±2) hours, 48 (±2) hours, 96 (±3) hours (4 days), 144 (±3) hours (6 days), 168 (±3) hours (7 days), 192 (±3) hours (8 days), and 240 (±3) hours (10 days) from the start of the injection.
- Clearance (CL) [ Time Frame: See Measure Description for complete time frame. Each participant was to complete PK sampling up to, and including, the 96-hour (4-day) timepoint for BeneFIX PK assessment and the 240-hour (10-day) timepoint for rFIXFc PK assessment. ]
The measure of the efficiency of the body to remove the drug and the unit is the volume of the plasma or blood cleared of drug per unit time. Assessment of FIX activity with BeneFIX was conducted following a required 120-hour (5-day) washout period, at these timepoints: predose, 10 (±2) minutes, 1 hour (±15 minutes), 3 hours (±15 minutes), 6 hours (±15 minutes), 24 (±2) hours, 48 (±2) hours, 72 (±3) hours, and 96 (±3) hours (4 days) from the start of the injection. Assessment of FIX activity and rFIXFc concentration was conducted following the initial dose of rFIXFc (after a required 120-hour [5-day] washout period) and at Week 26, at these timepoints: predose, 10 (±2) minutes, 1 hour (±15 minutes), 3 hours (±15 minutes), 6 hours (±15 minutes), 24 (±2) hours, 48 (±2) hours, 96 (±3) hours (4 days), 144 (±3) hours (6 days), 168 (±3) hours (7 days), 192 (±3) hours (8 days), and 240 (±3) hours (10 days) from the start of the injection.
- Mean Residence Time (MRT) [ Time Frame: See Measure Description for complete time frame. Each participant was to complete PK sampling up to, and including, the 96-hour (4-day) timepoint for BeneFIX PK assessment and the 240-hour (10-day) timepoint for rFIXFc PK assessment. ]
The average time for all the drug molecules to reside in the body. Assessment of FIX activity with BeneFIX was conducted following a required 120-hour (5-day) washout period, at these timepoints: predose, 10 (±2) minutes, 1 hour (±15 minutes), 3 hours (±15 minutes), 6 hours (±15 minutes), 24 (±2) hours, 48 (±2) hours, 72 (±3) hours, and 96 (±3) hours (4 days) from the start of the injection. Assessment of FIX activity and rFIXFc concentration was conducted following the initial dose of rFIXFc (after a required 120-hour [5-day] washout period) and at Week 26, at these timepoints: predose, 10 (±2) minutes, 1 hour (±15 minutes), 3 hours (±15 minutes), 6 hours (±15 minutes), 24 (±2) hours, 48 (±2) hours, 96 (±3) hours (4 days), 144 (±3) hours (6 days), 168 (±3) hours (7 days), 192 (±3) hours (8 days), and 240 (±3) hours (10 days) from the start of the injection.
- Volume in Steady State (Vss) [ Time Frame: See Measure Description for complete time frame. Each participant was to complete PK sampling up to, and including, the 96-hour (4-day) timepoint for BeneFIX PK assessment and the 240-hour (10-day) timepoint for rFIXFc PK assessment. ]
Volume of distribution at steady state. Assessment of FIX activity with BeneFIX was conducted following a required 120-hour (5-day) washout period, at these timepoints: predose, 10 (±2) minutes, 1 hour (±15 minutes), 3 hours (±15 minutes), 6 hours (±15 minutes), 24 (±2) hours, 48 (±2) hours, 72 (±3) hours, and 96 (±3) hours (4 days) from the start of the injection. Assessment of FIX activity and rFIXFc concentration was conducted following the initial dose of rFIXFc (after a required 120-hour [5-day] washout period) and at Week 26, at these timepoints: predose, 10 (±2) minutes, 1 hour (±15 minutes), 3 hours (±15 minutes), 6 hours (±15 minutes), 24 (±2) hours, 48 (±2) hours, 96 (±3) hours (4 days), 144 (±3) hours (6 days), 168 (±3) hours (7 days), 192 (±3) hours (8 days), and 240 (±3) hours (10 days) from the start of the injection.
- Incremental Recovery [ Time Frame: See Measure Description for complete time frame. Each participant was to complete PK sampling up to, and including, the 96-hour (4-day) timepoint for BeneFIX PK assessment and the 240-hour (10-day) timepoint for rFIXFc PK assessment. ]
IU/dL rise in plasma per IU/kg drug administered. Assessment of FIX activity with BeneFIX was conducted following a required 120-hour (5-day) washout period, at these timepoints: predose, 10 (±2) minutes, 1 hour (±15 minutes), 3 hours (±15 minutes), 6 hours (±15 minutes), 24 (±2) hours, 48 (±2) hours, 72 (±3) hours, and 96 (±3) hours (4 days) from the start of the injection. Assessment of FIX activity and rFIXFc concentration was conducted following the initial dose of rFIXFc (after a required 120-hour [5-day] washout period) and at Week 26, at these timepoints: predose, 10 (±2) minutes, 1 hour (±15 minutes), 3 hours (±15 minutes), 6 hours (±15 minutes), 24 (±2) hours, 48 (±2) hours, 96 (±3) hours (4 days), 144 (±3) hours (6 days), 168 (±3) hours (7 days), 192 (±3) hours (8 days), and 240 (±3) hours (10 days) from the start of the injection.
- Time to 1% and 3% FIX Activity [ Time Frame: See Measure Description for complete time frame. Each participant was to complete PK sampling up to, and including, the 96-hour (4-day) timepoint for BeneFIX PK assessment and the 240-hour (10-day) timepoint for rFIXFc PK assessment. ]
Time to reach 1 or 3 IU/dL (%) after a single dose. Assessment of FIX activity with BeneFIX was conducted following a required 120-hour (5-day) washout period, at these timepoints: predose, 10 (±2) minutes, 1 hour (±15 minutes), 3 hours (±15 minutes), 6 hours (±15 minutes), 24 (±2) hours, 48 (±2) hours, 72 (±3) hours, and 96 (±3) hours (4 days) from the start of the injection. Assessment of FIX activity and rFIXFc concentration was conducted following the initial dose of rFIXFc (after a required 120-hour [5-day] washout period) and at Week 26, at these timepoints: predose, 10 (±2) minutes, 1 hour (±15 minutes), 3 hours (±15 minutes), 6 hours (±15 minutes), 24 (±2) hours, 48 (±2) hours, 96 (±3) hours (4 days), 144 (±3) hours (6 days), 168 (±3) hours (7 days), 192 (±3) hours (8 days), and 240 (±3) hours (10 days) from the start of the injection.
- Number of Participants With Clinically Relevant Abnormalities or Relevant Changes From Baseline in Vital Signs [ Time Frame: up to 52 weeks ± 1 week ]
Number of participants with clinically relevant abnormalities or relevant changes from baseline in temperature, pulse (beats per minute [bpm]), systolic blood pressure (SBP), and diastolic blood pressure (DBP) are presented. Baseline (BL) is defined as the last non-missing evaluable assessment taken prior and closest to the first rFIXFc dose. Because the perioperative management period represents a unique clinical situation, safety data obtained during the surgical/rehabilitation period for participants in Arm 4 were included in listings and reviewed separately. Review of the listing was sufficient to assess this endpoint.
- Coagulation Parameter: Change From Pre-dose Values in Prothrombin Split Fragments 1+ 2 (F 1+2) [ Time Frame: Pre-dose, 1 hour post-dose, 6 hours post-dose, and 24 hours post-dose at baseline (120 hours before Day 1, for BeneFIX), Day 1, Week 26, and Week 52 (for rFIXFc) ]
Maximum value post-dosing is defined as maximum value over the 1-, 6-, and 24-hour evaluations.
- Coagulation Parameter: Change From Pre-dose Values in Thrombin-antithrombin (TAT) Complex [ Time Frame: Pre-dose, 1 hour post-dose, 6 hours post-dose, and 24 hours post-dose at baseline (120 hours before Day 1, for BeneFIX), Day 1, Week 26, and Week 52 (for rFIXFc) ]
Maximum value post-dosing is defined as maximum value over the 1-, 6-, and 24-hour evaluations.
- Coagulation Parameter: Change From Pre-dose Values in D-dimer [ Time Frame: Pre-dose, 1 hour post-dose, 6 hours post-dose, and 24 hours post-dose at baseline (120 hours before Day 1, for BeneFIX), Day 1, Week 26, and Week 52 (for rFIXFc) ]
Maximum value post-dosing is defined as maximum value over the 1-, 6-, and 24-hour evaluations.
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