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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/study/NCT01027364

Registration number

NCT01027364

Ethics application status

Date submitted

4/12/2009

Date registered

7/12/2009

Date last updated

19/12/2020

Titles & IDs

Public title

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

Scientific 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

Secondary ID [1]

2009-014295-21

Secondary ID [2]

998HB102

Universal Trial Number (UTN)

Trial acronym

Linked study record

Health condition

Health condition(s) or problem(s) studied:

Severe Hemophilia B

Condition category

Condition code

Blood

Clotting disorders

Human Genetics and Inherited Disorders

Other human genetics and inherited disorders

Intervention/exposure

Study type

Interventional

Description of intervention(s) / exposure

Experimental: Fixed Weekly Interval - 50 IU/kg rFIXFc via intravenous (IV) injection once every 7 days initially, then at a dose indicated by the participant's baseline pharmacokinetic (PK) assessment that ensured a target trough of 1% to 3% above baseline or higher, as clinically indicated. Adjustments to the initial weekly dose of rFIXFc (50 IU/kg) were to be made based on baseline PK assessments, occurrence of spontaneous bleeding episodes, and the trough levels, which were to be monitored at Weeks 4, 16, 26, and 39.

Prior to the first dose of rFIXFc, participants in the Sequential PK subgroup were to receive a single dose of 50 IU/kg BeneFIX administered IV in the clinic, followed by PK sampling. A single dose of 50 IU/kg rFIXFc was administered following a 120-hour washout from BeneFIX, followed by PK sampling for a baseline PK profiling. At Week 26 (±1 week) subjects were to receive a single dose of 50 IU/kg rFIXFc for repeat PK profiling.

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

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

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

Comparator / control treatment

Control group

Outcomes

Primary outcome [1]

Number of Participants With Potentially Clinically Significant Laboratory Abnormalities

Assessment method [1]

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.

Timepoint [1]

up to 52 weeks ± 1 week

Primary outcome [2]

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

Assessment method [2]

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.

Timepoint [2]

up to 52 weeks + 30 days ± 1 week

Primary outcome [3]

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

Assessment method [3]

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).

Timepoint [3]

up to 52 weeks + 30 days ± 1 week

Primary outcome [4]

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

Assessment method [4]

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).

Timepoint [4]

up to 52 weeks + 30 days ± 1 week

Primary outcome [5]

Incidence Rate of FIX Inhibitor Development

Assessment method [5]

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.

Timepoint [5]

up to 52 weeks ± 1 week

Primary outcome [6]

Annualized Bleeding Rate

Assessment method [6]

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.

Timepoint [6]

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

Primary outcome [7]

Comparison of Annualized Bleeding Rates

Assessment method [7]

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.

Timepoint [7]

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

Secondary outcome [1]

Participant Assessment of Response to Injections to Treat a Bleeding Episode

Assessment method [1]

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.

Timepoint [1]

up to 52 weeks ± 1 week

Secondary outcome [2]

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

Assessment method [2]

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.

Timepoint [2]

up to 52 weeks ± 1 week

Secondary outcome [3]

Annualized rFIXFc Consumption Per Participant

Assessment method [3]

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.

Timepoint [3]

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

Secondary outcome [4]

Average Weekly Dose For the Fixed Weekly Interval Prophylaxis Arm

Assessment method [4]

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).

Timepoint [4]

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

Secondary outcome [5]

Average Dosing Interval For the Individualized Interval Prophylaxis Arm

Assessment method [5]

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).

Timepoint [5]

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

Secondary outcome [6]

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

Assessment method [6]

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.

Timepoint [6]

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

Secondary outcome [7]

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

Assessment method [7]

Timepoint [7]

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

Secondary outcome [8]

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

Assessment method [8]

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.

Timepoint [8]

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

Secondary outcome [9]

Number of Injections Required for Resolution of a Bleeding Episode

Assessment method [9]

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.

Timepoint [9]

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

Secondary outcome [10]

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

Assessment method [10]

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.

Timepoint [10]

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

Secondary outcome [11]

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

Assessment method [11]

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.

Timepoint [11]

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

Secondary outcome [12]

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

Assessment method [12]

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.

Timepoint [12]

Baseline, Week 26

Secondary outcome [13]

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

Assessment method [13]

Timepoint [13]

Baseline, Week 52

Secondary outcome [14]

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

Assessment method [14]

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.

Timepoint [14]

Baseline, Week 26, Week 52

Secondary outcome [15]

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

Assessment method [15]

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.

Timepoint [15]

up to 52 weeks ± 1 week

Secondary outcome [16]

Number of Injections Required to Maintain Hemostasis During Major Surgery

Assessment method [16]

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.

Timepoint [16]

up to 52 weeks ± 1 week

Secondary outcome [17]

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

Assessment method [17]

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.

Timepoint [17]

up to 52 weeks ± 1 week

Secondary outcome [18]

Estimated Total Blood Loss During Major Surgery

Assessment method [18]

Timepoint [18]

up to 52 weeks ± 1 week

Secondary outcome [19]

Number of Transfusions Required Per Surgery

Assessment method [19]

Number of blood component transfusions during a single surgery.

Timepoint [19]

up to 52 weeks ± 1 week

Secondary outcome [20]

Maximum Concentration (Cmax)

Assessment method [20]

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.

Timepoint [20]

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.

Secondary outcome [21]

Area Under the Curve (AUC) Per Dose

Assessment method [21]

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.

Timepoint [21]

Secondary outcome [22]

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

Assessment method [22]

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.

Timepoint [22]

Secondary outcome [23]

Clearance (CL)

Assessment method [23]

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.

Timepoint [23]

Secondary outcome [24]

Mean Residence Time (MRT)

Assessment method [24]

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.

Timepoint [24]

Secondary outcome [25]

Volume in Steady State (Vss)

Assessment method [25]

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.

Timepoint [25]

Secondary outcome [26]

Incremental Recovery

Assessment method [26]

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.

Timepoint [26]

Secondary outcome [27]

Time to 1% and 3% FIX Activity

Assessment method [27]

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.

Timepoint [27]

Secondary outcome [28]

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

Assessment method [28]

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.

Timepoint [28]

up to 52 weeks ± 1 week

Secondary outcome [29]

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

Assessment method [29]

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

Timepoint [29]

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)

Secondary outcome [30]

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

Assessment method [30]

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

Timepoint [30]

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)

Secondary outcome [31]

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

Assessment method [31]

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

Timepoint [31]

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)

Eligibility

Key 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

Minimum age

12 Years

Maximum age

No limit

Sex

Males

Can healthy volunteers participate?

Key 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

Study design

Purpose of the study

Treatment

Allocation to intervention

Non-randomised trial

Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)

Methods used to generate the sequence in which subjects will be randomised (sequence generation)

Masking / blinding

Open (masking not used)

Who is / are masked / blinded?

Intervention assignment

Single group

Other design features

Phase

Phase 3

Type of endpoint/s

Statistical methods / analysis

Recruitment

Recruitment status

Completed

Data analysis

Reason for early stopping/withdrawal

Other reasons

Date of first participant enrolment

Anticipated

Actual

1/12/2009

Date of last participant enrolment

Anticipated

Actual

Date of last data collection

Anticipated

Actual

1/07/2012

Sample size

Target

Accrual to date

Final

123

Recruitment in Australia

Recruitment state(s)

NSW,SA,WA

Recruitment hospital [1]

Research Site - Camperdown

Recruitment hospital [2]

Research Site - Adelaide

Recruitment hospital [3]

Research Site - Perth

Recruitment postcode(s) [1]

- Camperdown

Recruitment postcode(s) [2]

- Adelaide

Recruitment postcode(s) [3]

- Perth

Recruitment outside Australia

Country [1]

United States of America

State/province [1]

Arizona

Country [2]

United States of America

State/province [2]

California

Country [3]

United States of America

State/province [3]

Colorado

Country [4]

United States of America

State/province [4]

Illinois

Country [5]

United States of America

State/province [5]

Indiana

Country [6]

United States of America

State/province [6]

Michigan

Country [7]

United States of America

State/province [7]

Pennsylvania

Country [8]

United States of America

State/province [8]

Washington

Country [9]

Belgium

State/province [9]

Bruxelles

Country [10]

Belgium

State/province [10]

Leuven

Country [11]

Brazil

State/province [11]

Campinas

Country [12]

Canada

State/province [12]

Alberta

Country [13]

Canada

State/province [13]

Ontario

Country [14]

Canada

State/province [14]

Quebec

Country [15]

Canada

State/province [15]

Vancouver

Country [16]

China

State/province [16]

Beijing

Country [17]

China

State/province [17]

Guangzhou

Country [18]

China

State/province [18]

Shanghai

Country [19]

China

State/province [19]

Tianjin

Country [20]

France

State/province [20]

Lyon

Country [21]

France

State/province [21]

Marseille

Country [22]

Germany

State/province [22]

Berlin

Country [23]

Germany

State/province [23]

Bonn

Country [24]

Hong Kong

State/province [24]

Pokfulam

Country [25]

Hong Kong

State/province [25]

Shatin

Country [26]

India

State/province [26]

Punjab

Country [27]

India

State/province [27]

Tamil Nadu

Country [28]

India

State/province [28]

Bangalore

Country [29]

India

State/province [29]

Pune

Country [30]

Italy

State/province [30]

Firenze

Country [31]

Italy

State/province [31]

Milano

Country [32]

Japan

State/province [32]

Kasihara-City

Country [33]

Japan

State/province [33]

Kawasaki City

Country [34]

Japan

State/province [34]

Kitakyushu

Country [35]

Japan

State/province [35]

Nagoya

Country [36]

Japan

State/province [36]

Suginami-ku

Country [37]

Japan

State/province [37]

Tokyo

Country [38]

Poland

State/province [38]

Lodz

Country [39]

Poland

State/province [39]

Warszawa

Country [40]

Russian Federation

State/province [40]

Moscow

Country [41]

Russian Federation

State/province [41]

St. Petersburg

Country [42]

South Africa

State/province [42]

Gauteng

Country [43]

South Africa

State/province [43]

Western Cape

Country [44]

Sweden

State/province [44]

Malmö

Country [45]

Sweden

State/province [45]

Stockholm

Country [46]

United Kingdom

State/province [46]

Cambridge

Country [47]

United Kingdom

State/province [47]

London

Funding & Sponsors

Primary sponsor type

Commercial sector/industry

Name

Bioverativ Therapeutics Inc.

Country

Other collaborator category [1]

Commercial sector/industry

Name [1]

Swedish Orphan Biovitrum

Country [1]

Ethics approval

Ethics application status

Summary

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.

Trial website

https://clinicaltrials.gov/study/NCT01027364

Trial related presentations / 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.

Public notes

Contacts

Principal investigator

Name

Medical Director

Address

Bioverativ Therapeutics Inc.

Country

Phone

Contact person for public queries

Name

Address

Country

Phone

Contact person for scientific queries

No information has been provided regarding IPD availability

What supporting documents are/will be available?

No Supporting Document Provided

Results publications and other study-related documents

Type	Citations or Other Details
Journal	Powell JS, Pasi KJ, Ragni MV, Ozelo MC, Valentino ... [More Details]

Results are available at https://clinicaltrials.gov/study/NCT01027364

Trial Review

For full trial details, please see the original record at https://clinicaltrials.gov/study/NCT01027364