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

Primary Purpose

Severe Hemophilia B

Status

Completed

Phase

Phase 3

Locations

International

Study Type

Interventional

Intervention

Factor IX (rFIXFc)

rFIX

About this trial

This is an interventional treatment trial for Severe Hemophilia B

Eligibility Criteria

12 Years - undefined (Child, Adult, Older Adult)MaleDoes not accept healthy volunteers

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

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Experimental

Arm Label

Fixed Weekly Interval

Individualized Interval

On Demand

Surgery

Arm 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 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.

Outcomes

Primary Outcome Measures

Number of Participants With Potentially Clinically Significant Laboratory Abnormalities

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.

Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs)

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.

Number of Participants With Non-serious Treatment-emergent Adverse Events (TEAEs) During the Surgical / Rehabilitation Period

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).

Number of Participants With Treatment-emergent Serious Adverse Events (TESAEs) During the Surgical / Rehabilitation Period

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).

Incidence Rate of FIX Inhibitor Development

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.

Annualized Bleeding Rate

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.

Comparison of Annualized Bleeding Rates

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

Participant Assessment of Response to Injections to Treat a Bleeding Episode

Participant's assessment of the response to the first rFIXFc injection for each bleeding episode. Percentages were based on the number of bleeding episodes for which a response was provided for the first injection, using the following 4-point scale: excellent=abrupt pain relief and/or improvement in signs of bleeding within approximately 8 hours after the initial injection; good=definite pain relief and/or improvement in signs of bleeding within approximately 8 hours after an injection, but possibly requiring more than one injection after 24 to 48 hours for complete resolution; moderate=probable or slight beneficial effect within 8 hours after the initial injection and requiring more than one injection; no response=no improvement, or condition worsened, within approximately 8 hours after the initial injection.

Physicians' Global Assessments of Participants' Response to Treatment With rFIXFc

Physicians assessed each participant's response to rFIXFc using a 4-point scale: excellent=bleeding episodes responded to less than or equal to the usual number of injections or less than or equal to the usual dose of rFIXFc, or the rate of breakthrough bleeding during prophylaxis was less than or equal to that usually observed; effective=most bleeding episodes responded to the same number of injections and dose, but some required more injections or higher doses, or there was a minor increase in the rate of breakthrough bleeding; partially effective=bleeding episodes most often required more injections and/or higher doses than expected, or adequate breakthrough bleeding prevention during prophylaxis required more frequent injections and/or higher doses; ineffective=routine failure to control hemostasis or hemostatic control required additional agents. Percentage of the total count of scale responses for all participants is presented. Multiple responses per participant are counted.

Annualized rFIXFc Consumption Per Participant

Consumption is calculated for the efficacy period (EP). In Arms 1 and 2, the EP started with date and time of first prophylactic dose following a completed PK sampling period and ended with last dose administered (for prophylaxis or a bleeding episode). In Arm 3, the EP started following last PK sampling timepoint and ended with either date of last contact or date of last entry into the eDiary, whichever was later. The EP was interrupted for the repeat PK period in Arm 1 (sequential PK subgroup) and for all surgical/rehabilitation periods (for both major and minor surgeries) in all 3 arms. Overall units (IU/kg) of annualized rFIXFc consumption = [Total rFIXFc IU/kg received during the EP / number of days in EP]*365.25.

Average Weekly Dose For the Fixed Weekly Interval Prophylaxis Arm

Average weekly dose = (total IU/kg of all eligible prophylactic doses in the included intervals / total number of days in the included intervals)*7. Eligible dose = the first of the 2 doses defining the interval. Participants could have multiple prophylactic dose changes. Prophylactic dosing = from first prophylactic injection received for rFIXFc to the last prophylactic injection on study. Intervals between 2 prophylactic doses separated by a bleed/surgery/PK visit were not included. In Arm 1, the efficacy period (EP) started with date and time of first prophylactic dose following a completed PK sampling period and ended with last dose administered (for prophylaxis or a bleeding episode). The EP was interrupted for the repeat PK period in Arm 1 (sequential PK subgroup) and for all surgical/rehabilitation periods (for both major and minor surgeries).

Average Dosing Interval For the Individualized Interval Prophylaxis Arm

Average dosing interval = sum of days in the included dosing intervals divided by the number of included intervals. Participants could have multiple prophylactic dose interval changes. Prophylactic dosing = from first prophylactic injection received for rFIXFc to the last prophylactic injection on study. Intervals between 2 prophylactic doses separated by a bleed/surgery/PK visit were not included. In Arm 2, the efficacy period (EP) started with date and time of first prophylactic dose following a completed PK sampling period and ended with last dose administered (for prophylaxis or a bleeding episode). The EP was interrupted for all surgical/rehabilitation periods (for both major and minor surgeries).

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

Annualized bleeding episodes = (number of bleeding episodes/number of days in efficacy period)*365.25. Please see the definition of the efficacy period (EP) in the Outcome Measure 4 Description. The EP was interrupted for the repeat PK period in Arm 1 (sequential PK subgroup) and for all surgical/rehabilitation periods (for both major and minor surgeries) in all 3 arms. A bleeding episode started from the first sign of a bleed, and ended 72 hours after the last treatment for the bleeding, within which any symptoms of bleeding at the same location, or injections less than or equal to 72 hours apart, were considered the same bleeding episode. Any bleeding at a different location was a separate bleeding episode regardless of time from the last injection.

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

Number of Days From Last Injection to Treat a New 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 follow-up injection administered >72 hours after the most recent injection given to treat a bleed was considered a new bleed at the same location and was classified as type=Unknown (bleeding episodes of this type were not evaluable). The first bleed for each participant could not be included in this analysis since there was no previous bleed from which to measure time. The number of days from the last injection to treat a bleed to a new bleeding episode was analyzed across all evaluable bleeding episodes per participant.

Number of Injections Required for Resolution of a Bleeding Episode

In Arms 1 and 2, the efficacy period (EP) started with date and time of first prophylactic dose following a completed PK sampling period and ended with last dose administered (for prophylaxis or a bleeding episode). In Arm 3, the EP started following last PK sampling timepoint and ended with either date of last contact or date of last entry into the eDiary, whichever was later. The EP was interrupted for the repeat PK period in Arm 1 and for all surgical/rehabilitation periods in all 3 arms. A bleeding episode started from the first sign of a bleed, and ended 72 hours after the last treatment for the bleeding, within which any symptoms of bleeding at the same location, or injections less than or equal to 72 hours apart, were considered the same bleeding episode. All injections given from the initial sign of a bleed until the last date/time within the bleed window are counted. The resolution of a bleed is defined as no sign of bleeding following injection for the bleed.

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

Please see the definition of the efficacy period (EP) in the Outcome Measure 4 Description. The EP was interrupted for the repeat PK period in Arm 1 (sequential PK subgroup) and for all surgical/rehabilitation periods (for both major and minor surgeries) in all 3 arms. A bleeding episode started from the first sign of a bleed, and ended 72 hours after the last treatment for the bleeding, within which any symptoms of bleeding at the same location, or injections less than or equal to 72 hours apart, were considered the same bleeding episode. All injections given from the initial sign of a bleed until the last date/time within the bleed window were counted. The resolution of a bleed was defined as no sign of bleeding following injection for the bleed. Bleeding episodes that presented in multiple locations are included as a single event in the overall summary for the number of injections to resolve that bleeding episode but are included in summaries for each location.

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

For each bleeding episode at one location, the total dose is the sum of the doses (IU/kg) administered across all injections given to treat that bleeding episode. Please see the definition of the efficacy period (EP) in the Outcome Measure 4 Description. The EP was interrupted for the repeat PK period in Arm 1 (sequential PK subgroup) and for all surgical/rehabilitation periods (for both major and minor surgeries) in all 3 arms. A bleeding episode started from the first sign of a bleed, and ended 72 hours after the last treatment for the bleeding, within which any symptoms of bleeding at the same location, or injections less than or equal to 72 hours apart, were considered the same bleeding episode. Bleeding episodes that presented in multiple locations are included as a single event in the overall summary for dose administered to resolve that bleeding episode but are included in the individual summaries for each location.

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

The Haem-A-QoL consists of items pertaining to 10 domains specific to living with hemophilia and was administered to adult participants (> 17 years). The areas covered by this instrument are: physical health, feeling, view of yourself, sports/leisure, school/work, dealing with hemophilia, and treatment (all 7 domains, during the last month) and future, family planning, and outlook for the future (all 3 domains, recently). Changes from baseline for the Haem-A-QoL questionnaire are summarized by prestudy treatment regimen (pooled for Arms 1 and 2). Lower scores represent better QoL; therefore, a negative change from baseline represents improvement during the course of the study. Scores on a scale range between 0 and 100.

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

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

The Haemo-QoL, a quality of life (QoL) assessment instrument for children and adolescents with hemophilia, was administered to participants from 13- to 17-years-old. This instrument assesses domains specific to living with hemophilia. For the Haemo-QoL, higher scores indicate a worse quality of life. Scores on a scale range between 0 and 100.

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

Based on the first assessment of hemostasis by the surgeon/investigator 24 hours or later post-surgery. Scaled responses: Excellent = 1, Good = 2, Fair = 3, Poor/none = 4.

Number of Injections Required to Maintain Hemostasis During Major Surgery

The number of injections to maintain hemostasis during surgery includes all injections for surgery purposes including the loading dose to the end date/time of surgery.

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

Mean dose per injection is the average dose for all injections (including loading dose) needed to maintain hemostasis during surgery. Total dose is the sum across all injections (including loading dose) needed to maintain hemostasis during surgery.

Estimated Total Blood Loss During Major Surgery

Number of Transfusions Required Per Surgery

Number of blood component transfusions during a single surgery.

Maximum Concentration (Cmax)

Maximum concentration during a dosing interval. Assessment of FIX activity with BeneFIX was conducted following a required 120-hour (5-day) washout period, at these timepoints: predose, 10 (±2) minutes, 1 hour (±15 minutes), 3 hours (±15 minutes), 6 hours (±15 minutes), 24 (±2) hours, 48 (±2) hours, 72 (±3) hours, and 96 (±3) hours (4 days) from the start of the injection. Assessment of FIX activity and rFIXFc concentration was conducted following the initial dose of rFIXFc (after a required 120-hour [5-day] washout period) and at Week 26, at these timepoints: predose, 10 (±2) minutes, 1 hour (±15 minutes), 3 hours (±15 minutes), 6 hours (±15 minutes), 24 (±2) hours, 48 (±2) hours, 96 (±3) hours (4 days), 144 (±3) hours (6 days), 168 (±3) hours (7 days), 192 (±3) hours (8 days), and 240 (±3) hours (10 days) from the start of the injection.

Area Under the Curve (AUC) Per Dose

Dose normalized area under the drug concentration-time curve. Assessment of FIX activity with BeneFIX was conducted following a required 120-hour (5-day) washout period, at these timepoints: predose, 10 (±2) minutes, 1 hour (±15 minutes), 3 hours (±15 minutes), 6 hours (±15 minutes), 24 (±2) hours, 48 (±2) hours, 72 (±3) hours, and 96 (±3) hours (4 days) from the start of the injection. Assessment of FIX activity and rFIXFc concentration was conducted following the initial dose of rFIXFc (after a required 120-hour [5-day] washout period) and at Week 26, at these timepoints: predose, 10 (±2) minutes, 1 hour (±15 minutes), 3 hours (±15 minutes), 6 hours (±15 minutes), 24 (±2) hours, 48 (±2) hours, 96 (±3) hours (4 days), 144 (±3) hours (6 days), 168 (±3) hours (7 days), 192 (±3) hours (8 days), and 240 (±3) hours (10 days) from the start of the injection.

Half Life (t1/2) Alpha and t1/2 Beta

Time required for the concentration of the drug to reach half of its original value. Alpha and beta half-life indicate distribution and elimination half-life in a two-compartment PK model. Assessment of FIX activity with BeneFIX was conducted following a required 120-hour (5-day) washout period, at these timepoints: predose, 10 (±2) minutes, 1 hour (±15 minutes), 3 hours (±15 minutes), 6 hours (±15 minutes), 24 (±2) hours, 48 (±2) hours, 72 (±3) hours, and 96 (±3) hours (4 days) from the start of the injection. Assessment of FIX activity and rFIXFc concentration was conducted following the initial dose of rFIXFc (after a required 120-hour [5-day] washout period) and at Week 26, at these timepoints: predose, 10 (±2) minutes, 1 hour (±15 minutes), 3 hours (±15 minutes), 6 hours (±15 minutes), 24 (±2) hours, 48 (±2) hours, 96 (±3) hours (4 days), 144 (±3) hours (6 days), 168 (±3) hours (7 days), 192 (±3) hours (8 days), and 240 (±3) hours (10 days) from the start of the injection.

Clearance (CL)

The measure of the efficiency of the body to remove the drug and the unit is the volume of the plasma or blood cleared of drug per unit time. Assessment of FIX activity with BeneFIX was conducted following a required 120-hour (5-day) washout period, at these timepoints: predose, 10 (±2) minutes, 1 hour (±15 minutes), 3 hours (±15 minutes), 6 hours (±15 minutes), 24 (±2) hours, 48 (±2) hours, 72 (±3) hours, and 96 (±3) hours (4 days) from the start of the injection. Assessment of FIX activity and rFIXFc concentration was conducted following the initial dose of rFIXFc (after a required 120-hour [5-day] washout period) and at Week 26, at these timepoints: predose, 10 (±2) minutes, 1 hour (±15 minutes), 3 hours (±15 minutes), 6 hours (±15 minutes), 24 (±2) hours, 48 (±2) hours, 96 (±3) hours (4 days), 144 (±3) hours (6 days), 168 (±3) hours (7 days), 192 (±3) hours (8 days), and 240 (±3) hours (10 days) from the start of the injection.

Mean Residence Time (MRT)

The average time for all the drug molecules to reside in the body. Assessment of FIX activity with BeneFIX was conducted following a required 120-hour (5-day) washout period, at these timepoints: predose, 10 (±2) minutes, 1 hour (±15 minutes), 3 hours (±15 minutes), 6 hours (±15 minutes), 24 (±2) hours, 48 (±2) hours, 72 (±3) hours, and 96 (±3) hours (4 days) from the start of the injection. Assessment of FIX activity and rFIXFc concentration was conducted following the initial dose of rFIXFc (after a required 120-hour [5-day] washout period) and at Week 26, at these timepoints: predose, 10 (±2) minutes, 1 hour (±15 minutes), 3 hours (±15 minutes), 6 hours (±15 minutes), 24 (±2) hours, 48 (±2) hours, 96 (±3) hours (4 days), 144 (±3) hours (6 days), 168 (±3) hours (7 days), 192 (±3) hours (8 days), and 240 (±3) hours (10 days) from the start of the injection.

Volume in Steady State (Vss)

Volume of distribution at steady state. Assessment of FIX activity with BeneFIX was conducted following a required 120-hour (5-day) washout period, at these timepoints: predose, 10 (±2) minutes, 1 hour (±15 minutes), 3 hours (±15 minutes), 6 hours (±15 minutes), 24 (±2) hours, 48 (±2) hours, 72 (±3) hours, and 96 (±3) hours (4 days) from the start of the injection. Assessment of FIX activity and rFIXFc concentration was conducted following the initial dose of rFIXFc (after a required 120-hour [5-day] washout period) and at Week 26, at these timepoints: predose, 10 (±2) minutes, 1 hour (±15 minutes), 3 hours (±15 minutes), 6 hours (±15 minutes), 24 (±2) hours, 48 (±2) hours, 96 (±3) hours (4 days), 144 (±3) hours (6 days), 168 (±3) hours (7 days), 192 (±3) hours (8 days), and 240 (±3) hours (10 days) from the start of the injection.

Incremental Recovery

IU/dL rise in plasma per IU/kg drug administered. Assessment of FIX activity with BeneFIX was conducted following a required 120-hour (5-day) washout period, at these timepoints: predose, 10 (±2) minutes, 1 hour (±15 minutes), 3 hours (±15 minutes), 6 hours (±15 minutes), 24 (±2) hours, 48 (±2) hours, 72 (±3) hours, and 96 (±3) hours (4 days) from the start of the injection. Assessment of FIX activity and rFIXFc concentration was conducted following the initial dose of rFIXFc (after a required 120-hour [5-day] washout period) and at Week 26, at these timepoints: predose, 10 (±2) minutes, 1 hour (±15 minutes), 3 hours (±15 minutes), 6 hours (±15 minutes), 24 (±2) hours, 48 (±2) hours, 96 (±3) hours (4 days), 144 (±3) hours (6 days), 168 (±3) hours (7 days), 192 (±3) hours (8 days), and 240 (±3) hours (10 days) from the start of the injection.

Time to 1% and 3% FIX Activity

Time to reach 1 or 3 IU/dL (%) after a single dose. Assessment of FIX activity with BeneFIX was conducted following a required 120-hour (5-day) washout period, at these timepoints: predose, 10 (±2) minutes, 1 hour (±15 minutes), 3 hours (±15 minutes), 6 hours (±15 minutes), 24 (±2) hours, 48 (±2) hours, 72 (±3) hours, and 96 (±3) hours (4 days) from the start of the injection. Assessment of FIX activity and rFIXFc concentration was conducted following the initial dose of rFIXFc (after a required 120-hour [5-day] washout period) and at Week 26, at these timepoints: predose, 10 (±2) minutes, 1 hour (±15 minutes), 3 hours (±15 minutes), 6 hours (±15 minutes), 24 (±2) hours, 48 (±2) hours, 96 (±3) hours (4 days), 144 (±3) hours (6 days), 168 (±3) hours (7 days), 192 (±3) hours (8 days), and 240 (±3) hours (10 days) from the start of the injection.

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

Number of participants with clinically relevant abnormalities or relevant changes from baseline in temperature, pulse (beats per minute [bpm]), systolic blood pressure (SBP), and diastolic blood pressure (DBP) are presented. Baseline (BL) is defined as the last non-missing evaluable assessment taken prior and closest to the first rFIXFc dose. Because the perioperative management period represents a unique clinical situation, safety data obtained during the surgical/rehabilitation period for participants in Arm 4 were included in listings and reviewed separately. Review of the listing was sufficient to assess this endpoint.

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

Maximum value post-dosing is defined as maximum value over the 1-, 6-, and 24-hour evaluations.

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

Maximum value post-dosing is defined as maximum value over the 1-, 6-, and 24-hour evaluations.

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

Maximum value post-dosing is defined as maximum value over the 1-, 6-, and 24-hour evaluations.

Full Information

NCT ID

NCT01027364

First Posted

December 4, 2009

Last Updated

December 16, 2020

Sponsor

Bioverativ Therapeutics Inc.

Collaborators

Swedish Orphan Biovitrum

1. Study Identification

Unique Protocol Identification Number

NCT01027364

Brief Title

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

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 Type

Interventional

2. Study Status

Record Verification Date

August 2018

Overall Recruitment Status

Completed

Study Start Date

December 2009 (undefined)

Primary Completion Date

July 2012 (Actual)

Study Completion Date

July 2012 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Bioverativ Therapeutics Inc.

Collaborators

Swedish Orphan Biovitrum

4. Oversight

Data Monitoring Committee

Yes

5. 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Severe Hemophilia B

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 3

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

Non-Randomized

Enrollment

123 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Fixed Weekly Interval

Arm Type

Experimental

Arm Description

Arm Title

Individualized Interval

Arm Type

Experimental

Arm Description

Arm Title

On Demand

Arm Type

Experimental

Arm Description

Arm Title

Surgery

Arm Type

Experimental

Arm Description

Intervention Type

Drug

Intervention Name(s)

Factor IX (rFIXFc)

Other Intervention Name(s)

Recombinant Human Factor IX Fc Fusion Protein

Intervention Type

Drug

Intervention Name(s)

rFIX

Other Intervention Name(s)

Recombinant Factor IX, BeneFIX®

Primary Outcome Measure Information:

Title

Number of Participants With Potentially Clinically Significant Laboratory Abnormalities

Description

Time Frame

up to 52 weeks ± 1 week

Title

Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs)

Description

Time Frame

up to 52 weeks + 30 days ± 1 week

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

Title

Number of Participants With Treatment-emergent Serious Adverse Events (TESAEs) During the Surgical / Rehabilitation Period

Description

Time Frame

up to 52 weeks + 30 days ± 1 week

Title

Incidence Rate of FIX Inhibitor Development

Description

Time Frame

up to 52 weeks ± 1 week

Title

Annualized Bleeding Rate

Description

Time Frame

up to 52 weeks ± 1 week (efficacy period as defined in description)

Title

Comparison of Annualized Bleeding Rates

Description

Time Frame

up to 52 weeks ± 1 week (efficacy period as defined in description)

Secondary Outcome Measure Information:

Title

Participant Assessment of Response to Injections to Treat a Bleeding Episode

Description

Time Frame

up to 52 weeks ± 1 week

Title

Physicians' Global Assessments of Participants' Response to Treatment With rFIXFc

Description

Time Frame

up to 52 weeks ± 1 week

Title

Annualized rFIXFc Consumption Per Participant

Description

Time Frame

up to 52 weeks ± 1 week (efficacy period as defined in description)

Title

Average Weekly Dose For the Fixed Weekly Interval Prophylaxis Arm

Description

Time Frame

up to 52 weeks ± 1 week (efficacy period as defined in description)

Title

Average Dosing Interval For the Individualized Interval Prophylaxis Arm

Description

Time Frame

up to 52 weeks ± 1 week (efficacy period as defined in description)

Title

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

Description

Time Frame

up to 52 weeks ± 1 week (efficacy period as defined in description)

Title

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

Description

Time Frame

up to 52 weeks ± 1 week (efficacy period as defined in description)

Title

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

Description

Time Frame

up to 52 weeks ± 1 week (efficacy period as defined in description)

Title

Number of Injections Required for Resolution of a Bleeding Episode

Description

Time Frame

up to 52 weeks ± 1 week (efficacy period as defined in description)

Title

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

Description

Time Frame

up to 52 weeks ± 1 week (efficacy period as defined in description)

Title

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

Description

Time Frame

up to 52 weeks ± 1 week (efficacy period as defined in description)

Title

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

Description

Time Frame

Baseline, Week 26

Title

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

Description

Time Frame

Baseline, Week 52

Title

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

Description

Time Frame

Baseline, Week 26, Week 52

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

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

Title

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

Description

Time Frame

up to 52 weeks ± 1 week

Title

Estimated Total Blood Loss During Major Surgery

Time Frame

up to 52 weeks ± 1 week

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

Title

Maximum Concentration (Cmax)

Description

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.

Title

Area Under the Curve (AUC) Per Dose

Description

Time Frame

Title

Half Life (t1/2) Alpha and t1/2 Beta

Description

Time Frame

Title

Clearance (CL)

Description

Time Frame

Title

Mean Residence Time (MRT)

Description

Time Frame

Title

Volume in Steady State (Vss)

Description

Time Frame

Title

Incremental Recovery

Description

Time Frame

Title

Time to 1% and 3% FIX Activity

Description

Time Frame

Title

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

Description

Time Frame

up to 52 weeks ± 1 week

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)

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)

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)

10. Eligibility

Sex

Male

Minimum Age & Unit of Time

12 Years

Accepts Healthy Volunteers

Eligibility Criteria

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

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Medical Director

Organizational Affiliation

Bioverativ Therapeutics Inc.

Official's Role

Study Director

Facility Information:

Facility Name

Research Site

City

Phoenix

State/Province

Arizona

Country

United States

Facility Name

Research Site

City

Sacramento

State/Province

California

Country

United States

Facility Name

Research Site

City

Aurora

State/Province

Colorado

Country

United States

Facility Name

Research Site

City

Chicago

State/Province

Illinois

Country

United States

Facility Name

Research Site

City

Indianapolis

State/Province

Indiana

Country

United States

Facility Name

Research Site

City

East Lansing

State/Province

Michigan

Country

United States

Facility Name

Research Site

City

Philadelphia

State/Province

Pennsylvania

Country

United States

Facility Name

Research Site

City

Pittsburgh

State/Province

Pennsylvania

Country

United States

Facility Name

Research Site

City

Seattle

State/Province

Washington

Country

United States

Facility Name

Research Site

City

Camperdown

State/Province

New South Wales

Country

Australia

Facility Name

Research Site

City

Adelaide

State/Province

South Australia

Country

Australia

Facility Name

Research Site

City

Perth

State/Province

Western Australia

Country

Australia

Facility Name

Research Site

City

Bruxelles

Country

Belgium

Facility Name

Research Site

City

Leuven

Country

Belgium

Facility Name

Research Site

City

Campinas

Country

Brazil

Facility Name

Research Site

City

Calgary

State/Province

Alberta

Country

Canada

Facility Name

Research Site

City

Toronto

State/Province

Ontario

Country

Canada

Facility Name

Research Site

City

Montreal

State/Province

Quebec

Country

Canada

Facility Name

Research Site

City

Vancouver

Country

Canada

Facility Name

Research site

City

Beijing

Country

China

Facility Name

Research Site

City

Guangzhou

Country

China

Facility Name

Research Site

City

Shanghai

Country

China

Facility Name

Research Site

City

Tianjin

Country

China

Facility Name

Research Site

City

Lyon

Country

France

Facility Name

Research Site

City

Marseille

Country

France

Facility Name

Research Site

City

Berlin

Country

Germany

Facility Name

Research Site

City

Bonn

Country

Germany

Facility Name

Research Site

City

Pokfulam

Country

Hong Kong

Facility Name

Research Site

City

Shatin

Country

Hong Kong

Facility Name

Research Site

City

Ludhiana

State/Province

Punjab

Country

India

Facility Name

Research Site

City

Vellore

State/Province

Tamil Nadu

Country

India

Facility Name

Research Site

City

Bangalore

Country

India

Facility Name

Research Site

City

Pune

Country

India

Facility Name

Research Site

City

Firenze

Country

Italy

Facility Name

Research Site

City

Milano

Country

Italy

Facility Name

Research Site

City

Kasihara-City

Country

Japan

Facility Name

Research Site

City

Kawasaki City

Country

Japan

Facility Name

Research Site

City

Kitakyushu

Country

Japan

Facility Name

Research Site

City

Nagoya

Country

Japan

Facility Name

Ressearch Site

City

Suginami-ku

Country

Japan

Facility Name

Research Site

City

Tokyo

Country

Japan

Facility Name

Research Site

City

Lodz

Country

Poland

Facility Name

Research Site

City

Warszawa

Country

Poland

Facility Name

Research Site

City

Moscow

Country

Russian Federation

Facility Name

Research Site

City

St. Petersburg

Country

Russian Federation

Facility Name

Research Site

City

Johannesburg

State/Province

Gauteng

Country

South Africa

Facility Name

Research Site

City

Cape Town

State/Province

Western Cape

Country

South Africa

Facility Name

Research Site

City

Malmö

Country

Sweden

Facility Name

Research Site

City

Stockholm

Country

Sweden

Facility Name

Research Site

City

Cambridge

Country

United Kingdom

Facility Name

Research Site

City

London

Country

United Kingdom

12. IPD Sharing Statement

Citations:

PubMed Identifier

24304002

Citation

Powell JS, Pasi KJ, Ragni MV, Ozelo MC, Valentino LA, Mahlangu JN, Josephson NC, Perry D, Manco-Johnson MJ, Apte S, Baker RI, Chan GC, Novitzky N, Wong RS, Krassova S, Allen G, Jiang H, Innes A, Li S, Cristiano LM, Goyal J, Sommer JM, Dumont JA, Nugent K, Vigliani G, Brennan A, Luk A, Pierce GF; B-LONG Investigators. Phase 3 study of recombinant factor IX Fc fusion protein in hemophilia B. N Engl J Med. 2013 Dec 12;369(24):2313-23. doi: 10.1056/NEJMoa1305074. Epub 2013 Dec 4.

Results Reference

result

Learn more about this trial

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

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

Severe Hemophilia B

About this trial

Eligibility Criteria

Sites / Locations

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Outcomes

Primary Outcome Measures

Secondary Outcome Measures

Full Information

1. Study Identification

2. Study Status

3. Sponsor/Collaborators

4. Oversight

5. Study Description

6. Conditions and Keywords

7. Study Design

8. Arms, Groups, and Interventions

10. Eligibility

12. IPD Sharing Statement

Learn more about this trial