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    Clinical Trial Results:
    A Phase 3b Open-label, Multicenter, Safety and Efficacy Extension Study of a Recombinant Coagulation Factor IX Albumin Fusion Protein (rIX-FP) in Subjects with Hemophilia B

    Summary
    EudraCT number
    		 2012-005489-37
    Trial protocol
    		 DE   IT   CZ   BG   ES   AT  
    Global end of trial date
    02 Jun 2021

    Results information
    Results version number
    		 v1(current)
    This version publication date
    26 Nov 2021
    First version publication date
    26 Nov 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CSL654_3003
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02053792
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    CSL Behring GmbH
    Sponsor organisation address
    Emil-von-Behring Str. 76, Marburg, Germany, 35041
    Public contact
    Clinical Trial Coordinator, CSL Behring GmbH, 049 642139 3304, clinicaltrials@cslbehring.com
    Scientific contact
    Clinical Trial Coordinator, CSL Behring GmbH, 049 642139 3304, clinicaltrials@cslbehring.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-001107-PIP01-10
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    29 Jun 2021
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    02 Jun 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the safety of rIX-FP as measured by new cases of inhibitors against FIX in subjects with severe hemophilia B.
    Protection of trial subjects
    If a subject is withdrawn from the study or further participation is declined, they will continue to have access to medical care and will be treated as per routine medical practice.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    06 Feb 2014
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Australia: 5
    Country: Number of subjects enrolled
    Philippines: 2
    Country: Number of subjects enrolled
    United States: 6
    Country: Number of subjects enrolled
    Canada: 1
    Country: Number of subjects enrolled
    Israel: 15
    Country: Number of subjects enrolled
    Japan: 9
    Country: Number of subjects enrolled
    Malaysia: 2
    Country: Number of subjects enrolled
    South Africa: 2
    Country: Number of subjects enrolled
    Spain: 6
    Country: Number of subjects enrolled
    Austria: 5
    Country: Number of subjects enrolled
    Bulgaria: 4
    Country: Number of subjects enrolled
    Czechia: 3
    Country: Number of subjects enrolled
    France: 14
    Country: Number of subjects enrolled
    Germany: 11
    Country: Number of subjects enrolled
    Italy: 12
    Worldwide total number of subjects
    97
    EEA total number of subjects
    55
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    13
    Children (2-11 years)
    25
    Adolescents (12-17 years)
    5
    Adults (18-64 years)
    54
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Approximately 115 male PTPs and PUPs with hemophilia B were planned to be enrolled, including all eligible PTPs from CSLB-sponsored rIX-FP lead-in studies, approximately 10 PTPs who required major, nonemergency surgery, and approximately 20 PUPs.

    Period 1
    Period 1 title
    Overall (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 CSL654 (PTPs)
    Arm description
    		 Previously treated patients (PTPs) will administer CSL654 (rIX-FP) by intravenous infusion as routine prophylaxis, prevention, and on-demand treatment during a treatment period of approximately 5 years or the time it took to reach 100 EDs.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Recombinant fusion protein linking coagulation factor IX with albumin
    Investigational medicinal product code
    CSL654
    Other name
    rIX-FP
    Pharmaceutical forms
    Powder and solvent for solution for injection/infusion
    Routes of administration
    Intravenous use, Subcutaneous use
    Dosage and administration details
    Previously treated patients (PTPs) will administer rIX-FP by intravenous infusion as routine prophylaxis, prevention, and on-demand treatment during a treatment period of approximately 5 years. The dose of rIX-FP administered will be based on the subject's previous rIX-FP use and/or pharmacokinetic data.

    Arm title
    		 CSL654 (PUPs)
    Arm description
    		 Previously untreated patients (PUPs) administered CSL654 (rIX-FP) intravenously as weekly prophylaxis and/or on-demand treatment during the first 12 months, and as weekly routine prophylaxis thereafter up to 3 years or the time it takes to achieve 50 EDs..
    Arm type
    		 Experimental

    Investigational medicinal product name
    CSL654
    Investigational medicinal product code
    Other name
    rIX-FP
    Pharmaceutical forms
    Powder and solvent for solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects will administer rIX-FP by intravenous infusion as routine prophylaxis, prevention, and on-demand treatment during a treatment period of approximately 3 years. The dose of rIX-FP administered will be based on the subject's previous rIX-FP use and/or pharmacokinetic data.

    Number of subjects in period 1
    		CSL654 (PTPs) CSL654 (PUPs)
    Started
    83
    14
    Completed
    77
    10
    Not completed
    6
    4
         Adverse event, serious fatal
    1
    -
         Consent withdrawn by subject
    2
    2
         Physician decision
    -
    1
         Unknown
    2
    1
         Lack of efficacy
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    CSL654 (PTPs)
    Reporting group description
    		 Previously treated patients (PTPs) will administer CSL654 (rIX-FP) by intravenous infusion as routine prophylaxis, prevention, and on-demand treatment during a treatment period of approximately 5 years or the time it took to reach 100 EDs.

    Reporting group title
    CSL654 (PUPs)
    Reporting group description
    		 Previously untreated patients (PUPs) administered CSL654 (rIX-FP) intravenously as weekly prophylaxis and/or on-demand treatment during the first 12 months, and as weekly routine prophylaxis thereafter up to 3 years or the time it takes to achieve 50 EDs..

    Reporting group values
    		 CSL654 (PTPs) CSL654 (PUPs) Total
    Number of subjects
    		 83 14 97
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 13 13
        Children (2-11 years)
    		 24 1 25
        Adolescents (12-17 years)
    		 5 0 5
        Adults (18-64 years)
    		 54 0 54
        From 65-84 years
    		 0 0 0
        85 years and over
    		 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 27.7 ( 17.81 ) 1.3 ( 3.11 ) -
    Gender categorical
    Units: Subjects
        Female
    		 0 0 0
        Male
    		 83 14 97

    End points

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    End points reporting groups
    Reporting group title
    CSL654 (PTPs)
    Reporting group description
    		 Previously treated patients (PTPs) will administer CSL654 (rIX-FP) by intravenous infusion as routine prophylaxis, prevention, and on-demand treatment during a treatment period of approximately 5 years or the time it took to reach 100 EDs.

    Reporting group title
    CSL654 (PUPs)
    Reporting group description
    		 Previously untreated patients (PUPs) administered CSL654 (rIX-FP) intravenously as weekly prophylaxis and/or on-demand treatment during the first 12 months, and as weekly routine prophylaxis thereafter up to 3 years or the time it takes to achieve 50 EDs..

    Primary: Total number of subjects who develop inhibitors against factor IX (FIX)

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    End point title
    		 Total number of subjects who develop inhibitors against factor IX (FIX) [1]
    End point description
    End point type
    Primary
    End point timeframe
    For PTPs: up to 5 years or the time it takes to achieve 100 exposure days (EDs). For PUPs: up to 3 years or the time it takes to achieve 50 EDs.
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive statistics used
    End point values
    		 CSL654 (PTPs) CSL654 (PUPs)
    Number of subjects analysed
    83
    12
    Units: subjects
        number (not applicable)
    0
    1
    No statistical analyses for this end point

    Primary: Incremental recovery of 50 IU/kg CSL654 in previously untreated patients (PUPs)

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    End point title
    		 Incremental recovery of 50 IU/kg CSL654 in previously untreated patients (PUPs) [2] [3]
    End point description
    End point type
    Primary
    End point timeframe
    30 minutes after CSL654 infusion
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive statistics used because study is per guideline and not powered for this endpoint.
    [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only PUPs for this endpoint
    End point values
    		 CSL654 (PUPs)
    Number of subjects analysed
    8
    Units: (IU/dL)/(IU/kg)
    arithmetic mean (standard deviation)
        Uncorrected FIX Activity
    1.295 ( 0.3578 )
        Baseline-corrected FIX Activity
    1.231 ( 0.3729 )
    No statistical analyses for this end point

    Secondary: Total Annualized Bleeding Rate (ABR) by Prophylaxis Regimen (PTPs)

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    End point title
    		 Total Annualized Bleeding Rate (ABR) by Prophylaxis Regimen (PTPs) [4]
    End point description
    End point type
    Secondary
    End point timeframe
    For PTPs: up to 5 years or the time it takes to achieve 100 exposure days (EDs).
    Notes
    [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Descriptive statistics derived only for PTPs
    End point values
    		 CSL654 (PTPs)
    Number of subjects analysed
    83 [5]
    Units: Bleeds/Year/Subject
    arithmetic mean (standard deviation)
        7-Day Regimen (n=41)
    2.89 ( 3.115 )
        10-Day Regimen (n=23)
    2.72 ( 2.827 )
        14-Day Regimen (n=48)
    2.72 ( 3.395 )
        21-Day Regimen (n=11)
    1.19 ( 1.572 )
    Notes
    [5] - Subjects may be assigned under multiple regimens, but will be counted only once in any given regimen
    No statistical analyses for this end point

    Secondary: Spontaneous ABR by Prophylaxis Regimen (PTPs)

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    End point title
    		 Spontaneous ABR by Prophylaxis Regimen (PTPs) [6]
    End point description
    End point type
    Secondary
    End point timeframe
    For PTPs: up to 5 years or the time it takes to achieve 100 exposure days (EDs).
    Notes
    [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only PTPs for this endpoint
    End point values
    		 CSL654 (PTPs)
    Number of subjects analysed
    83 [7]
    Units: Bleeds/Year/Subject
    arithmetic mean (standard deviation)
        7-Day Regimen (n=41)
    0.95 ( 1.672 )
        10-Day Regimen (n=23)
    0.98 ( 1.689 )
        14-Day Regimen (n=48)
    1.32 ( 2.205 )
        21-Day Regimen (n=11)
    0.60 ( 1.408 )
    Notes
    [7] - Subjects may be assigned under multiple regimens, but will be counted only once in any given regimen
    No statistical analyses for this end point

    Secondary: Total ABR for On-demand Regimen vs. 14-Day Regimen (PTPs)

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    End point title
    		 Total ABR for On-demand Regimen vs. 14-Day Regimen (PTPs) [8]
    End point description
    End point type
    Secondary
    End point timeframe
    For PTPs: up to 5 years or the time it takes to achieve 100 exposure days (EDs).
    Notes
    [8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only PTPs for this endpoint
    End point values
    		 CSL654 (PTPs)
    Number of subjects analysed
    14
    Units: Bleeds/Year/Subject
    arithmetic mean (standard deviation)
        On-demand Regimen (n=14)
    17.51 ( 7.130 )
        14-Day Regimen (n=14)
    3.01 ( 4.204 )
    No statistical analyses for this end point

    Secondary: Spontaneous ABR for On-demand Regimen vs. 14-Day Regimen (PTPs)

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    End point title
    		 Spontaneous ABR for On-demand Regimen vs. 14-Day Regimen (PTPs) [9]
    End point description
    End point type
    Secondary
    End point timeframe
    For PTPs: up to 5 years or the time it takes to achieve 100 exposure days (EDs).
    Notes
    [9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only PTPs for this endpoint
    End point values
    		 CSL654 (PTPs)
    Number of subjects analysed
    14
    Units: Bleeds/Year/Subject
    arithmetic mean (standard deviation)
        On-demand Regimen (n=14)
    13.17 ( 5.873 )
        14-Day Regimen (n=14)
    1.93 ( 3.363 )
    No statistical analyses for this end point

    Secondary: CSL654 consumed per month per subject during routine prophylaxis treatment

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    End point title
    		 CSL654 consumed per month per subject during routine prophylaxis treatment
    End point description
    End point type
    Secondary
    End point timeframe
    For PTPs: up to 5 years or the time it takes to achieve 100 exposure days (EDs). For PUPs: up to 3 years or the time it takes to achieve 50 EDs.
    End point values
    		 CSL654 (PTPs) CSL654 (PUPs)
    Number of subjects analysed
    83
    12
    Units: IU/kg
        arithmetic mean (standard deviation)
    181.8 ( 35.16 )
    188.53 ( 24.096 )
    No statistical analyses for this end point

    Secondary: Percentage of participants with at least one treatment emergent adverse event (TEAE) and the percentage of participants with at least one CSL654-related TEAE

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    End point title
    		 Percentage of participants with at least one treatment emergent adverse event (TEAE) and the percentage of participants with at least one CSL654-related TEAE
    End point description
    End point type
    Secondary
    End point timeframe
    For PTPs: up to 5 years or the time it takes to achieve 100 exposure days (EDs). For PUPs: up to 3 years or the time it takes to achieve 50 EDs.
    End point values
    		 CSL654 (PTPs) CSL654 (PUPs)
    Number of subjects analysed
    83
    12
    Units: Percent
    number (not applicable)
        AEs
    89.2
    91.7
        Related AEs
    1.2
    16.7
    No statistical analyses for this end point

    Secondary: Number of Participants with Investigator's Overall Clinical Assessment of Hemostatic Efficacy for the Treatment of Major Bleeding Events with CSL654 (PUPs)

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    End point title
    		 Number of Participants with Investigator's Overall Clinical Assessment of Hemostatic Efficacy for the Treatment of Major Bleeding Events with CSL654 (PUPs) [10]
    End point description
    The investigator will rate the efficacy of the CSL654 treatment based on a hemostatic efficacy four point rating scale of "excellent, good, moderate or poor/no response
    End point type
    Secondary
    End point timeframe
    Up to 3 years or the time it takes to achieve 50 EDs
    Notes
    [10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only PUPs for this endpoint
    End point values
    		 CSL654 (PUPs)
    Number of subjects analysed
    0 [11]
    Units: Participants
    number (not applicable)
        Excellent
        Good
        Moderate
        Poor/No response
    Notes
    [11] - No major bleeding events were reported.
    No statistical analyses for this end point

    Secondary: Total ABR for Subjects >=12 years: 7-Day Regimen vs. 14-Day Regimen (PTPs)

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    End point title
    		 Total ABR for Subjects >=12 years: 7-Day Regimen vs. 14-Day Regimen (PTPs) [12]
    End point description
    End point type
    Secondary
    End point timeframe
    For PTPs: up to 5 years or the time it takes to achieve 100 exposure days (EDs).
    Notes
    [12] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only PTPs for this endpoint
    End point values
    		 CSL654 (PTPs)
    Number of subjects analysed
    41
    Units: Bleeds/Year/Subject
    arithmetic mean (standard deviation)
        7-Day Regimen
    1.12 ( 1.697 )
        14-Day Regimen
    2.19 ( 3.000 )
    No statistical analyses for this end point

    Secondary: Spontaneous ABR for Subjects >=12 years: 7-Day Regimen vs. 14-Day Regimen (PTPs)

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    End point title
    		 Spontaneous ABR for Subjects >=12 years: 7-Day Regimen vs. 14-Day Regimen (PTPs) [13]
    End point description
    End point type
    Secondary
    End point timeframe
    For PTPs: up to 5 years or the time it takes to achieve 100 exposure days (EDs).
    Notes
    [13] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only PTPs for this endpoint
    End point values
    		 CSL654 (PTPs)
    Number of subjects analysed
    41
    Units: Bleeds/Year/Subject
    arithmetic mean (standard deviation)
        7-Day Regimen
    0.49 ( 1.135 )
        14-Day Regimen
    1.33 ( 2.349 )
    No statistical analyses for this end point

    Secondary: Total ABR for Subjects >=12 years: 7-Day Regimen vs. (10 or 14)-Day Regimen (PTPs)

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    End point title
    		 Total ABR for Subjects >=12 years: 7-Day Regimen vs. (10 or 14)-Day Regimen (PTPs) [14]
    End point description
    End point type
    Secondary
    End point timeframe
    For PTPs: up to 5 years or the time it takes to achieve 100 exposure days (EDs).
    Notes
    [14] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only PTPs for this endpoint
    End point values
    		 CSL654 (PTPs)
    Number of subjects analysed
    49
    Units: Bleeds/Year/Subject
    arithmetic mean (standard deviation)
        7-Day Regimen
    1.31 ( 1.868 )
        (10 or 14)-Day Regimen
    2.01 ( 2.700 )
    No statistical analyses for this end point

    Secondary: Spontaneous ABR for Subjects >=12 years: 7-Day Regimen vs. (10 or 14)-Day Regimen (PTPs)

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    End point title
    		 Spontaneous ABR for Subjects >=12 years: 7-Day Regimen vs. (10 or 14)-Day Regimen (PTPs) [15]
    End point description
    End point type
    Secondary
    End point timeframe
    For PTPs: up to 5 years or the time it takes to achieve 100 exposure days (EDs).
    Notes
    [15] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only PTPs for this endpoint
    End point values
    		 CSL654 (PTPs)
    Number of subjects analysed
    49
    Units: Bleeds/Year/Subject
    arithmetic mean (standard deviation)
        7-Day Regimen
    0.57 ( 1.192 )
        (10 or 14)-Day Regimen
    1.05 ( 2.022 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    For PTPs: up to 5 years or the time it takes to achieve 100 exposure days (EDs). For PUPs: up to 3 years or the time it takes to achieve 50 EDs.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21.0
    Reporting groups
    Reporting group title
    CSL654 (PTPs)
    Reporting group description
    		 Subjects will administer CSL654 (rIX-FP) by intravenous infusion as routine prophylaxis, prevention, and on-demand treatment during a treatment period of approximately 5 years.

    Reporting group title
    CSL654 (PUPs)
    Reporting group description
    		 For previously untreated patients, subjects will administer CSL654 (rIX-FP) intravenously as weekly prophylaxis and/or on-demand treatment during the first 12 months, and as weekly routine prophylaxis thereafter.

    Serious adverse events
    		 CSL654 (PTPs) CSL654 (PUPs)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    17 / 83 (20.48%)
    5 / 12 (41.67%)
         number of deaths (all causes)
    1
    0
         number of deaths resulting from adverse events
    1
    0
    Investigations
    Serum ferritin decreased
         subjects affected / exposed
    1 / 83 (1.20%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anti factor IX antibody increased
         subjects affected / exposed
    0 / 83 (0.00%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Head injury
         subjects affected / exposed
    3 / 83 (3.61%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Contusion
         subjects affected / exposed
    1 / 83 (1.20%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Extradural Haematoma
         subjects affected / exposed
    1 / 83 (1.20%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscle injury
         subjects affected / exposed
    1 / 83 (1.20%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Road traffic accident
         subjects affected / exposed
    1 / 83 (1.20%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    1 / 83 (1.20%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural haemorrhage
         subjects affected / exposed
    1 / 83 (1.20%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Haematoma
         subjects affected / exposed
    1 / 83 (1.20%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral Ischaemia
         subjects affected / exposed
    1 / 83 (1.20%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Haemorrhage intracranial
         subjects affected / exposed
    1 / 83 (1.20%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Blood and lymphatic system disorders
    Iron deficiency anaemia
         subjects affected / exposed
    2 / 83 (2.41%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anaemia
         subjects affected / exposed
    1 / 83 (1.20%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Haemorrhoids
         subjects affected / exposed
    1 / 83 (1.20%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Large intestine polyp
         subjects affected / exposed
    1 / 83 (1.20%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophagitis
         subjects affected / exposed
    1 / 83 (1.20%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Epistaxis
         subjects affected / exposed
    1 / 83 (1.20%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    1 / 83 (1.20%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Haemarthrosis
         subjects affected / exposed
    2 / 83 (2.41%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arthralgia
         subjects affected / exposed
    1 / 83 (1.20%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arthritis
         subjects affected / exposed
    1 / 83 (1.20%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemophilic arthropathy
         subjects affected / exposed
    1 / 83 (1.20%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Joint Swelling
         subjects affected / exposed
    1 / 83 (1.20%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Abscess Jaw
         subjects affected / exposed
    1 / 83 (1.20%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    1 / 83 (1.20%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peritonsillar abscess
         subjects affected / exposed
    1 / 83 (1.20%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 83 (0.00%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    0 / 83 (0.00%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    0 / 83 (0.00%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 CSL654 (PTPs) CSL654 (PUPs)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    69 / 83 (83.13%)
    11 / 12 (91.67%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    5 / 83 (6.02%)
    0 / 12 (0.00%)
         occurrences all number
    5
    0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    15 / 83 (18.07%)
    6 / 12 (50.00%)
         occurrences all number
    24
    9
    Catheter site bruise
         subjects affected / exposed
    0 / 83 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    Influenza like illness
         subjects affected / exposed
    0 / 83 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    0 / 83 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    3
    Selective IgA immunodeficiency
         subjects affected / exposed
    0 / 83 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    6 / 83 (7.23%)
    2 / 12 (16.67%)
         occurrences all number
    7
    2
    Psychiatric disorders
    Irritability
         subjects affected / exposed
    0 / 83 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    7 / 83 (8.43%)
    2 / 12 (16.67%)
         occurrences all number
    12
    6
    Laceration
         subjects affected / exposed
    6 / 83 (7.23%)
    2 / 12 (16.67%)
         occurrences all number
    7
    2
    Fall
         subjects affected / exposed
    4 / 83 (4.82%)
    4 / 12 (33.33%)
         occurrences all number
    4
    6
    Head injury
         subjects affected / exposed
    3 / 83 (3.61%)
    3 / 12 (25.00%)
         occurrences all number
    4
    5
    Mouth injury
         subjects affected / exposed
    0 / 83 (0.00%)
    2 / 12 (16.67%)
         occurrences all number
    0
    2
    Arthropod bite
         subjects affected / exposed
    0 / 83 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    3
    Accident
         subjects affected / exposed
    0 / 83 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    Skin abrasion
         subjects affected / exposed
    0 / 83 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    Soft tissue injury
         subjects affected / exposed
    0 / 83 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    Tongue injury
         subjects affected / exposed
    0 / 83 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    Congenital, familial and genetic disorders
    Factor VII deficiency
         subjects affected / exposed
    0 / 83 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    Nervous system disorders
    Headache
         subjects affected / exposed
    11 / 83 (13.25%)
    0 / 12 (0.00%)
         occurrences all number
    21
    0
    Tongue biting
         subjects affected / exposed
    0 / 83 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    Gastrointestinal disorders
    Dental caries
         subjects affected / exposed
    10 / 83 (12.05%)
    1 / 12 (8.33%)
         occurrences all number
    12
    1
    Diarrhoea
         subjects affected / exposed
    6 / 83 (7.23%)
    1 / 12 (8.33%)
         occurrences all number
    6
    1
    Toothache
         subjects affected / exposed
    5 / 83 (6.02%)
    0 / 12 (0.00%)
         occurrences all number
    6
    0
    Constipation
         subjects affected / exposed
    4 / 83 (4.82%)
    2 / 12 (16.67%)
         occurrences all number
    5
    3
    Teething
         subjects affected / exposed
    0 / 83 (0.00%)
    2 / 12 (16.67%)
         occurrences all number
    0
    2
    Abdominal pain
         subjects affected / exposed
    0 / 83 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    Gingival disorder
         subjects affected / exposed
    0 / 83 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    Vomiting
         subjects affected / exposed
    3 / 83 (3.61%)
    1 / 12 (8.33%)
         occurrences all number
    3
    1
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    2 / 83 (2.41%)
    2 / 12 (16.67%)
         occurrences all number
    5
    4
    Dermatitis diaper
         subjects affected / exposed
    0 / 83 (0.00%)
    2 / 12 (16.67%)
         occurrences all number
    0
    2
    Urticaria
         subjects affected / exposed
    0 / 83 (0.00%)
    2 / 12 (16.67%)
         occurrences all number
    0
    2
    Ingrowing nail
         subjects affected / exposed
    0 / 83 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    Nail bed inflammation
         subjects affected / exposed
    0 / 83 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    0 / 83 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    25 / 83 (30.12%)
    0 / 12 (0.00%)
         occurrences all number
    35
    0
    Pain in extremity
         subjects affected / exposed
    8 / 83 (9.64%)
    0 / 12 (0.00%)
         occurrences all number
    10
    0
    Musculoskeletal pain
         subjects affected / exposed
    6 / 83 (7.23%)
    0 / 12 (0.00%)
         occurrences all number
    8
    0
    Soft tissue swelling
         subjects affected / exposed
    0 / 83 (0.00%)
    2 / 12 (16.67%)
         occurrences all number
    0
    5
    Haemophilic arthropathy
         subjects affected / exposed
    2 / 83 (2.41%)
    1 / 12 (8.33%)
         occurrences all number
    3
    1
    Muscle spasms
         subjects affected / exposed
    0 / 83 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    15 / 83 (18.07%)
    3 / 12 (25.00%)
         occurrences all number
    25
    14
    Gastroenteritis
         subjects affected / exposed
    10 / 83 (12.05%)
    1 / 12 (8.33%)
         occurrences all number
    10
    1
    Influenza
         subjects affected / exposed
    6 / 83 (7.23%)
    1 / 12 (8.33%)
         occurrences all number
    6
    2
    Sinusitis
         subjects affected / exposed
    5 / 83 (6.02%)
    0 / 12 (0.00%)
         occurrences all number
    6
    0
    Tonsillitis
         subjects affected / exposed
    5 / 83 (6.02%)
    0 / 12 (0.00%)
         occurrences all number
    8
    0
    Bronchitis
         subjects affected / exposed
    4 / 83 (4.82%)
    2 / 12 (16.67%)
         occurrences all number
    8
    6
    Upper respiratory tract infection
         subjects affected / exposed
    4 / 83 (4.82%)
    3 / 12 (25.00%)
         occurrences all number
    6
    7
    Ear infection
         subjects affected / exposed
    3 / 83 (3.61%)
    1 / 12 (8.33%)
         occurrences all number
    3
    2
    Rhinitis
         subjects affected / exposed
    3 / 83 (3.61%)
    2 / 12 (16.67%)
         occurrences all number
    3
    2
    Viral infection
         subjects affected / exposed
    2 / 83 (2.41%)
    1 / 12 (8.33%)
         occurrences all number
    2
    2
    Pharyngitis streptococcal
         subjects affected / exposed
    0 / 83 (0.00%)
    2 / 12 (16.67%)
         occurrences all number
    0
    3
    Hand-foot-and-mouth disease
         subjects affected / exposed
    0 / 83 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    2
    Otitis media
         subjects affected / exposed
    0 / 83 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    2
    Croup infectious
         subjects affected / exposed
    0 / 83 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    Eye infection
         subjects affected / exposed
    0 / 83 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    Eyelid boil
         subjects affected / exposed
    0 / 83 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    Gastrointestinal infection
         subjects affected / exposed
    0 / 83 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    Otitis media chronic
         subjects affected / exposed
    0 / 83 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    Otitis media viral
         subjects affected / exposed
    0 / 83 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    Paronychia
         subjects affected / exposed
    0 / 83 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    Respiratory syncytial virus infection
         subjects affected / exposed
    0 / 83 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    Respiratory tract infection viral
         subjects affected / exposed
    0 / 83 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    Streptococcal infection
         subjects affected / exposed
    0 / 83 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    Urinary tract infection
         subjects affected / exposed
    0 / 83 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    Wound infection
         subjects affected / exposed
    0 / 83 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 83 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    17 Sep 2013
    1. Addition of a third group of subjects (Arm 3) to the study design. Arm 3 comprises subjects who have not previously completed a CSL-sponsored rIX-FP lead-in study and who are scheduled to have a major non-emergency surgery within 8 weeks from the start of the initial pharmacokinetic rIX-FP (100 IU/kg) evaluation period. 2. Change in the sample size from 85 to 95. 3. Clarification that the exploratory objective relating to quality of life is limited to subjects from the CSL654_3002 lead-in study. 4. Minor corrections and clarifications, including word modifications and administrative changes.
    03 Jun 2014
    - Per agreement with The Paediatric Committee (PDCO) /European Medicines Agency, study in previously untreated patients (PUPs) is added into this study. 1. To add PUPs with severe hemophilia B (FIX activity ≤2%) who have never been treated with FIX clotting factor products (except previous exposure to blood components) as study Arm 4. 2. Change in the sample size from 95 to 115, to include at least 20 PUPs. 3. Independent Data Monitoring Committee is being utilized to provide an independent evaluation of the study.
    14 Oct 2015
    Addition of substudy to assess the pharmacokinetics and safety following subcutaneous administration of rIX-FP in hemophilia B subjects. This substudy will comprise subjects who are currently enrolled in the main study protocol CSL654_3003.
    02 Dec 2016
    1. Main study: Addition of the ABR for total treated bleeding episodes to the comparisons between prophylaxis regimens for subjects from Study CSL654_3001. Addition of multiple testing procedure to control the overall Type I error rate for ABR and spontaneous annual bleeding rate (AsBR) comparisons between prophylaxis regimens. 2. Main study: Update of overall study duration and study participation of Arms 1, 2 and 3 subjects to approximately 5 years, and addition of visits beyond 36 months. 3. Main study and subcutaneous (SC) substudy: Addition of final analyses of the a) previously treated patient (PTP) data when all PTPs have completed the study and b) SC substudy data when all subjects have completed the SC substudy. 4. Main study: Minor corrections and clarifications, including word modifications and administrative changes throughout the document. 5. SC substudy: Change in SC dosing in Cohort 3 from single to repeated SC dosing (including home treatment). 6. SC substudy: Addition of optional Cohort 4 for repeated SC dosing that will be opened if additional data are needed to inform further clinical development. 7. SC substudy: Addition of details regarding local tolerability assessments. 8. SC substudy: Addition of SC substudy information to the main study protocol where relevant (eg, objectives and endpoints).
    03 Feb 2020
    1. Adjustment of number of PUPs from “at least 20” to “at least 13” to reflect PDCO opinion to allow early termination of PUP enrolment. 2. As study has been completed for PTPs, adjustment of number of PTPs in final PTP analysis (N=83). 3. Adjustment of overall number of subjects to reflect 1 and 2. 4. The frequency of the CSL Safety Management Team meetings has been updated from approximately every 6 months to approximately every 3 months, to reflect an internal process change.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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