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    Clinical Trial Results:
    A multicenter, open-label, multiple-dose, dose escalation study to investigate the pharmacokinetics, efficacy, and safety of rVIIa-FP (CSL689) in subjects with hemophilia (A or B) and inhibitors.

    Summary
    EudraCT number
    		 2012-001309-26
    Trial protocol
    		 DE   GB   ES   IT  
    Global end of trial date
    28 Mar 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    04 Oct 2018
    First version publication date
    04 Oct 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CSL689_2001
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02484638
    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
    Trial Registration Coordinator, CSL Behring GmbH, clinicaltrials@cslbehring.com
    Scientific contact
    Trial Registration Coordinator, CSL Behring GmbH, clinicaltrials@cslbehring.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-001886-PIP15-01
    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?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    15 May 2018
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    28 Mar 2018
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    Part 1 [Pharmacokinetic (PK) part]: To evaluate the single-dose PK of CSL689 (low dose, high dose) in subjects with hemophilia A or B and inhibitors and to compare with the single-dose PK of Eptacog alfa (low dose or high dose). Part 2 (Dose-evaluation part): To determine the best dose ("population-based best dose") of the 2 CSL689 dose levels evaluated. Part 3 (Repeated-dose part): To evaluate the clinical efficacy of the population-based best dose of CSL689 for on-demand therapy of bleeding events in subjects with hemophilia A or B and inhibitors.
    Protection of trial subjects
    This study was carried out in accordance with the International Conference on Harmonisation Good Clinical Practice guidelines and standard operating procedures for clinical research and development at CSL Behring.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    23 Jul 2015
    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
    Georgia: 2
    Country: Number of subjects enrolled
    Italy: 2
    Country: Number of subjects enrolled
    Japan: 1
    Country: Number of subjects enrolled
    Malaysia: 2
    Country: Number of subjects enrolled
    Russian Federation: 2
    Country: Number of subjects enrolled
    South Africa: 3
    Country: Number of subjects enrolled
    Serbia: 1
    Country: Number of subjects enrolled
    Thailand: 4
    Country: Number of subjects enrolled
    Ukraine: 5
    Country: Number of subjects enrolled
    Spain: 1
    Country: Number of subjects enrolled
    United Kingdom: 1
    Country: Number of subjects enrolled
    France: 1
    Worldwide total number of subjects
    25
    EEA total number of subjects
    5
    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)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    3
    Adults (18-64 years)
    22
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Performed as a multicenter study in 12 countries (France, Georgia, Great Britain, Italy, Japan, Malaysia, Russia, Serbia, South Africa, Spain, Thailand, and Ukraine). Study conducted at clinics and home of subjects.

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

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 NovoSeven (low dose)
    Arm description
    		 Single injection of 0.09 mg/kg NovoSeven rFVIIa in Part 1 (PK module)
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Eptacog alfa
    Investigational medicinal product code
    Other name
    NovoSeven
    Pharmaceutical forms
    Powder and solvent for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Delivered by intravenous injection of 0.09 mg/kg

    Arm title
    		 NovoSeven (high dose)
    Arm description
    		 Single injection of 0.27 mg/kg NovoSeven rFVIIa in Part 1 (PK module)
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Eptacog alfa
    Investigational medicinal product code
    Other name
    NovoSeven
    Pharmaceutical forms
    Powder and solvent for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Delivered by intravenous injection of 0.27 mg/kg

    Arm title
    		 CSL689 (low dose)
    Arm description
    		 • Part 1 (PK module): single injection of low-dose CSL689 (0.75 mg/kg) for PK evaluation • Part 2 (Dose evaluation module): up to 2 injections of low-dose CSL689 per bleeding event (bleeding events 1 to 3*) • Part 3 (Repeated dose module): up to 3 injections of low-dose CSL689 per bleeding event * Note: All subjects in the low-dose arm will be treated with high-dose CSL689 (1.5 mg/kg) for bleeding events 4-6 in Part 2
    Arm type
    		 Experimental

    Investigational medicinal product name
    Recombinant fusion protein, linking activated coagulation factor VII with albumin (rVIIa-FP)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder and solvent for suspension for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Delivered by intravenous injection at 0.75 mg/kg

    Arm title
    		 CSL689 (high dose)
    Arm description
    		 • Part 1 (PK module): single injection of high-dose CSL689 (1.5 mg/kg) for PK evaluation • Part 2 (Dose evaluation module): up to 2 injections of high-dose CSL689 per bleeding event (bleeding events 4 to 6*) • Part 3 (Repeated dose module): up to 3 injections of high-dose CSL689 per bleeding event * Note: All subjects in the high-dose arm will be treated with low-dose CSL689 (0.75 mg/kg) for bleeding events 1-3 in Part 2
    Arm type
    		 Experimental

    Investigational medicinal product name
    Recombinant fusion protein, linking activated coagulation factor VII with albumin (rVIIa-FP)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder and solvent for suspension for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Delivered by intravenous injection at 1.5 mg/kg

    Number of subjects in period 1
    		NovoSeven (low dose) NovoSeven (high dose) CSL689 (low dose) CSL689 (high dose)
    Started
    6
    7
    8
    4
    Completed
    6
    4
    3
    4
    Not completed
    0
    3
    5
    0
         Consent withdrawn by subject
    -
    3
    2
    -
         Terminated by sponsor
    -
    -
    1
    -
         Other reason
    -
    -
    1
    -
         Lack of efficacy
    -
    -
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall Trial
    Reporting group description
    		 -

    Reporting group values
    		 Overall Trial Total
    Number of subjects
    		 25 25
    Age categorical
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 0 0
        Adolescents (12-17 years)
    		 3 3
        Adults (18-64 years)
    		 22 22
        From 65-84 years
    		 0 0
        85 years and over
    		 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 32.5 ( 13.59 ) -
    Gender categorical
    Units: Subjects
        Female
    		 0 0
        Male
    		 25 25

    End points

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    End points reporting groups
    Reporting group title
    NovoSeven (low dose)
    Reporting group description
    		 Single injection of 0.09 mg/kg NovoSeven rFVIIa in Part 1 (PK module)

    Reporting group title
    NovoSeven (high dose)
    Reporting group description
    		 Single injection of 0.27 mg/kg NovoSeven rFVIIa in Part 1 (PK module)

    Reporting group title
    CSL689 (low dose)
    Reporting group description
    		 • Part 1 (PK module): single injection of low-dose CSL689 (0.75 mg/kg) for PK evaluation • Part 2 (Dose evaluation module): up to 2 injections of low-dose CSL689 per bleeding event (bleeding events 1 to 3*) • Part 3 (Repeated dose module): up to 3 injections of low-dose CSL689 per bleeding event * Note: All subjects in the low-dose arm will be treated with high-dose CSL689 (1.5 mg/kg) for bleeding events 4-6 in Part 2

    Reporting group title
    CSL689 (high dose)
    Reporting group description
    		 • Part 1 (PK module): single injection of high-dose CSL689 (1.5 mg/kg) for PK evaluation • Part 2 (Dose evaluation module): up to 2 injections of high-dose CSL689 per bleeding event (bleeding events 4 to 6*) • Part 3 (Repeated dose module): up to 3 injections of high-dose CSL689 per bleeding event * Note: All subjects in the high-dose arm will be treated with low-dose CSL689 (0.75 mg/kg) for bleeding events 1-3 in Part 2

    Subject analysis set title
    Safety Population (SP)
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The Safety Population included all subjects who received any quantity of investigational product (CSL689 or NovoSeven® rFVIIa)

    Subject analysis set title
    Pharmacokinetic Population (PK)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    The PK Population included all subjects from the Safety Population with at least 1 analyzable PK sample.

    Subject analysis set title
    Efficacy Population (EP)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    The Efficacy Population included all subjects who received at least one dose of CSL689 as on-demand treatment during Dose Evaluation and Repeated Dose Module.

    Primary: Area under the FVIIa activity versus time curve from time zero to the last sample with quantifiable FVIIa activity (AUC0-last) in the PK module (PK)

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    End point title
    		 Area under the FVIIa activity versus time curve from time zero to the last sample with quantifiable FVIIa activity (AUC0-last) in the PK module (PK) [1]
    End point description
    End point type
    Primary
    End point timeframe
    Up to 24 hours for NovoSeven and up to 120 hours for CSL689 post injection
    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: Only descriptive statistics were used
    End point values
    		 NovoSeven (low dose) NovoSeven (high dose) CSL689 (low dose) CSL689 (high dose)
    Number of subjects analysed
    6
    6
    8
    4 [2]
    Units: h*IU/mL
    arithmetic mean (standard deviation)
        with baseline correction
    111.8 ( 20.395 )
    325.0 ( 55.064 )
    443.8 ( 145.22 )
    891.3 ( 265.50 )
        without baseline correction
    113.6 ( 21.371 )
    327.0 ( 55.717 )
    464.1 ( 132.37 )
    895.1 ( 266.77 )
    Notes
    [2] - Subjects from the NovoSeven arms also received high dose of CSL689, N=15
    No statistical analyses for this end point

    Primary: Incremental Recovery in the PK module (PK)

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    End point title
    		 Incremental Recovery in the PK module (PK) [3]
    End point description
    End point type
    Primary
    End point timeframe
    Up to 24 hours for NovoSeven and up to 120 hours for CSL689 post injection
    Notes
    [3] - 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: Only descriptive statistics were used
    End point values
    		 NovoSeven (low dose) NovoSeven (high dose) CSL689 (low dose) CSL689 (high dose)
    Number of subjects analysed
    6
    6
    8
    4 [4]
    Units: (IU/dL)/(IU/kg)
    arithmetic mean (standard deviation)
        with baseline correction
    0.9805 ( 0.11697 )
    0.9670 ( 0.19661 )
    1.557 ( 0.46535 )
    1.391 ( 0.35815 )
        without baseline correction
    0.9823 ( 0.11961 )
    0.9672 ( 0.19648 )
    1.571 ( 0.45955 )
    1.394 ( 0.35785 )
    Notes
    [4] - Subjects from the NovoSeven arms also received high dose of CSL689, N=15
    No statistical analyses for this end point

    Primary: Elimination half-life (t1/2) in the PK module (PK)

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    End point title
    		 Elimination half-life (t1/2) in the PK module (PK) [5]
    End point description
    End point type
    Primary
    End point timeframe
    Up to 24 hours for NovoSeven and up to 120 hours for CSL689 post injection
    Notes
    [5] - 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: Only descriptive statistics were used
    End point values
    		 NovoSeven (low dose) NovoSeven (high dose) CSL689 (low dose) CSL689 (high dose)
    Number of subjects analysed
    6
    6
    8
    4 [6]
    Units: hours
    arithmetic mean (standard deviation)
        with baseline correction
    2.980 ( 0.48613 )
    2.600 ( 0.26488 )
    9.141 ( 3.0035 )
    8.713 ( 1.1558 )
        without baseline correction
    3.473 ( 0.52812 )
    2.795 ( 0.37623 )
    14.21 ( 3.8290 )
    9.402 ( 1.8629 )
    Notes
    [6] - Subjects from the NovoSeven arms also received high dose of CSL689, N=15
    No statistical analyses for this end point

    Primary: Total clearance in the PK module (PK)

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    End point title
    		 Total clearance in the PK module (PK) [7]
    End point description
    End point type
    Primary
    End point timeframe
    Up to 24 hours for NovoSeven and up to 120 hours for CSL689 post injection
    Notes
    [7] - 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: Only descriptive statistics were used
    End point values
    		 NovoSeven (low dose) NovoSeven (high dose) CSL689 (low dose) CSL689 (high dose)
    Number of subjects analysed
    6
    6
    8
    4 [8]
    Units: mL/h/kg
    arithmetic mean (standard deviation)
        with baseline correction
    41.07 ( 6.4273 )
    42.58 ( 7.6064 )
    7.280 ( 2.6120 )
    7.149 ( 2.9154 )
        without baseline correction
    40.33 ( 6.5292 )
    42.28 ( 7.7021 )
    6.825 ( 2.3415 )
    7.112 ( 2.8984 )
    Notes
    [8] - Subjects from the NovoSeven arms also received high dose of CSL689, N=15
    No statistical analyses for this end point

    Primary: Percentage of bleeding events successfully treated with 1 injection of CSL689 in the dose evaluation module (EP)

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    End point title
    		 Percentage of bleeding events successfully treated with 1 injection of CSL689 in the dose evaluation module (EP) [9] [10]
    End point description
    End point type
    Primary
    End point timeframe
    Up to 8 hours after first CSL689 injection for each bleeding event
    Notes
    [9] - 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: Only descriptive statistics were used
    [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 CSL689 was used in this module
    End point values
    		 CSL689 (low dose) CSL689 (high dose)
    Number of subjects analysed
    8 [11]
    4 [12]
    Units: Percent of bleeding events
        number (confidence interval 95%)
    63.6 (51.59 to 74.12)
    55.0 (40.91 to 68.33)
    Notes
    [11] - Subjects from all groups received both doses of CSL689, N=23
    [12] - Subjects from all groups received both doses of CSL689, N=20
    No statistical analyses for this end point

    Secondary: Percentage of bleeding events successfully treated with 1 or 2 injections of CSL689 in the dose evaluation module (EP)

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    End point title
    		 Percentage of bleeding events successfully treated with 1 or 2 injections of CSL689 in the dose evaluation module (EP) [13]
    End point description
    End point type
    Secondary
    End point timeframe
    Up to 8 hours after first CSL689 injection for each bleeding event
    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 CSL689 was used in this module
    End point values
    		 CSL689 (low dose) CSL689 (high dose)
    Number of subjects analysed
    8 [14]
    4 [15]
    Units: Percent of bleeding events
        number (confidence interval 95%)
    93.9 (85.33 to 97.54)
    95.0 (81.42 to 98.80)
    Notes
    [14] - Subjects from all groups received both doses of CSL689, N=23
    [15] - Subjects from all groups received both doses of CSL689, N=20
    No statistical analyses for this end point

    Secondary: Number and percentage of bleeding events requiring >1 injection of CSL689 in the dose evaluation module (EP)

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    End point title
    		 Number and percentage of bleeding events requiring >1 injection of CSL689 in the dose evaluation module (EP) [16]
    End point description
    End point type
    Secondary
    End point timeframe
    Up to 8 hours after first CSL689 injection for each bleeding event
    Notes
    [16] - 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 CSL689 was used in this module
    End point values
    		 CSL689 (low dose) CSL689 (high dose)
    Number of subjects analysed
    8 [17]
    4 [18]
    Units: bleeding events
    number (not applicable)
        Number
    24
    27
        Percent
    36.4
    45.0
    Notes
    [17] - Subjects from all groups received both doses of CSL689, N=23
    [18] - Subjects from all groups received both doses of CSL689, N=20
    No statistical analyses for this end point

    Secondary: Number of CSL689 injections per bleeding episode in the dose evaluation module (EP)

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    End point title
    		 Number of CSL689 injections per bleeding episode in the dose evaluation module (EP) [19]
    End point description
    End point type
    Secondary
    End point timeframe
    Up to 16 hours after first CSL689 injection for each bleeding event
    Notes
    [19] - 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 CSL689 was used in this module
    End point values
    		 CSL689 (low dose) CSL689 (high dose)
    Number of subjects analysed
    8 [20]
    4 [21]
    Units: Injections per bleed
        arithmetic mean (standard deviation)
    1.4 ( 0.49 )
    1.4 ( 0.57 )
    Notes
    [20] - Subjects from all groups received both doses of CSL689, N=23
    [21] - Subjects from all groups received both doses of CSL689, N=20
    No statistical analyses for this end point

    Secondary: Total dose of CSL689 required per bleeding episode in the dose evaluation module (SP)

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    End point title
    		 Total dose of CSL689 required per bleeding episode in the dose evaluation module (SP) [22]
    End point description
    End point type
    Secondary
    End point timeframe
    Up to 16 hours after first CSL689 injection for each bleeding event
    Notes
    [22] - 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 CSL689 was used in this module
    End point values
    		 CSL689 (low dose) CSL689 (high dose)
    Number of subjects analysed
    8 [23]
    4 [24]
    Units: mg
        arithmetic mean (standard deviation)
    226.7 ( 105.71 )
    518.5 ( 149.05 )
    Notes
    [23] - Subjects from all groups received both doses of CSL689, N=23
    [24] - Subjects from all groups received both doses of CSL689, N=20
    No statistical analyses for this end point

    Secondary: Percentage of bleeding events successfully treated with 1 injection in the repeated dose module (EP)

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    End point title
    		 Percentage of bleeding events successfully treated with 1 injection in the repeated dose module (EP) [25]
    End point description
    End point type
    Secondary
    End point timeframe
    Up to 8 hours after first CSL689 injection
    Notes
    [25] - 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 CSL689 was used in this module
    End point values
    		 CSL689 (low dose) CSL689 (high dose)
    Number of subjects analysed
    6
    4 [26]
    Units: Percent of bleeding events
        number (not applicable)
    25.0
    47.7
    Notes
    [26] - Subjects are counted more than once due to dose assignments in modules, N=13
    No statistical analyses for this end point

    Secondary: Percentage of bleeding events successfully treated with 1 injection of CSL689 analyzing the first bleeding event of each subject only in the repeated dose module (EP)

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    End point title
    		 Percentage of bleeding events successfully treated with 1 injection of CSL689 analyzing the first bleeding event of each subject only in the repeated dose module (EP) [27]
    End point description
    End point type
    Secondary
    End point timeframe
    Up to 8 hours after first CSL689 injection for first bleeding event
    Notes
    [27] - 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 CSL689 was used in this module
    End point values
    		 CSL689 (low dose) CSL689 (high dose)
    Number of subjects analysed
    6
    4 [28]
    Units: Percent of bleeding events
        number (not applicable)
    16.7
    46.2
    Notes
    [28] - Subjects are counted more than once due to dose assignments in modules, N=13
    No statistical analyses for this end point

    Secondary: Percentage of bleeding events successfully treated with 1 or 2 injections of CSL689 in the repeated dose module (EP)

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    End point title
    		 Percentage of bleeding events successfully treated with 1 or 2 injections of CSL689 in the repeated dose module (EP) [29]
    End point description
    End point type
    Secondary
    End point timeframe
    Up to 24 hours after first CSL689 injection for each bleeding event
    Notes
    [29] - 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 CSL689 was used in this module
    End point values
    		 CSL689 (low dose) CSL689 (high dose)
    Number of subjects analysed
    6
    4 [30]
    Units: Percent of bleeding events
        number (not applicable)
    88.9
    80.7
    Notes
    [30] - Subjects are counted more than once due to dose assignments in modules, N=13
    No statistical analyses for this end point

    Secondary: Percentage of bleeding events succesfully treated with 1, 2, or 3 injections of CSL689 in the repeated dose module (EP)

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    End point title
    		 Percentage of bleeding events succesfully treated with 1, 2, or 3 injections of CSL689 in the repeated dose module (EP) [31]
    End point description
    End point type
    Secondary
    End point timeframe
    Up to 24 hours after first CSL689 injection for each bleeding event
    Notes
    [31] - 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 CSL689 was used in this module
    End point values
    		 CSL689 (low dose) CSL689 (high dose)
    Number of subjects analysed
    6
    4 [32]
    Units: Percent of bleeding events
        number (not applicable)
    97.2
    95.5
    Notes
    [32] - Subjects are counted more than once due to dose assignments in modules, N=13
    No statistical analyses for this end point

    Secondary: Percentage of bleeding events with only "definite" or "abrupt" subject-reported assessment of pain relief with CSL689 in the repeated dose module (EP)

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    End point title
    		 Percentage of bleeding events with only "definite" or "abrupt" subject-reported assessment of pain relief with CSL689 in the repeated dose module (EP) [33]
    End point description
    "Definite" is defined as significant or recognized pain relief; "Abrupt" is defined as rapid, quick, or immediate pain relief. Only joint and muscle bleeds, which have the assessments of pain relief conducted, are summarized.
    End point type
    Secondary
    End point timeframe
    Up to 24 hours after CSL689 injection for each bleeding event
    Notes
    [33] - 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 CSL689 was used in this module
    End point values
    		 CSL689 (low dose) CSL689 (high dose)
    Number of subjects analysed
    6
    4 [34]
    Units: Percent of bleeding events
        number (not applicable)
    75.8
    91.6
    Notes
    [34] - Subjects are counted more than once due to dose assignments in modules, N=13
    No statistical analyses for this end point

    Secondary: Percentage of bleeding events with "Good" or "Excellent" investigator-reported assessment of treatment response with CSL689 in the repeated dose module (EP)

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    End point title
    		 Percentage of bleeding events with "Good" or "Excellent" investigator-reported assessment of treatment response with CSL689 in the repeated dose module (EP) [35]
    End point description
    "Good" is defined as improvement in signs of bleeding after 1 injection with CSL689 and achieved hemostasis after 2 injections with CSL689; "Excellent" is defined as pain relief after 1 injection with CSL689 and no additional injections are required to achieve hemostasis.
    End point type
    Secondary
    End point timeframe
    Up to 9 months
    Notes
    [35] - 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 CSL689 was used in this module
    End point values
    		 CSL689 (low dose) CSL689 (high dose)
    Number of subjects analysed
    6
    4 [36]
    Units: Percent of bleeding events
        number (not applicable)
    88.9
    79.5
    Notes
    [36] - Subjects are counted more than once due to dose assignments in modules, N=13
    No statistical analyses for this end point

    Secondary: Number and percentage of bleeding events requiring >1 injection of CSL689 in the repeated dose module (EP)

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    End point title
    		 Number and percentage of bleeding events requiring >1 injection of CSL689 in the repeated dose module (EP) [37]
    End point description
    End point type
    Secondary
    End point timeframe
    Up to 8 hours after first CSL689 injection for each bleeding event
    Notes
    [37] - 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 CSL689 was used in this module
    End point values
    		 CSL689 (low dose) CSL689 (high dose)
    Number of subjects analysed
    8 [38]
    4 [39]
    Units: Bleeding events
    number (not applicable)
        Number
    27
    46
        Percent
    75.0
    52.3
    Notes
    [38] - Subjects are counted more than once due to dose assignments in modules, N=19
    [39] - Subjects are counted more than once due to dose assignments in modules, N=19
    No statistical analyses for this end point

    Secondary: Percentage of bleeding events successfully treated with 1 injection of CSL689 using a bootstrap bias corrected and accelerated 95% confidence interval in the repeated dose module (EP)

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    End point title
    		 Percentage of bleeding events successfully treated with 1 injection of CSL689 using a bootstrap bias corrected and accelerated 95% confidence interval in the repeated dose module (EP) [40]
    End point description
    End point type
    Secondary
    End point timeframe
    Up to 9 months
    Notes
    [40] - 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 CSL689 was used in this module
    End point values
    		 CSL689 (low dose) CSL689 (high dose)
    Number of subjects analysed
    6
    4 [41]
    Units: Percent of bleeding events
        number (confidence interval 95%)
    2.2 (1.2 to 5.4)
    1.2 (0.8 to 1.9)
    Notes
    [41] - Subjects are counted more than once due to dose assignments in modules, N=13
    No statistical analyses for this end point

    Secondary: Percentage of recurrences in the repeated dose module (EP)

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    End point title
    		 Percentage of recurrences in the repeated dose module (EP) [42]
    End point description
    Recurrences is defined as a bleeding in the same joint/anatomical location within 24 hours after an initial “good” or“excellent” response assessed by investigator.
    End point type
    Secondary
    End point timeframe
    Up to 9 months
    Notes
    [42] - 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 CSL689 was used in this module
    End point values
    		 CSL689 (low dose) CSL689 (high dose)
    Number of subjects analysed
    6
    4 [43]
    Units: Percent of recurrences
        number (not applicable)
    0
    0
    Notes
    [43] - Subjects are counted more than once due to dose assignments in modules, N=13
    No statistical analyses for this end point

    Secondary: Percentage of Bleeding Events with ultrarapid progression in the repeated dose module (EP)

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    End point title
    		 Percentage of Bleeding Events with ultrarapid progression in the repeated dose module (EP) [44]
    End point description
    Bleeding events with ultrarapid progression is defined as overt, uncontrolled hemorrhage and/or progressive increase in pain and/or rapid progression in hematoma size.
    End point type
    Secondary
    End point timeframe
    Up to 9 months
    Notes
    [44] - 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 CSL689 was used in this module
    End point values
    		 CSL689 (low dose) CSL689 (high dose)
    Number of subjects analysed
    6
    4 [45]
    Units: Percent of bleeding events
        number (not applicable)
    0
    0
    Notes
    [45] - Subjects are counted more than once due to dose assignments in modules, N=13
    No statistical analyses for this end point

    Secondary: Percentage of bleeding events requiring maintenance dosing in the repeated dose module (EP)

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    End point title
    		 Percentage of bleeding events requiring maintenance dosing in the repeated dose module (EP) [46]
    End point description
    Maintenance dosing is defined as post-hemostatic injections of CSL689 to maintain hemostasis, prevention of rebleeding or delayed bleeding and improve hematoma resorption after successful initial control of a bleeding event.
    End point type
    Secondary
    End point timeframe
    Up to 9 months
    Notes
    [46] - 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 CSL689 was used in this module
    End point values
    		 CSL689 (low dose) CSL689 (high dose)
    Number of subjects analysed
    6
    4 [47]
    Units: Percent of bleeding events
        number (not applicable)
    0
    0
    Notes
    [47] - Subjects are counted more than once due to dose assignments in modules, N=13
    No statistical analyses for this end point

    Secondary: Number of CSL689 injections per bleeding episode in the repeated dose module (EP)

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    End point title
    		 Number of CSL689 injections per bleeding episode in the repeated dose module (EP) [48]
    End point description
    End point type
    Secondary
    End point timeframe
    Up to 24 hours after first CSL689 injection for each bleeding event
    Notes
    [48] - 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 CSL689 was used in this module
    End point values
    		 CSL689 (low dose) CSL689 (high dose)
    Number of subjects analysed
    6
    4 [49]
    Units: Injections per bleed
        arithmetic mean (standard deviation)
    1.9 ( 0.59 )
    1.7 ( 0.76 )
    Notes
    [49] - Subjects are counted more than once due to dose assignments in modules, N=13
    No statistical analyses for this end point

    Secondary: Total dose of CSL689 required per bleeding episode in the repeated dose module (EP)

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    End point title
    		 Total dose of CSL689 required per bleeding episode in the repeated dose module (EP) [50]
    End point description
    End point type
    Secondary
    End point timeframe
    Up to 24 hours after first CSL689 injection for each bleeding event
    Notes
    [50] - 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 CSL689 was used in this module
    End point values
    		 CSL689 (low dose) CSL689 (high dose)
    Number of subjects analysed
    6
    4 [51]
    Units: mg
        arithmetic mean (standard deviation)
    579.2 ( 469.62 )
    1124.0 ( 650.06 )
    Notes
    [51] - Subjects are counted more than once due to dose assignments in modules, N=13
    No statistical analyses for this end point

    Secondary: Number and percentage of subjects with treatment emergent adverse events (TEAEs) in the PK module (SP)

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    End point title
    		 Number and percentage of subjects with treatment emergent adverse events (TEAEs) in the PK module (SP)
    End point description
    End point type
    Secondary
    End point timeframe
    Up to 28 days
    End point values
    		 NovoSeven (low dose) NovoSeven (high dose) CSL689 (low dose) CSL689 (high dose)
    Number of subjects analysed
    6
    7
    8
    4 [52]
    Units: Subjects with TEAEs
    number (not applicable)
        Number
    0
    0
    1
    4
        Percent
    0
    0
    12.5
    25.0
    Notes
    [52] - Subjects from the NovoSeven arms also received high dose of CSL689, N=16
    No statistical analyses for this end point

    Secondary: Number and percentage of subjects with TEAEs in the dose evaluation module (SP)

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    End point title
    		 Number and percentage of subjects with TEAEs in the dose evaluation module (SP) [53]
    End point description
    End point type
    Secondary
    End point timeframe
    Up to 9 months
    Notes
    [53] - 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 CSL689 was used in this module
    End point values
    		 CSL689 (low dose) CSL689 (high dose)
    Number of subjects analysed
    8 [54]
    4 [55]
    Units: Subjects with TEAEs
    number (not applicable)
        Number
    8
    8
        Percent
    34.8
    40.0
    Notes
    [54] - Subjects from all groups received both doses of CSL689, N=23
    [55] - Subjects from all groups received both doses of CSL689, N=20
    No statistical analyses for this end point

    Secondary: Number and percentage of subjects with TEAEs in the repeated dose module (SP)

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    End point title
    		 Number and percentage of subjects with TEAEs in the repeated dose module (SP) [56]
    End point description
    End point type
    Secondary
    End point timeframe
    Up to 6 months
    Notes
    [56] - 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 CSL689 was used in this module
    End point values
    		 CSL689 (low dose) CSL689 (high dose)
    Number of subjects analysed
    6
    4 [57]
    Units: Subjects with TEAEs
    number (not applicable)
        Number
    3
    4
        Percent
    50.0
    30.8
    Notes
    [57] - Subjects are counted more than once due to dose assignments in modules, N=13
    No statistical analyses for this end point

    Secondary: Number and percentage of subjects with TEAEs related to CSL689 in the PK module (SP)

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    End point title
    		 Number and percentage of subjects with TEAEs related to CSL689 in the PK module (SP) [58]
    End point description
    End point type
    Secondary
    End point timeframe
    Up to 28 days
    Notes
    [58] - 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 CSL689 was used in this module
    End point values
    		 CSL689 (low dose) CSL689 (high dose)
    Number of subjects analysed
    8
    4 [59]
    Units: Subjects
    number (not applicable)
        Number
    0
    0
        Percent
    0
    0
    Notes
    [59] - Subjects from the NovoSeven arms also received high dose of CSL689, N=16
    No statistical analyses for this end point

    Secondary: Number and percentage of subjects with TEAEs related to CSL689 in the dose evaluation module (SP)

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    End point title
    		 Number and percentage of subjects with TEAEs related to CSL689 in the dose evaluation module (SP) [60]
    End point description
    End point type
    Secondary
    End point timeframe
    Up to 9 months
    Notes
    [60] - 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 CSL689 was used in this module
    End point values
    		 CSL689 (low dose) CSL689 (high dose)
    Number of subjects analysed
    8 [61]
    4 [62]
    Units: Subjects
    number (not applicable)
        Number
    1
    0
        Percent
    4.3
    0
    Notes
    [61] - Subjects from all groups received both doses of CSL689, N=23
    [62] - Subjects from all groups received both doses of CSL689, N=20
    No statistical analyses for this end point

    Secondary: Number and percentage of subjects with TEAEs related to CSL689 in the repeated dose module (SP)

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    End point title
    		 Number and percentage of subjects with TEAEs related to CSL689 in the repeated dose module (SP) [63]
    End point description
    End point type
    Secondary
    End point timeframe
    Up to 6 months
    Notes
    [63] - 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 CSL689 was used in this module
    End point values
    		 CSL689 (low dose) CSL689 (high dose)
    Number of subjects analysed
    6
    4 [64]
    Units: Subjects
    number (not applicable)
        Number
    0
    0
        Percent
    0
    0
    Notes
    [64] - Subjects are counted more than once due to dose assignments in modules, N=13
    No statistical analyses for this end point

    Secondary: Number and percentage of subjects with inhibitors against Factor VII (FVII) in the PK module (SP)

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    End point title
    		 Number and percentage of subjects with inhibitors against Factor VII (FVII) in the PK module (SP)
    End point description
    End point type
    Secondary
    End point timeframe
    Up to 28 days
    End point values
    		 NovoSeven (low dose) NovoSeven (high dose) CSL689 (low dose) CSL689 (high dose)
    Number of subjects analysed
    6
    7
    8
    4
    Units: Subjects
    number (not applicable)
        Number
    0
    0
    0
    0
        Percent
    0
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Number and percentage of subjects with inhibitors against FVII in the dose evaluation module (SP)

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    End point title
    		 Number and percentage of subjects with inhibitors against FVII in the dose evaluation module (SP) [65]
    End point description
    End point type
    Secondary
    End point timeframe
    Up to 9 months
    Notes
    [65] - 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 CSL689 was used in this module
    End point values
    		 CSL689 (low dose) CSL689 (high dose)
    Number of subjects analysed
    8 [66]
    4 [67]
    Units: Subjects
    number (not applicable)
        Number
    0
    0
        Percent
    0
    0
    Notes
    [66] - Subjects from all groups received both doses of CSL689, N=23
    [67] - Subjects from all groups received both doses of CSL689, N=20
    No statistical analyses for this end point

    Secondary: Number and percentage of subjects with inhibitors against FVII in the repeated dose module (SP)

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    End point title
    		 Number and percentage of subjects with inhibitors against FVII in the repeated dose module (SP) [68]
    End point description
    End point type
    Secondary
    End point timeframe
    Up to 6 months
    Notes
    [68] - 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 CSL689 was used in this module
    End point values
    		 CSL689 (low dose) CSL689 (high dose)
    Number of subjects analysed
    6
    4 [69]
    Units: Subjects
    number (not applicable)
        Number
    0
    0
        Percent
    0
    0
    Notes
    [69] - Subjects are counted more than once due to dose assignments in modules, N=13
    No statistical analyses for this end point

    Secondary: Area under the FVIIa activity versus time curve from time zero extrapolated to infinity (AUC0-infinity) in the PK module (PK)

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    End point title
    		 Area under the FVIIa activity versus time curve from time zero extrapolated to infinity (AUC0-infinity) in the PK module (PK)
    End point description
    End point type
    Secondary
    End point timeframe
    Up to 24 hours for NovoSeven and up to 120 hours for CSL689 post injection
    End point values
    		 NovoSeven (low dose) NovoSeven (high dose) CSL689 (low dose) CSL689 (high dose)
    Number of subjects analysed
    6
    6
    8
    4 [70]
    Units: h*IU/mL
    arithmetic mean (standard deviation)
        with baseline correction
    112.2 ( 20.293 )
    325.3 ( 55.273 )
    444.1 ( 145.06 )
    905.8 ( 271.85 )
        without baseline correction
    114.2 ( 21.170 )
    327.7 ( 55.766 )
    464.9 ( 132.59 )
    910.3 ( 273.30 )
    Notes
    [70] - Subjects from the NovoSeven arms also received high dose of CSL689, N=15
    No statistical analyses for this end point

    Secondary: Maximum observed plasma FVIIa concentration (Cmax) in the PK module (PK)

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    End point title
    		 Maximum observed plasma FVIIa concentration (Cmax) in the PK module (PK)
    End point description
    End point type
    Secondary
    End point timeframe
    Up to 24 hours for NovoSeven and up to 120 hours for CSL689 post injection
    End point values
    		 NovoSeven (low dose) NovoSeven (high dose) CSL689 (low dose) CSL689 (high dose)
    Number of subjects analysed
    6
    6
    8
    4 [71]
    Units: IU/mL
    arithmetic mean (standard deviation)
        with baseline correction
    44.10 ( 5.8237 )
    130.5 ( 26.883 )
    45.38 ( 13.888 )
    77.12 ( 18.683 )
        without baseline correction
    44.17 ( 5.8312 )
    130.5 ( 26.883 )
    45.81 ( 13.684 )
    77.15 ( 18.679 )
    Notes
    [71] - Subjects from the NovoSeven arms also received high dose of CSL689, N=13
    No statistical analyses for this end point

    Secondary: Time corresponding to occurrence of Cmax (Tmax) in the PK module (PK)

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    End point title
    		 Time corresponding to occurrence of Cmax (Tmax) in the PK module (PK)
    End point description
    End point type
    Secondary
    End point timeframe
    Up to 24 hours for NovoSeven and up to 120 hours for CSL689 post injection
    End point values
    		 NovoSeven (low dose) NovoSeven (high dose) CSL689 (low dose) CSL689 (high dose)
    Number of subjects analysed
    6
    6
    8
    4 [72]
    Units: hours
    median (full range (min-max))
        with baseline correction
    0.5000 (0.500 to 0.583)
    0.5750 (0.500 to 0.650)
    0.2500 (0.250 to 0.500)
    0.5000 (0.250 to 0.583)
        without baseline correction
    0.5000 (0.500 to 0.583)
    0.5750 (0.500 to 0.650)
    0.2500 (0.250 to 0.500)
    0.5000 (0.250 to 0.583)
    Notes
    [72] - Subjects from the NovoSeven arms also received high dose of CSL689, N=13
    No statistical analyses for this end point

    Secondary: Volume of distribution at steady state (Vss) in the PK module (PK)

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    End point title
    		 Volume of distribution at steady state (Vss) in the PK module (PK)
    End point description
    End point type
    Secondary
    End point timeframe
    Up to 24 hours for NovoSeven and up to 120 hours for CSL689 post injection
    End point values
    		 NovoSeven (low dose) NovoSeven (high dose) CSL689 (low dose) CSL689 (high dose)
    Number of subjects analysed
    6
    6
    8
    4 [73]
    Units: mL/kg
    arithmetic mean (standard deviation)
        with baseline correction
    130.5 ( 19.685 )
    123.4 ( 19.045 )
    72.19 ( 28.984 )
    87.41 ( 37.460 )
        withouit baseline correction
    136.7 ( 19.253 )
    125.8 ( 19.716 )
    76.66 ( 30.415 )
    87.93 ( 37.357 )
    Notes
    [73] - Subjects from the NovoSeven arms also received high dose of CSL689, N=15
    No statistical analyses for this end point

    Secondary: Mean residence time (MRT) in the PK module (PK)

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    End point title
    		 Mean residence time (MRT) in the PK module (PK)
    End point description
    End point type
    Secondary
    End point timeframe
    Up to 24 hours for NovoSeven and up to 120 hours for CSL689 post injection
    End point values
    		 NovoSeven (low dose) NovoSeven (high dose) CSL689 (low dose) CSL689 (high dose)
    Number of subjects analysed
    6
    6
    8
    4 [74]
    Units: hours
    arithmetic mean (standard deviation)
        with baseline correction
    3.195 ( 0.35297 )
    2.927 ( 0.34881 )
    10.10 ( 1.9013 )
    12.40 ( 1.8022 )
        without baseline correction
    3.415 ( 0.36828 )
    3.003 ( 0.40168 )
    11.17 ( 1.0191 )
    12.54 ( 1.8812 )
    Notes
    [74] - Subjects from the NovoSeven arms also received high dose of CSL689, N=15
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    23 July 2015- 28 March 2018
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.1
    Reporting groups
    Reporting group title
    NovoSeven (low dose)
    Reporting group description
    		 -

    Reporting group title
    NovoSeven (high dose)
    Reporting group description
    		 -

    Reporting group title
    CSL689 (low dose)
    Reporting group description
    		 -

    Reporting group title
    CSL689 (high dose)
    Reporting group description
    		 -

    Serious adverse events
    		 NovoSeven (low dose) NovoSeven (high dose) CSL689 (low dose) CSL689 (high dose)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 NovoSeven (low dose) NovoSeven (high dose) CSL689 (low dose) CSL689 (high dose)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 24 (4.17%)
    7 / 22 (31.82%)
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 24 (4.17%)
    2 / 22 (9.09%)
         occurrences all number
    0
    0
    1
    2
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 24 (0.00%)
    2 / 22 (9.09%)
         occurrences all number
    0
    0
    0
    2
    Infections and infestations
    Rhinitis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 24 (0.00%)
    2 / 22 (9.09%)
         occurrences all number
    0
    0
    0
    3
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 24 (0.00%)
    2 / 22 (9.09%)
         occurrences all number
    0
    0
    0
    2

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    04 Feb 2015
    • Addition of adequate safety stopping rules • Simplification of treatment response evaluation • Specification of the success criteria for the Repeated Dose Module and provision of the algorithm for selection of the final dose • Change of the success criteria from 15% to 25% and modification of the sample size estimation • Additional evaluation of inhibitor assessment
    28 Apr 2016
    • Introduce 4 new PK time-points to Block B (i.e., 15 min, 0,5, 2, 4, 6, 10, 24, 48, 72, 96, and 120 hours after the start of injection) and extend the observation/sample collection period from 48 to 120 hours • Clarify that Block B would only open to enroll an additional 12 subjects following a recommendation from the IDMC • Update of inclusion criteria #5 to increase the permitted body weight • Increase the window for screening subjects in Blocks B and C from 14 days to 21 days • Include events of hypersensitivity and catheter related complications (e.g., line infections and clotting) as adverse events of special interest • The new PK time-points were added to Block B after the PK analysis of 6 subjects from Block A1 showed that additional PK time-points were required to support full characterization of the CSL689 PK profile
    21 Mar 2017
    • Addition of an age group-specific hemophilia quality of life (QoL) questionnaire at beginning as a baseline and at the end of Block C • Enrollment of more than 12 subjects in Block B to compensate for subjects who discontinued participation • Updates according to the Statistical Analysis Plan amendment

    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.
    Although two subjects had confirmed antibodies directed against the rFVIIa part of CSL689, these antibodies were already pre-existing at screening and were not the result of CSL689 administration during the study. No clinical symptoms were reported.
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