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    Clinical Trial Results:
    A Phase III Open Label, Multicenter, Extension Study to Assess the Safety and Efficacy of Recombinant Coagulation Factor VIII (rVIII-SingleChain, CSL627) in Subjects with Severe Hemophilia A

    Summary
    EudraCT number
    		 2013-003262-13
    Trial protocol
    		 IT   GB   DE   CZ   HU   ES   NL   AT   PL   PT   IE  
    Global end of trial date
    19 Jan 2021

    Results information
    Results version number
    		 v1(current)
    This version publication date
    22 Jul 2021
    First version publication date
    22 Jul 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CSL627_3001
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02172950
    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
    Clin.Trial Registration Coordinator, CSL Behring GmbH, 34 91708 86 00, clinicaltrials@cslbehring.com
    Scientific contact
    Clin.Trial Registration Coordinator, CSL Behring GmbH, 34 91708 86 00, clinicaltrials@cslbehring.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    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
    12 Feb 2021
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    19 Jan 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study is to evaluate the safety of long term use of rVIII-SingleChain
    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
    13 Oct 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: 11
    Country: Number of subjects enrolled
    Canada: 1
    Country: Number of subjects enrolled
    Georgia: 5
    Country: Number of subjects enrolled
    Japan: 7
    Country: Number of subjects enrolled
    Lebanon: 12
    Country: Number of subjects enrolled
    Malaysia: 15
    Country: Number of subjects enrolled
    Philippines: 18
    Country: Number of subjects enrolled
    South Africa: 22
    Country: Number of subjects enrolled
    Switzerland: 1
    Country: Number of subjects enrolled
    Thailand: 10
    Country: Number of subjects enrolled
    Ukraine: 17
    Country: Number of subjects enrolled
    United States: 22
    Country: Number of subjects enrolled
    Netherlands: 12
    Country: Number of subjects enrolled
    Poland: 36
    Country: Number of subjects enrolled
    Portugal: 5
    Country: Number of subjects enrolled
    Romania: 4
    Country: Number of subjects enrolled
    Spain: 6
    Country: Number of subjects enrolled
    United Kingdom: 1
    Country: Number of subjects enrolled
    Austria: 6
    Country: Number of subjects enrolled
    Czechia: 2
    Country: Number of subjects enrolled
    France: 7
    Country: Number of subjects enrolled
    Germany: 10
    Country: Number of subjects enrolled
    Hungary: 2
    Country: Number of subjects enrolled
    Ireland: 5
    Country: Number of subjects enrolled
    Italy: 9
    Worldwide total number of subjects
    246
    EEA total number of subjects
    104
    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)
    17
    Children (2-11 years)
    74
    Adolescents (12-17 years)
    23
    Adults (18-64 years)
    131
    From 65 to 84 years
    1
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 This multicenter, non-randomized, open-label, multiple-arm phase 3 extension study continued to investigate the safety and efficacy of rVIII-SingleChain in PTPs and PUPs with severe hemophilia A (FVIII activity levels < 1%).

    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
    		 CSL627: Previously treated patients (PTPs)
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    rVIII-SingleChain
    Investigational medicinal product code
    CSL627
    Other name
    Pharmaceutical forms
    Powder and solvent for solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    The rVIII-SingleChain drug product is recombinant factor VIII (rFVIII) and was administered by IV injection. The rVIII-SingleChain dose and dosing schedule were determined at the investigator’s discretion.

    Arm title
    		 CSL627: Previously untreated patients (PUPs)
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    rVIII-SingleChain
    Investigational medicinal product code
    CSL627
    Other name
    Pharmaceutical forms
    Powder and solvent for solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    The rVIII-SingleChain drug product is recombinant factor VIII (rFVIII) and was administered by IV injection. The rVIII-SingleChain dose and dosing schedule were determined at the investigator’s discretion.

    Number of subjects in period 1
    		CSL627: Previously treated patients (PTPs) CSL627: Previously untreated patients (PUPs)
    Started
    222
    24
    Completed
    197
    19
    Not completed
    25
    5
         Adverse event, serious fatal
    1
    -
         Consent withdrawn by subject
    10
    -
         Physician decision
    3
    3
         Patient relocated overseas
    1
    -
         Adverse event, non-fatal
    4
    1
         Patient went to other country
    1
    -
         Patient locating overseas
    -
    1
         Patient moving
    1
    -
         Patient traveling
    1
    -
         Expected protocol violation
    1
    -
         Lost to follow-up
    1
    -
         Lack of efficacy
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    CSL627: Previously treated patients (PTPs)
    Reporting group description
    		 -

    Reporting group title
    CSL627: Previously untreated patients (PUPs)
    Reporting group description
    		 -

    Reporting group values
    		 CSL627: Previously treated patients (PTPs) CSL627: Previously untreated patients (PUPs) Total
    Number of subjects
    		 222 24 246
    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 17 17
        Children (2-11 years)
    		 67 7 74
        Adolescents (12-17 years)
    		 23 0 23
        Adults (18-64 years)
    		 131 0 131
        From 65-84 years
    		 1 0 1
        85 years and over
    		 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 22.5 ( 14.55 ) 1.4 ( 1.18 ) -
    Gender categorical
    Units: Subjects
        Female
    		 0 0 0
        Male
    		 222 24 246

    End points

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    End points reporting groups
    Reporting group title
    CSL627: Previously treated patients (PTPs)
    Reporting group description
    		 -

    Reporting group title
    CSL627: Previously untreated patients (PUPs)
    Reporting group description
    		 -

    Primary: Incidence of inhibitor formation to FVIII in PTPs with 100 Exposure Days (EDs) to CSL627

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    End point title
    		 Incidence of inhibitor formation to FVIII in PTPs with 100 Exposure Days (EDs) to CSL627 [1] [2]
    End point description
    End point type
    Primary
    End point timeframe
    Up to 5 years
    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 were used for this endpoint.
    [2] - 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: This endpoint is only for PTPs.
    End point values
    		 CSL627: Previously treated patients (PTPs)
    Number of subjects analysed
    198
    Units: Percent
        number (not applicable)
    0
    No statistical analyses for this end point

    Primary: Number of PUPs with high-titer inhibitor formation to FVIII with at least 50 EDs to CSL627

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    End point title
    		 Number of PUPs with high-titer inhibitor formation to FVIII with at least 50 EDs to CSL627 [3] [4]
    End point description
    High-titer inhibitor is defined as an inhibitor titer of ≥ 5 Bethesda units/mL.
    End point type
    Primary
    End point timeframe
    Up to 5 years
    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: Descriptive statistics were used for this endpoint.
    [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: This endpoint is only for PUPs.
    End point values
    		 CSL627: Previously untreated patients (PUPs)
    Number of subjects analysed
    24
    Units: Number
        number (not applicable)
    5
    No statistical analyses for this end point

    Primary: Percent treatment success for major bleeding episodes in PUPs

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    End point title
    		 Percent treatment success for major bleeding episodes in PUPs [5] [6]
    End point description
    Major bleeding episodes treated successfully where treatment success for a bleeding episode is defined as a rating of "excellent" or "good" on the investigator's clinical assessment of hemostatic efficacy 4-point scale "excellent, good, moderate or poor/no response". Major bleeding episodes are defined as bleeding episodes for which a subject is required to seek treatment at the hemophilia center or that threatens the subject's life or loss of limb.
    End point type
    Primary
    End point timeframe
    Up to 5 years
    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: Descriptive statistics were used for this endpoint.
    [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: This endpoint is only for PUPs.
    End point values
    		 CSL627: Previously untreated patients (PUPs)
    Number of subjects analysed
    23
    Units: percent
    number (not applicable)
        Number of major bleeds
    1
        Percent of major bleeds successfully treated
    100
    No statistical analyses for this end point

    Primary: Annualized spontaneous bleeding rate in PUPs

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    End point title
    		 Annualized spontaneous bleeding rate in PUPs [7] [8]
    End point description
    The annualized spontaneous bleeding rate for PUPs taking prophylaxis and on-demand treatment regimens.
    End point type
    Primary
    End point timeframe
    Up to 5 years
    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: Descriptive statistics were used for this endpoint.
    [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: This endpoint is only for PUPs.
    End point values
    		 CSL627: Previously untreated patients (PUPs)
    Number of subjects analysed
    23
    Units: Spontaneous bleeds
    arithmetic mean (standard deviation)
        On-demand (n=12)
    1.90 ( 2.252 )
        Prophylaxis (n=23)
    4.04 ( 6.374 )
    No statistical analyses for this end point

    Secondary: Treatment success in PTPs

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    End point title
    		 Treatment success in PTPs [9]
    End point description
    Percentage of bleeding episodes treated successfully where treatment success for a bleeding episode is defined as a rating of "excellent" or "good" on the investigator's clinical assessment of hemostatic efficacy 4-point scale "excellent, good, moderate or poor/no response".
    End point type
    Secondary
    End point timeframe
    Up to 5 years
    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: The endpoint is only for PTPs
    End point values
    		 CSL627: Previously treated patients (PTPs)
    Number of subjects analysed
    222 [10]
    Units: percent
    number (confidence interval 95%)
        Percent of bleeding events successfully treated
    87.1 (75.3 to 93.7)
    Notes
    [10] - Number of treated bleeding events = 2413.
    No statistical analyses for this end point

    Secondary: Annualized bleeding rate in PTPs and PUPs

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    End point title
    		 Annualized bleeding rate in PTPs and PUPs
    End point description
    End point type
    Secondary
    End point timeframe
    Up to 5 years
    End point values
    		 CSL627: Previously treated patients (PTPs) CSL627: Previously untreated patients (PUPs)
    Number of subjects analysed
    222 [11]
    23 [12]
    Units: Number of bleeds per year
    number (confidence interval 95%)
        On-demand
    28.6 (26.8 to 30.6)
    3.4 (2.4 to 4.7)
        Prophylaxis
    2.8 (2.7 to 3.0)
    5.7 (5.1 to 6.4)
    Notes
    [11] - On-demand (n=11); Prophylaxis (n=209)
    [12] - On-demand (n=10); Prophylaxis (n=23)
    No statistical analyses for this end point

    Secondary: Percentage of bleeding episodes requiring 1, 2, 3 or > 3 infusions of CSL627 to achieve hemostasis

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    End point title
    		 Percentage of bleeding episodes requiring 1, 2, 3 or > 3 infusions of CSL627 to achieve hemostasis
    End point description
    End point type
    Secondary
    End point timeframe
    Up to 5 years
    End point values
    		 CSL627: Previously treated patients (PTPs) CSL627: Previously untreated patients (PUPs)
    Number of subjects analysed
    222
    24
    Units: percent
    number (not applicable)
        Number of treated bleeds
    2413
    315
        1 infusion
    71.5
    77.5
        2 infusions
    14.8
    11.4
        3 infusions
    6.9
    5.4
        >3 infusions
    6.3
    3.5
    No statistical analyses for this end point

    Secondary: Hemostatic efficacy of CSL627 for PTPs and PUPs who undergo surgery

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    End point title
    		 Hemostatic efficacy of CSL627 for PTPs and PUPs who undergo surgery
    End point description
    The investigator will rate the efficacy of the rVIII-SingleChain treatment during surgery based on a hemostatic efficacy four point rating scale of "excellent, good, moderate or poor/no response".
    End point type
    Secondary
    End point timeframe
    From the start of surgery through the post-operative recovery (generally up to 14 days after surgery)
    End point values
    		 CSL627: Previously treated patients (PTPs) CSL627: Previously untreated patients (PUPs)
    Number of subjects analysed
    24
    3
    Units: Number
    number (not applicable)
        Number of surgeries
    32
    3
        Excellent
    28
    3
        Good
    4
    0
        Moderate
    0
    0
        Poor/No response
    0
    0
    No statistical analyses for this end point

    Secondary: Incidence of inhibitor formation to FVIII after 10 EDs and after 50 EDs in PTPs

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    End point title
    		 Incidence of inhibitor formation to FVIII after 10 EDs and after 50 EDs in PTPs [13]
    End point description
    End point type
    Secondary
    End point timeframe
    Up to 5 years
    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: The endpoint is only for PTPs
    End point values
    		 CSL627: Previously treated patients (PTPs)
    Number of subjects analysed
    198
    Units: percent
    number (not applicable)
        after 10 EDs
    0
        after 50 EDs
    0
    No statistical analyses for this end point

    Secondary: Percentage of PTPs and PUPs developing antibodies against CSL627

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    End point title
    		 Percentage of PTPs and PUPs developing antibodies against CSL627
    End point description
    End point type
    Secondary
    End point timeframe
    Up to 5 years
    End point values
    		 CSL627: Previously treated patients (PTPs) CSL627: Previously untreated patients (PUPs)
    Number of subjects analysed
    222
    24
    Units: percent
        number (not applicable)
    15.3
    70.8
    No statistical analyses for this end point

    Secondary: Percentage of PTPs and PUPs developing antibodies to Chinese hamster ovary (CHO) proteins

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    End point title
    		 Percentage of PTPs and PUPs developing antibodies to Chinese hamster ovary (CHO) proteins
    End point description
    End point type
    Secondary
    End point timeframe
    Up to 5 years
    End point values
    		 CSL627: Previously treated patients (PTPs) CSL627: Previously untreated patients (PUPs)
    Number of subjects analysed
    222
    24
    Units: percent
        number (not applicable)
    0
    0
    No statistical analyses for this end point

    Secondary: Number of PUPs with high-titer inhibitor formation to FVIII in PUPs after 10 EDs with CSL627

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    End point title
    		 Number of PUPs with high-titer inhibitor formation to FVIII in PUPs after 10 EDs with CSL627 [14]
    End point description
    High-titer inhibitor is defined as an inhibitor titer of ≥ 5 Bethesda units/mL.
    End point type
    Secondary
    End point timeframe
    Up to 5 years
    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: The endpoint is only for PUPs
    End point values
    		 CSL627: Previously untreated patients (PUPs)
    Number of subjects analysed
    24
    Units: Number
        number (not applicable)
    4
    No statistical analyses for this end point

    Secondary: Number of PUPs with low-titer inhibitor formation to FVIII after 10 EDs and after 50 EDs with CSL627

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    End point title
    		 Number of PUPs with low-titer inhibitor formation to FVIII after 10 EDs and after 50 EDs with CSL627 [15]
    End point description
    Low-titer inhibitor is defined as an inhibitor titer of less than 5 Bethesda units/mL.
    End point type
    Secondary
    End point timeframe
    Up to 5 years
    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: The endpoint is only for PUPs
    End point values
    		 CSL627: Previously untreated patients (PUPs)
    Number of subjects analysed
    24
    Units: Number
    number (not applicable)
        after 10 EDs
    4
        after 50 EDs
    0
    No statistical analyses for this end point

    Secondary: Incidence of total inhibitor formation to FVIII in PUPs

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    End point title
    		 Incidence of total inhibitor formation to FVIII in PUPs [16]
    End point description
    End point type
    Secondary
    End point timeframe
    Up to 5 years
    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: The endpoint is only for PUPs
    End point values
    		 CSL627: Previously untreated patients (PUPs)
    Number of subjects analysed
    24
    Units: percent
        number (not applicable)
    50.0
    No statistical analyses for this end point

    Secondary: Percent treatment success for non-major bleeding episodes in PUPs

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    End point title
    		 Percent treatment success for non-major bleeding episodes in PUPs [17]
    End point description
    Percentage of bleeding episodes treated successfully where treatment success for a bleeding episode is defined as a rating of "excellent" or "good" on the investigator's clinical assessment of hemostatic efficacy 4-point scale "excellent, good, moderate or poor/no response". Non-major bleeding episodes are those not requiring treatment at the hemophilia center or not threatening subject's life or loss of limb.
    End point type
    Secondary
    End point timeframe
    Up to 5 years
    Notes
    [17] - 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: The endpoint is only for PUPs
    End point values
    		 CSL627: Previously untreated patients (PUPs)
    Number of subjects analysed
    24 [18]
    Units: percent
        number (confidence interval 95%)
    92.1 (87.0 to 95.3)
    Notes
    [18] - Number of treated bleeding events = 315
    No statistical analyses for this end point

    Secondary: Mean number of on-demand infusions of CSL627

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    End point title
    		 Mean number of on-demand infusions of CSL627
    End point description
    End point type
    Secondary
    End point timeframe
    Up to 5 years
    End point values
    		 CSL627: Previously treated patients (PTPs) CSL627: Previously untreated patients (PUPs)
    Number of subjects analysed
    11
    12
    Units: number of infusions
    arithmetic mean (standard deviation)
        per subject per month
    6.26 ( 4.778 )
    1.23 ( 1.296 )
        per subject per year
    75.18 ( 57.335 )
    14.75 ( 15.547 )
    No statistical analyses for this end point

    Secondary: Mean on-demand dose administered of CSL627

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    End point title
    		 Mean on-demand dose administered of CSL627
    End point description
    End point type
    Secondary
    End point timeframe
    Up to 5 years
    End point values
    		 CSL627: Previously treated patients (PTPs) CSL627: Previously untreated patients (PUPs)
    Number of subjects analysed
    11
    12
    Units: IU/kg
    arithmetic mean (standard deviation)
        per subject per month
    210.39 ( 188.106 )
    41.93 ( 44.643 )
        per subject per year
    2524.69 ( 2257.278 )
    503.16 ( 535.712 )
    No statistical analyses for this end point

    Secondary: Mean prophylaxis dose administered of CSL627

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    End point title
    		 Mean prophylaxis dose administered of CSL627
    End point description
    End point type
    Secondary
    End point timeframe
    Up to 5 years
    End point values
    		 CSL627: Previously treated patients (PTPs) CSL627: Previously untreated patients (PUPs)
    Number of subjects analysed
    211
    23
    Units: IU/kg
    arithmetic mean (standard deviation)
        per subject per month
    380.95 ( 130.079 )
    389.30 ( 243.191 )
        per subject per year
    4571.35 ( 1560.944 )
    4671.54 ( 2918.288 )
    No statistical analyses for this end point

    Secondary: Mean total amount of CSL627 administered during surgery period in PTPs

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    End point title
    		 Mean total amount of CSL627 administered during surgery period in PTPs [19]
    End point description
    End point type
    Secondary
    End point timeframe
    Day of surgery up to 336 hours post-surgery
    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: The endpoint is only for PTPs
    End point values
    		 CSL627: Previously treated patients (PTPs)
    Number of subjects analysed
    24
    Units: IU
        arithmetic mean (standard deviation)
    51663.0 ( 62033.25 )
    No statistical analyses for this end point

    Secondary: Percentage of PUPs with clinically significant abnormal vital signs values after first infusion of CSL627

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    End point title
    		 Percentage of PUPs with clinically significant abnormal vital signs values after first infusion of CSL627 [20]
    End point description
    Vital signs assessments include heart rate, blood pressure, and body temperature. Clinical significance of an abnormality will be assessed by the investigator.
    End point type
    Secondary
    End point timeframe
    Up to 6 hours after first infusion
    Notes
    [20] - 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: The endpoint is only for PUPs
    End point values
    		 CSL627: Previously untreated patients (PUPs)
    Number of subjects analysed
    24
    Units: percent
        number (not applicable)
    0
    No statistical analyses for this end point

    Secondary: Percentage of PUPs with treatment-emergent clinically significant abnormal vital signs values

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    End point title
    		 Percentage of PUPs with treatment-emergent clinically significant abnormal vital signs values [21]
    End point description
    Vital signs assessments include heart rate, blood pressure, and body temperature. Clinical significance of an abnormality will be assessed by the investigator.
    End point type
    Secondary
    End point timeframe
    Up to 5 years
    Notes
    [21] - 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: The endpoint is only for PUPs
    End point values
    		 CSL627: Previously untreated patients (PUPs)
    Number of subjects analysed
    24
    Units: percent
        number (not applicable)
    0
    No statistical analyses for this end point

    Secondary: Total amount of CSL627 administered during surgery period in PUPs

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    End point title
    		 Total amount of CSL627 administered during surgery period in PUPs [22]
    End point description
    End point type
    Secondary
    End point timeframe
    Day of surgery up to 336 hours post-surgery
    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: The endpoint is only for PUPs
    End point values
    		 CSL627: Previously untreated patients (PUPs)
    Number of subjects analysed
    3
    Units: IU
    number (not applicable)
        Subject 1
    15693
        Subject 2
    5631
        Subject 3
    7330
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to 5 years
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21.1
    Reporting groups
    Reporting group title
    CSL627: Previously treated patients (PTPs)
    Reporting group description
    		 -

    Reporting group title
    CSL627: Previously untreated patients (PUPs)
    Reporting group description
    		 -

    Serious adverse events
    		 CSL627: Previously treated patients (PTPs) CSL627: Previously untreated patients (PUPs)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    23 / 222 (10.36%)
    14 / 24 (58.33%)
         number of deaths (all causes)
    1
    0
         number of deaths resulting from adverse events
    0
    0
    Investigations
    Anti factor VIII antibody positive
         subjects affected / exposed
    0 / 222 (0.00%)
    6 / 24 (25.00%)
         occurrences causally related to treatment / all
    0 / 0
    6 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Inhibiting antibodies positive
         subjects affected / exposed
    0 / 222 (0.00%)
    5 / 24 (20.83%)
         occurrences causally related to treatment / all
    0 / 0
    5 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Road traffic accident
         subjects affected / exposed
    2 / 222 (0.90%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal injury
         subjects affected / exposed
    1 / 222 (0.45%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Periprosthetic fracture
         subjects affected / exposed
    1 / 222 (0.45%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin laceration
         subjects affected / exposed
    1 / 222 (0.45%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    0 / 222 (0.00%)
    2 / 24 (8.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound haemorrhage
         subjects affected / exposed
    0 / 222 (0.00%)
    1 / 24 (4.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Shock
         subjects affected / exposed
    1 / 222 (0.45%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vasospasm
         subjects affected / exposed
    1 / 222 (0.45%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhage
         subjects affected / exposed
    0 / 222 (0.00%)
    1 / 24 (4.17%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Generalised tonic-clonic seizure
         subjects affected / exposed
    1 / 222 (0.45%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Lennox-Gastaut syndrome
         subjects affected / exposed
    1 / 222 (0.45%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    1 / 222 (0.45%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    1 / 222 (0.45%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Factor VIII inhibition
         subjects affected / exposed
    0 / 222 (0.00%)
    1 / 24 (4.17%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Blindness transient
         subjects affected / exposed
    1 / 222 (0.45%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Social circumstances
    Pregnancy of partner
         subjects affected / exposed
    1 / 222 (0.45%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    1 / 222 (0.45%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenal ulcer
         subjects affected / exposed
    1 / 222 (0.45%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis erosive
         subjects affected / exposed
    1 / 222 (0.45%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 222 (0.45%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhoids
         subjects affected / exposed
    1 / 222 (0.45%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mouth haemorrhage
         subjects affected / exposed
    0 / 222 (0.00%)
    1 / 24 (4.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Nephritis
         subjects affected / exposed
    1 / 222 (0.45%)
    0 / 24 (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
    Haemophilic arthropathy
         subjects affected / exposed
    3 / 222 (1.35%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscle haemorrhage
         subjects affected / exposed
    1 / 222 (0.45%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal stiffness
         subjects affected / exposed
    1 / 222 (0.45%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tendinous contracture
         subjects affected / exposed
    1 / 222 (0.45%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscle spasms
         subjects affected / exposed
    0 / 222 (0.00%)
    1 / 24 (4.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    2 / 222 (0.90%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    1 / 222 (0.45%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 222 (0.45%)
    0 / 24 (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
    1 / 222 (0.45%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound infection
         subjects affected / exposed
    1 / 222 (0.45%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    0 / 222 (0.00%)
    1 / 24 (4.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acinetobacter infection
         subjects affected / exposed
    0 / 222 (0.00%)
    1 / 24 (4.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    1 / 222 (0.45%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 CSL627: Previously treated patients (PTPs) CSL627: Previously untreated patients (PUPs)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    130 / 222 (58.56%)
    23 / 24 (95.83%)
    Vascular disorders
    Haematoma
         subjects affected / exposed
    2 / 222 (0.90%)
    2 / 24 (8.33%)
         occurrences all number
    2
    3
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    14 / 222 (6.31%)
    15 / 24 (62.50%)
         occurrences all number
    18
    44
    Malaise
         subjects affected / exposed
    0 / 222 (0.00%)
    2 / 24 (8.33%)
         occurrences all number
    0
    4
    Immune system disorders
    Allergy to arthropod sting
         subjects affected / exposed
    0 / 222 (0.00%)
    2 / 24 (8.33%)
         occurrences all number
    0
    5
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    13 / 222 (5.86%)
    6 / 24 (25.00%)
         occurrences all number
    19
    13
    Rhinorrhoea
         subjects affected / exposed
    3 / 222 (1.35%)
    2 / 24 (8.33%)
         occurrences all number
    3
    3
    Bronchospasm
         subjects affected / exposed
    0 / 222 (0.00%)
    2 / 24 (8.33%)
         occurrences all number
    0
    4
    Investigations
    Coronavirus test positive
         subjects affected / exposed
    0 / 222 (0.00%)
    2 / 24 (8.33%)
         occurrences all number
    0
    2
    Inhibiting antibodies positive
         subjects affected / exposed
    0 / 222 (0.00%)
    2 / 24 (8.33%)
         occurrences all number
    0
    2
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    11 / 222 (4.95%)
    3 / 24 (12.50%)
         occurrences all number
    12
    5
    Head injury
         subjects affected / exposed
    11 / 222 (4.95%)
    1 / 24 (4.17%)
         occurrences all number
    11
    3
    Contusion
         subjects affected / exposed
    11 / 222 (4.95%)
    0 / 24 (0.00%)
         occurrences all number
    13
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    20 / 222 (9.01%)
    0 / 24 (0.00%)
         occurrences all number
    29
    0
    Blood and lymphatic system disorders
    Iron deficiency anaemia
         subjects affected / exposed
    2 / 222 (0.90%)
    3 / 24 (12.50%)
         occurrences all number
    3
    3
    Ear and labyrinth disorders
    Ear pain
         subjects affected / exposed
    4 / 222 (1.80%)
    2 / 24 (8.33%)
         occurrences all number
    4
    2
    Gastrointestinal disorders
    Dental caries
         subjects affected / exposed
    11 / 222 (4.95%)
    0 / 24 (0.00%)
         occurrences all number
    11
    0
    Diarrhoea
         subjects affected / exposed
    5 / 222 (2.25%)
    5 / 24 (20.83%)
         occurrences all number
    5
    6
    Vomiting
         subjects affected / exposed
    4 / 222 (1.80%)
    3 / 24 (12.50%)
         occurrences all number
    5
    8
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    6 / 222 (2.70%)
    3 / 24 (12.50%)
         occurrences all number
    6
    3
    Eczema
         subjects affected / exposed
    1 / 222 (0.45%)
    3 / 24 (12.50%)
         occurrences all number
    1
    3
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    20 / 222 (9.01%)
    1 / 24 (4.17%)
         occurrences all number
    28
    1
    Joint swelling
         subjects affected / exposed
    4 / 222 (1.80%)
    2 / 24 (8.33%)
         occurrences all number
    5
    2
    Haemarthrosis
         subjects affected / exposed
    2 / 222 (0.90%)
    2 / 24 (8.33%)
         occurrences all number
    3
    2
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    40 / 222 (18.02%)
    9 / 24 (37.50%)
         occurrences all number
    73
    15
    Upper respiratory tract infection
         subjects affected / exposed
    25 / 222 (11.26%)
    7 / 24 (29.17%)
         occurrences all number
    37
    18
    Influenza
         subjects affected / exposed
    14 / 222 (6.31%)
    4 / 24 (16.67%)
         occurrences all number
    16
    6
    Tonsillitis
         subjects affected / exposed
    13 / 222 (5.86%)
    5 / 24 (20.83%)
         occurrences all number
    17
    5
    Rhinitis
         subjects affected / exposed
    7 / 222 (3.15%)
    6 / 24 (25.00%)
         occurrences all number
    7
    10
    Ear infection
         subjects affected / exposed
    5 / 222 (2.25%)
    5 / 24 (20.83%)
         occurrences all number
    8
    9
    Conjunctivitis
         subjects affected / exposed
    6 / 222 (2.70%)
    3 / 24 (12.50%)
         occurrences all number
    6
    4
    Bronchitis
         subjects affected / exposed
    5 / 222 (2.25%)
    3 / 24 (12.50%)
         occurrences all number
    7
    3
    Varicella
         subjects affected / exposed
    2 / 222 (0.90%)
    6 / 24 (25.00%)
         occurrences all number
    2
    7
    Otitis media
         subjects affected / exposed
    3 / 222 (1.35%)
    4 / 24 (16.67%)
         occurrences all number
    5
    5
    Viral rhinitis
         subjects affected / exposed
    1 / 222 (0.45%)
    2 / 24 (8.33%)
         occurrences all number
    1
    2
    Scarlet fever
         subjects affected / exposed
    0 / 222 (0.00%)
    2 / 24 (8.33%)
         occurrences all number
    0
    2
    Tinea capitis
         subjects affected / exposed
    0 / 222 (0.00%)
    2 / 24 (8.33%)
         occurrences all number
    2
    2

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    28 Mar 2014
    -Update of section on previous clinical study experience to reflect the start of pediatric Study 3002. -Removal of the overall caregiver / subject assessment of hemostatic efficacy for subjects ≥ 12 to ≤ 65 years of age to provide consistent means of evaluation for pain and symptom relief for all subjects in the study. -Clarification for symptom and pain relief assessments.
    05 Jun 2015
    -Addition of Arm 3 (PTPs who were not currently participating in a rVIII-SingleChain study). -Addition of confirmed inhibitors as SAEs.
    27 Jan 2017
    -Addition of final blood sample collection for inhibitor assessment at the EOS Visit for Arm 1 PTPs. -Addition of exploratory objective and 2 associated exploratory endpoints for inhibitor incidence in PTPs. -Extension of the individual subject participation / estimated time to reach the required number of EDs. -Change in number of study sites. -Removal of subject’s assessment of bleeding / pain relief.
    01 Oct 2019
    -Change in number of expected enrolled subjects into Arm 2 PUPs from 50 to 24. -Removal of "at least 50" with respect to number of enrolled subjects. -Change in the inhibitor treatment period from 18 to 24 months. -Clarification for reporting inhibitor relapse SAE. -Clarification in the definition of inhibitor diagnosis. -Change in maximum duration of individual subject participation in the ITI substudy from 24 to 30 months.
    26 May 2020
    -Change in the number of EDs from 150 to 75 EDs that PUPs in Arm 2 needed to complete the study.

    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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