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Study of Recombinant Factor IX Fc Fusion Protein (rFIXFc) in Participants With Hemophilia B

Sponsor
Bioverativ Therapeutics Inc. (Industry)
Overall Status
Completed
CT.gov ID
NCT01027364
Collaborator
Swedish Orphan Biovitrum (Industry)
123
Enrollment
51
Locations
4
Arms
31
Duration (Months)
2.4
Patients Per Site
0.1
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The primary objectives of the study were: to evaluate the safety and tolerability of rFIXFc; to evaluate the efficacy of rFIXFc in all treatment arms; to evaluate the effectiveness of prophylaxis over on-demand (episodic) therapy by comparing the annualized number of bleeding episodes between participants receiving rFIXFc on each prevention (prophylaxis) regimen and participants receiving rFIXFc on an episodic regimen. The secondary objectives of the study were: to evaluate and assess the pharmacokinetic (PK) parameter estimates of rFIXFc and rFIX (BeneFIX®) at baseline in the Sequential PK subgroup as well as rFIXFc at Week 26 (±1 week); to evaluate participants' response to treatment; to evaluate rFIXFc consumption.

Condition or Disease Intervention/Treatment Phase
Phase 3

Study Design

Study Type:
Interventional
Actual Enrollment :
123 participants
Allocation:
Non-Randomized
Intervention Model:
Single Group Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
B-LONG: An Open-Label, Multicenter Evaluation of the Safety, Pharmacokinetics, and Efficacy of Recombinant, Long-acting Coagulation Factor IX Fc Fusion Protein (rFIXFc) in the Prevention and Treatment of Bleeding in Previously Treated Subjects With Severe Hemophilia B
Study Start Date :
Dec 1, 2009
Actual Primary Completion Date :
Jul 1, 2012
Actual Study Completion Date :
Jul 1, 2012

Arms and Interventions

Arm Intervention/Treatment
Experimental: Fixed Weekly Interval

50 IU/kg rFIXFc via intravenous (IV) injection once every 7 days initially, then at a dose indicated by the participant's baseline pharmacokinetic (PK) assessment that ensured a target trough of 1% to 3% above baseline or higher, as clinically indicated. Adjustments to the initial weekly dose of rFIXFc (50 IU/kg) were to be made based on baseline PK assessments, occurrence of spontaneous bleeding episodes, and the trough levels, which were to be monitored at Weeks 4, 16, 26, and 39. Prior to the first dose of rFIXFc, participants in the Sequential PK subgroup were to receive a single dose of 50 IU/kg BeneFIX administered IV in the clinic, followed by PK sampling. A single dose of 50 IU/kg rFIXFc was administered following a 120-hour washout from BeneFIX, followed by PK sampling for a baseline PK profiling. At Week 26 (±1 week) subjects were to receive a single dose of 50 IU/kg rFIXFc for repeat PK profiling.

Drug: Factor IX (rFIXFc)
Other Names:
  • Recombinant Human Factor IX Fc Fusion Protein

    • Drug: rFIX
    Other Names:
  • Recombinant Factor IX
  • BeneFIX®

    		•
    Experimental: Individualized Interval

    100 IU/kg rFIXFc via IV injection once every 10 days initially, then at an interval derived from the baseline PK assessment that ensured a target trough of 1% to 3% above baseline or higher, as clinically indicated. Adjustments to the initial 10-day interval were to be made based on baseline PK assessments and trough levels, which were monitored at Weeks 4, 16, 26, and 39.

    Drug: Factor IX (rFIXFc)
    Other Names:
  • Recombinant Human Factor IX Fc Fusion Protein

    		•
    Experimental: On Demand

    20 to 100 IU/kg rFIXFc via IV injection, or the dose indicated by the participant's baseline PK to target a plasma level of 20% to 100%, as needed for the treatment of mild to severe bleeding episodes

    Drug: Factor IX (rFIXFc)
    Other Names:
  • Recombinant Human Factor IX Fc Fusion Protein

    		•
    Experimental: Surgery

    The surgical period and dosing are dependent on the type of surgery the participant undergoes. Participants who started the study in one of the other treatment arms prior to surgery will return to the original treatment arm. Participants who joined the study in the Surgery arm will be assigned to one of the other treatment arms following post-operative rehabilitation.

    Drug: Factor IX (rFIXFc)
    Other Names:
  • Recombinant Human Factor IX Fc Fusion Protein

    		•

    Outcome Measures

    Primary Outcome Measures

    1. Number of Participants With Potentially Clinically Significant Laboratory Abnormalities [up to 52 weeks ± 1 week]

      Clinical laboratory evaluations included hematology and blood chemistry. Table does not include laboratory tests evaluated during the surgical/rehabilitation period. 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. ULN=upper limit of normal.

    2. Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs) [up to 52 weeks + 30 days ± 1 week]

      AE=any untoward medical occurrence that did not necessarily have a causal relationship with this treatment, and could be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of study product, whether related or not. TE=event present prior to receiving the first injection of BeneFIX or rFIXFc that subsequently worsened in severity or not present prior to receiving the first injection but subsequently appeared before last visit on study. Serious AE (SAE)=AE resulting in death, immediate risk of death, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability/incapacity, or a congenital/anomaly/birth defect, or any other medically important event. Related=related, possibly related, and relationship missing. Data include AEs emergent during the surgical/rehabilitation period; AE data are included in each treatment arm only for the time each participant was enrolled in that arm.

    3. Number of Participants With Non-serious Treatment-emergent Adverse Events (TEAEs) During the Surgical / Rehabilitation Period [up to 52 weeks + 30 days ± 1 week]

      AE=any untoward medical occurrence that did not necessarily have a causal relationship with this treatment, and could be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of study product, whether related or not. TEAE=AE present prior to receiving the first injection of BeneFIX or rFIXFc that subsequently worsened in severity or was not present prior to receiving the first injection but subsequently appeared before last visit on study. Participants are counted once if they report multiple events in the same system organ class (SOC) or preferred term (PT). Coded using the Medical Dictionary for Regulatory Activities (MedDRA), version 15.0 dictionary. The following SOCs are abbreviated in the table: Immune System (IS); Injury, Poisoning, and Procedural (IPP); Metabolism and Nutrition (MN); Musculoskeletal and Connective Tissue (MCT); Respiratory, Thoracic and Mediastinal (RTM); Skin and Subcutaneous Tissue (SST).

    4. Number of Participants With Treatment-emergent Serious Adverse Events (TESAEs) During the Surgical / Rehabilitation Period [up to 52 weeks + 30 days ± 1 week]

      SAE=AE resulting in death, immediate risk of death, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability/incapacity, or a congenital/anomaly/birth defect, or any other medically important event. TESAE=SAE present prior to receiving the first injection of BeneFIX or rFIXFc that subsequently worsened in severity or was not present prior to receiving the first injection but subsequently appeared before last visit on study. Participants are counted once if they report multiple events in the same system organ class (SOC) or preferred term (PT). Coded using the Medical Dictionary for Regulatory Activities (MedDRA), version 15.0 dictionary. The following SOC is abbreviated in the table: Injury, Poisoning, and Procedural (IPP).

    5. Incidence Rate of FIX Inhibitor Development [up to 52 weeks ± 1 week]

      An inhibitor test result ≥0.6 Bethesda units (BU)/mL, identified and confirmed by re-testing of a second sample obtained within 2 to 4 weeks, was considered positive. Both tests were to be performed using the Nijmegen-modified Bethesda Assay by the central laboratory. The incidence rates along with the 95% CI were summarized for all titers for subjects with 50 or more exposure days (EDs) to rFIXFc and a valid inhibitor test after the 50th exposure. In addition, the incidence rates for all subjects regardless of their exposure days to rFIXFc were also summarized. The 95% CI was calculated using Clopper-Pearson exact method.

    6. Annualized Bleeding Rate [up to 52 weeks ± 1 week (efficacy period as defined in description)]

      Annualized bleeding episodes = (number of bleeding episodes / number of days in the respective period)*365.25. In Arms 1 and 2, the efficacy period (EP) started with date and time of first prophylactic dose following a completed pharmacokinetic (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. 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.

    7. Comparison of Annualized Bleeding Rates [up to 52 weeks ± 1 week (efficacy period as defined in description)]

      Estimated with a factor for arm, based on whole study duration for all participants. Annualized bleeding episodes = (number of bleeding episodes / number of days in the respective period)*365.25. 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.

    Secondary Outcome Measures

    1. Participant Assessment of Response to Injections to Treat a Bleeding Episode [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.

    2. Physicians' Global Assessments of Participants' Response to Treatment With rFIXFc [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.

    3. Annualized rFIXFc Consumption Per Participant [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.

    4. Average Weekly Dose For the Fixed Weekly Interval Prophylaxis Arm [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).

    5. Average Dosing Interval For the Individualized Interval Prophylaxis Arm [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).

    6. Annualized Bleeding Rate by Type of Bleed (Spontaneous and Traumatic) [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.

    7. Annualized Bleeding Rate by Location of Bleed (Joint, Muscle, Internal, Skin/Mucosa) [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.

    8. Number of Days From Last Injection to Treat a New Bleeding Episode [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.

    9. Number of Injections Required for Resolution of a Bleeding Episode [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.

    10. Number of Injections Required for Resolution of a Bleeding Episode by Location of Bleed [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.

    11. Total Dose Per Injection Required for Resolution of a Bleeding Episode by Location of Bleed [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.

    12. Hemophilia-Specific Quality of Life Index for Adults (Haem-A-QoL) Questionnaire: Change From Baseline to Week 26 [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.

    13. Haem-A-QoL Questionnaire for Adults: Change From Baseline to Week 52 [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.

    14. Hemophilia-Specific Quality of Life Index for Children (Haemo-QoL) Questionnaire: Change From Baseline to Week 26 and Week 52 [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.

    15. Investigators'/Surgeons' Assessment of Participants' Response to rFIXFc for Major Surgery [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.

    16. Number of Injections Required to Maintain Hemostasis During Major Surgery [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.

    17. Dose Per Injection and Total Dose Required to Maintain Hemostasis During Major Surgery [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.

    18. Estimated Total Blood Loss During Major Surgery [up to 52 weeks ± 1 week]

    19. Number of Transfusions Required Per Surgery [up to 52 weeks ± 1 week]

      Number of blood component transfusions during a single surgery.

    20. Maximum Concentration (Cmax) [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.

    21. Area Under the Curve (AUC) Per Dose [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.

    22. Half Life (t1/2) Alpha and t1/2 Beta [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.

    23. Clearance (CL) [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.

    24. Mean Residence Time (MRT) [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.

    25. Volume in Steady State (Vss) [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.

    26. Incremental Recovery [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.

    27. Time to 1% and 3% FIX Activity [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.

    28. Number of Participants With Clinically Relevant Abnormalities or Relevant Changes From Baseline in Vital Signs [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.

    29. Coagulation Parameter: Change From Pre-dose Values in Prothrombin Split Fragments 1+ 2 (F 1+2) [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.

    30. Coagulation Parameter: Change From Pre-dose Values in Thrombin-antithrombin (TAT) Complex [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.

    31. Coagulation Parameter: Change From Pre-dose Values in D-dimer [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.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    12 Years and Older
    Sexes Eligible for Study:
    Male
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria:

    • Male and 12 years of age and older and weigh at least 40 kg

    • Diagnosed with hemophilia B (baseline Factor IX level less than or equal to 2%)

    • History of at least 100 exposure days to any Factor IX product

    • Platelet count ≥100,000 cells/μL

    Exclusion Criteria:

    • History of Factor IX inhibitors

    • Kidney or liver dysfunction

    • Diagnosed with another coagulation defect other than hemophilia B

    • Prior history of anaphylaxis associated with any Factor IX or intravenous (IV) immunoglobulin administration

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Research Site Phoenix Arizona United States
    2 Research Site Sacramento California United States
    3 Research Site Aurora Colorado United States
    4 Research Site Chicago Illinois United States
    5 Research Site Indianapolis Indiana United States
    6 Research Site East Lansing Michigan United States
    7 Research Site Philadelphia Pennsylvania United States
    8 Research Site Pittsburgh Pennsylvania United States
    9 Research Site Seattle Washington United States
    10 Research Site Camperdown New South Wales Australia
    11 Research Site Adelaide South Australia Australia
    12 Research Site Perth Western Australia Australia
    13 Research Site Bruxelles Belgium
    14 Research Site Leuven Belgium
    15 Research Site Campinas Brazil
    16 Research Site Calgary Alberta Canada
    17 Research Site Toronto Ontario Canada
    18 Research Site Montreal Quebec Canada
    19 Research Site Vancouver Canada
    20 Research site Beijing China
    21 Research Site Guangzhou China
    22 Research Site Shanghai China
    23 Research Site Tianjin China
    24 Research Site Lyon France
    25 Research Site Marseille France
    26 Research Site Berlin Germany
    27 Research Site Bonn Germany
    28 Research Site Pokfulam Hong Kong
    29 Research Site Shatin Hong Kong
    30 Research Site Ludhiana Punjab India
    31 Research Site Vellore Tamil Nadu India
    32 Research Site Bangalore India
    33 Research Site Pune India
    34 Research Site Firenze Italy
    35 Research Site Milano Italy
    36 Research Site Kasihara-City Japan
    37 Research Site Kawasaki City Japan
    38 Research Site Kitakyushu Japan
    39 Research Site Nagoya Japan
    40 Ressearch Site Suginami-ku Japan
    41 Research Site Tokyo Japan
    42 Research Site Lodz Poland
    43 Research Site Warszawa Poland
    44 Research Site Moscow Russian Federation
    45 Research Site St. Petersburg Russian Federation
    46 Research Site Johannesburg Gauteng South Africa
    47 Research Site Cape Town Western Cape South Africa
    48 Research Site Malmö Sweden
    49 Research Site Stockholm Sweden
    50 Research Site Cambridge United Kingdom
    51 Research Site London United Kingdom

    Sponsors and Collaborators

    • Bioverativ Therapeutics Inc.
    • Swedish Orphan Biovitrum

    Investigators

    • Study Director: Medical Director, Bioverativ Therapeutics Inc.

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    None provided.
    Responsible Party:
    Bioverativ Therapeutics Inc.
    ClinicalTrials.gov Identifier:
    NCT01027364
    Other Study ID Numbers:
    • 998HB102
    • 2009-014295-21
    First Posted:
    Dec 7, 2009
    Last Update Posted:
    Dec 19, 2020
    Last Verified:
    Aug 1, 2018
    Additional relevant MeSH terms:
    Hemophilia A
    Hemophilia B

    Study Results

    Participant Flow

    Recruitment Details
    Pre-assignment Detail
    Arm/Group Title Arm 1: Weekly Prophylaxis Arm 2: Individualized Interval Prophylaxis Arm 3: Episodic (On Demand) Arm 4: Perioperative Management
    Arm/Group Description 50 IU/kg rFIXFc via intravenous (IV) injection once every 7 days initially, then at a dose indicated by the participant's baseline pharmacokinetic (PK) assessment that ensured a target trough of 1% to 3% above baseline or higher, as clinically indicated. Adjustments to the initial weekly dose of rFIXFc (50 IU/kg) were to be made based on baseline PK assessments, occurrence of spontaneous bleeding episodes, and the trough levels, which were to be monitored at Weeks 4, 16, 26, and 39. Prior to the first dose of rFIXFc, participants in the Sequential PK subgroup were to receive a single dose of 50 IU/kg BeneFIX administered IV in the clinic, followed by PK sampling. A single dose of 50 IU/kg rFIXFc was administered following a 120-hour washout from BeneFIX, followed by PK sampling for a baseline PK profiling. At Week 26 (±1 week) subjects were to receive a single dose of 50 IU/kg rFIXFc for repeat PK profiling. 100 IU/kg rFIXFc via IV injection once every 10 days initially, then at an interval derived from the baseline PK assessment that ensured a target trough of 1% to 3% above baseline or higher, as clinically indicated. Adjustments to the initial 10-day interval were to be made based on baseline PK assessments and trough levels, which were monitored at Weeks 4, 16, 26, and 39. 20 to 100 IU/kg rFIXFc via IV injection, or the dose indicated by the participant's baseline PK to target a plasma level of 20% to 100%, as needed for the treatment of mild to severe bleeding episodes The surgical period and dosing were dependent on the type of surgery the participant underwent. Participants who started the study in one of the other treatment arms prior to surgery returned to the original treatment arm. Participants who joined the study in the Surgery arm were assigned to one of the other treatment arms following post-operative rehabilitation.
    Period Title: Overall Study
    STARTED 63 29 27 4
    Enrolled in Sequential PK Subgroup 22 0 0 0
    Joined Arm 4 for Surgery Then Returned 5 0 1 0
    Started Arm 4 Then Joined Another Arm 2 0 0 0
    COMPLETED 59 27 26 3
    NOT COMPLETED 4 2 1 1

    Baseline Characteristics

    Arm/Group Title Arm 1: Weekly Prophylaxis Arm 2: Individualized Interval Prophylaxis Arm 3: Episodic (On Demand) Arm 4: Perioperative Management Total
    Arm/Group Description 50 IU/kg rFIXFc via intravenous (IV) injection once every 7 days initially, then at a dose indicated by the participant's baseline pharmacokinetic (PK) assessment that ensured a target trough of 1% to 3% above baseline or higher, as clinically indicated. Adjustments to the initial weekly dose of rFIXFc (50 IU/kg) were to be made based on baseline PK assessments, occurrence of spontaneous bleeding episodes, and the trough levels, which were to be monitored at Weeks 4, 16, 26, and 39. Prior to the first dose of rFIXFc, participants in the Sequential PK subgroup were to receive a single dose of 50 IU/kg BeneFIX administered IV in the clinic, followed by PK sampling. A single dose of 50 IU/kg rFIXFc was administered following a 120-hour washout from BeneFIX, followed by PK sampling for a baseline PK profiling. At Week 26 (±1 week) subjects were to receive a single dose of 50 IU/kg rFIXFc for repeat PK profiling. 100 IU/kg rFIXFc via IV injection once every 10 days initially, then at an interval derived from the baseline PK assessment that ensured a target trough of 1% to 3% above baseline or higher, as clinically indicated. Adjustments to the initial 10-day interval were to be made based on baseline PK assessments and trough levels, which were monitored at Weeks 4, 16, 26, and 39. 20 to 100 IU/kg rFIXFc via IV injection, or the dose indicated by the participant's baseline PK to target a plasma level of 20% to 100%, as needed for the treatment of mild to severe bleeding episodes The surgical period and dosing were dependent on the type of surgery the participant underwent. Participants who started the study in one of the other treatment arms prior to surgery returned to the original treatment arm. Participants who joined the study in the Surgery arm were assigned to one of the other treatment arms following post-operative rehabilitation. Total of all reporting groups
    Overall Participants 63 29 27 4 123
    Age (years) [Median (Full Range) ]
    Median (Full Range) [years]
    28.0
    33.0
    36.0
    40.5
    30.0
    Sex: Female, Male (Count of Participants)
    Female
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Male
    63
    100%
    29
    100%
    27
    100%
    4
    100%
    123
    100%

    Outcome Measures

    1. Primary Outcome
    Title Number of Participants With Potentially Clinically Significant Laboratory Abnormalities
    Description Clinical laboratory evaluations included hematology and blood chemistry. Table does not include laboratory tests evaluated during the surgical/rehabilitation period. 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. ULN=upper limit of normal.
    Time Frame up to 52 weeks ± 1 week

    Outcome Measure Data

    Analysis Population Description
    Safety Analysis Set: participants who received at least 1 dose of BeneFIX or rFIXFc; n=the number of participants with at least one post-baseline value. For this study, a table was not generated for potentially clinically significant laboratory abnormalities for participants in the perioperative management/surgical arm (Arm 4).
    Arm/Group Title Arm 1: Weekly Prophylaxis Arm 2: Individualized Interval Prophylaxis Arm 3: Episodic (On Demand)
    Arm/Group Description 50 IU/kg rFIXFc via intravenous (IV) injection once every 7 days initially, then at a dose indicated by the participant's baseline pharmacokinetic (PK) assessment that ensured a target trough of 1% to 3% above baseline or higher, as clinically indicated. Adjustments to the initial weekly dose of rFIXFc (50 IU/kg) were to be made based on baseline PK assessments, occurrence of spontaneous bleeding episodes, and the trough levels, which were to be monitored at Weeks 4, 16, 26, and 39. Prior to the first dose of rFIXFc, participants in the Sequential PK subgroup were to receive a single dose of 50 IU/kg BeneFIX administered IV in the clinic, followed by PK sampling. A single dose of 50 IU/kg rFIXFc was administered following a 120-hour washout from BeneFIX, followed by PK sampling for a baseline PK profiling. At Week 26 (±1 week) subjects were to receive a single dose of 50 IU/kg rFIXFc for repeat PK profiling. 100 IU/kg rFIXFc via IV injection once every 10 days initially, then at an interval derived from the baseline PK assessment that ensured a target trough of 1% to 3% above baseline or higher, as clinically indicated. Adjustments to the initial 10-day interval were to be made based on baseline PK assessments and trough levels, which were monitored at Weeks 4, 16, 26, and 39. 20 to 100 IU/kg rFIXFc via IV injection, or the dose indicated by the participant's baseline PK to target a plasma level of 20% to 100%, as needed for the treatment of mild to severe bleeding episodes
    Measure Participants 63 29 27
    White Blood Cells <3.0*10^9/L; n=62, 28, 27
    2
    3.2%
    0
    0%
    2
    7.4%
    White Blood Cells >=16*10^9/L; n=62, 28, 27
    0
    0%
    0
    0%
    0
    0%
    Lymphocytes <0.8*10^9/L; n=60, 28, 26
    1
    1.6%
    2
    6.9%
    3
    11.1%
    Lymphocytes >12*10^9/L; n=60, 28, 26
    0
    0%
    0
    0%
    0
    0%
    Neutrophils <1.5*10^9/L; n=60, 28, 26
    2
    3.2%
    0
    0%
    1
    3.7%
    Neutrophils >13.5*10^9/L; n=60, 28, 26
    0
    0%
    0
    0%
    0
    0%
    Monocytes >2.5*10^9/L; n=60, 28, 26
    0
    0%
    0
    0%
    0
    0%
    Eosinophils >1.6*10^9/L; n=60, 28, 26
    0
    0%
    0
    0%
    0
    0%
    Basophils >1.6*10^9/L; n=60, 28, 26
    0
    0%
    0
    0%
    0
    0%
    Red Blood Cells <=3.5*10^12/L; n=62, 28, 27
    1
    1.6%
    0
    0%
    0
    0%
    Red Blood Cells >=6.4*10^12/L; n=62, 28, 27
    0
    0%
    0
    0%
    0
    0%
    Hemoglobin <=115 g/L; n=62, 28, 27
    1
    1.6%
    0
    0%
    0
    0%
    Hemoglobin >=190 g/L; n=62, 28, 27
    0
    0%
    0
    0%
    0
    0%
    Hematocrit <=37%; n=62, 28, 27
    4
    6.3%
    0
    0%
    2
    7.4%
    Hematocrit >=60%; n=62, 28, 27
    0
    0%
    0
    0%
    0
    0%
    Platelets <=75*10^9/L; n=62, 28, 27
    0
    0%
    0
    0%
    1
    3.7%
    Platelets >=700*10^9/L; n=62, 28, 27
    0
    0%
    0
    0%
    0
    0%
    Alanine Aminotransferase >=3*ULN; n=62, 28, 27
    0
    0%
    0
    0%
    2
    7.4%
    Aspartate Aminotransferase >=3*ULN; n=62, 28, 27
    2
    3.2%
    1
    3.4%
    1
    3.7%
    Alkaline Phosphatase >=3*ULN; n=62, 28, 27
    0
    0%
    0
    0%
    0
    0%
    Total Bilirubin >=34.2 µmol/L; n=62, 28, 27
    1
    1.6%
    0
    0%
    0
    0%
    Blood Urea Nitrogen >=10.7 mmol/L; n=62, 28, 27
    1
    1.6%
    0
    0%
    0
    0%
    Creatinine >=176.8 µmol/L; n=62, 28, 27
    1
    1.6%
    0
    0%
    0
    0%
    Sodium <=126 mmol/L; n=62, 28, 27
    0
    0%
    0
    0%
    0
    0%
    Sodium >=156 mmol/L; n=62, 28, 27
    0
    0%
    0
    0%
    0
    0%
    Potassium <=3 mmol/L; n=62, 28, 27
    0
    0%
    0
    0%
    0
    0%
    Potassium >=6 mmol/L; n=62, 28, 27
    0
    0%
    0
    0%
    0
    0%
    Chloride <=90 mmol/L; n=62, 28, 27
    0
    0%
    0
    0%
    0
    0%
    Chloride >=118 mmol/L; n=62, 28, 27
    0
    0%
    0
    0%
    0
    0%
    Phosphate <=0.55 mmol/L n=62, 28, 27
    0
    0%
    0
    0%
    1
    3.7%
    Phosphate >=1.71 mmol/L; n=62, 28, 27
    1
    1.6%
    1
    3.4%
    0
    0%
    Glucose <=2.22 mmol/L; n=62, 28, 27
    0
    0%
    0
    0%
    0
    0%
    Glucose >=9.71 mmol/L; n=62, 28, 27
    4
    6.3%
    1
    3.4%
    0
    0%
    Albumin <=25 g/L; n=62, 28, 27
    0
    0%
    0
    0%
    0
    0%
    Total Protein <=45 g/L; n=62, 28, 27
    0
    0%
    0
    0%
    0
    0%
    Total Protein >=100 g/L; n=62, 28, 27
    0
    0%
    0
    0%
    0
    0%
    2. Primary Outcome
    Title Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs)
    Description AE=any untoward medical occurrence that did not necessarily have a causal relationship with this treatment, and could be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of study product, whether related or not. TE=event present prior to receiving the first injection of BeneFIX or rFIXFc that subsequently worsened in severity or not present prior to receiving the first injection but subsequently appeared before last visit on study. Serious AE (SAE)=AE resulting in death, immediate risk of death, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability/incapacity, or a congenital/anomaly/birth defect, or any other medically important event. Related=related, possibly related, and relationship missing. Data include AEs emergent during the surgical/rehabilitation period; AE data are included in each treatment arm only for the time each participant was enrolled in that arm.
    Time Frame up to 52 weeks + 30 days ± 1 week

    Outcome Measure Data

    Analysis Population Description
    Safety Analysis Set: participants who received at least 1 dose of BeneFIX or rFIXFc. A participant may have been in more than one group (i.e., participants in Arm 4 who were also in Arm 1, 2, or 3; please see Participant Flow for details). Participants with at least one TESAE reported are included in the TEAE count.
    Arm/Group Title Arm 1: Weekly Prophylaxis-BeneFIX Arm 1: Weekly Prophylaxis-rFIXFc Arm 2: Individualized Interval Prophylaxis Arm 3: Episodic (On Demand) Arm 4: Perioperative Management
    Arm/Group Description 50 IU/kg rFIXFc via intravenous (IV) injection once every 7 days initially, then at a dose indicated by the participant's baseline pharmacokinetic (PK) assessment that ensured a target trough of 1% to 3% above baseline or higher, as clinically indicated. Adjustments to the initial weekly dose of rFIXFc (50 IU/kg) were to be made based on baseline PK assessments, occurrence of spontaneous bleeding episodes, and the trough levels, which were to be monitored at Weeks 4, 16, 26, and 39. Prior to the first dose of rFIXFc, participants in the Sequential PK subgroup were to receive a single dose of 50 IU/kg BeneFIX administered IV in the clinic, followed by PK sampling. A single dose of 50 IU/kg rFIXFc was administered following a 120-hour washout from BeneFIX, followed by PK sampling for a baseline PK profiling. At Week 26 (±1 week) subjects were to receive a single dose of 50 IU/kg rFIXFc for repeat PK profiling. 50 IU/kg rFIXFc via intravenous (IV) injection once every 7 days initially, then at a dose indicated by the participant's baseline pharmacokinetic (PK) assessment that ensured a target trough of 1% to 3% above baseline or higher, as clinically indicated. Adjustments to the initial weekly dose of rFIXFc (50 IU/kg) were to be made based on baseline PK assessments, occurrence of spontaneous bleeding episodes, and the trough levels, which were to be monitored at Weeks 4, 16, 26, and 39. Prior to the first dose of rFIXFc, participants in the Sequential PK subgroup were to receive a single dose of 50 IU/kg BeneFIX administered IV in the clinic, followed by PK sampling. A single dose of 50 IU/kg rFIXFc was administered following a 120-hour washout from BeneFIX, followed by PK sampling for a baseline PK profiling. At Week 26 (±1 week) subjects were to receive a single dose of 50 IU/kg rFIXFc for repeat PK profiling. 100 IU/kg rFIXFc via IV injection once every 10 days initially, then at an interval derived from the baseline PK assessment that ensured a target trough of 1% to 3% above baseline or higher, as clinically indicated. Adjustments to the initial 10-day interval were to be made based on baseline PK assessments and trough levels, which were monitored at Weeks 4, 16, 26, and 39. 20 to 100 IU/kg rFIXFc via IV injection, or the dose indicated by the participant's baseline PK to target a plasma level of 20% to 100%, as needed for the treatment of mild to severe bleeding episodes The surgical period and dosing were dependent on the type of surgery the participant underwent. Participants who started the study in one of the other treatment arms prior to surgery returned to the original treatment arm. Participants who joined the study in the Surgery arm were assigned to one of the other treatment arms following post-operative rehabilitation.
    Measure Participants 23 63 29 27 12
    >=1 TEAE
    2
    3.2%
    45
    155.2%
    23
    85.2%
    20
    500%
    10
    8.1%
    >=1 Related TEAE
    0
    0%
    5
    17.2%
    4
    14.8%
    1
    25%
    0
    0%
    >=1 TESAE
    0
    0%
    5
    17.2%
    4
    14.8%
    4
    100%
    3
    2.4%
    >=1 Related TESAE
    0
    0%
    0
    0%
    1
    3.7%
    0
    0%
    0
    0%
    3. Primary Outcome
    Title Number of Participants With Non-serious Treatment-emergent Adverse Events (TEAEs) During the Surgical / Rehabilitation Period
    Description AE=any untoward medical occurrence that did not necessarily have a causal relationship with this treatment, and could be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of study product, whether related or not. TEAE=AE present prior to receiving the first injection of BeneFIX or rFIXFc that subsequently worsened in severity or was not present prior to receiving the first injection but subsequently appeared before last visit on study. Participants are counted once if they report multiple events in the same system organ class (SOC) or preferred term (PT). Coded using the Medical Dictionary for Regulatory Activities (MedDRA), version 15.0 dictionary. The following SOCs are abbreviated in the table: Immune System (IS); Injury, Poisoning, and Procedural (IPP); Metabolism and Nutrition (MN); Musculoskeletal and Connective Tissue (MCT); Respiratory, Thoracic and Mediastinal (RTM); Skin and Subcutaneous Tissue (SST).
    Time Frame up to 52 weeks + 30 days ± 1 week

    Outcome Measure Data

    Analysis Population Description
    Safety Analysis Set: participants who received at least 1 dose of BeneFIX or rFIXFc. A participant may have been in more than one group (i.e., participants in Arm 4 who were also in Arm 1, 2, or 3; please see Participant Flow for details).
    Arm/Group Title Arm 4: Perioperative Management
    Arm/Group Description The surgical period and dosing were dependent on the type of surgery the participant underwent. Participants who started the study in one of the other treatment arms prior to surgery returned to the original treatment arm. Participants who joined the study in the Surgery arm were assigned to one of the other treatment arms following post-operative rehabilitation.
    Measure Participants 12
    Measure Participants With At Least 1 TEAE 8
    SOC: Blood/Lymphatic System Disorders; PT: Anaemia
    2
    3.2%
    SOC: Ear and Labyrinth Disorders; PT: Vertigo
    1
    1.6%
    SOC: Gastrointestinal Disorders; PT: Constipation
    1
    1.6%
    SOC: Gastrointestinal Disorders; PT: Nausea
    1
    1.6%
    SOC: Gastrointestinal Disorders; PT: Vomiting
    1
    1.6%
    SOC: General Disorders; PT: Asthenia
    1
    1.6%
    SOC: General Disorders; PT: Infusion Site Pain
    1
    1.6%
    SOC: IS Disorders; PT: Drug Hypersensitivity
    1
    1.6%
    SOC: Infections/Infestations; PT: Cellulitis
    1
    1.6%
    SOC: IPP Complications; PT: Incision Site Pain
    1
    1.6%
    SOC: IPP Complications; PT: Procedural Pain
    1
    1.6%
    SOC: IPP Complications; PT: Wound Complication
    1
    1.6%
    SOC: Investigations; PT: Weight Increased
    1
    1.6%
    SOC: MN Disorders; PT: Decreased Appetite
    1
    1.6%
    SOC: MCT Disorders; PT: Muscle Spasms
    1
    1.6%
    SOC: Nervous System Disorders; PT: Dizziness
    2
    3.2%
    SOC: Nervous System Disorders; PT: Headache
    1
    1.6%
    SOC: Nervous System (NS) Disorders; PT: Neuralgia
    1
    1.6%
    SOC: NS Disorders; PT: Neuropathy Peripheral
    1
    1.6%
    SOC: Psychiatric Disorders; PT: Anxiety
    1
    1.6%
    SOC: Psychiatric Disorders; PT: Insomnia
    1
    1.6%
    SOC: RTM Disorders; PT: Dyspnoea
    1
    1.6%
    SOC: RTM Disorders; Oropharyngeal Pain
    1
    1.6%
    SOC: SST Disorders; PT: Hyperhidrosis
    1
    1.6%
    SOC: Vascular Disorders; PT: Hypertension
    1
    1.6%
    SOC: Vascular Disorders; PT: Hypotension
    1
    1.6%
    4. Primary Outcome
    Title Number of Participants With Treatment-emergent Serious Adverse Events (TESAEs) During the Surgical / Rehabilitation Period
    Description SAE=AE resulting in death, immediate risk of death, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability/incapacity, or a congenital/anomaly/birth defect, or any other medically important event. TESAE=SAE present prior to receiving the first injection of BeneFIX or rFIXFc that subsequently worsened in severity or was not present prior to receiving the first injection but subsequently appeared before last visit on study. Participants are counted once if they report multiple events in the same system organ class (SOC) or preferred term (PT). Coded using the Medical Dictionary for Regulatory Activities (MedDRA), version 15.0 dictionary. The following SOC is abbreviated in the table: Injury, Poisoning, and Procedural (IPP).
    Time Frame up to 52 weeks + 30 days ± 1 week

    Outcome Measure Data

    Analysis Population Description
    Safety Analysis Set: participants who received at least 1 dose of BeneFIX or rFIXFc. A participant may have been in more than one group (i.e., participants in Arm 4 who were also in Arm 1, 2, or 3; please see Participant Flow for details).
    Arm/Group Title Arm 4: Perioperative Management
    Arm/Group Description The surgical period and dosing were dependent on the type of surgery the participant underwent. Participants who started the study in one of the other treatment arms prior to surgery returned to the original treatment arm. Participants who joined the study in the Surgery arm were assigned to one of the other treatment arms following post-operative rehabilitation.
    Measure Participants 12
    Measure Participants With At Least 1 TESAE 3
    SOC: Cardiac Disorders; PT: Tachycardia
    1
    1.6%
    SOC: Infections/Infestations; PT: Bacterial Sepsis
    1
    1.6%
    SOC: Infections/Infestations; PT: Pilondial Cyst
    1
    1.6%
    SOC: Infections/Infestations; PT: Tooth Abscess
    1
    1.6%
    SOC: IPP Complications; PT: Limb Crushing Injury
    1
    1.6%
    5. Secondary Outcome
    Title Participant Assessment of Response to Injections to Treat a Bleeding Episode
    Description 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.
    Time Frame up to 52 weeks ± 1 week

    Outcome Measure Data

    Analysis Population Description
    Full Analysis Set: participants who received at least 1 dose of rFIXFc and had a bleeding episode; participants with a non-evaluable bleeding episode are counted in the 'number of participants analyzed,' but not the percentages.
    Arm/Group Title Arm 1: Weekly Prophylaxis Arm 2: Individualized Interval Prophylaxis Arm 3: Episodic (On Demand)
    Arm/Group Description 50 IU/kg rFIXFc via intravenous (IV) injection once every 7 days initially, then at a dose indicated by the participant's baseline pharmacokinetic (PK) assessment that ensured a target trough of 1% to 3% above baseline or higher, as clinically indicated. Adjustments to the initial weekly dose of rFIXFc (50 IU/kg) were to be made based on baseline PK assessments, occurrence of spontaneous bleeding episodes, and the trough levels, which were to be monitored at Weeks 4, 16, 26, and 39. Prior to the first dose of rFIXFc, participants in the Sequential PK subgroup were to receive a single dose of 50 IU/kg BeneFIX administered IV in the clinic, followed by PK sampling. A single dose of 50 IU/kg rFIXFc was administered following a 120-hour washout from BeneFIX, followed by PK sampling for a baseline PK profiling. At Week 26 (±1 week) subjects were to receive a single dose of 50 IU/kg rFIXFc for repeat PK profiling. 100 IU/kg rFIXFc via IV injection once every 10 days initially, then at an interval derived from the baseline PK assessment that ensured a target trough of 1% to 3% above baseline or higher, as clinically indicated. Adjustments to the initial 10-day interval were to be made based on baseline PK assessments and trough levels, which were monitored at Weeks 4, 16, 26, and 39. 20 to 100 IU/kg rFIXFc via IV injection, or the dose indicated by the participant's baseline PK to target a plasma level of 20% to 100%, as needed for the treatment of mild to severe bleeding episodes
    Measure Participants 47 15 27
    Measure Bleeding Episodes 156 63 394
    Excellent or Good
    78.8
    74.6
    87.1
    Excellent
    35.3
    31.7
    37.3
    Good
    43.6
    42.9
    49.7
    Moderate
    18.6
    22.2
    11.9
    No Response
    2.6
    3.2
    1.0
    6. Secondary Outcome
    Title Physicians' Global Assessments of Participants' Response to Treatment With rFIXFc
    Description 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.
    Time Frame up to 52 weeks ± 1 week

    Outcome Measure Data

    Analysis Population Description
    Full Analysis Set: participants who received at least 1 dose of rFIXFc, had evaluable efficacy assessments, and had nonmissing observations at time point.
    Arm/Group Title Arm 1: Weekly Prophylaxis Arm 2: Individualized Interval Prophylaxis Arm 3: Episodic (On Demand)
    Arm/Group Description 50 IU/kg rFIXFc via intravenous (IV) injection once every 7 days initially, then at a dose indicated by the participant's baseline pharmacokinetic (PK) assessment that ensured a target trough of 1% to 3% above baseline or higher, as clinically indicated. Adjustments to the initial weekly dose of rFIXFc (50 IU/kg) were to be made based on baseline PK assessments, occurrence of spontaneous bleeding episodes, and the trough levels, which were to be monitored at Weeks 4, 16, 26, and 39. Prior to the first dose of rFIXFc, participants in the Sequential PK subgroup were to receive a single dose of 50 IU/kg BeneFIX administered IV in the clinic, followed by PK sampling. A single dose of 50 IU/kg rFIXFc was administered following a 120-hour washout from BeneFIX, followed by PK sampling for a baseline PK profiling. At Week 26 (±1 week) subjects were to receive a single dose of 50 IU/kg rFIXFc for repeat PK profiling. 100 IU/kg rFIXFc via IV injection once every 10 days initially, then at an interval derived from the baseline PK assessment that ensured a target trough of 1% to 3% above baseline or higher, as clinically indicated. Adjustments to the initial 10-day interval were to be made based on baseline PK assessments and trough levels, which were monitored at Weeks 4, 16, 26, and 39. 20 to 100 IU/kg rFIXFc via IV injection, or the dose indicated by the participant's baseline PK to target a plasma level of 20% to 100%, as needed for the treatment of mild to severe bleeding episodes
    Measure Participants 61 26 27
    Measure Responses 267 123 96
    Excellent
    74.5
    73.2
    58.3
    Effective
    24.3
    26.0
    39.6
    Partially Effective
    1.1
    0.8
    2.1
    Ineffective
    0
    0
    0
    7. Secondary Outcome
    Title Annualized rFIXFc Consumption Per Participant
    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.
    Time Frame up to 52 weeks ± 1 week (efficacy period as defined in description)

    Outcome Measure Data

    Analysis Population Description
    Full Analysis Set: participants who received at least 1 dose of rFIXFc with evaluable data in the efficacy period. 'Overall' n=all participants in the Full Analysis Set with evaluable data in the efficacy period; 'Last 3 Months on Study' n=all participants in the Full Analysis Set with evaluable data and >=6 months on study.
    Arm/Group Title Arm 1: Weekly Prophylaxis Arm 2: Individualized Interval Prophylaxis Arm 3: Episodic (On Demand)
    Arm/Group Description 50 IU/kg rFIXFc via intravenous (IV) injection once every 7 days initially, then at a dose indicated by the participant's baseline pharmacokinetic (PK) assessment that ensured a target trough of 1% to 3% above baseline or higher, as clinically indicated. Adjustments to the initial weekly dose of rFIXFc (50 IU/kg) were to be made based on baseline PK assessments, occurrence of spontaneous bleeding episodes, and the trough levels, which were to be monitored at Weeks 4, 16, 26, and 39. Prior to the first dose of rFIXFc, participants in the Sequential PK subgroup were to receive a single dose of 50 IU/kg BeneFIX administered IV in the clinic, followed by PK sampling. A single dose of 50 IU/kg rFIXFc was administered following a 120-hour washout from BeneFIX, followed by PK sampling for a baseline PK profiling. At Week 26 (±1 week) subjects were to receive a single dose of 50 IU/kg rFIXFc for repeat PK profiling. 100 IU/kg rFIXFc via IV injection once every 10 days initially, then at an interval derived from the baseline PK assessment that ensured a target trough of 1% to 3% above baseline or higher, as clinically indicated. Adjustments to the initial 10-day interval were to be made based on baseline PK assessments and trough levels, which were monitored at Weeks 4, 16, 26, and 39. 20 to 100 IU/kg rFIXFc via IV injection, or the dose indicated by the participant's baseline PK to target a plasma level of 20% to 100%, as needed for the treatment of mild to severe bleeding episodes
    Measure Participants 61 26 27
    Overall (n=61, 26, 27)
    2686.94
    (825.969)
    3371.92
    (649.690)
    936.70
    (481.764)
    Last 3 months on study (n=58, 26, 27)
    2467.32
    (978.529)
    3497.78
    (957.377)
    957.73
    (699.640)
    8. Secondary Outcome
    Title Average Weekly Dose For the Fixed Weekly Interval Prophylaxis Arm
    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).
    Time Frame up to 52 weeks ± 1 week (efficacy period as defined in description)

    Outcome Measure Data

    Analysis Population Description
    Full Analysis Set: participants in Arm 1 who received at least 1 dose of rFIXFc with evaluable data. 'Overall' n=participants with evaluable data; 'Last 3 Months on Study' n=participants with evaluable data and >=6 months on study.
    Arm/Group Title Arm 1: Weekly Prophylaxis
    Arm/Group Description 50 IU/kg rFIXFc via intravenous (IV) injection once every 7 days initially, then at a dose indicated by the participant's baseline pharmacokinetic (PK) assessment that ensured a target trough of 1% to 3% above baseline or higher, as clinically indicated. Adjustments to the initial weekly dose of rFIXFc (50 IU/kg) were to be made based on baseline PK assessments, occurrence of spontaneous bleeding episodes, and the trough levels, which were to be monitored at Weeks 4, 16, 26, and 39. Prior to the first dose of rFIXFc, participants in the Sequential PK subgroup were to receive a single dose of 50 IU/kg BeneFIX administered IV in the clinic, followed by PK sampling. A single dose of 50 IU/kg rFIXFc was administered following a 120-hour washout from BeneFIX, followed by PK sampling for a baseline PK profiling. At Week 26 (±1 week) subjects were to receive a single dose of 50 IU/kg rFIXFc for repeat PK profiling.
    Measure Participants 61
    Overall (n=61)
    46.26
    (11.304)
    Last 3 months on study (n=58)
    43.10
    (15.395)
    9. Secondary Outcome
    Title Average Dosing Interval For the Individualized Interval Prophylaxis Arm
    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).
    Time Frame up to 52 weeks ± 1 week (efficacy period as defined in description)

    Outcome Measure Data

    Analysis Population Description
    Full Analysis Set: participants in Arm 2 who received at least 1 dose of rFIXFc with >=6 months on study and evaluable data.
    Arm/Group Title Arm 2: Individualized Interval Prophylaxis
    Arm/Group Description 100 IU/kg rFIXFc via IV injection once every 10 days initially, then at an interval derived from the baseline PK assessment that ensured a target trough of 1% to 3% above baseline or higher, as clinically indicated. Adjustments to the initial 10-day interval were to be made based on baseline PK assessments and trough levels, which were monitored at Weeks 4, 16, 26, and 39.
    Measure Participants 26
    Overall
    12.53
    (2.018)
    Last 3 months on study
    14.00
    (2.864)
    10. Secondary Outcome
    Title Annualized Bleeding Rate by Type of Bleed (Spontaneous and Traumatic)
    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.
    Time Frame up to 52 weeks ± 1 week (efficacy period as defined in description)

    Outcome Measure Data

    Analysis Population Description
    Full Analysis Set: participants who received at least 1 dose of rFIXFc with evaluable data.
    Arm/Group Title Arm 1: Weekly Prophylaxis Arm 2: Individualized Interval Prophylaxis Arm 3: Episodic (On Demand)
    Arm/Group Description 50 IU/kg rFIXFc via intravenous (IV) injection once every 7 days initially, then at a dose indicated by the participant's baseline pharmacokinetic (PK) assessment that ensured a target trough of 1% to 3% above baseline or higher, as clinically indicated. Adjustments to the initial weekly dose of rFIXFc (50 IU/kg) were to be made based on baseline PK assessments, occurrence of spontaneous bleeding episodes, and the trough levels, which were to be monitored at Weeks 4, 16, 26, and 39. Prior to the first dose of rFIXFc, participants in the Sequential PK subgroup were to receive a single dose of 50 IU/kg BeneFIX administered IV in the clinic, followed by PK sampling. A single dose of 50 IU/kg rFIXFc was administered following a 120-hour washout from BeneFIX, followed by PK sampling for a baseline PK profiling. At Week 26 (±1 week) subjects were to receive a single dose of 50 IU/kg rFIXFc for repeat PK profiling. 100 IU/kg rFIXFc via IV injection once every 10 days initially, then at an interval derived from the baseline PK assessment that ensured a target trough of 1% to 3% above baseline or higher, as clinically indicated. Adjustments to the initial 10-day interval were to be made based on baseline PK assessments and trough levels, which were monitored at Weeks 4, 16, 26, and 39. 20 to 100 IU/kg rFIXFc via IV injection, or the dose indicated by the participant's baseline PK to target a plasma level of 20% to 100%, as needed for the treatment of mild to severe bleeding episodes
    Measure Participants 61 26 27
    Spontaneous
    1.04
    (2.154)
    0.88
    (1.780)
    11.78
    (11.096)
    Traumatic
    0.99
    (1.539)
    0.00
    (2.065)
    2.21
    (7.214)
    Unknown
    0.00
    (0.603)
    0.00
    (0.705)
    0.00
    (1.043)
    11. Secondary Outcome
    Title Annualized Bleeding Rate by Location of Bleed (Joint, Muscle, Internal, Skin/Mucosa)
    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.
    Time Frame up to 52 weeks ± 1 week (efficacy period as defined in description)

    Outcome Measure Data

    Analysis Population Description
    Full Analysis Set: participants who received at least 1 dose of rFIXFc with evaluable data.
    Arm/Group Title Arm 1: Weekly Prophylaxis Arm 2: Individualized Interval Prophylaxis Arm 3: Episodic (On Demand)
    Arm/Group Description 50 IU/kg rFIXFc via intravenous (IV) injection once every 7 days initially, then at a dose indicated by the participant's baseline pharmacokinetic (PK) assessment that ensured a target trough of 1% to 3% above baseline or higher, as clinically indicated. Adjustments to the initial weekly dose of rFIXFc (50 IU/kg) were to be made based on baseline PK assessments, occurrence of spontaneous bleeding episodes, and the trough levels, which were to be monitored at Weeks 4, 16, 26, and 39. Prior to the first dose of rFIXFc, participants in the Sequential PK subgroup were to receive a single dose of 50 IU/kg BeneFIX administered IV in the clinic, followed by PK sampling. A single dose of 50 IU/kg rFIXFc was administered following a 120-hour washout from BeneFIX, followed by PK sampling for a baseline PK profiling. At Week 26 (±1 week) subjects were to receive a single dose of 50 IU/kg rFIXFc for repeat PK profiling. 100 IU/kg rFIXFc via IV injection once every 10 days initially, then at an interval derived from the baseline PK assessment that ensured a target trough of 1% to 3% above baseline or higher, as clinically indicated. Adjustments to the initial 10-day interval were to be made based on baseline PK assessments and trough levels, which were monitored at Weeks 4, 16, 26, and 39. 20 to 100 IU/kg rFIXFc via IV injection, or the dose indicated by the participant's baseline PK to target a plasma level of 20% to 100%, as needed for the treatment of mild to severe bleeding episodes
    Measure Participants 61 26 27
    Joint
    1.11
    (2.678)
    0.36
    (2.498)
    13.58
    (10.418)
    Muscle
    0.00
    (1.273)
    0.00
    (0.902)
    3.96
    (3.733)
    Internal
    0.00
    (0.562)
    0.00
    (0.448)
    0.00
    (0.893)
    Skin/Mucosa
    0.00
    (0.668)
    0.00
    (0.472)
    0.00
    (2.968)
    12. Secondary Outcome
    Title Number of Days From Last Injection to Treat a New Bleeding Episode
    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.
    Time Frame up to 52 weeks ± 1 week (efficacy period as defined in description)

    Outcome Measure Data

    Analysis Population Description
    Full Analysis Set: participants who received at least 1 dose of rFIXFc and at least 1 evaluable bleeding episode.
    Arm/Group Title Arm 1: Weekly Prophylaxis Arm 2: Individualized Interval Prophylaxis Arm 3: Episodic (On Demand)
    Arm/Group Description 50 IU/kg rFIXFc via intravenous (IV) injection once every 7 days initially, then at a dose indicated by the participant's baseline pharmacokinetic (PK) assessment that ensured a target trough of 1% to 3% above baseline or higher, as clinically indicated. Adjustments to the initial weekly dose of rFIXFc (50 IU/kg) were to be made based on baseline PK assessments, occurrence of spontaneous bleeding episodes, and the trough levels, which were to be monitored at Weeks 4, 16, 26, and 39. Prior to the first dose of rFIXFc, participants in the Sequential PK subgroup were to receive a single dose of 50 IU/kg BeneFIX administered IV in the clinic, followed by PK sampling. A single dose of 50 IU/kg rFIXFc was administered following a 120-hour washout from BeneFIX, followed by PK sampling for a baseline PK profiling. At Week 26 (±1 week) subjects were to receive a single dose of 50 IU/kg rFIXFc for repeat PK profiling. 100 IU/kg rFIXFc via IV injection once every 10 days initially, then at an interval derived from the baseline PK assessment that ensured a target trough of 1% to 3% above baseline or higher, as clinically indicated. Adjustments to the initial 10-day interval were to be made based on baseline PK assessments and trough levels, which were monitored at Weeks 4, 16, 26, and 39. 20 to 100 IU/kg rFIXFc via IV injection, or the dose indicated by the participant's baseline PK to target a plasma level of 20% to 100%, as needed for the treatment of mild to severe bleeding episodes
    Measure Participants 35 13 27
    Measure Evaluable Bleeding Episodes 110 45 359
    Per Bleeding Episode
    40.78
    (57.184)
    39.48
    (63.228)
    13.42
    (21.837)
    Per Participant
    59.52
    (49.610)
    76.13
    (37.451)
    19.67
    (40.576)
    13. Secondary Outcome
    Title Number of Injections Required for Resolution of a Bleeding Episode
    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.
    Time Frame up to 52 weeks ± 1 week (efficacy period as defined in description)

    Outcome Measure Data

    Analysis Population Description
    Full Analysis Set: participants who received at least 1 dose of rFIXFc and had at least 1 bleeding episode.
    Arm/Group Title Arm 1: Weekly Prophylaxis Arm 2: Individualized Interval Prophylaxis Arm 3: Episodic (On Demand)
    Arm/Group Description 50 IU/kg rFIXFc via intravenous (IV) injection once every 7 days initially, then at a dose indicated by the participant's baseline pharmacokinetic (PK) assessment that ensured a target trough of 1% to 3% above baseline or higher, as clinically indicated. Adjustments to the initial weekly dose of rFIXFc (50 IU/kg) were to be made based on baseline PK assessments, occurrence of spontaneous bleeding episodes, and the trough levels, which were to be monitored at Weeks 4, 16, 26, and 39. Prior to the first dose of rFIXFc, participants in the Sequential PK subgroup were to receive a single dose of 50 IU/kg BeneFIX administered IV in the clinic, followed by PK sampling. A single dose of 50 IU/kg rFIXFc was administered following a 120-hour washout from BeneFIX, followed by PK sampling for a baseline PK profiling. At Week 26 (±1 week) subjects were to receive a single dose of 50 IU/kg rFIXFc for repeat PK profiling. 100 IU/kg rFIXFc via IV injection once every 10 days initially, then at an interval derived from the baseline PK assessment that ensured a target trough of 1% to 3% above baseline or higher, as clinically indicated. Adjustments to the initial 10-day interval were to be made based on baseline PK assessments and trough levels, which were monitored at Weeks 4, 16, 26, and 39. 20 to 100 IU/kg rFIXFc via IV injection, or the dose indicated by the participant's baseline PK to target a plasma level of 20% to 100%, as needed for the treatment of mild to severe bleeding episodes
    Measure Participants 47 15 27
    Measure Bleeding Episodes 167 67 402
    Per Bleeding Episode
    1.0
    (0.56)
    1.0
    (0.53)
    1.0
    (0.31)
    Per Participant
    1.00
    (0.50)
    1.09
    (0.30)
    1.04
    (0.32)
    14. Secondary Outcome
    Title Number of Injections Required for Resolution of a Bleeding Episode by Location of Bleed
    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.
    Time Frame up to 52 weeks ± 1 week (efficacy period as defined in description)

    Outcome Measure Data

    Analysis Population Description
    Full Analysis Set: participants who received at least 1 dose of rFIXFc, had a bleeding episode, and had evaluable efficacy assessments; n=total number of bleeds at given location.
    Arm/Group Title Arm 1: Weekly Prophylaxis Arm 2: Individualized Interval Prophylaxis Arm 3: Episodic (On Demand)
    Arm/Group Description 50 IU/kg rFIXFc via intravenous (IV) injection once every 7 days initially, then at a dose indicated by the participant's baseline pharmacokinetic (PK) assessment that ensured a target trough of 1% to 3% above baseline or higher, as clinically indicated. Adjustments to the initial weekly dose of rFIXFc (50 IU/kg) were to be made based on baseline PK assessments, occurrence of spontaneous bleeding episodes, and the trough levels, which were to be monitored at Weeks 4, 16, 26, and 39. Prior to the first dose of rFIXFc, participants in the Sequential PK subgroup were to receive a single dose of 50 IU/kg BeneFIX administered IV in the clinic, followed by PK sampling. A single dose of 50 IU/kg rFIXFc was administered following a 120-hour washout from BeneFIX, followed by PK sampling for a baseline PK profiling. At Week 26 (±1 week) subjects were to receive a single dose of 50 IU/kg rFIXFc for repeat PK profiling. 100 IU/kg rFIXFc via IV injection once every 10 days initially, then at an interval derived from the baseline PK assessment that ensured a target trough of 1% to 3% above baseline or higher, as clinically indicated. Adjustments to the initial 10-day interval were to be made based on baseline PK assessments and trough levels, which were monitored at Weeks 4, 16, 26, and 39. 20 to 100 IU/kg rFIXFc via IV injection, or the dose indicated by the participant's baseline PK to target a plasma level of 20% to 100%, as needed for the treatment of mild to severe bleeding episodes
    Measure Participants 47 15 27
    Joint (n=125, 52, 314)
    1.0
    1.0
    1.0
    Muscle (n=35, 10, 90)
    1.0
    1.0
    1.0
    Internal (n=9, 3, 11)
    1.0
    2.0
    1.0
    Skin/Mucosa (n=11, 4, 21)
    1.0
    1.0
    1.0
    15. Secondary Outcome
    Title Total Dose Per Injection Required for Resolution of a Bleeding Episode by Location of Bleed
    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.
    Time Frame up to 52 weeks ± 1 week (efficacy period as defined in description)

    Outcome Measure Data

    Analysis Population Description
    Full Analysis Set: participants who received at least 1 dose of rFIXFc, had a bleeding episode, and had complete information on the dose administered to treat a bleeding episode; n=total number of bleeding episodes at this location.
    Arm/Group Title Arm 1: Weekly Prophylaxis Arm 2: Individualized Interval Prophylaxis Arm 3: Episodic (On Demand)
    Arm/Group Description 50 IU/kg rFIXFc via intravenous (IV) injection once every 7 days initially, then at a dose indicated by the participant's baseline pharmacokinetic (PK) assessment that ensured a target trough of 1% to 3% above baseline or higher, as clinically indicated. Adjustments to the initial weekly dose of rFIXFc (50 IU/kg) were to be made based on baseline PK assessments, occurrence of spontaneous bleeding episodes, and the trough levels, which were to be monitored at Weeks 4, 16, 26, and 39. Prior to the first dose of rFIXFc, participants in the Sequential PK subgroup were to receive a single dose of 50 IU/kg BeneFIX administered IV in the clinic, followed by PK sampling. A single dose of 50 IU/kg rFIXFc was administered following a 120-hour washout from BeneFIX, followed by PK sampling for a baseline PK profiling. At Week 26 (±1 week) subjects were to receive a single dose of 50 IU/kg rFIXFc for repeat PK profiling. 100 IU/kg rFIXFc via IV injection once every 10 days initially, then at an interval derived from the baseline PK assessment that ensured a target trough of 1% to 3% above baseline or higher, as clinically indicated. Adjustments to the initial 10-day interval were to be made based on baseline PK assessments and trough levels, which were monitored at Weeks 4, 16, 26, and 39. 20 to 100 IU/kg rFIXFc via IV injection, or the dose indicated by the participant's baseline PK to target a plasma level of 20% to 100%, as needed for the treatment of mild to severe bleeding episodes
    Measure Participants 47 15 27
    Joint (n=124, 52, 313)
    50.14
    45.29
    46.73
    Muscle (n=35, 10, 90)
    55.56
    67.17
    46.57
    Internal (n=9, 3, 11)
    48.72
    70.26
    46.73
    Skin/Mucosa (n=11, 4, 21)
    46.89
    48.48
    22.22
    16. Secondary Outcome
    Title Hemophilia-Specific Quality of Life Index for Adults (Haem-A-QoL) Questionnaire: Change From Baseline to Week 26
    Description 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.
    Time Frame Baseline, Week 26

    Outcome Measure Data

    Analysis Population Description
    Full Analysis Set: participants in the 2 prophylaxis arms (Arms 1 and 2) over 17 years of age who received at least 1 dose of rFIXFc and had an assessment. n=participants who had specified assessment at given timepoint.
    Arm/Group Title Pre-study Regimen: Prophylaxis (Arms 1 and 2 Pooled) Pre-study Regimen: On Demand (Arms 1 and 2 Pooled)
    Arm/Group Description Participants from the Weekly or Individualized Interval Prophylaxis Arms (Arms 1 or 2) who had a prophylaxis pre-study regimen. Participants from the Weekly or Individualized Interval Prophylaxis Arms (Arms 1 or 2) who had an on-demand pre-study regimen.
    Measure Participants 27 31
    Total Score (n=27, 26)
    -6.82
    -6.25
    Physical Health (n=27, 31)
    -10.00
    -15.00
    Feeling (n=27, 31)
    0.00
    0.00
    View of Yourself (n=27, 30)
    -5.00
    -5.00
    Sports and Leisure (n=22, 21)
    -7.50
    -20.0
    Work and School (n=22, 25)
    0.00
    -6.25
    Dealing with Hemophilia (n=27, 31)
    0.00
    -8.33
    Treatment (n=27, 31)
    -6.25
    0.00
    Future (n=26, 30)
    -5.00
    0.00
    Family Planning (n=15, 13)
    0.00
    0.00
    Partnership and Sexuality (n=26, 30)
    0.00
    0.00
    17. Secondary Outcome
    Title Haem-A-QoL Questionnaire for Adults: Change From Baseline to Week 52
    Description 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.
    Time Frame Baseline, Week 52

    Outcome Measure Data

    Analysis Population Description
    Full Analysis Set: participants in the 2 prophylaxis arms (Arms 1 and 2) over 17 years of age who received at least 1 dose of rFIXFc and had an assessment. n=participants who had specified assessment at given timepoint.
    Arm/Group Title Pre-study Regimen: Prophylaxis (Arms 1 and 2 Pooled) Pre-study Regimen: On Demand (Arms 1 and 2 Pooled)
    Arm/Group Description Participants from the Weekly or Individualized Interval Prophylaxis Arms (Arms 1 or 2) who had a prophylaxis pre-study regimen. Participants from the Weekly or Individualized Interval Prophylaxis Arms (Arms 1 or 2) who had an on-demand pre-study regimen.
    Measure Participants 27 24
    Total Score (n=25, 19)
    -4.35
    -6.06
    Physical Health (n=26, 23)
    -10.00
    -15.00
    Feeling (n=26, 23)
    0.00
    0.00
    View of Yourself (n=26, 24)
    -7.50
    -5.00
    Sports and Leisure (n=20, 16)
    -0.62
    -17.50
    Work and School (n=22, 20)
    0.00
    -3.13
    Dealing with Hemophilia (n=27, 24)
    0.00
    4.17
    Treatment (n=27, 24)
    -6.25
    -4.69
    Future (n=26, 23)
    -5.00
    -5.00
    Family Planning (n=14, 11)
    0.00
    0.00
    18. Secondary Outcome
    Title Hemophilia-Specific Quality of Life Index for Children (Haemo-QoL) Questionnaire: Change From Baseline to Week 26 and Week 52
    Description 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.
    Time Frame Baseline, Week 26, Week 52

    Outcome Measure Data

    Analysis Population Description
    No summary analysis was done for this outcome measure due to the small number of participants completing the questionnaire.
    Arm/Group Title Pre-study Regimen: Prophylaxis (Arms 1 and 2 Pooled) Pre-study Regimen: On Demand (Arms 1 and 2 Pooled)
    Arm/Group Description Child and adolescent participants from the Weekly or Individualized Interval Prophylaxis Arms (Arms 1 or 2) who had a prophylaxis pre-study regimen. Child and adolescent participants from the Weekly or Individualized Interval Prophylaxis Arms (Arms 1 or 2) who had an on-demand pre-study regimen.
    Measure Participants 0 0
    19. Secondary Outcome
    Title Investigators'/Surgeons' Assessment of Participants' Response to rFIXFc for Major Surgery
    Description 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.
    Time Frame up to 52 weeks ± 1 week

    Outcome Measure Data

    Analysis Population Description
    Participants in Arm 4 who received at least 1 dose of rFIXFc.
    Arm/Group Title Arm 4: Perioperative Management
    Arm/Group Description The surgical period and dosing were dependent on the type of surgery the participant underwent. Participants who started the study in one of the other treatment arms prior to surgery returned to the original treatment arm. Participants who joined the study in the Surgery arm were assigned to one of the other treatment arms following post-operative rehabilitation.
    Measure Participants 12
    Measure Major Surgeries 14
    Excellent or Good
    14
    Excellent
    13
    Good
    1
    Fair
    0
    Poor/None
    0
    20. Secondary Outcome
    Title Number of Injections Required to Maintain Hemostasis During Major Surgery
    Description 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.
    Time Frame up to 52 weeks ± 1 week

    Outcome Measure Data

    Analysis Population Description
    Participants in Arm 4 who received at least 1 dose of rFIXFc.
    Arm/Group Title Arm 4: Perioperative Management
    Arm/Group Description The surgical period and dosing were dependent on the type of surgery the participant underwent. Participants who started the study in one of the other treatment arms prior to surgery returned to the original treatment arm. Participants who joined the study in the Surgery arm were assigned to one of the other treatment arms following post-operative rehabilitation.
    Measure Participants 12
    Measure Major Surgeries 14
    Median (Full Range) [injections]
    1.00
    (0.825)
    21. Secondary Outcome
    Title Dose Per Injection and Total Dose Required to Maintain Hemostasis During Major Surgery
    Description 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.
    Time Frame up to 52 weeks ± 1 week

    Outcome Measure Data

    Analysis Population Description
    Participants in Arm 4 who received at least 1 dose of rFIXFc.
    Arm/Group Title Arm 4: Perioperative Management
    Arm/Group Description The surgical period and dosing were dependent on the type of surgery the participant underwent. Participants who started the study in one of the other treatment arms prior to surgery returned to the original treatment arm. Participants who joined the study in the Surgery arm were assigned to one of the other treatment arms following post-operative rehabilitation.
    Measure Participants 12
    Measure Major Surgeries 14
    Dose per Injection
    90.91
    (30.869)
    Total Dose
    102.59
    (60.930)
    22. Secondary Outcome
    Title Estimated Total Blood Loss During Major Surgery
    Description
    Time Frame up to 52 weeks ± 1 week

    Outcome Measure Data

    Analysis Population Description
    Participants in Arm 4 who received at least 1 dose of rFIXFc.
    Arm/Group Title Arm 4: Perioperative Management
    Arm/Group Description The surgical period and dosing were dependent on the type of surgery the participant underwent. Participants who started the study in one of the other treatment arms prior to surgery returned to the original treatment arm. Participants who joined the study in the Surgery arm were assigned to one of the other treatment arms following post-operative rehabilitation.
    Measure Participants 12
    Measure Major Surgeries 14
    Median (Full Range) [mL]
    65.50
    (95.161)
    23. Primary Outcome
    Title Incidence Rate of FIX Inhibitor Development
    Description An inhibitor test result ≥0.6 Bethesda units (BU)/mL, identified and confirmed by re-testing of a second sample obtained within 2 to 4 weeks, was considered positive. Both tests were to be performed using the Nijmegen-modified Bethesda Assay by the central laboratory. The incidence rates along with the 95% CI were summarized for all titers for subjects with 50 or more exposure days (EDs) to rFIXFc and a valid inhibitor test after the 50th exposure. In addition, the incidence rates for all subjects regardless of their exposure days to rFIXFc were also summarized. The 95% CI was calculated using Clopper-Pearson exact method.
    Time Frame up to 52 weeks ± 1 week

    Outcome Measure Data

    Analysis Population Description
    Safety Analysis Set: participants who received at least 1 dose of of rFIXFc and who had a valid inhibitor test; n=number of participants with given number of exposure days who had a valid inhibitor test.
    Arm/Group Title Arm 1: Weekly Prophylaxis Arm 2: Individualized Interval Prophylaxis Arm 3: Episodic (On Demand) Arm 4: Perioperative Management Total
    Arm/Group Description 50 IU/kg rFIXFc via intravenous (IV) injection once every 7 days initially, then at a dose indicated by the participant's baseline pharmacokinetic (PK) assessment that ensured a target trough of 1% to 3% above baseline or higher, as clinically indicated. Adjustments to the initial weekly dose of rFIXFc (50 IU/kg) were to be made based on baseline PK assessments, occurrence of spontaneous bleeding episodes, and the trough levels, which were to be monitored at Weeks 4, 16, 26, and 39. Prior to the first dose of rFIXFc, participants in the Sequential PK subgroup were to receive a single dose of 50 IU/kg BeneFIX administered IV in the clinic, followed by PK sampling. A single dose of 50 IU/kg rFIXFc was administered following a 120-hour washout from BeneFIX, followed by PK sampling for a baseline PK profiling. At Week 26 (±1 week) subjects were to receive a single dose of 50 IU/kg rFIXFc for repeat PK profiling. 100 IU/kg rFIXFc via IV injection once every 10 days initially, then at an interval derived from the baseline PK assessment that ensured a target trough of 1% to 3% above baseline or higher, as clinically indicated. Adjustments to the initial 10-day interval were to be made based on baseline PK assessments and trough levels, which were monitored at Weeks 4, 16, 26, and 39. 20 to 100 IU/kg rFIXFc via IV injection, or the dose indicated by the participant's baseline PK to target a plasma level of 20% to 100%, as needed for the treatment of mild to severe bleeding episodes The surgical period and dosing were dependent on the type of surgery the participant underwent. Participants who started the study in one of the other treatment arms prior to surgery returned to the original treatment arm. Participants who joined the study in the Surgery arm were assigned to one of the other treatment arms following post-operative rehabilitation. All participants from Arms 1-4
    Measure Participants 63 27 27 4 121
    Participants with>=50 EDs to rFIXFc(n=52,2,0,1,55)
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    All participants (n=63, 27, 27, 4, 121)
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    24. Secondary Outcome
    Title Number of Transfusions Required Per Surgery
    Description Number of blood component transfusions during a single surgery.
    Time Frame up to 52 weeks ± 1 week

    Outcome Measure Data

    Analysis Population Description
    Participants in Arm 4 who received at least 1 dose of rFIXFc.
    Arm/Group Title Arm 4: Perioperative Management
    Arm/Group Description The surgical period and dosing were dependent on the type of surgery the participant underwent. Participants who started the study in one of the other treatment arms prior to surgery returned to the original treatment arm. Participants who joined the study in the Surgery arm were assigned to one of the other treatment arms following post-operative rehabilitation.
    Measure Participants 12
    Measure Major Surgeries 14
    0 transfusions
    12
    1 transfusion
    0
    2 transfusions
    1
    3 transfusions
    0
    >3 transfusions
    1
    25. Secondary Outcome
    Title Maximum Concentration (Cmax)
    Description 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.
    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.

    Outcome Measure Data

    Analysis Population Description
    Participants in the Sequential PK Subgroup who have evaluable PK profiles for both BeneFIX and baseline rFIXFc.
    Arm/Group Title Arm 1: Weekly Prophylaxis - Sequential PK Subgroup
    Arm/Group Description Prior to the first dose of rFIXFc, participants in the Sequential PK subgroup were to receive a single dose of 50 IU/kg BeneFIX administered IV in the clinic, followed by PK sampling. A single dose of 50 IU/kg rFIXFc was administered following a 120-hour washout from BeneFIX, followed by PK sampling for a baseline PK profiling. At Week 26 (±1 week) subjects were to receive a single dose of 50 IU/kg rFIXFc for repeat PK profiling. All participants in Arm 1 received 50 IU/kg rFIXFc via intravenous (IV) injection once every 7 days initially, then at a dose indicated by the participant's baseline pharmacokinetic (PK) assessment that ensured a target trough of 1% to 3% above baseline or higher, as clinically indicated. Adjustments to the initial weekly dose of rFIXFc (50 IU/kg) were to be made based on baseline PK assessments, occurrence of spontaneous bleeding episodes, and the trough levels, which were to be monitored at Weeks 4, 16, 26, and 39.
    Measure Participants 22
    rFIXFc Baseline
    40.81
    BeneFIX
    43.08
    26. Secondary Outcome
    Title Area Under the Curve (AUC) Per Dose
    Description 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.
    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.

    Outcome Measure Data

    Analysis Population Description
    Participants in the Sequential PK Subgroup who have evaluable PK profiles for both BeneFIX and baseline rFIXFc.
    Arm/Group Title Arm 1: Weekly Prophylaxis - Sequential PK Subgroup
    Arm/Group Description Prior to the first dose of rFIXFc, participants in the Sequential PK subgroup were to receive a single dose of 50 IU/kg BeneFIX administered IV in the clinic, followed by PK sampling. A single dose of 50 IU/kg rFIXFc was administered following a 120-hour washout from BeneFIX, followed by PK sampling for a baseline PK profiling. At Week 26 (±1 week) subjects were to receive a single dose of 50 IU/kg rFIXFc for repeat PK profiling. All participants in Arm 1 received 50 IU/kg rFIXFc via intravenous (IV) injection once every 7 days initially, then at a dose indicated by the participant's baseline pharmacokinetic (PK) assessment that ensured a target trough of 1% to 3% above baseline or higher, as clinically indicated. Adjustments to the initial weekly dose of rFIXFc (50 IU/kg) were to be made based on baseline PK assessments, occurrence of spontaneous bleeding episodes, and the trough levels, which were to be monitored at Weeks 4, 16, 26, and 39.
    Measure Participants 22
    rFIXFc Baseline
    31.32
    BeneFIX
    15.77
    27. Secondary Outcome
    Title Half Life (t1/2) Alpha and t1/2 Beta
    Description 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.
    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.

    Outcome Measure Data

    Analysis Population Description
    Participants in the Sequential PK Subgroup who have evaluable PK profiles for both BeneFIX and baseline rFIXFc.
    Arm/Group Title Arm 1: Weekly Prophylaxis - Sequential PK Subgroup
    Arm/Group Description Prior to the first dose of rFIXFc, participants in the Sequential PK subgroup were to receive a single dose of 50 IU/kg BeneFIX administered IV in the clinic, followed by PK sampling. A single dose of 50 IU/kg rFIXFc was administered following a 120-hour washout from BeneFIX, followed by PK sampling for a baseline PK profiling. At Week 26 (±1 week) subjects were to receive a single dose of 50 IU/kg rFIXFc for repeat PK profiling. All participants in Arm 1 received 50 IU/kg rFIXFc via intravenous (IV) injection once every 7 days initially, then at a dose indicated by the participant's baseline pharmacokinetic (PK) assessment that ensured a target trough of 1% to 3% above baseline or higher, as clinically indicated. Adjustments to the initial weekly dose of rFIXFc (50 IU/kg) were to be made based on baseline PK assessments, occurrence of spontaneous bleeding episodes, and the trough levels, which were to be monitored at Weeks 4, 16, 26, and 39.
    Measure Participants 22
    rFIXFc Baseline: t1/2 alpha
    5.0279
    BeneFIX: t1/2 alpha
    2.4113
    rFIXFc Baseline: t1/2 beta
    82.12
    BeneFIX: t1/2 beta
    33.77
    28. Secondary Outcome
    Title Clearance (CL)
    Description 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.
    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.

    Outcome Measure Data

    Analysis Population Description
    Participants in the Sequential PK Subgroup who have evaluable PK profiles for both BeneFIX and baseline rFIXFc.
    Arm/Group Title Arm 1: Weekly Prophylaxis - Sequential PK Subgroup
    Arm/Group Description Prior to the first dose of rFIXFc, participants in the Sequential PK subgroup were to receive a single dose of 50 IU/kg BeneFIX administered IV in the clinic, followed by PK sampling. A single dose of 50 IU/kg rFIXFc was administered following a 120-hour washout from BeneFIX, followed by PK sampling for a baseline PK profiling. At Week 26 (±1 week) subjects were to receive a single dose of 50 IU/kg rFIXFc for repeat PK profiling. All participants in Arm 1 received 50 IU/kg rFIXFc via intravenous (IV) injection once every 7 days initially, then at a dose indicated by the participant's baseline pharmacokinetic (PK) assessment that ensured a target trough of 1% to 3% above baseline or higher, as clinically indicated. Adjustments to the initial weekly dose of rFIXFc (50 IU/kg) were to be made based on baseline PK assessments, occurrence of spontaneous bleeding episodes, and the trough levels, which were to be monitored at Weeks 4, 16, 26, and 39.
    Measure Participants 22
    rFIXFc Baseline
    3.193
    BeneFIX
    6.340
    29. Secondary Outcome
    Title Mean Residence Time (MRT)
    Description 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.
    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.

    Outcome Measure Data

    Analysis Population Description
    Participants in the Sequential PK Subgroup who have evaluable PK profiles for both BeneFIX and baseline rFIXFc.
    Arm/Group Title Arm 1: Weekly Prophylaxis - Sequential PK Subgroup
    Arm/Group Description Prior to the first dose of rFIXFc, participants in the Sequential PK subgroup were to receive a single dose of 50 IU/kg BeneFIX administered IV in the clinic, followed by PK sampling. A single dose of 50 IU/kg rFIXFc was administered following a 120-hour washout from BeneFIX, followed by PK sampling for a baseline PK profiling. At Week 26 (±1 week) subjects were to receive a single dose of 50 IU/kg rFIXFc for repeat PK profiling. All participants in Arm 1 received 50 IU/kg rFIXFc via intravenous (IV) injection once every 7 days initially, then at a dose indicated by the participant's baseline pharmacokinetic (PK) assessment that ensured a target trough of 1% to 3% above baseline or higher, as clinically indicated. Adjustments to the initial weekly dose of rFIXFc (50 IU/kg) were to be made based on baseline PK assessments, occurrence of spontaneous bleeding episodes, and the trough levels, which were to be monitored at Weeks 4, 16, 26, and 39.
    Measure Participants 22
    rFIXFc Baseline
    98.60
    BeneFIX
    41.19
    30. Secondary Outcome
    Title Volume in Steady State (Vss)
    Description 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.
    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.

    Outcome Measure Data

    Analysis Population Description
    Participants in the Sequential PK Subgroup who have evaluable PK profiles for both BeneFIX and baseline rFIXFc.
    Arm/Group Title Arm 1: Weekly Prophylaxis - Sequential PK Subgroup
    Arm/Group Description Prior to the first dose of rFIXFc, participants in the Sequential PK subgroup were to receive a single dose of 50 IU/kg BeneFIX administered IV in the clinic, followed by PK sampling. A single dose of 50 IU/kg rFIXFc was administered following a 120-hour washout from BeneFIX, followed by PK sampling for a baseline PK profiling. At Week 26 (±1 week) subjects were to receive a single dose of 50 IU/kg rFIXFc for repeat PK profiling. All participants in Arm 1 received 50 IU/kg rFIXFc via intravenous (IV) injection once every 7 days initially, then at a dose indicated by the participant's baseline pharmacokinetic (PK) assessment that ensured a target trough of 1% to 3% above baseline or higher, as clinically indicated. Adjustments to the initial weekly dose of rFIXFc (50 IU/kg) were to be made based on baseline PK assessments, occurrence of spontaneous bleeding episodes, and the trough levels, which were to be monitored at Weeks 4, 16, 26, and 39.
    Measure Participants 22
    rFIXFc Baseline
    314.8
    BeneFIX
    261.1
    31. Secondary Outcome
    Title Incremental Recovery
    Description 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 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.

    Outcome Measure Data

    Analysis Population Description
    Participants in the Sequential PK Subgroup who have evaluable PK profiles for both BeneFIX and baseline rFIXFc.
    Arm/Group Title Arm 1: Weekly Prophylaxis - Sequential PK Subgroup
    Arm/Group Description Prior to the first dose of rFIXFc, participants in the Sequential PK subgroup were to receive a single dose of 50 IU/kg BeneFIX administered IV in the clinic, followed by PK sampling. A single dose of 50 IU/kg rFIXFc was administered following a 120-hour washout from BeneFIX, followed by PK sampling for a baseline PK profiling. At Week 26 (±1 week) subjects were to receive a single dose of 50 IU/kg rFIXFc for repeat PK profiling. All participants in Arm 1 received 50 IU/kg rFIXFc via intravenous (IV) injection once every 7 days initially, then at a dose indicated by the participant's baseline pharmacokinetic (PK) assessment that ensured a target trough of 1% to 3% above baseline or higher, as clinically indicated. Adjustments to the initial weekly dose of rFIXFc (50 IU/kg) were to be made based on baseline PK assessments, occurrence of spontaneous bleeding episodes, and the trough levels, which were to be monitored at Weeks 4, 16, 26, and 39.
    Measure Participants 22
    rFIXFc Baseline
    0.9211
    BeneFIX
    0.9451
    32. Secondary Outcome
    Title Time to 1% and 3% FIX Activity
    Description 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.
    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.

    Outcome Measure Data

    Analysis Population Description
    Participants in the Sequential PK Subgroup who have evaluable PK profiles for both BeneFIX and baseline rFIXFc.
    Arm/Group Title Arm 1: Weekly Prophylaxis - Sequential PK Subgroup
    Arm/Group Description Prior to the first dose of rFIXFc, participants in the Sequential PK subgroup were to receive a single dose of 50 IU/kg BeneFIX administered IV in the clinic, followed by PK sampling. A single dose of 50 IU/kg rFIXFc was administered following a 120-hour washout from BeneFIX, followed by PK sampling for a baseline PK profiling. At Week 26 (±1 week) subjects were to receive a single dose of 50 IU/kg rFIXFc for repeat PK profiling. All participants in Arm 1 received 50 IU/kg rFIXFc via intravenous (IV) injection once every 7 days initially, then at a dose indicated by the participant's baseline pharmacokinetic (PK) assessment that ensured a target trough of 1% to 3% above baseline or higher, as clinically indicated. Adjustments to the initial weekly dose of rFIXFc (50 IU/kg) were to be made based on baseline PK assessments, occurrence of spontaneous bleeding episodes, and the trough levels, which were to be monitored at Weeks 4, 16, 26, and 39.
    Measure Participants 22
    rFIXFc Baseline: 1% Activity
    11.224
    BeneFIX: 1% Activity
    5.087
    rFIXFc Baseline: 3% Activity
    5.767
    BeneFIX: 3% Activity
    2.832
    33. Secondary Outcome
    Title Number of Participants With Clinically Relevant Abnormalities or Relevant Changes From Baseline in Vital Signs
    Description 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.
    Time Frame up to 52 weeks ± 1 week

    Outcome Measure Data

    Analysis Population Description
    Safety Analysis Set: participants who received at least 1 dose of BeneFIX or rFIXFc; a table was not generated for participants in the perioperative management/surgical arm (Arm 4). n=participants with a baseline assessment and at least one post-baseline assessment for temperature or at least one post-baseline assessment for pulse, SBP, and DBP.
    Arm/Group Title Arm 1: Weekly Prophylaxis Arm 2: Individualized Interval Prophylaxis Arm 3: Episodic (On Demand)
    Arm/Group Description 50 IU/kg rFIXFc via intravenous (IV) injection once every 7 days initially, then at a dose indicated by the participant's baseline pharmacokinetic (PK) assessment that ensured a target trough of 1% to 3% above baseline or higher, as clinically indicated. Adjustments to the initial weekly dose of rFIXFc (50 IU/kg) were to be made based on baseline PK assessments, occurrence of spontaneous bleeding episodes, and the trough levels, which were to be monitored at Weeks 4, 16, 26, and 39. Prior to the first dose of rFIXFc, participants in the Sequential PK subgroup were to receive a single dose of 50 IU/kg BeneFIX administered IV in the clinic, followed by PK sampling. A single dose of 50 IU/kg rFIXFc was administered following a 120-hour washout from BeneFIX, followed by PK sampling for a baseline PK profiling. At Week 26 (±1 week) subjects were to receive a single dose of 50 IU/kg rFIXFc for repeat PK profiling. 100 IU/kg rFIXFc via IV injection once every 10 days initially, then at an interval derived from the baseline PK assessment that ensured a target trough of 1% to 3% above baseline or higher, as clinically indicated. Adjustments to the initial 10-day interval were to be made based on baseline PK assessments and trough levels, which were monitored at Weeks 4, 16, 26, and 39. 20 to 100 IU/kg rFIXFc via IV injection, or the dose indicated by the participant's baseline PK to target a plasma level of 20% to 100%, as needed for the treatment of mild to severe bleeding episodes
    Measure Participants 63 29 27
    Temperature: >38°C and ≥1°C ↑ from BL, n=61,28,24
    0
    0%
    0
    0%
    0
    0%
    Pulse: >120 bpm or >20 bpm ↑ from BL, n=62,28,24
    1
    1.6%
    2
    6.9%
    0
    0%
    Pulse: <50 bpm or >20 bpm ↓ from BL, n=62,28,24
    2
    3.2%
    1
    3.4%
    0
    0%
    SBP: >180 mm Hg or >40 mm Hg ↑ from BL, n=62,28,24
    0
    0%
    1
    3.4%
    0
    0%
    SBP: <90 mm Hg or >30 mm Hg ↓ from BL, n=62,28,24
    4
    6.3%
    1
    3.4%
    0
    0%
    DBP: >105 mm Hg or >30 mm Hg ↑ from BL, n=62,28,24
    3
    4.8%
    0
    0%
    0
    0%
    DBP: <50 mm Hg or >20 mm Hg ↓ from BL, n=62,28,24
    5
    7.9%
    4
    13.8%
    0
    0%
    34. Secondary Outcome
    Title Coagulation Parameter: Change From Pre-dose Values in Prothrombin Split Fragments 1+ 2 (F 1+2)
    Description Maximum value post-dosing is defined as maximum value over the 1-, 6-, and 24-hour evaluations.
    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)

    Outcome Measure Data

    Analysis Population Description
    The Sequential PK subgroup consisted of all participants who had evaluable PK profiles for both BeneFIX and baseline rFIXFc, and/or evaluable PK profiles for both baseline and repeat rFIXFc at Week 26 (±1 week). n=participants with an assessment at given time point.
    Arm/Group Title Sequential PK Subgroup: BeneFIX Sequential PK Subgroup: rFIXFc Day 1 Sequential PK Subgroup: rFIXFc Week 26 Sequential PK Subgroup: rFIXFc Week 52
    Arm/Group Description Prior to the first dose of rFIXFc, participants in the Sequential PK subgroup were to receive a single dose of 50 IU/kg BeneFIX administered IV in the clinic, followed by PK sampling. A single dose of 50 IU/kg rFIXFc was administered following a 120-hour washout from BeneFIX, followed by PK sampling for a baseline PK profiling. At Week 26 (±1 week) subjects were to receive a single dose of 50 IU/kg rFIXFc for repeat PK profiling. All participants in Arm 1 received 50 IU/kg rFIXFc via intravenous (IV) injection once every 7 days initially, then at a dose indicated by the participant's baseline PK assessment that ensured a target trough of 1% to 3% above baseline or higher, as clinically indicated. Adjustments to the initial weekly dose of rFIXFc (50 IU/kg) were to be made based on baseline PK assessments, occurrence of spontaneous bleeding episodes, and the trough levels, which were to be monitored at Weeks 4, 16, 26, and 39. Prior to the first dose of rFIXFc, participants in the Sequential PK subgroup were to receive a single dose of 50 IU/kg BeneFIX administered IV in the clinic, followed by PK sampling. A single dose of 50 IU/kg rFIXFc was administered following a 120-hour washout from BeneFIX, followed by PK sampling for a baseline PK profiling. At Week 26 (±1 week) subjects were to receive a single dose of 50 IU/kg rFIXFc for repeat PK profiling. All participants in Arm 1 received 50 IU/kg rFIXFc via intravenous (IV) injection once every 7 days initially, then at a dose indicated by the participant's baseline PK assessment that ensured a target trough of 1% to 3% above baseline or higher, as clinically indicated. Adjustments to the initial weekly dose of rFIXFc (50 IU/kg) were to be made based on baseline PK assessments, occurrence of spontaneous bleeding episodes, and the trough levels, which were to be monitored at Weeks 4, 16, 26, and 39. Prior to the first dose of rFIXFc, participants in the Sequential PK subgroup were to receive a single dose of 50 IU/kg BeneFIX administered IV in the clinic, followed by PK sampling. A single dose of 50 IU/kg rFIXFc was administered following a 120-hour washout from BeneFIX, followed by PK sampling for a baseline PK profiling. At Week 26 (±1 week) subjects were to receive a single dose of 50 IU/kg rFIXFc for repeat PK profiling. All participants in Arm 1 received 50 IU/kg rFIXFc via intravenous (IV) injection once every 7 days initially, then at a dose indicated by the participant's baseline PK assessment that ensured a target trough of 1% to 3% above baseline or higher, as clinically indicated. Adjustments to the initial weekly dose of rFIXFc (50 IU/kg) were to be made based on baseline PK assessments, occurrence of spontaneous bleeding episodes, and the trough levels, which were to be monitored at Weeks 4, 16, 26, and 39. Prior to the first dose of rFIXFc, participants in the Sequential PK subgroup were to receive a single dose of 50 IU/kg BeneFIX administered IV in the clinic, followed by PK sampling. A single dose of 50 IU/kg rFIXFc was administered following a 120-hour washout from BeneFIX, followed by PK sampling for a baseline PK profiling. At Week 26 (±1 week) subjects were to receive a single dose of 50 IU/kg rFIXFc for repeat PK profiling. All participants in Arm 1 received 50 IU/kg rFIXFc via intravenous (IV) injection once every 7 days initially, then at a dose indicated by the participant's baseline PK assessment that ensured a target trough of 1% to 3% above baseline or higher, as clinically indicated. Adjustments to the initial weekly dose of rFIXFc (50 IU/kg) were to be made based on baseline PK assessments, occurrence of spontaneous bleeding episodes, and the trough levels, which were to be monitored at Weeks 4, 16, 26, and 39.
    Measure Participants 23 23 23 23
    Pre-dosing Value (n=23, 23, 20, 19)
    134.1
    (64.93)
    130.0
    (57.55)
    131.6
    (42.43)
    176.7
    (112.36)
    Change at 1 Hour Post-dosing (n=23, 22, 20, 0)
    73.4
    (171.68)
    8.6
    (39.14)
    1.3
    (51.64)
    NA
    (NA)
    Change at 6 Hours Post-dosing (n=23, 22, 20, 0)
    7.8
    (55.45)
    8.3
    (38.66)
    -4.4
    (45.95)
    NA
    (NA)
    Change at 24 Hours Post-dosing (n=23, 22, 18, 0)
    -3.7
    (34.39)
    9.8
    (45.62)
    1.7
    (27.14)
    NA
    (NA)
    Maximum Post-dosing Change (n=23, 23, 19, 0)
    83.0
    (168.71)
    30.9
    (48.52)
    20.4
    (49.38)
    NA
    (NA)
    35. Secondary Outcome
    Title Coagulation Parameter: Change From Pre-dose Values in Thrombin-antithrombin (TAT) Complex
    Description Maximum value post-dosing is defined as maximum value over the 1-, 6-, and 24-hour evaluations.
    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)

    Outcome Measure Data

    Analysis Population Description
    The Sequential PK subgroup consisted of all participants who had evaluable PK profiles for both BeneFIX and baseline rFIXFc, and/or evaluable PK profiles for both baseline and repeat rFIXFc at Week 26 (±1 week). n=participants with an assessment at given time point.
    Arm/Group Title Sequential PK Subgroup: BeneFIX Sequential PK Subgroup: rFIXFc Day 1 Sequential PK Subgroup: rFIXFc Week 26 Sequential PK Subgroup: rFIXFc Week 52
    Arm/Group Description Prior to the first dose of rFIXFc, participants in the Sequential PK subgroup were to receive a single dose of 50 IU/kg BeneFIX administered IV in the clinic, followed by PK sampling. A single dose of 50 IU/kg rFIXFc was administered following a 120-hour washout from BeneFIX, followed by PK sampling for a baseline PK profiling. At Week 26 (±1 week) subjects were to receive a single dose of 50 IU/kg rFIXFc for repeat PK profiling. All participants in Arm 1 received 50 IU/kg rFIXFc via intravenous (IV) injection once every 7 days initially, then at a dose indicated by the participant's baseline PK assessment that ensured a target trough of 1% to 3% above baseline or higher, as clinically indicated. Adjustments to the initial weekly dose of rFIXFc (50 IU/kg) were to be made based on baseline PK assessments, occurrence of spontaneous bleeding episodes, and the trough levels, which were to be monitored at Weeks 4, 16, 26, and 39. Prior to the first dose of rFIXFc, participants in the Sequential PK subgroup were to receive a single dose of 50 IU/kg BeneFIX administered IV in the clinic, followed by PK sampling. A single dose of 50 IU/kg rFIXFc was administered following a 120-hour washout from BeneFIX, followed by PK sampling for a baseline PK profiling. At Week 26 (±1 week) subjects were to receive a single dose of 50 IU/kg rFIXFc for repeat PK profiling. All participants in Arm 1 received 50 IU/kg rFIXFc via intravenous (IV) injection once every 7 days initially, then at a dose indicated by the participant's baseline PK assessment that ensured a target trough of 1% to 3% above baseline or higher, as clinically indicated. Adjustments to the initial weekly dose of rFIXFc (50 IU/kg) were to be made based on baseline PK assessments, occurrence of spontaneous bleeding episodes, and the trough levels, which were to be monitored at Weeks 4, 16, 26, and 39. Prior to the first dose of rFIXFc, participants in the Sequential PK subgroup were to receive a single dose of 50 IU/kg BeneFIX administered IV in the clinic, followed by PK sampling. A single dose of 50 IU/kg rFIXFc was administered following a 120-hour washout from BeneFIX, followed by PK sampling for a baseline PK profiling. At Week 26 (±1 week) subjects were to receive a single dose of 50 IU/kg rFIXFc for repeat PK profiling. All participants in Arm 1 received 50 IU/kg rFIXFc via intravenous (IV) injection once every 7 days initially, then at a dose indicated by the participant's baseline PK assessment that ensured a target trough of 1% to 3% above baseline or higher, as clinically indicated. Adjustments to the initial weekly dose of rFIXFc (50 IU/kg) were to be made based on baseline PK assessments, occurrence of spontaneous bleeding episodes, and the trough levels, which were to be monitored at Weeks 4, 16, 26, and 39. Prior to the first dose of rFIXFc, participants in the Sequential PK subgroup were to receive a single dose of 50 IU/kg BeneFIX administered IV in the clinic, followed by PK sampling. A single dose of 50 IU/kg rFIXFc was administered following a 120-hour washout from BeneFIX, followed by PK sampling for a baseline PK profiling. At Week 26 (±1 week) subjects were to receive a single dose of 50 IU/kg rFIXFc for repeat PK profiling. All participants in Arm 1 received 50 IU/kg rFIXFc via intravenous (IV) injection once every 7 days initially, then at a dose indicated by the participant's baseline PK assessment that ensured a target trough of 1% to 3% above baseline or higher, as clinically indicated. Adjustments to the initial weekly dose of rFIXFc (50 IU/kg) were to be made based on baseline PK assessments, occurrence of spontaneous bleeding episodes, and the trough levels, which were to be monitored at Weeks 4, 16, 26, and 39.
    Measure Participants 23 23 23 23
    Pre-dosing Value (n=23, 23, 20, 19)
    2.87
    (2.891)
    2.87
    (2.230)
    3.11
    (4.075)
    4.28
    (7.588)
    Change at 1 Hour Post-dosing (n=23, 22, 20, 0)
    6.67
    (15.491)
    1.05
    (4.019)
    0.11
    (5.813)
    NA
    (NA)
    Change at 6 Hours Post-dosing (n=23, 22, 20, 0)
    1.91
    (7.303)
    1.07
    (4.686)
    -0.09
    (5.763)
    NA
    (NA)
    Change at 24 Hours Post-dosing (n=23, 22, 18, 0)
    -0.58
    (2.968)
    0.81
    (6.095)
    -1.10
    (4.308)
    NA
    (NA)
    Maximum Post-dosing Change (n=23, 23, 19, 0)
    7.42
    (15.416)
    3.63
    (7.000)
    0.32
    (5.969)
    NA
    (NA)
    36. Secondary Outcome
    Title Coagulation Parameter: Change From Pre-dose Values in D-dimer
    Description Maximum value post-dosing is defined as maximum value over the 1-, 6-, and 24-hour evaluations.
    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)

    Outcome Measure Data

    Analysis Population Description
    The Sequential PK subgroup consisted of all participants who had evaluable PK profiles for both BeneFIX and baseline rFIXFc, and/or evaluable PK profiles for both baseline and repeat rFIXFc at Week 26 (±1 week). n=participants with an assessment at given time point.
    Arm/Group Title Sequential PK Subgroup: BeneFIX Sequential PK Subgroup: rFIXFc Day 1 Sequential PK Subgroup: rFIXFc Week 26 Sequential PK Subgroup: rFIXFc Week 52
    Arm/Group Description Prior to the first dose of rFIXFc, participants in the Sequential PK subgroup were to receive a single dose of 50 IU/kg BeneFIX administered IV in the clinic, followed by PK sampling. A single dose of 50 IU/kg rFIXFc was administered following a 120-hour washout from BeneFIX, followed by PK sampling for a baseline PK profiling. At Week 26 (±1 week) subjects were to receive a single dose of 50 IU/kg rFIXFc for repeat PK profiling. All participants in Arm 1 received 50 IU/kg rFIXFc via intravenous (IV) injection once every 7 days initially, then at a dose indicated by the participant's baseline PK assessment that ensured a target trough of 1% to 3% above baseline or higher, as clinically indicated. Adjustments to the initial weekly dose of rFIXFc (50 IU/kg) were to be made based on baseline PK assessments, occurrence of spontaneous bleeding episodes, and the trough levels, which were to be monitored at Weeks 4, 16, 26, and 39. Prior to the first dose of rFIXFc, participants in the Sequential PK subgroup were to receive a single dose of 50 IU/kg BeneFIX administered IV in the clinic, followed by PK sampling. A single dose of 50 IU/kg rFIXFc was administered following a 120-hour washout from BeneFIX, followed by PK sampling for a baseline PK profiling. At Week 26 (±1 week) subjects were to receive a single dose of 50 IU/kg rFIXFc for repeat PK profiling. All participants in Arm 1 received 50 IU/kg rFIXFc via intravenous (IV) injection once every 7 days initially, then at a dose indicated by the participant's baseline PK assessment that ensured a target trough of 1% to 3% above baseline or higher, as clinically indicated. Adjustments to the initial weekly dose of rFIXFc (50 IU/kg) were to be made based on baseline PK assessments, occurrence of spontaneous bleeding episodes, and the trough levels, which were to be monitored at Weeks 4, 16, 26, and 39. Prior to the first dose of rFIXFc, participants in the Sequential PK subgroup were to receive a single dose of 50 IU/kg BeneFIX administered IV in the clinic, followed by PK sampling. A single dose of 50 IU/kg rFIXFc was administered following a 120-hour washout from BeneFIX, followed by PK sampling for a baseline PK profiling. At Week 26 (±1 week) subjects were to receive a single dose of 50 IU/kg rFIXFc for repeat PK profiling. All participants in Arm 1 received 50 IU/kg rFIXFc via intravenous (IV) injection once every 7 days initially, then at a dose indicated by the participant's baseline PK assessment that ensured a target trough of 1% to 3% above baseline or higher, as clinically indicated. Adjustments to the initial weekly dose of rFIXFc (50 IU/kg) were to be made based on baseline PK assessments, occurrence of spontaneous bleeding episodes, and the trough levels, which were to be monitored at Weeks 4, 16, 26, and 39. Prior to the first dose of rFIXFc, participants in the Sequential PK subgroup were to receive a single dose of 50 IU/kg BeneFIX administered IV in the clinic, followed by PK sampling. A single dose of 50 IU/kg rFIXFc was administered following a 120-hour washout from BeneFIX, followed by PK sampling for a baseline PK profiling. At Week 26 (±1 week) subjects were to receive a single dose of 50 IU/kg rFIXFc for repeat PK profiling. All participants in Arm 1 received 50 IU/kg rFIXFc via intravenous (IV) injection once every 7 days initially, then at a dose indicated by the participant's baseline PK assessment that ensured a target trough of 1% to 3% above baseline or higher, as clinically indicated. Adjustments to the initial weekly dose of rFIXFc (50 IU/kg) were to be made based on baseline PK assessments, occurrence of spontaneous bleeding episodes, and the trough levels, which were to be monitored at Weeks 4, 16, 26, and 39.
    Measure Participants 23 23 23 23
    Pre-dosing Value (n=23, 22, 20, 19)
    153.0
    (119.37)
    176.2
    (165.48)
    120.5
    (73.38)
    134.7
    (151.36)
    Change at 1 Hour Post-dosing (n=23, 21, 20, 0)
    35.9
    (101.80)
    89.6
    (509.24)
    -5.9
    (28.18)
    NA
    (NA)
    Change at 6 Hours Post-dosing (n=23, 21, 20, 0)
    47.6
    (259.70)
    -39.6
    (134.42)
    -9.4
    (16.84)
    NA
    (NA)
    Change at 24 Hours Post-dosing (n=23, 21, 18, 0)
    20.0
    (85.93)
    -31.0
    (138.22)
    -8.2
    (26.06)
    NA
    (NA)
    Maximum Post-dosing Change (n=23, 22, 19, 0)
    95.7
    (266.98)
    100.6
    (494.70)
    4.8
    (16.10)
    NA
    (NA)
    37. Primary Outcome
    Title Annualized Bleeding Rate
    Description Annualized bleeding episodes = (number of bleeding episodes / number of days in the respective period)*365.25. In Arms 1 and 2, the efficacy period (EP) started with date and time of first prophylactic dose following a completed pharmacokinetic (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. 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.
    Time Frame up to 52 weeks ± 1 week (efficacy period as defined in description)

    Outcome Measure Data

    Analysis Population Description
    Full Analysis Set: participants who received at least 1 dose of rFIXFc.
    Arm/Group Title Arm 1: Weekly Prophylaxis Arm 2: Individualized Interval Prophylaxis Arm 3: Episodic (On Demand)
    Arm/Group Description 50 IU/kg rFIXFc via intravenous (IV) injection once every 7 days initially, then at a dose indicated by the participant's baseline pharmacokinetic (PK) assessment that ensured a target trough of 1% to 3% above baseline or higher, as clinically indicated. Adjustments to the initial weekly dose of rFIXFc (50 IU/kg) were to be made based on baseline PK assessments, occurrence of spontaneous bleeding episodes, and the trough levels, which were to be monitored at Weeks 4, 16, 26, and 39. Prior to the first dose of rFIXFc, participants in the Sequential PK subgroup were to receive a single dose of 50 IU/kg BeneFIX administered IV in the clinic, followed by PK sampling. A single dose of 50 IU/kg rFIXFc was administered following a 120-hour washout from BeneFIX, followed by PK sampling for a baseline PK profiling. At Week 26 (±1 week) subjects were to receive a single dose of 50 IU/kg rFIXFc for repeat PK profiling. 100 IU/kg rFIXFc via IV injection once every 10 days initially, then at an interval derived from the baseline PK assessment that ensured a target trough of 1% to 3% above baseline or higher, as clinically indicated. Adjustments to the initial 10-day interval were to be made based on baseline PK assessments and trough levels, which were monitored at Weeks 4, 16, 26, and 39. 20 to 100 IU/kg rFIXFc via IV injection, or the dose indicated by the participant's baseline PK to target a plasma level of 20% to 100%, as needed for the treatment of mild to severe bleeding episodes
    Measure Participants 61 26 27
    Median (Inter-Quartile Range) [episodes per participant per year]
    2.95
    1.38
    17.69
    38. Primary Outcome
    Title Comparison of Annualized Bleeding Rates
    Description Estimated with a factor for arm, based on whole study duration for all participants. Annualized bleeding episodes = (number of bleeding episodes / number of days in the respective period)*365.25. 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.
    Time Frame up to 52 weeks ± 1 week (efficacy period as defined in description)

    Outcome Measure Data

    Analysis Population Description
    Full Analysis Set: participants who received at least 1 dose of rFIXFc.
    Arm/Group Title Arm 1: Weekly Prophylaxis Arm 2: Individualized Interval Prophylaxis Arm 3: Episodic (On Demand)
    Arm/Group Description 50 IU/kg rFIXFc via intravenous (IV) injection once every 7 days initially, then at a dose indicated by the participant's baseline pharmacokinetic (PK) assessment that ensured a target trough of 1% to 3% above baseline or higher, as clinically indicated. Adjustments to the initial weekly dose of rFIXFc (50 IU/kg) were to be made based on baseline PK assessments, occurrence of spontaneous bleeding episodes, and the trough levels, which were to be monitored at Weeks 4, 16, 26, and 39. Prior to the first dose of rFIXFc, participants in the Sequential PK subgroup were to receive a single dose of 50 IU/kg BeneFIX administered IV in the clinic, followed by PK sampling. A single dose of 50 IU/kg rFIXFc was administered following a 120-hour washout from BeneFIX, followed by PK sampling for a baseline PK profiling. At Week 26 (±1 week) subjects were to receive a single dose of 50 IU/kg rFIXFc for repeat PK profiling. 100 IU/kg rFIXFc via IV injection once every 10 days initially, then at an interval derived from the baseline PK assessment that ensured a target trough of 1% to 3% above baseline or higher, as clinically indicated. Adjustments to the initial 10-day interval were to be made based on baseline PK assessments and trough levels, which were monitored at Weeks 4, 16, 26, and 39. 20 to 100 IU/kg rFIXFc via IV injection, or the dose indicated by the participant's baseline PK to target a plasma level of 20% to 100%, as needed for the treatment of mild to severe bleeding episodes
    Measure Participants 61 26 27
    Number (95% Confidence Interval) [episodes per participant per year]
    3.12
    2.40
    18.67
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Arm 1: Weekly Prophylaxis, Arm 3: Episodic (On Demand)
    Comments The null hypothesis for the primary endpoint is no difference between any prevention regimen and the on-demand regimen. The sample size of this study was mainly based on clinical rather than statistical considerations. However it was projected to have > 95% power at the 2-sided 0.05 level of significance, based upon this hypothesis test.
    Type of Statistical Test Superiority or Other (legacy)
    Comments
    Statistical Test of Hypothesis p-Value <0.001
    Comments A hierarchical approach was applied to the comparison of the annualized bleeding rates between the prophylaxis arms and the episodic arm.
    Method negative binomial model
    Comments
    Method of Estimation Estimation Parameter Bleeding Rate Ratio
    Estimated Value 0.17
    Confidence Interval (2-Sided) 95%
    0.11 to 0.24
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Arm 2: Individualized Interval Prophylaxis, Arm 3: Episodic (On Demand)
    Comments The null hypothesis for the primary endpoint is no difference between any prevention regimen and the on-demand regimen. The sample size of this study was mainly based on clinical rather than statistical considerations.
    Type of Statistical Test Superiority or Other (legacy)
    Comments
    Statistical Test of Hypothesis p-Value <0.001
    Comments A hierarchical approach was applied to the comparison of the annualized bleeding rates between the prophylaxis arms and the episodic arm.
    Method negative binomial model
    Comments
    Method of Estimation Estimation Parameter Bleeding Rate Ratio
    Estimated Value 0.13
    Confidence Interval (2-Sided) 95%
    0.08 to 0.20
    Parameter Dispersion Type:
    Value:
    Estimation Comments

    Adverse Events

    Time Frame up to 52 weeks + 30 days ± 1 week
    Adverse Event Reporting Description As the perioperative management period represents a unique clinical situation, safety data obtained during the surgical/rehabilitation period for Arm 4 subjects were analyzed separately per the Analysis Plan, and not included within the Arms 1-3 analysis. See Outcome Measures 3 and 4 for AE/SAE data for the surgical/rehabilitation period, Arm 4.
    Arm/Group Title Arm 1: Weekly Prophylaxis Arm 2: Individualized Interval Prophylaxis Arm 3: Episodic (On Demand)
    Arm/Group Description 50 IU/kg rFIXFc via intravenous (IV) injection once every 7 days initially, then at a dose indicated by the participant's baseline pharmacokinetic (PK) assessment that ensured a target trough of 1% to 3% above baseline or higher, as clinically indicated. Adjustments to the initial weekly dose of rFIXFc (50 IU/kg) were to be made based on baseline PK assessments, occurrence of spontaneous bleeding episodes, and the trough levels, which were to be monitored at Weeks 4, 16, 26, and 39. Prior to the first dose of rFIXFc, participants in the Sequential PK subgroup were to receive a single dose of 50 IU/kg BeneFIX administered IV in the clinic, followed by PK sampling. A single dose of 50 IU/kg rFIXFc was administered following a 120-hour washout from BeneFIX, followed by PK sampling for a baseline PK profiling. At Week 26 (±1 week) subjects were to receive a single dose of 50 IU/kg rFIXFc for repeat PK profiling. 100 IU/kg rFIXFc via IV injection once every 10 days initially, then at an interval derived from the baseline PK assessment that ensured a target trough of 1% to 3% above baseline or higher, as clinically indicated. Adjustments to the initial 10-day interval were to be made based on baseline PK assessments and trough levels, which were monitored at Weeks 4, 16, 26, and 39. 20 to 100 IU/kg rFIXFc via IV injection, or the dose indicated by the participant's baseline PK to target a plasma level of 20% to 100%, as needed for the treatment of mild to severe bleeding episodes
    All Cause Mortality
    Arm 1: Weekly Prophylaxis Arm 2: Individualized Interval Prophylaxis Arm 3: Episodic (On Demand)
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total / (NaN) / (NaN) / (NaN)
    Serious Adverse Events
    Arm 1: Weekly Prophylaxis Arm 2: Individualized Interval Prophylaxis Arm 3: Episodic (On Demand)
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 5/63 (7.9%) 4/29 (13.8%) 4/27 (14.8%)
    Cardiac disorders
    Angina pectoris 1/63 (1.6%) 0/29 (0%) 0/27 (0%)
    Gastrointestinal disorders
    Abdominal adhesions 1/63 (1.6%) 0/29 (0%) 0/27 (0%)
    Inguinal hernia 0/63 (0%) 0/29 (0%) 1/27 (3.7%)
    Intestinal obstruction 0/63 (0%) 0/29 (0%) 1/27 (3.7%)
    Small intestinal obstruction 0/63 (0%) 0/29 (0%) 1/27 (3.7%)
    Upper gastrointestinal haemorrhage 0/63 (0%) 1/29 (3.4%) 0/27 (0%)
    Infections and infestations
    Cellulitis 1/63 (1.6%) 0/29 (0%) 1/27 (3.7%)
    Device related infection 1/63 (1.6%) 0/29 (0%) 0/27 (0%)
    Peritonsillar abscess 0/63 (0%) 1/29 (3.4%) 0/27 (0%)
    Injury, poisoning and procedural complications
    Road traffic accident 0/63 (0%) 0/29 (0%) 1/27 (3.7%)
    Musculoskeletal and connective tissue disorders
    Arthralgia 1/63 (1.6%) 0/29 (0%) 0/27 (0%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Hepatic neoplasm malignant 0/63 (0%) 1/29 (3.4%) 0/27 (0%)
    Renal and urinary disorders
    Obstructive uropathy 0/63 (0%) 1/29 (3.4%) 0/27 (0%)
    Other (Not Including Serious) Adverse Events
    Arm 1: Weekly Prophylaxis Arm 2: Individualized Interval Prophylaxis Arm 3: Episodic (On Demand)
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 29/63 (46%) 17/29 (58.6%) 11/27 (40.7%)
    Gastrointestinal disorders
    Nausea 1/63 (1.6%) 2/29 (6.9%) 0/27 (0%)
    Immune system disorders
    Allergy to arthropod bite 0/63 (0%) 2/29 (6.9%) 0/27 (0%)
    Infections and infestations
    Nasopharyngitis 13/63 (20.6%) 4/29 (13.8%) 1/27 (3.7%)
    Influenza 5/63 (7.9%) 0/29 (0%) 4/27 (14.8%)
    Upper respiratory tract infection 4/63 (6.3%) 2/29 (6.9%) 1/27 (3.7%)
    Sinusitis 3/63 (4.8%) 2/29 (6.9%) 0/27 (0%)
    Injury, poisoning and procedural complications
    Laceration 1/63 (1.6%) 2/29 (6.9%) 0/27 (0%)
    Investigations
    Weight increased 1/63 (1.6%) 0/29 (0%) 2/27 (7.4%)
    Musculoskeletal and connective tissue disorders
    Arthralgia 6/63 (9.5%) 2/29 (6.9%) 0/27 (0%)
    Musculoskeletal pain 2/63 (3.2%) 2/29 (6.9%) 0/27 (0%)
    Back pain 0/63 (0%) 1/29 (3.4%) 2/27 (7.4%)
    Nervous system disorders
    Headache 2/63 (3.2%) 2/29 (6.9%) 2/27 (7.4%)
    Dizziness 3/63 (4.8%) 2/29 (6.9%) 0/27 (0%)
    Respiratory, thoracic and mediastinal disorders
    Cough 0/63 (0%) 0/29 (0%) 3/27 (11.1%)
    Vascular disorders
    Hypertension 3/63 (4.8%) 2/29 (6.9%) 1/27 (3.7%)

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

    Principal Investigators are NOT employed by the organization sponsoring the study.

    Our agreement is subject to confidentiality but generally the PI can publish, for noncommercial purposes only, results and methods of the trial, but no other Sponsor Confidential Information. PI must give Sponsor no less than 60 days to review any manuscript for a proposed publication and must delay publication for up to an additional 90 days thereafter if Sponsor needs to file any patent application to protect any of Sponsor's intellectual property contained in the proposed publication.

    Results Point of Contact

    Name/Title Bioverativ Study Medical Director
    Organization Bioverativ
    Phone
    Email clinicaltrials@bioverativ.com
    Responsible Party:
    Bioverativ Therapeutics Inc.
    ClinicalTrials.gov Identifier:
    NCT01027364
    Other Study ID Numbers:
    • 998HB102
    • 2009-014295-21
    First Posted:
    Dec 7, 2009
    Last Update Posted:
    Dec 19, 2020
    Last Verified:
    Aug 1, 2018