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Trial details imported from ClinicalTrials.gov
For full trial details, please see the original record at
https://clinicaltrials.gov/ct2/show/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
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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
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Secondary ID [1]
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2009-014295-21
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Secondary ID [2]
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998HB102
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Universal Trial Number (UTN)
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Trial acronym
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Linked study record
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Health condition
Health condition(s) or problem(s) studied:
Severe Hemophilia B
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Condition category
Condition code
Blood
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Clotting disorders
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Human Genetics and Inherited Disorders
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Other human genetics and inherited disorders
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Intervention/exposure
Study type
Interventional
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Description of intervention(s) / exposure
Treatment: Drugs - Factor IX (rFIXFc)
Treatment: Drugs - rFIX
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.
Treatment: Drugs: Factor IX (rFIXFc)
Treatment: Drugs: rFIX
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Intervention code [1]
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Treatment: Drugs
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Comparator / control treatment
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Control group
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Outcomes
Primary outcome [1]
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Number of Participants With Potentially Clinically Significant Laboratory Abnormalities
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Assessment method [1]
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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.
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Timepoint [1]
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up to 52 weeks ± 1 week
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Primary outcome [2]
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Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs)
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Assessment method [2]
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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.
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Timepoint [2]
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up to 52 weeks + 30 days ± 1 week
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Primary outcome [3]
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Number of Participants With Non-serious Treatment-emergent Adverse Events (TEAEs) During the Surgical / Rehabilitation Period
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Assessment method [3]
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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).
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Timepoint [3]
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up to 52 weeks + 30 days ± 1 week
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Primary outcome [4]
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Number of Participants With Treatment-emergent Serious Adverse Events (TESAEs) During the Surgical / Rehabilitation Period
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Assessment method [4]
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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).
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Timepoint [4]
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up to 52 weeks + 30 days ± 1 week
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Primary outcome [5]
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Incidence Rate of FIX Inhibitor Development
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Assessment method [5]
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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.
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Timepoint [5]
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up to 52 weeks ± 1 week
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Primary outcome [6]
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Annualized Bleeding Rate
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Assessment method [6]
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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.
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Timepoint [6]
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up to 52 weeks ± 1 week (efficacy period as defined in description)
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Primary outcome [7]
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Comparison of Annualized Bleeding Rates
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Assessment method [7]
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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.
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Timepoint [7]
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up to 52 weeks ± 1 week (efficacy period as defined in description)
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Secondary outcome [1]
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Participant Assessment of Response to Injections to Treat a Bleeding Episode
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Assessment method [1]
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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.
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Timepoint [1]
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up to 52 weeks ± 1 week
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Secondary outcome [2]
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Physicians' Global Assessments of Participants' Response to Treatment With rFIXFc
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Assessment method [2]
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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.
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Timepoint [2]
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up to 52 weeks ± 1 week
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Secondary outcome [3]
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Annualized rFIXFc Consumption Per Participant
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Assessment method [3]
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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.
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Timepoint [3]
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up to 52 weeks ± 1 week (efficacy period as defined in description)
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Secondary outcome [4]
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Average Weekly Dose For the Fixed Weekly Interval Prophylaxis Arm
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Assessment method [4]
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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).
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Timepoint [4]
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up to 52 weeks ± 1 week (efficacy period as defined in description)
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Secondary outcome [5]
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Average Dosing Interval For the Individualized Interval Prophylaxis Arm
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Assessment method [5]
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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).
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Timepoint [5]
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up to 52 weeks ± 1 week (efficacy period as defined in description)
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Secondary outcome [6]
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Annualized Bleeding Rate by Type of Bleed (Spontaneous and Traumatic)
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Assessment method [6]
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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.
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Timepoint [6]
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up to 52 weeks ± 1 week (efficacy period as defined in description)
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Secondary outcome [7]
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Annualized Bleeding Rate by Location of Bleed (Joint, Muscle, Internal, Skin/Mucosa)
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Assessment method [7]
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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.
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Timepoint [7]
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up to 52 weeks ± 1 week (efficacy period as defined in description)
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Secondary outcome [8]
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Number of Days From Last Injection to Treat a New Bleeding Episode
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Assessment method [8]
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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.
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Timepoint [8]
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up to 52 weeks ± 1 week (efficacy period as defined in description)
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Secondary outcome [9]
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Number of Injections Required for Resolution of a Bleeding Episode
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Assessment method [9]
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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.
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Timepoint [9]
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up to 52 weeks ± 1 week (efficacy period as defined in description)
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Secondary outcome [10]
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Number of Injections Required for Resolution of a Bleeding Episode by Location of Bleed
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Assessment method [10]
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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.
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Timepoint [10]
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up to 52 weeks ± 1 week (efficacy period as defined in description)
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Secondary outcome [11]
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Total Dose Per Injection Required for Resolution of a Bleeding Episode by Location of Bleed
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Assessment method [11]
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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.
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Timepoint [11]
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up to 52 weeks ± 1 week (efficacy period as defined in description)
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Secondary outcome [12]
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Hemophilia-Specific Quality of Life Index for Adults (Haem-A-QoL) Questionnaire: Change From Baseline to Week 26
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Assessment method [12]
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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.
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Timepoint [12]
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Baseline, Week 26
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Secondary outcome [13]
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Haem-A-QoL Questionnaire for Adults: Change From Baseline to Week 52
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Assessment method [13]
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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.
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Timepoint [13]
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Baseline, Week 52
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Secondary outcome [14]
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Hemophilia-Specific Quality of Life Index for Children (Haemo-QoL) Questionnaire: Change From Baseline to Week 26 and Week 52
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Assessment method [14]
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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.
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Timepoint [14]
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Baseline, Week 26, Week 52
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Secondary outcome [15]
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Investigators'/Surgeons' Assessment of Participants' Response to rFIXFc for Major Surgery
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Assessment method [15]
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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.
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Timepoint [15]
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up to 52 weeks ± 1 week
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Secondary outcome [16]
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Number of Injections Required to Maintain Hemostasis During Major Surgery
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Assessment method [16]
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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.
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Timepoint [16]
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up to 52 weeks ± 1 week
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Secondary outcome [17]
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Dose Per Injection and Total Dose Required to Maintain Hemostasis During Major Surgery
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Assessment method [17]
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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.
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Timepoint [17]
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up to 52 weeks ± 1 week
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Secondary outcome [18]
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Estimated Total Blood Loss During Major Surgery
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Assessment method [18]
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0
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Timepoint [18]
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up to 52 weeks ± 1 week
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Secondary outcome [19]
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Number of Transfusions Required Per Surgery
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Assessment method [19]
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Number of blood component transfusions during a single surgery.
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Timepoint [19]
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up to 52 weeks ± 1 week
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Secondary outcome [20]
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Maximum Concentration (Cmax)
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Assessment method [20]
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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.
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Timepoint [20]
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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.
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Secondary outcome [21]
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Area Under the Curve (AUC) Per Dose
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Assessment method [21]
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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.
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Timepoint [21]
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0
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.
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Secondary outcome [22]
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Half Life (t1/2) Alpha and t1/2 Beta
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Assessment method [22]
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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.
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Timepoint [22]
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0
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.
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Secondary outcome [23]
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Clearance (CL)
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Assessment method [23]
0
0
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.
Query!
Timepoint [23]
0
0
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.
Query!
Secondary outcome [24]
0
0
Mean Residence Time (MRT)
Query!
Assessment method [24]
0
0
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.
Query!
Timepoint [24]
0
0
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.
Query!
Secondary outcome [25]
0
0
Volume in Steady State (Vss)
Query!
Assessment method [25]
0
0
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.
Query!
Timepoint [25]
0
0
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.
Query!
Secondary outcome [26]
0
0
Incremental Recovery
Query!
Assessment method [26]
0
0
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.
Query!
Timepoint [26]
0
0
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.
Query!
Secondary outcome [27]
0
0
Time to 1% and 3% FIX Activity
Query!
Assessment method [27]
0
0
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.
Query!
Timepoint [27]
0
0
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.
Query!
Secondary outcome [28]
0
0
Number of Participants With Clinically Relevant Abnormalities or Relevant Changes From Baseline in Vital Signs
Query!
Assessment method [28]
0
0
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.
Query!
Timepoint [28]
0
0
up to 52 weeks ± 1 week
Query!
Secondary outcome [29]
0
0
Coagulation Parameter: Change From Pre-dose Values in Prothrombin Split Fragments 1+ 2 (F 1+2)
Query!
Assessment method [29]
0
0
Maximum value post-dosing is defined as maximum value over the 1-, 6-, and 24-hour evaluations.
Query!
Timepoint [29]
0
0
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)
Query!
Secondary outcome [30]
0
0
Coagulation Parameter: Change From Pre-dose Values in Thrombin-antithrombin (TAT) Complex
Query!
Assessment method [30]
0
0
Maximum value post-dosing is defined as maximum value over the 1-, 6-, and 24-hour evaluations.
Query!
Timepoint [30]
0
0
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)
Query!
Secondary outcome [31]
0
0
Coagulation Parameter: Change From Pre-dose Values in D-dimer
Query!
Assessment method [31]
0
0
Maximum value post-dosing is defined as maximum value over the 1-, 6-, and 24-hour evaluations.
Query!
Timepoint [31]
0
0
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)
Query!
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
Query!
Minimum age
12
Years
Query!
Query!
Maximum age
No limit
Query!
Query!
Sex
Males
Query!
Can healthy volunteers participate?
No
Query!
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
Query!
Study design
Purpose of the study
Treatment
Query!
Allocation to intervention
Non-randomised trial
Query!
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Query!
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Query!
Masking / blinding
Open (masking not used)
Query!
Who is / are masked / blinded?
Query!
Query!
Query!
Query!
Intervention assignment
Single group
Query!
Other design features
Query!
Phase
Phase 3
Query!
Type of endpoint/s
Query!
Statistical methods / analysis
Query!
Recruitment
Recruitment status
Completed
Query!
Data analysis
Query!
Reason for early stopping/withdrawal
Query!
Other reasons
Query!
Date of first participant enrolment
Anticipated
Query!
Actual
1/12/2009
Query!
Date of last participant enrolment
Anticipated
Query!
Actual
Query!
Date of last data collection
Anticipated
Query!
Actual
1/07/2012
Query!
Sample size
Target
Query!
Accrual to date
Query!
Final
123
Query!
Recruitment in Australia
Recruitment state(s)
NSW,SA,WA
Query!
Recruitment hospital [1]
0
0
Research Site - Camperdown
Query!
Recruitment hospital [2]
0
0
Research Site - Adelaide
Query!
Recruitment hospital [3]
0
0
Research Site - Perth
Query!
Recruitment postcode(s) [1]
0
0
- Camperdown
Query!
Recruitment postcode(s) [2]
0
0
- Adelaide
Query!
Recruitment postcode(s) [3]
0
0
- Perth
Query!
Recruitment outside Australia
Country [1]
0
0
United States of America
Query!
State/province [1]
0
0
Arizona
Query!
Country [2]
0
0
United States of America
Query!
State/province [2]
0
0
California
Query!
Country [3]
0
0
United States of America
Query!
State/province [3]
0
0
Colorado
Query!
Country [4]
0
0
United States of America
Query!
State/province [4]
0
0
Illinois
Query!
Country [5]
0
0
United States of America
Query!
State/province [5]
0
0
Indiana
Query!
Country [6]
0
0
United States of America
Query!
State/province [6]
0
0
Michigan
Query!
Country [7]
0
0
United States of America
Query!
State/province [7]
0
0
Pennsylvania
Query!
Country [8]
0
0
United States of America
Query!
State/province [8]
0
0
Washington
Query!
Country [9]
0
0
Belgium
Query!
State/province [9]
0
0
Bruxelles
Query!
Country [10]
0
0
Belgium
Query!
State/province [10]
0
0
Leuven
Query!
Country [11]
0
0
Brazil
Query!
State/province [11]
0
0
Campinas
Query!
Country [12]
0
0
Canada
Query!
State/province [12]
0
0
Alberta
Query!
Country [13]
0
0
Canada
Query!
State/province [13]
0
0
Ontario
Query!
Country [14]
0
0
Canada
Query!
State/province [14]
0
0
Quebec
Query!
Country [15]
0
0
Canada
Query!
State/province [15]
0
0
Vancouver
Query!
Country [16]
0
0
China
Query!
State/province [16]
0
0
Beijing
Query!
Country [17]
0
0
China
Query!
State/province [17]
0
0
Guangzhou
Query!
Country [18]
0
0
China
Query!
State/province [18]
0
0
Shanghai
Query!
Country [19]
0
0
China
Query!
State/province [19]
0
0
Tianjin
Query!
Country [20]
0
0
France
Query!
State/province [20]
0
0
Lyon
Query!
Country [21]
0
0
France
Query!
State/province [21]
0
0
Marseille
Query!
Country [22]
0
0
Germany
Query!
State/province [22]
0
0
Berlin
Query!
Country [23]
0
0
Germany
Query!
State/province [23]
0
0
Bonn
Query!
Country [24]
0
0
Hong Kong
Query!
State/province [24]
0
0
Pokfulam
Query!
Country [25]
0
0
Hong Kong
Query!
State/province [25]
0
0
Shatin
Query!
Country [26]
0
0
India
Query!
State/province [26]
0
0
Punjab
Query!
Country [27]
0
0
India
Query!
State/province [27]
0
0
Tamil Nadu
Query!
Country [28]
0
0
India
Query!
State/province [28]
0
0
Bangalore
Query!
Country [29]
0
0
India
Query!
State/province [29]
0
0
Pune
Query!
Country [30]
0
0
Italy
Query!
State/province [30]
0
0
Firenze
Query!
Country [31]
0
0
Italy
Query!
State/province [31]
0
0
Milano
Query!
Country [32]
0
0
Japan
Query!
State/province [32]
0
0
Kasihara-City
Query!
Country [33]
0
0
Japan
Query!
State/province [33]
0
0
Kawasaki City
Query!
Country [34]
0
0
Japan
Query!
State/province [34]
0
0
Kitakyushu
Query!
Country [35]
0
0
Japan
Query!
State/province [35]
0
0
Nagoya
Query!
Country [36]
0
0
Japan
Query!
State/province [36]
0
0
Suginami-ku
Query!
Country [37]
0
0
Japan
Query!
State/province [37]
0
0
Tokyo
Query!
Country [38]
0
0
Poland
Query!
State/province [38]
0
0
Lodz
Query!
Country [39]
0
0
Poland
Query!
State/province [39]
0
0
Warszawa
Query!
Country [40]
0
0
Russian Federation
Query!
State/province [40]
0
0
Moscow
Query!
Country [41]
0
0
Russian Federation
Query!
State/province [41]
0
0
St. Petersburg
Query!
Country [42]
0
0
South Africa
Query!
State/province [42]
0
0
Gauteng
Query!
Country [43]
0
0
South Africa
Query!
State/province [43]
0
0
Western Cape
Query!
Country [44]
0
0
Sweden
Query!
State/province [44]
0
0
Malmö
Query!
Country [45]
0
0
Sweden
Query!
State/province [45]
0
0
Stockholm
Query!
Country [46]
0
0
United Kingdom
Query!
State/province [46]
0
0
Cambridge
Query!
Country [47]
0
0
United Kingdom
Query!
State/province [47]
0
0
London
Query!
Funding & Sponsors
Primary sponsor type
Commercial sector/Industry
Query!
Name
Bioverativ Therapeutics Inc.
Query!
Address
Query!
Country
Query!
Other collaborator category [1]
0
0
Commercial sector/Industry
Query!
Name [1]
0
0
Swedish Orphan Biovitrum
Query!
Address [1]
0
0
Query!
Country [1]
0
0
Query!
Ethics approval
Ethics application status
Query!
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.
Query!
Trial website
https://clinicaltrials.gov/ct2/show/NCT01027364
Query!
Trial related presentations / publications
Query!
Public notes
Query!
Contacts
Principal investigator
Name
0
0
Medical Director
Query!
Address
0
0
Bioverativ Therapeutics Inc.
Query!
Country
0
0
Query!
Phone
0
0
Query!
Fax
0
0
Query!
Email
0
0
Query!
Contact person for public queries
Name
0
0
Query!
Address
0
0
Query!
Country
0
0
Query!
Phone
0
0
Query!
Fax
0
0
Query!
Email
0
0
Query!
Contact person for scientific queries
Summary Results
For IPD and results data, please see
https://clinicaltrials.gov/ct2/show/NCT01027364
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