Severe Hemophilia BPhase 3NCT01027364
Study of Recombinant Factor IX Fc Fusion Protein (rFIXFc) in Participants With Hemophilia B
A Phase 3 study testing Factor IX (rFIXFc) and rFIX in people with Severe Hemophilia B, run by Bioverativ Therapeutics Inc. at 51 sites in 17 countries.
Trial 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… Read more about this study
- Who is it for?
- Ages 12 years and older, men only
- Conditions the study is for
- Severe Hemophilia B
- What is being tested?
- Factor IX (rFIXFc) and rFIX
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 123 participants
- Where
- 51 sitesin 17 countries
- Study dates
- Dec 2009to Jul 2012
- Phase
- Phase 3
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 12 years and older
- Men only
- No healthy volunteers
- Child, Adult, Older adult
Who may be able to join
- 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
Who cannot join
- 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
Trial locations and contacts
51 sites in 17 countries.
51 sites in 17 countries
United States9 sites
Research Site
Aurora, Colorado
Research Site
Chicago, Illinois
Research Site
East Lansing, Michigan
Research Site
Indianapolis, Indiana
Research Site
Philadelphia, Pennsylvania
Research Site
Phoenix, Arizona
Research Site
Pittsburgh, Pennsylvania
Research Site
Sacramento, California
Research Site
Seattle, Washington
Japan6 sites
Research Site
Kasihara-City
Research Site
Kawasaki
Research Site
Kitakyushu
Research Site
Nagoya
Ressearch Site
Suginami-ku
Research Site
Tokyo
Canada4 sites
Research Site
Calgary, Alberta
Research Site
Montreal, Quebec
Research Site
Toronto, Ontario
Research Site
Vancouver
China4 sites
Research site
Beijing
Research Site
Guangzhou
Research Site
Shanghai
Research Site
Tianjin
India4 sites
Research Site
Bangalore
Research Site
Ludhiana, Punjab
Research Site
Pune
Research Site
Vellore, Tamil Nadu
Australia3 sites
Research Site
Adelaide, South Australia
Research Site
Camperdown, New South Wales
Research Site
Perth, Western Australia
South Africa2 sites
Research Site
Cape Town, Western Cape
Research Site
Johannesburg, Gauteng
About this study
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
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.
- Conditions
- Severe Hemophilia B
- Being tested
- Factor IX (rFIXFc), rFIX
- Medical subject headings
- Hemophilia B
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Factor IX (rFIXFc)Drug
Also called Recombinant Human Factor IX Fc Fusion Protein
rFIXDrug
Also called Recombinant Factor IX, BeneFIX®
| Study group | Role | What they receive |
|---|---|---|
| Fixed Weekly Interval | Experimental | 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. Receives: Drug: Factor IX (rFIXFc); Drug: rFIX |
| Individualized Interval | Experimental | 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. Receives: Drug: Factor IX (rFIXFc) |
| On Demand | Experimental | 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 Receives: Drug: Factor IX (rFIXFc) |
| Surgery | Experimental | 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. Receives: Drug: Factor IX (rFIXFc) |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: up to 52 weeks ± 1 week
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.
Measured: up to 52 weeks + 30 days ± 1 week
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).
Measured: up to 52 weeks + 30 days ± 1 week
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).
Measured: up to 52 weeks + 30 days ± 1 week
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.
Measured: up to 52 weeks ± 1 week
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.
Measured: up to 52 weeks ± 1 week (efficacy period as defined in description)
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.
Measured: up to 52 weeks ± 1 week (efficacy period as defined in description)
Secondary outcomes (31)
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.
Measured: up to 52 weeks ± 1 week
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.
Measured: up to 52 weeks ± 1 week
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.
Measured: up to 52 weeks ± 1 week (efficacy period as defined in description)
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).
Measured: up to 52 weeks ± 1 week (efficacy period as defined in description)
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).
Measured: up to 52 weeks ± 1 week (efficacy period as defined in description)
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.
Measured: up to 52 weeks ± 1 week (efficacy period as defined in description)
Annualized Bleeding Rate by Location of Bleed (Joint, Muscle, Internal, Skin/Mucosa)
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.
Measured: up to 52 weeks ± 1 week (efficacy period as defined in description)
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.
Measured: up to 52 weeks ± 1 week (efficacy period as defined in description)
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.
Measured: up to 52 weeks ± 1 week (efficacy period as defined in description)
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.
Measured: up to 52 weeks ± 1 week (efficacy period as defined in description)
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.
Measured: up to 52 weeks ± 1 week (efficacy period as defined in description)
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.
Measured: Baseline, Week 26
Haem-A-QoL Questionnaire for Adults: Change From Baseline to 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.
Measured: Baseline, 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.
Measured: Baseline, Week 26, Week 52
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.
Measured: up to 52 weeks ± 1 week
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.
Measured: up to 52 weeks ± 1 week
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.
Measured: up to 52 weeks ± 1 week
Estimated Total Blood Loss During Major Surgery
Measured: up to 52 weeks ± 1 week
Number of Transfusions Required Per Surgery
Number of blood component transfusions during a single surgery.
Measured: up to 52 weeks ± 1 week
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.
Measured: 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.
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.
Measured: 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.
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.
Measured: 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.
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.
Measured: 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.
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.
Measured: 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 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.
Measured: 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.
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.
Measured: 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 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.
Measured: 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.
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.
Measured: up to 52 weeks ± 1 week
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.
Measured: 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)
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.
Measured: 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)
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.
Measured: 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)
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted7 Dec 2009 (estimated)
- Study startDec 2009
- Primary completionJul 2012
- Study completionJul 2012
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (2)Papers the sponsor has linked to this study.
- Other trials for Severe Hemophilia BStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 123 participants (actual)
Sponsor and investigators
- Lead sponsor
- Bioverativ Therapeutics Inc.
- Sponsor type
- Industry (pharma, biotech, devices)
- Collaborators
- Swedish Orphan Biovitrum
- Responsible party
- Sponsor
- Investigators
- Medical Director, Study director, Bioverativ Therapeutics Inc.
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01027364
- Sponsor's protocol ID
- 998HB102
- Other IDs
- 2009-014295-21, 2009
- Status last verified
- Aug 2018
- First submitted
- 4 Dec 2009
- Last updated
- 19 Dec 2020
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
Publications
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.
PubMed 24304002Shapiro AD, Kulkarni R, Ragni MV, Chambost H, Mahlangu J, Oldenburg J, Nolan B, Ozelo MC, Foster MC, Willemze A, Barnowski C, Jain N, Winding B, Dumont J, Lethagen S, Barnes C, Pasi KJ. Post hoc longitudinal assessment of the efficacy and safety of recombinant factor IX Fc fusion protein in hemophilia B. Blood Adv. 2023 Jul 11;7(13):3049-3057. doi: 10.1182/bloodadvances.2022009230.
PubMed 36848635
Study at a glance
From the registry record, last updated by the sponsor on 19 Dec 2020. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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
- ClinicalTrials.gov ID
- NCT01027364
- Acronym / sponsor ID
- 998HB102
- Conditions
- Severe Hemophilia B
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 123 participants (actual)
- Lead sponsor
- Bioverativ Therapeutics Inc.Industry (pharma, biotech, devices)
- Collaborators
- Swedish Orphan Biovitrum
- Study start
- Dec 2009
- Primary completion
- Jul 2012 (actual)
- Study completion
- Jul 2012 (actual)
- First posted
- 7 Dec 2009 (estimated)
- Results
- Posted 4 Sep 2014
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 4
| Arm | Type | Receives |
|---|---|---|
| Fixed Weekly Interval | Experimental | Drug: Factor IX (rFIXFc), Drug: rFIX50 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. |
| Individualized Interval | Experimental | Drug: Factor IX (rFIXFc)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. |
| On Demand | Experimental | Drug: Factor IX (rFIXFc)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 |
| Surgery | Experimental | Drug: Factor IX (rFIXFc)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. |
Who may qualify
- Ages
- 12 years and older
- Sex
- Male only
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult, Older adult
Key inclusion criteria (4 listed)
- 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
Key exclusion criteria (4 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Factor IX (rFIXFc)Also: Recombinant Human Factor IX Fc Fusion Protein | Drug | Fixed Weekly Interval, Individualized Interval, On Demand, Surgery |
| rFIXAlso: Recombinant Factor IX, BeneFIX® | Drug | Fixed Weekly Interval |
Primary outcome
Number of Participants With Potentially Clinically Significant Laboratory Abnormalities
Time frame: 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.
Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs)
Time frame: 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.
Number of Participants With Non-serious Treatment-emergent Adverse Events (TEAEs) During the Surgical / Rehabilitation Period
Time frame: 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).
Number of Participants With Treatment-emergent Serious Adverse Events (TESAEs) During the Surgical / Rehabilitation Period
Time frame: 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).
Incidence Rate of FIX Inhibitor Development
Time frame: 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.
Annualized Bleeding Rate
Time frame: up to 52 weeks ± 1 week (efficacy period as defined in description)
Annualized bleeding episodes = (number of bleeding episodes / number of days in 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
Time frame: 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.
31 secondary outcomes
Participant Assessment of Response to Injections to Treat a Bleeding Episode
Time frame: up to 52 weeks ± 1 week
Physicians' Global Assessments of Participants' Response to Treatment With rFIXFc
Time frame: up to 52 weeks ± 1 week
Annualized rFIXFc Consumption Per Participant
Time frame: up to 52 weeks ± 1 week (efficacy period as defined in description)
Average Weekly Dose For the Fixed Weekly Interval Prophylaxis Arm
Time frame: up to 52 weeks ± 1 week (efficacy period as defined in description)
Average Dosing Interval For the Individualized Interval Prophylaxis Arm
Time frame: up to 52 weeks ± 1 week (efficacy period as defined in description)
Annualized Bleeding Rate by Type of Bleed (Spontaneous and Traumatic)
Time frame: up to 52 weeks ± 1 week (efficacy period as defined in description)
Annualized Bleeding Rate by Location of Bleed (Joint, Muscle, Internal, Skin/Mucosa)
Time frame: up to 52 weeks ± 1 week (efficacy period as defined in description)
Number of Days From Last Injection to Treat a New Bleeding Episode
Time frame: up to 52 weeks ± 1 week (efficacy period as defined in description)
Number of Injections Required for Resolution of a Bleeding Episode
Time frame: up to 52 weeks ± 1 week (efficacy period as defined in description)
Number of Injections Required for Resolution of a Bleeding Episode by Location of Bleed
Time frame: up to 52 weeks ± 1 week (efficacy period as defined in description)
Total Dose Per Injection Required for Resolution of a Bleeding Episode by Location of Bleed
Time frame: up to 52 weeks ± 1 week (efficacy period as defined in description)
Hemophilia-Specific Quality of Life Index for Adults (Haem-A-QoL) Questionnaire: Change From Baseline to Week 26
Time frame: Baseline, Week 26
Haem-A-QoL Questionnaire for Adults: Change From Baseline to Week 52
Time frame: Baseline, Week 52
Hemophilia-Specific Quality of Life Index for Children (Haemo-QoL) Questionnaire: Change From Baseline to Week 26 and Week 52
Time frame: Baseline, Week 26, Week 52
Investigators'/Surgeons' Assessment of Participants' Response to rFIXFc for Major Surgery
Time frame: up to 52 weeks ± 1 week
Number of Injections Required to Maintain Hemostasis During Major Surgery
Time frame: up to 52 weeks ± 1 week
Dose Per Injection and Total Dose Required to Maintain Hemostasis During Major Surgery
Time frame: up to 52 weeks ± 1 week
Estimated Total Blood Loss During Major Surgery
Time frame: up to 52 weeks ± 1 week
Number of Transfusions Required Per Surgery
Time frame: up to 52 weeks ± 1 week
Maximum Concentration (Cmax)
Time frame: See Measure Description for complete time frame. Each participant was to complete PK sampling up to, and including, the 96-hour (4-day) timepoint for BeneFIX PK assessment and the 240-hour (10-day) timepoint for rFIXFc PK assessment.
Area Under the Curve (AUC) Per Dose
Time frame: See Measure Description for complete time frame. Each participant was to complete PK sampling up to, and including, the 96-hour (4-day) timepoint for BeneFIX PK assessment and the 240-hour (10-day) timepoint for rFIXFc PK assessment.
Half Life (t1/2) Alpha and t1/2 Beta
Time frame: See Measure Description for complete time frame. Each participant was to complete PK sampling up to, and including, the 96-hour (4-day) timepoint for BeneFIX PK assessment and the 240-hour (10-day) timepoint for rFIXFc PK assessment.
Clearance (CL)
Time frame: See Measure Description for complete time frame. Each participant was to complete PK sampling up to, and including, the 96-hour (4-day) timepoint for BeneFIX PK assessment and the 240-hour (10-day) timepoint for rFIXFc PK assessment.
Mean Residence Time (MRT)
Time frame: See Measure Description for complete time frame. Each participant was to complete PK sampling up to, and including, the 96-hour (4-day) timepoint for BeneFIX PK assessment and the 240-hour (10-day) timepoint for rFIXFc PK assessment.
Volume in Steady State (Vss)
Time frame: See Measure Description for complete time frame. Each participant was to complete PK sampling up to, and including, the 96-hour (4-day) timepoint for BeneFIX PK assessment and the 240-hour (10-day) timepoint for rFIXFc PK assessment.
Incremental Recovery
Time frame: See Measure Description for complete time frame. Each participant was to complete PK sampling up to, and including, the 96-hour (4-day) timepoint for BeneFIX PK assessment and the 240-hour (10-day) timepoint for rFIXFc PK assessment.
Time to 1% and 3% FIX Activity
Time frame: See Measure Description for complete time frame. Each participant was to complete PK sampling up to, and including, the 96-hour (4-day) timepoint for BeneFIX PK assessment and the 240-hour (10-day) timepoint for rFIXFc PK assessment.
Number of Participants With Clinically Relevant Abnormalities or Relevant Changes From Baseline in Vital Signs
Time frame: up to 52 weeks ± 1 week
Coagulation Parameter: Change From Pre-dose Values in Prothrombin Split Fragments 1+ 2 (F 1+2)
Time frame: Pre-dose, 1 hour post-dose, 6 hours post-dose, and 24 hours post-dose at baseline (120 hours before Day 1, for BeneFIX), Day 1, Week 26, and Week 52 (for rFIXFc)
Coagulation Parameter: Change From Pre-dose Values in Thrombin-antithrombin (TAT) Complex
Time frame: Pre-dose, 1 hour post-dose, 6 hours post-dose, and 24 hours post-dose at baseline (120 hours before Day 1, for BeneFIX), Day 1, Week 26, and Week 52 (for rFIXFc)
Coagulation Parameter: Change From Pre-dose Values in D-dimer
Time frame: Pre-dose, 1 hour post-dose, 6 hours post-dose, and 24 hours post-dose at baseline (120 hours before Day 1, for BeneFIX), Day 1, Week 26, and Week 52 (for rFIXFc)
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 19 Dec 2020.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Results publication: PubMed 24304002Powell 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.
- Derived from this study: PubMed 36848635Shapiro AD, Kulkarni R, Ragni MV, Chambost H, Mahlangu J, Oldenburg J, Nolan B, Ozelo MC, Foster MC, Willemze A, Barnowski C, Jain N, Winding B, Dumont J, Lethagen S, Barnes C, Pasi KJ. Post hoc longitudinal assessment of the efficacy and safety of recombinant factor IX Fc fusion protein in hemophilia B. Blood Adv. 2023 Jul 11;7(13):3049-3057. doi: 10.1182/bloodadvances.2022009230.
Related trials for Severe Hemophilia B
Active, not recruitingPhase 3
A Study to Evaluate the Efficacy and Safety of Factor IX Gene Therapy With PF-06838435 in Adult Males With Moderately Severe to Severe Hemophilia B
Hemophilia B
RecruitingPhase 3
Open-Label Extension Study of Marstacimab in Hemophilia Participants With or Without Inhibitors
Hemophilia A, Hemophilia B
RecruitingPhase 1/2
A Study to Investigate the Safety and Effectiveness of a Coagulation Factor IX Gene Insertion Therapy (REGV131-LNP1265) in Pediatric, Adolescent and Adult Participants With Hemophilia B
Hemophilia B
RecruitingPhase 3
Phase 3, Open-label, Single-dose Study of CSL222 in Adolescent Male Subjects (≥ 12 to < 18 Years of Age) With Severe or Moderately Severe Hemophilia B
Hemophilia B
RecruitingPhase 3
A Clinical Trial of Study Medicine (Marstacimab) in Pediatric Patients With Hemophilia A or Hemophilia B
Hemophilia A, Hemophilia B
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Medical Director study director
Bioverativ Therapeutics Inc.
51 sites in 17 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing Factor IX (rFIXFc) and rFIX in people with Severe Hemophilia B, run by Bioverativ Therapeutics Inc. at 51 sites in 17 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 4 inclusion and 4 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 19 Dec 2020. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 51 sites in United States, Japan, Canada, China, India and 12 more countries. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 4 Sep 2014). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Number of Participants With Potentially Clinically Significant Laboratory Abnormalities (time frame: up to 52 weeks ± 1 week). The study lists 7 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT01027364, which also lists 2 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 19 Dec 2020.