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    Clinical Trial Results:
    Efficacy and safety of turoctocog alfa for prophylaxis and treatment of bleeding episodes in previously treated Chinese patients with haemophilia A

    Summary
    EudraCT number
    		 2013-004791-35
    Trial protocol
    		 Outside EU/EEA  
    Global end of trial date
    12 Dec 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    22 Jun 2019
    First version publication date
    22 Jun 2019
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    NN7008-4028
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02938585
    WHO universal trial number (UTN)
    		 U1111-1150-0765
    Sponsors
    Sponsor organisation name
    Novo Nordisk A/S
    Sponsor organisation address
    Novo Allé, Bagsvaerd, Denmark, 2880
    Public contact
    Clinical Reporting Anchor and Disclosure (1452), Novo Nordisk A/S, clinicaltrials@novonordisk.com
    Scientific contact
    Clinical Reporting Anchor and Disclosure (1452), Novo Nordisk A/S, clinicaltrials@novonordisk.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
    03 Jun 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    16 Mar 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    12 Dec 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the clinical efficacy of turoctocog alfa in the treatment of bleeding episodes in Chinese patients with severe haemophilia A (FVIII≤1%).
    Protection of trial subjects
    The trial was conducted in accordance with the Declaration of Helsinki and ICH Good Clinical Practice, including archiving of essential documents.
    Background therapy
    		 Not applicable.
    Evidence for comparator
    		 Not applicable.
    Actual start date of recruitment
    12 Dec 2016
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    China: 68
    Worldwide total number of subjects
    68
    EEA total number of subjects
    0
    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)
    42
    Adolescents (12-17 years)
    11
    Adults (18-64 years)
    15
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 The trial was conducted at 10 sites in mainland China.

    Pre-assignment
    Screening details
    		 Study design: This was an open-label and non-randomised trial. Participants with severe haemophilia A were administered a prophylaxis (preventive) or on-demand regimen of turoctocog alfa (trial product) at the investigator’s discretion.

    Period 1
    Period 1 title
    Main phase: 6 months
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded
    Blinding implementation details
    Not Applicable

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Small children (0 to <6 years)
    Arm description
    		 Participants were to receive turoctocog alfa for a minimum of 6 months as either prophylaxis or on-demand treatment at the investigator’s discretion.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Turoctocog alfa
    Investigational medicinal product code
    Other name
    NovoEight®
    Pharmaceutical forms
    Powder and solution for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    The recommended prophylaxis starting dose was 30 IU/kg. Prophylaxis doses ranged from 25−50 IU/kg with every-second-day treatment, or 25−60 IU/kg with 3-times-weekly treatment. Bleeds were treated with one or more turoctocog alfa intravenous (i.v.) bolus injections. The individual dose levels were decided by the investigator based on recommendations from the World Federation of Hemophilia (WFH). Participants who underwent surgery were treated with turoctocog alfa according to WFH recommendations and the following guidance: Minor surgery; to maintain coagulation factor VIII (FVIII) activity levels at 30−60 IU/dL. Major surgery; to maintain FVIII activity levels at 80−100 IU/dL pre- and postoperatively.

    Arm title
    		 Older children (6 to <12 years)
    Arm description
    		 Participants were to receive turoctocog alfa for a minimum of 6 months as either prophylaxis or on-demand treatment at the investigator’s discretion.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Turoctocog alfa
    Investigational medicinal product code
    Other name
    NovoEight®
    Pharmaceutical forms
    Powder and solution for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    The recommended prophylaxis starting dose was 30 IU/kg. Prophylaxis doses ranged from 25−50 IU/kg with every-second-day treatment, or 25−60 IU/kg with 3-times-weekly treatment. Bleeds were treated with one or more turoctocog alfa i.v. bolus injections. The individual dose levels were decided by the investigator based on recommendations from the WFH. Participants who underwent surgery were treated with turoctocog alfa according to WFH recommendations and the following guidance: Minor surgery; to maintain FVIII activity levels at 30−60 IU/dL. Major surgery; to maintain FVIII activity levels at 80−100 IU/dL pre- and postoperatively.

    Arm title
    		 Adolescents (12 to <18 years)
    Arm description
    		 Participants were to receive turoctocog alfa for a minimum of 6 months as either prophylaxis or on-demand treatment at the investigator’s discretion.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Turoctocog alfa
    Investigational medicinal product code
    Other name
    NovoEight®
    Pharmaceutical forms
    Powder and solution for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    The recommended prophylaxis starting dose was 25 IU/kg. Prophylaxis doses ranged from 20−40 IU/kg with every-second-day treatment, or 20−50 IU/kg with 3-times-weekly treatment. Bleeds were treated with one or more turoctocog alfa i.v. bolus injections. The individual dose levels were decided by the investigator based on recommendations from the WFH. Participants who underwent surgery were treated with turoctocog alfa according to WFH recommendations and the following guidance: Minor surgery; to maintain FVIII activity levels at 30−60 IU/dL. Major surgery; to maintain FVIII activity levels at 80−100 IU/dL pre- and postoperatively.

    Arm title
    		 Adults (>=18 years)
    Arm description
    		 Participants were to receive turoctocog alfa for a minimum of 6 months as either prophylaxis or on-demand treatment at the investigator’s discretion.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Turoctocog alfa
    Investigational medicinal product code
    Other name
    NovoEight®
    Pharmaceutical forms
    Powder and solution for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    The recommended prophylaxis starting dose was 25 IU/kg. Prophylaxis doses ranged from 20−40 IU/kg with every-second-day treatment, or 20−50 IU/kg with 3-times-weekly treatment. Bleeds were treated with one or more turoctocog alfa i.v. bolus injections. The individual dose levels were decided by the investigator based on recommendations from the WFH. Participants who underwent surgery were treated with turoctocog alfa according to WFH recommendations and the following guidance: Minor surgery; to maintain FVIII activity levels at 30−60 IU/dL. Major surgery; to maintain FVIII activity levels at 80−100 IU/dL pre- and postoperatively.

    Number of subjects in period 1
    		Small children (0 to <6 years) Older children (6 to <12 years) Adolescents (12 to <18 years) Adults (>=18 years)
    Started
    9
    33
    11
    15
    Completed
    9
    32
    11
    14
    Not completed
    0
    1
    0
    1
         Consent withdrawn by subject
    -
    -
    -
    1
         Withdrawal by parent or guardian
    -
    1
    -
    -
    Period 2
    Period 2 title
    Extension phase: Up to approx. 18 months
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded
    Blinding implementation details
    Not Applicable

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Small children (0 to <6 years)
    Arm description
    		 Participants who completed 6 months of treatment (prophylaxis or on-demand) in the main phase, were to continue the same treatment for up to approximately 18 months. Participants were allowed to switch between treatments ‘in the extension phase’.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Turoctocog alfa
    Investigational medicinal product code
    Other name
    NovoEight®
    Pharmaceutical forms
    Powder and solution for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    The recommended prophylaxis starting dose was 30 IU/kg. Prophylaxis doses ranged from 25−50 IU/kg with every-second-day treatment, or 25−60 IU/kg with 3-times-weekly treatment. Bleeds were treated with one or more turoctocog alfa i.v. bolus injections. The individual dose levels were decided by the investigator based on recommendations from the WFH. Participants who underwent surgery were treated with turoctocog alfa according to WFH recommendations and the following guidance: Minor surgery; to maintain FVIII activity levels at 30−60 IU/dL. Major surgery; to maintain FVIII activity levels at 80−100 IU/dL pre- and postoperatively.

    Arm title
    		 Older children (6 to <12 years)
    Arm description
    		 Participants who completed 6 months of treatment (prophylaxis or on-demand) in the main phase, were to continue the same treatment for up to approximately 18 months. Participants were allowed to switch between treatments ‘in the extension phase’.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Turoctocog alfa
    Investigational medicinal product code
    Other name
    NovoEight®
    Pharmaceutical forms
    Powder and solution for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    The recommended prophylaxis starting dose was 30 IU/kg. Prophylaxis doses ranged from 25−50 IU/kg with every-second-day treatment, or 25−60 IU/kg with 3-times-weekly treatment. Bleeds were treated with one or more turoctocog alfa i.v. bolus injections. The individual dose levels were decided by the investigator based on recommendations from the WFH. Participants who underwent surgery were treated with turoctocog alfa according to WFH recommendations and the following guidance: Minor surgery; to maintain FVIII activity levels at 30−60 IU/dL. Major surgery; to maintain FVIII activity levels at 80−100 IU/dL pre- and postoperatively.

    Arm title
    		 Adolescents (12 to <18 years)
    Arm description
    		 Participants who completed 6 months of treatment (prophylaxis or on-demand) in the main phase, were to continue the same treatment for up to approximately 18 months. Participants were allowed to switch between treatments ‘in the extension phase’.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Turoctocog alfa
    Investigational medicinal product code
    Other name
    NovoEight®
    Pharmaceutical forms
    Powder and solution for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    The recommended prophylaxis starting dose was 25 IU/kg. Prophylaxis doses ranged from 20−40 IU/kg with every-second-day treatment, or 20−50 IU/kg with 3-times-weekly treatment. Bleeds were treated with one or more turoctocog alfa i.v. bolus injections. The individual dose levels were decided by the investigator based on recommendations from the WFH. Participants who underwent surgery were treated with turoctocog alfa according to WFH recommendations and the following guidance: Minor surgery; to maintain FVIII activity levels at 30−60 IU/dL. Major surgery; to maintain FVIII activity levels at 80−100 IU/dL pre- and postoperatively.

    Arm title
    		 Adults (>=18 years)
    Arm description
    		 Participants who completed 6 months of treatment (prophylaxis or on-demand) in the main phase, were to continue the same treatment for up to approximately 18 months. Participants were allowed to switch between treatments ‘in the extension phase’.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Turoctocog alfa
    Investigational medicinal product code
    Other name
    NovoEight®
    Pharmaceutical forms
    Powder and solution for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    The recommended prophylaxis starting dose was 25 IU/kg. Prophylaxis doses ranged from 20−40 IU/kg with every-second-day treatment, or 20−50 IU/kg with 3-times-weekly treatment. Bleeds were treated with one or more turoctocog alfa i.v. bolus injections. The individual dose levels were decided by the investigator based on recommendations from the WFH. Participants who underwent surgery were treated with turoctocog alfa according to WFH recommendations and the following guidance: Minor surgery; to maintain FVIII activity levels at 30−60 IU/dL. Major surgery; to maintain FVIII activity levels at 80−100 IU/dL pre- and postoperatively.

    Number of subjects in period 2 [1]
    		Small children (0 to <6 years) Older children (6 to <12 years) Adolescents (12 to <18 years) Adults (>=18 years)
    Started
    9
    32
    11
    12
    Completed
    9
    32
    11
    10
    Not completed
    0
    0
    0
    2
         Consent withdrawn by subject
    -
    -
    -
    2
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: 2 participants completed the main period, but withdrew their consent before entering the extension period.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Small children (0 to <6 years)
    Reporting group description
    		 Participants were to receive turoctocog alfa for a minimum of 6 months as either prophylaxis or on-demand treatment at the investigator’s discretion.

    Reporting group title
    Older children (6 to <12 years)
    Reporting group description
    		 Participants were to receive turoctocog alfa for a minimum of 6 months as either prophylaxis or on-demand treatment at the investigator’s discretion.

    Reporting group title
    Adolescents (12 to <18 years)
    Reporting group description
    		 Participants were to receive turoctocog alfa for a minimum of 6 months as either prophylaxis or on-demand treatment at the investigator’s discretion.

    Reporting group title
    Adults (>=18 years)
    Reporting group description
    		 Participants were to receive turoctocog alfa for a minimum of 6 months as either prophylaxis or on-demand treatment at the investigator’s discretion.

    Reporting group values
    		 Small children (0 to <6 years) Older children (6 to <12 years) Adolescents (12 to <18 years) Adults (>=18 years) Total
    Number of subjects
    		 9 33 11 15 68
    Age categorical
    Units: Subjects
        Children (2-11 years)
    		 9 33 0 0 42
        Adolescents (12-17 years)
    		 0 0 11 0 11
        Adults (18-64 years)
    		 0 0 0 15 15
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 4.00 ( 1.12 ) 8.70 ( 1.91 ) 14.55 ( 1.92 ) 31.00 ( 11.20 ) -
    Sex: Female, Male
    Units: Subjects
        Female
    		 0 0 0 0 0
        Male
    		 9 33 11 15 68

    End points

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    End points reporting groups
    Reporting group title
    Small children (0 to <6 years)
    Reporting group description
    		 Participants were to receive turoctocog alfa for a minimum of 6 months as either prophylaxis or on-demand treatment at the investigator’s discretion.

    Reporting group title
    Older children (6 to <12 years)
    Reporting group description
    		 Participants were to receive turoctocog alfa for a minimum of 6 months as either prophylaxis or on-demand treatment at the investigator’s discretion.

    Reporting group title
    Adolescents (12 to <18 years)
    Reporting group description
    		 Participants were to receive turoctocog alfa for a minimum of 6 months as either prophylaxis or on-demand treatment at the investigator’s discretion.

    Reporting group title
    Adults (>=18 years)
    Reporting group description
    		 Participants were to receive turoctocog alfa for a minimum of 6 months as either prophylaxis or on-demand treatment at the investigator’s discretion.
    Reporting group title
    Small children (0 to <6 years)
    Reporting group description
    		 Participants who completed 6 months of treatment (prophylaxis or on-demand) in the main phase, were to continue the same treatment for up to approximately 18 months. Participants were allowed to switch between treatments ‘in the extension phase’.

    Reporting group title
    Older children (6 to <12 years)
    Reporting group description
    		 Participants who completed 6 months of treatment (prophylaxis or on-demand) in the main phase, were to continue the same treatment for up to approximately 18 months. Participants were allowed to switch between treatments ‘in the extension phase’.

    Reporting group title
    Adolescents (12 to <18 years)
    Reporting group description
    		 Participants who completed 6 months of treatment (prophylaxis or on-demand) in the main phase, were to continue the same treatment for up to approximately 18 months. Participants were allowed to switch between treatments ‘in the extension phase’.

    Reporting group title
    Adults (>=18 years)
    Reporting group description
    		 Participants who completed 6 months of treatment (prophylaxis or on-demand) in the main phase, were to continue the same treatment for up to approximately 18 months. Participants were allowed to switch between treatments ‘in the extension phase’.

    Subject analysis set title
    Small children (0 to <6 years)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The full analysis set (FAS) included all dosed participants with data after dosing.

    Subject analysis set title
    Older children (6 to <12 years)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The FAS included all dosed participants with data after dosing.

    Subject analysis set title
    Adolescents (12 to <18 years)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The FAS included all dosed participants with data after dosing.

    Subject analysis set title
    Adults (>=18 years)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The FAS included all dosed participants with data after dosing.

    Primary: Haemostatic effect of turoctocog alfa when used for treatment of bleeds, assessed on a four-point scale for haemostatic response (excellent, good, moderate and none): 6 months

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    End point title
    		 Haemostatic effect of turoctocog alfa when used for treatment of bleeds, assessed on a four-point scale for haemostatic response (excellent, good, moderate and none): 6 months [1]
    End point description
    The haemostatic effect of turoctocog alfa when used for treatment of bleeding episodes in both prophylaxis and on-demand regimen was evaluated during the main phase of 6 months. The effect was assessed on a four-point scale for haemostatic response, excellent, good, moderate and none. Results are based on the full analysis set, which included all dosed participants with data after dosing. “Number of subjects analysed” should be read as “number of bleeding episodes treated with turoctocog alfa, both in prophylaxis and on-demand regimen”.
    End point type
    Primary
    End point timeframe
    During the main phase (6 months duration per patient)
    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: The evaluation of the primary endpoint was based mainly upon descriptive statistics. Hence, no statistical analysis was performed.
    End point values
    		 Small children (0 to <6 years) Older children (6 to <12 years) Adolescents (12 to <18 years) Adults (>=18 years)
    Number of subjects analysed
    48 [2]
    245 [3]
    28 [4]
    290 [5]
    Units: Bleeding episodes
        Excellent
    35
    156
    20
    190
        Good
    12
    73
    8
    87
        Moderate
    1
    15
    0
    13
        None
    0
    0
    0
    0
        Missing
    0
    1
    0
    0
    Notes
    [2] - Out of 9 participants in the FAS, 6 had 48 bleeding episodes
    [3] - Out of 33 participants in the FAS, 20 had 245 bleeding episodes
    [4] - Out of 11 participants in the FAS, 6 had 28 bleeding episodes
    [5] - Out of 15 participants in the FAS, 15 had 290 bleeding episodes
    No statistical analyses for this end point

    Secondary: Haemostatic effect of turoctocog alfa when used for treatment of bleeds, assessed on a four-point scale for haemostatic response (excellent, good, moderate and none): 24 months

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    End point title
    		 Haemostatic effect of turoctocog alfa when used for treatment of bleeds, assessed on a four-point scale for haemostatic response (excellent, good, moderate and none): 24 months
    End point description
    The haemostatic effect of turoctocog alfa when used for treatment of bleeding episodes in both prophylaxis and on-demand regimen was evaluated during the trial period of 24 months (main + extended phase). The effect was assessed on a four-point scale for haemostatic response, excellent, good, moderate and none. Results are based on the FAS. “Number of subjects analysed” should be read as “number of bleeding episodes treated with turoctocog alfa, both in prophylaxis and on-demand regimen”.
    End point type
    Secondary
    End point timeframe
    During the trial period of 24 months
    End point values
    		 Small children (0 to <6 years) Older children (6 to <12 years) Adolescents (12 to <18 years) Adults (>=18 years)
    Number of subjects analysed
    65 [6]
    405 [7]
    53 [8]
    402 [9]
    Units: Bleeding episodes
        Excellent
    45
    275
    42
    272
        Good
    18
    103
    11
    116
        Moderate
    2
    26
    0
    14
        None
    0
    0
    0
    0
        Missing
    0
    1
    0
    0
    Notes
    [6] - Out of 9 participants in the FAS, 7 had 65 bleeding episodes
    [7] - Out of 33 participants in the FAS, 24 had 405 bleeding episodes
    [8] - Out of 11 participants in the FAS, 8 had 53 bleeding episodes
    [9] - Out of 15 participants in the FAS, 15 had 402 bleeding episodes
    No statistical analyses for this end point

    Secondary: Incidence rate of inhibitory antibodies against FVIII (≥0.6 Bethesda unit (BU)): 6 months

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    End point title
    		 Incidence rate of inhibitory antibodies against FVIII (≥0.6 Bethesda unit (BU)): 6 months
    End point description
    Incidence rate of inhibitory antibodies against FVIII (≥0.6 BU, presented as percentage of participants) in both prophylaxis and on-demand regimen was evaluated during the main phase of 6 months. Results are based on the FAS. “Number of subjects analysed” = number of participants, both on prophylaxis and on-demand regimen.
    End point type
    Secondary
    End point timeframe
    During the main phase of 6 months
    End point values
    		 Small children (0 to <6 years) Older children (6 to <12 years) Adolescents (12 to <18 years) Adults (>=18 years)
    Number of subjects analysed
    9
    33
    11
    15
    Units: Percentage of participants
    0
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Incidence rate of inhibitory antibodies against FVIII (≥0.6 Bethesda unit (BU)): 24 months

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    End point title
    		 Incidence rate of inhibitory antibodies against FVIII (≥0.6 Bethesda unit (BU)): 24 months
    End point description
    Incidence rate of inhibitory antibodies against FVIII (≥0.6 BU, presented as percentage of participants) in both prophylaxis and on-demand regimen was evaluated during the trial period of 24 months (main + extended phase). Results are based on the FAS. “Number of subjects analysed” = number of participants, both on prophylaxis and on-demand regimen.
    End point type
    Secondary
    End point timeframe
    During the trial period of 24 months
    End point values
    		 Small children (0 to <6 years) Older children (6 to <12 years) Adolescents (12 to <18 years) Adults (>=18 years)
    Number of subjects analysed
    9
    33
    11
    15
    Units: Percentage of participants
    0
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Number of bleeds (total bleeds assessed as annual bleeding rate) per patient: 6 months

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    End point title
    		 Number of bleeds (total bleeds assessed as annual bleeding rate) per patient: 6 months
    End point description
    Number of bleeds (total bleeds assessed as annual bleeding rate [ABR]) per participant in the prophylaxis regimen was evaluated during the main phase of 6 months. The annual bleeding rate was analysed by a negative binomial model. Presented result are ‘negative binomial estimate of ABR’ and corresponding 95% confidence interval (CI). Results are based on the FAS. “Number of subjects analysed” = number of participants in the prophylaxis regimen.
    End point type
    Secondary
    End point timeframe
    During the main phase of 6 months
    End point values
    		 Small children (0 to <6 years) Older children (6 to <12 years) Adolescents (12 to <18 years) Adults (>=18 years)
    Number of subjects analysed
    8
    26
    10
    7
    Units: Bleeding episodes/year/participant
        number (confidence interval 95%)
    4.36 (1.71 to 11.14)
    4.11 (2.15 to 7.87)
    2.34 (0.81 to 6.72)
    10.67 (5.53 to 20.57)
    No statistical analyses for this end point

    Secondary: Number of bleeds (total bleeds assessed as annual bleeding rate) per patient: 24 months

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    End point title
    		 Number of bleeds (total bleeds assessed as annual bleeding rate) per patient: 24 months
    End point description
    Number of bleeds (total bleeds assessed as ABR) per participant in the prophylaxis regimen was evaluated during the trial period of 24 months (main + extended phase). The annual bleeding rate was analysed by a negative binomial model. Presented result are ‘negative binomial estimate of ABR’ and corresponding 95% CI. Results are based on the FAS. “Number of subjects analysed” = number of participants in the prophylaxis regimen.
    End point type
    Secondary
    End point timeframe
    During the trial period of 24 months
    End point values
    		 Small children (0 to <6 years) Older children (6 to <12 years) Adolescents (12 to <18 years) Adults (>=18 years)
    Number of subjects analysed
    9
    31
    11
    12
    Units: Bleeding episodes/year/participant
        number (confidence interval 95%)
    2.28 (1.02 to 5.10)
    2.63 (1.53 to 4.51)
    1.97 (0.83 to 4.67)
    4.97 (1.96 to 12.60)
    No statistical analyses for this end point

    Secondary: Consumption of turoctocog alfa for bleeding treatment: Average dose to treat a bleed (6 months)

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    End point title
    		 Consumption of turoctocog alfa for bleeding treatment: Average dose to treat a bleed (6 months)
    End point description
    Average dose of turoctocog alfa consumed to treat a bleed in both prophylaxis and on-demand regimen was evaluated during the main phase of 6 months. Results are based on the FAS. “Number of subjects analysed” should be read as the number of turoctocog alfa doses taken by the participants to treat the bleeding episodes, both in prophylaxis and on-demand regimen.
    End point type
    Secondary
    End point timeframe
    During the main phase of 6 months
    End point values
    		 Small children (0 to <6 years) Older children (6 to <12 years) Adolescents (12 to <18 years) Adults (>=18 years)
    Number of subjects analysed
    69
    361
    60
    400
    Units: IU/kg BW
        arithmetic mean (standard deviation)
    42.96 ( 5.35 )
    36.69 ( 14.04 )
    46.79 ( 5.31 )
    20.29 ( 6.48 )
    No statistical analyses for this end point

    Secondary: Consumption of turoctocog alfa for bleeding treatment: Average dose to treat a bleed (24 months)

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    End point title
    		 Consumption of turoctocog alfa for bleeding treatment: Average dose to treat a bleed (24 months)
    End point description
    Average dose of turoctocog alfa consumed to treat a bleed in both prophylaxis and on-demand regimen was evaluated during the trial period of 24 months (main + extended phase). Results are based on the FAS. “Number of subjects analysed” should be read as the number of turoctocog alfa doses taken by the participants to treat the bleeding episodes, both in prophylaxis and on-demand regimen.
    End point type
    Secondary
    End point timeframe
    During the trial period of 24 months
    End point values
    		 Small children (0 to <6 years) Older children (6 to <12 years) Adolescents (12 to <18 years) Adults (>=18 years)
    Number of subjects analysed
    94
    624
    95
    565
    Units: IU/kg BW
        arithmetic mean (standard deviation)
    43.99 ( 6.95 )
    36.00 ( 12.32 )
    43.58 ( 6.93 )
    21.07 ( 7.49 )
    No statistical analyses for this end point

    Secondary: Consumption of turoctocog alfa for bleeding treatment: Number of injections per bleed (6 months)

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    End point title
    		 Consumption of turoctocog alfa for bleeding treatment: Number of injections per bleed (6 months)
    End point description
    Consumption of turoctocog alfa (number of injections per bleed) for bleeding treatment in both prophylaxis and on-demand regimen was evaluated during the main phase of 6 months. Results are based on the FAS. “Number of subjects analysed” should be read as “number of bleeding episodes treated with turoctocog alfa, both in prophylaxis and on-demand regimen”.
    End point type
    Secondary
    End point timeframe
    During the main phase of 6 months
    End point values
    		 Small children (0 to <6 years) Older children (6 to <12 years) Adolescents (12 to <18 years) Adults (>=18 years)
    Number of subjects analysed
    48
    245
    28
    290
    Units: Number of injections
        arithmetic mean (standard deviation)
    1.31 ( 0.59 )
    1.22 ( 0.61 )
    1.07 ( 0.26 )
    1.29 ( 0.89 )
    No statistical analyses for this end point

    Secondary: Consumption of turoctocog alfa for bleeding treatment: Number of injections per bleed (24 months)

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    End point title
    		 Consumption of turoctocog alfa for bleeding treatment: Number of injections per bleed (24 months)
    End point description
    Consumption of turoctocog alfa (number of injections per bleed) for bleeding treatment in both prophylaxis and on-demand regimen was evaluated during the trial period of 24 months (main + extended phase). Results are based on the FAS. “Number of subjects analysed” should be read as “number of bleeding episodes treated with turoctocog alfa, both in prophylaxis and on-demand regimen”.
    End point type
    Secondary
    End point timeframe
    During the trial period of 24 months
    End point values
    		 Small children (0 to <6 years) Older children (6 to <12 years) Adolescents (12 to <18 years) Adults (>=18 years)
    Number of subjects analysed
    65
    405
    53
    402
    Units: Number of injections
        arithmetic mean (standard deviation)
    1.34 ( 0.62 )
    1.30 ( 0.88 )
    1.09 ( 0.30 )
    1.33 ( 1.21 )
    No statistical analyses for this end point

    Secondary: Consumption of turoctocog alfa for bleeding treatment: IU/kg per bleed (6 months)

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    End point title
    		 Consumption of turoctocog alfa for bleeding treatment: IU/kg per bleed (6 months)
    End point description
    Consumption of turoctocog alfa (IU/kg BW per bleed) for bleeding treatment in both prophylaxis and on-demand regimen was evaluated during the main phase of 6 months. Results are based on the FAS. “Number of subjects analysed” should be read as “number of bleeding episodes treated with turoctocog alfa, both in prophylaxis and on-demand regimen”.
    End point type
    Secondary
    End point timeframe
    During the main phase of 6 months
    End point values
    		 Small children (0 to <6 years) Older children (6 to <12 years) Adolescents (12 to <18 years) Adults (>=18 years)
    Number of subjects analysed
    48
    245
    28
    290
    Units: IU/kg BW
        arithmetic mean (standard deviation)
    56.60 ( 25.32 )
    42.37 ( 26.54 )
    48.82 ( 15.05 )
    26.20 ( 17.55 )
    No statistical analyses for this end point

    Secondary: Consumption of turoctocog alfa for bleeding treatment: IU/kg per bleed (24 months)

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    End point title
    		 Consumption of turoctocog alfa for bleeding treatment: IU/kg per bleed (24 months)
    End point description
    Consumption of turoctocog alfa (IU/kg BW per bleed) for bleeding treatment in both prophylaxis and on-demand regimen was evaluated during the trial period of 24 months (main + extended phase). Results are based on the FAS. “Number of subjects analysed” should be read as “number of bleeding episodes treated with turoctocog alfa, both in prophylaxis and on-demand regimen”.
    End point type
    Secondary
    End point timeframe
    During the trial period of 24 months
    End point values
    		 Small children (0 to <6 years) Older children (6 to <12 years) Adolescents (12 to <18 years) Adults (>=18 years)
    Number of subjects analysed
    65
    405
    53
    402
    Units: IU/kg BW
        arithmetic mean (standard deviation)
    59.01 ( 28.61 )
    44.75 ( 34.15 )
    45.07 ( 15.33 )
    27.44 ( 22.52 )
    No statistical analyses for this end point

    Secondary: Consumption of turoctocog alfa during prophylaxis treatment per participant: Average prophylaxis dose (6 months)

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    End point title
    		 Consumption of turoctocog alfa during prophylaxis treatment per participant: Average prophylaxis dose (6 months)
    End point description
    Average preventive dose of turoctocog alfa consumed per participant in the prophylaxis regimen was evaluated during the main phase of 6 months. Results are based on the FAS. “Number of subjects analysed” should be read as the “number of preventive turoctocog alfa doses taken by the participants in the prophylaxis regimen”.
    End point type
    Secondary
    End point timeframe
    During the main phase of 6 months
    End point values
    		 Small children (0 to <6 years) Older children (6 to <12 years) Adolescents (12 to <18 years) Adults (>=18 years)
    Number of subjects analysed
    530
    1689
    661
    484
    Units: IU/kg BW
        arithmetic mean (standard deviation)
    47.05 ( 9.21 )
    39.46 ( 7.12 )
    35.40 ( 7.41 )
    37.28 ( 5.22 )
    No statistical analyses for this end point

    Secondary: Consumption of turoctocog alfa during prophylaxis treatment per participant: Average prophylaxis dose (24 months)

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    End point title
    		 Consumption of turoctocog alfa during prophylaxis treatment per participant: Average prophylaxis dose (24 months)
    End point description
    Average preventive dose of turoctocog alfa consumed per participant in the prophylaxis regimen was evaluated during the trial period of 24 months (main + extended phase). Results are based on the FAS. “Number of subjects analysed” should be read as the “number of preventive turoctocog alfa doses taken by the participants in the prophylaxis regimen”.
    End point type
    Secondary
    End point timeframe
    During the trial period of 24 months
    End point values
    		 Small children (0 to <6 years) Older children (6 to <12 years) Adolescents (12 to <18 years) Adults (>=18 years)
    Number of subjects analysed
    2314
    6729
    2794
    1999
    Units: IU/kg BW
        arithmetic mean (standard deviation)
    47.97 ( 8.00 )
    40.33 ( 7.05 )
    36.20 ( 7.15 )
    38.13 ( 7.51 )
    No statistical analyses for this end point

    Secondary: Consumption of turoctocog alfa during prophylaxis treatment per participant: IU/kg per month (6 months)

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    End point title
    		 Consumption of turoctocog alfa during prophylaxis treatment per participant: IU/kg per month (6 months)
    End point description
    Preventive dose of turoctocog alfa (IU/kg body weight (BW) per month) per participant in the prophylaxis regimen was evaluated during the main phase of 6 months. Results are based on the FAS. “Number of subjects analysed” = number of participants in the prophylaxis regimen.
    End point type
    Secondary
    End point timeframe
    During the main phase of 6 months
    End point values
    		 Small children (0 to <6 years) Older children (6 to <12 years) Adolescents (12 to <18 years) Adults (>=18 years)
    Number of subjects analysed
    8
    26
    10
    7
    Units: IU/kg BW/month/participant
        arithmetic mean (standard deviation)
    600.3 ( 112.6 )
    522.5 ( 87.59 )
    454.5 ( 92.79 )
    500.7 ( 84.39 )
    No statistical analyses for this end point

    Secondary: Consumption of turoctocog alfa during prophylaxis treatment per participant: IU/kg per month (24 months)

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    End point title
    		 Consumption of turoctocog alfa during prophylaxis treatment per participant: IU/kg per month (24 months)
    End point description
    Preventive dose of turoctocog alfa (IU/kg BW per month) per participant in the prophylaxis regimen was evaluated during the trial period of 24 months (main + extended phase). Results are based on the FAS. “Number of subjects analysed” = number of participants in the prophylaxis regimen.
    End point type
    Secondary
    End point timeframe
    During the trial period of 24 months
    End point values
    		 Small children (0 to <6 years) Older children (6 to <12 years) Adolescents (12 to <18 years) Adults (>=18 years)
    Number of subjects analysed
    9
    31
    11
    12
    Units: IU/kg BW/month/participant
        arithmetic mean (standard deviation)
    606.3 ( 118.5 )
    533.0 ( 82.90 )
    467.6 ( 91.40 )
    490.8 ( 115.7 )
    No statistical analyses for this end point

    Secondary: Consumption of turoctocog alfa during prophylaxis treatment per participant: IU/kg per year (6 months)

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    End point title
    		 Consumption of turoctocog alfa during prophylaxis treatment per participant: IU/kg per year (6 months)
    End point description
    Preventive dose of turoctocog alfa (IU/kg body weight per year) per participant in the prophylaxis regimen was evaluated during the main phase of 6 months. Results are based on the FAS. “Number of subjects analysed” = number of participants in the prophylaxis regimen.
    End point type
    Secondary
    End point timeframe
    During the main phase of 6 months
    End point values
    		 Small children (0 to <6 years) Older children (6 to <12 years) Adolescents (12 to <18 years) Adults (>=18 years)
    Number of subjects analysed
    8
    26
    10
    7
    Units: IU/kg BW/year/participant
        arithmetic mean (standard deviation)
    7204 ( 1351 )
    6270 ( 1051 )
    5454 ( 1113 )
    6009 ( 1013 )
    No statistical analyses for this end point

    Secondary: Consumption of turoctocog alfa during prophylaxis treatment per participant: IU/kg per year (24 months)

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    End point title
    		 Consumption of turoctocog alfa during prophylaxis treatment per participant: IU/kg per year (24 months)
    End point description
    Preventive dose of turoctocog alfa (IU/kg body weight per year) per participant in the prophylaxis regimen was evaluated during the trial period of 24 months (main + extended phase). Results are based on the FAS. “Number of subjects analysed” = number of participants in the prophylaxis regimen.
    End point type
    Secondary
    End point timeframe
    During the trial period of 24 months
    End point values
    		 Small children (0 to <6 years) Older children (6 to <12 years) Adolescents (12 to <18 years) Adults (>=18 years)
    Number of subjects analysed
    9
    31
    11
    12
    Units: IU/kg BW/year/participant
        arithmetic mean (standard deviation)
    7276 ( 1422 )
    6396 ( 994.7 )
    5611 ( 1097 )
    5890 ( 1388 )
    No statistical analyses for this end point

    Secondary: Total consumption of turoctocog alfa per participant: IU/kg per month (6 months)

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    End point title
    		 Total consumption of turoctocog alfa per participant: IU/kg per month (6 months)
    End point description
    Total consumption of turoctocog alfa (IU/kg body weight per month) per participant in both prophylaxis and on-demand regimen was evaluated during the main phase of 6 months. Results are based on the FAS. “Number of subjects analysed” = number of participants both on prophylaxis and on-demand regimen.
    End point type
    Secondary
    End point timeframe
    During the main phase of 6 months
    End point values
    		 Small children (0 to <6 years) Older children (6 to <12 years) Adolescents (12 to <18 years) Adults (>=18 years)
    Number of subjects analysed
    9
    33
    11
    15
    Units: IU/kg BW/month/participant
        arithmetic mean (standard deviation)
    603.5 ( 141.2 )
    496.0 ( 146.7 )
    479.6 ( 103.9 )
    377.2 ( 218.9 )
    No statistical analyses for this end point

    Secondary: Total consumption of turoctocog alfa per participant: IU/kg per month (24 months)

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    End point title
    		 Total consumption of turoctocog alfa per participant: IU/kg per month (24 months)
    End point description
    Total consumption of turoctocog alfa (IU/kg body weight per month) per participant in both prophylaxis and on-demand regimen was evaluated during the trial period of 24 months (main + extended phase). Results are based on the FAS. “Number of subjects analysed” = number of participants both on prophylaxis and on-demand regimen.
    End point type
    Secondary
    End point timeframe
    During the trial period of 24 months
    End point values
    		 Small children (0 to <6 years) Older children (6 to <12 years) Adolescents (12 to <18 years) Adults (>=18 years)
    Number of subjects analysed
    9
    33
    11
    15
    Units: IU/kg BW/month/participant
        arithmetic mean (standard deviation)
    615.3 ( 123.8 )
    516.7 ( 121.1 )
    477.0 ( 94.37 )
    429.1 ( 192.7 )
    No statistical analyses for this end point

    Secondary: Total consumption of turoctocog alfa per participant: IU/kg per year (6 months)

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    End point title
    		 Total consumption of turoctocog alfa per participant: IU/kg per year (6 months)
    End point description
    Total consumption of turoctocog alfa (IU/kg body weight per year) per participant in both prophylaxis and on-demand regimen was evaluated during the main phase of 6 months. Results are based on the FAS. “Number of subjects analysed” = number of participants both on prophylaxis and on-demand regimen.
    End point type
    Secondary
    End point timeframe
    During the main phase of 6 months
    End point values
    		 Small children (0 to <6 years) Older children (6 to <12 years) Adolescents (12 to <18 years) Adults (>=18 years)
    Number of subjects analysed
    9
    33
    11
    15
    Units: IU/kg BW/year/participant
        arithmetic mean (standard deviation)
    7242 ( 1695 )
    5951 ( 1760 )
    5756 ( 1247 )
    4527 ( 2627 )
    No statistical analyses for this end point

    Secondary: Total consumption of turoctocog alfa per participant: IU/kg per year (24 months)

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    End point title
    		 Total consumption of turoctocog alfa per participant: IU/kg per year (24 months)
    End point description
    Total consumption of turoctocog alfa (IU/kg body weight per year) per participant in both prophylaxis and on-demand regimen was evaluated during the trial period of 24 months (main + extended phase). Results are based on the FAS. “Number of subjects analysed” = number of participants both on prophylaxis and on-demand regimen.
    End point type
    Secondary
    End point timeframe
    During the trial period of 24 months
    End point values
    		 Small children (0 to <6 years) Older children (6 to <12 years) Adolescents (12 to <18 years) Adults (>=18 years)
    Number of subjects analysed
    9
    33
    11
    15
    Units: IU/kg BW/year/participant
        arithmetic mean (standard deviation)
    7384 ( 1486 )
    6201 ( 1453 )
    5724 ( 1132 )
    5149 ( 2312 )
    No statistical analyses for this end point

    Secondary: Frequency of adverse events (AEs): 6 months

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    End point title
    		 Frequency of adverse events (AEs): 6 months
    End point description
    Frequency of adverse events (AEs) are presented as rate of events, which was calculated as the number of AEs per patient years. All presented AEs are treatment emergent (TEAEs), which were defined as the events reported after trial product administration until the end of the post-treatment follow-up period. AEs were recorded during the main phase of 6 months. Results are based on the safety analysis set, which included participants, who received at least one dose of the trial product. “Number of subjects analysed” = all participants in the safety analysis set.
    End point type
    Secondary
    End point timeframe
    During the main phase of 6 months
    End point values
    		 Small children (0 to <6 years) Older children (6 to <12 years) Adolescents (12 to <18 years) Adults (>=18 years)
    Number of subjects analysed
    9
    33
    11
    15
    Units: Rate of events
        number (not applicable)
    4.908
    2.093
    2.325
    1.922
    No statistical analyses for this end point

    Secondary: Frequency of adverse events (AEs): 24 months

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    End point title
    		 Frequency of adverse events (AEs): 24 months
    End point description
    Frequency of AEs are presented as rate of events, which was calculated as the number of AEs per patient years. All presented AEs are TEAEs. AEs were recorded during the trial period of 24 months (main + extended phase). Results are based on the safety analysis set, which included participants, who received at least one dose of the trial product. “Number of subjects analysed” = all participants in the safety analysis set.
    End point type
    Secondary
    End point timeframe
    During the trial period of 24 months
    End point values
    		 Small children (0 to <6 years) Older children (6 to <12 years) Adolescents (12 to <18 years) Adults (>=18 years)
    Number of subjects analysed
    9
    33
    11
    15
    Units: Rate of events
        number (not applicable)
    2.941
    1.210
    1.074
    1.123
    No statistical analyses for this end point

    Secondary: Frequency of serious adverse events (SAEs): 6 months

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    End point title
    		 Frequency of serious adverse events (SAEs): 6 months
    End point description
    Frequency of SAEs are presented as rate of events, which was calculated as the number of SAEs per patient years. All the SAEs were treatment emergent and recorded during the main phase of 6 months. Results are based on the safety analysis set. “Number of subjects analysed” = all participants in the safety analysis set.
    End point type
    Secondary
    End point timeframe
    During the main phase of 6 months
    End point values
    		 Small children (0 to <6 years) Older children (6 to <12 years) Adolescents (12 to <18 years) Adults (>=18 years)
    Number of subjects analysed
    9
    33
    11
    15
    Units: Rate of events
        number (not applicable)
    0
    0
    0.634
    0
    No statistical analyses for this end point

    Secondary: Frequency of serious adverse events (SAEs): 24 months

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    End point title
    		 Frequency of serious adverse events (SAEs): 24 months
    End point description
    Frequency of SAEs are presented as rate of events, which was calculated as the number of SAEs per patient years. All the SAEs were treatment emergent and recorded during the trial period of 24 months (main + extended phase). Results are based on the safety analysis set. “Number of subjects analysed” = all participants in the safety analysis set.
    End point type
    Secondary
    End point timeframe
    During the trial period of 24 months
    End point values
    		 Small children (0 to <6 years) Older children (6 to <12 years) Adolescents (12 to <18 years) Adults (>=18 years)
    Number of subjects analysed
    9
    33
    11
    15
    Units: Rate of events
        number (not applicable)
    0.065
    0
    0.161
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All presented AEs are treatment emergent (TEAEs), which were defined as the events reported after trial product administration (day 1) until the end of the post-treatment follow-up period (i.e. month 24 + 14 days).
    Adverse event reporting additional description
    All the AE values are based on the safety analysis set.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21
    Reporting groups
    Reporting group title
    Small children (0 to <6 years)
    Reporting group description
    		 Participants were to receive turoctocog alfa for 6 months in the main phase and up to approximately 18 months in the extension phase of this study.

    Reporting group title
    Older children (6 to <12 years)
    Reporting group description
    		 Participants were to receive turoctocog alfa for 6 months in the main phase and up to approximately 18 months in the extension phase of this study.

    Reporting group title
    Adolescents (12 to <18 years)
    Reporting group description
    		 Participants were to receive turoctocog alfa for 6 months in the main phase and up to approximately 18 months in the extension phase of this study.

    Reporting group title
    Adults (>=18 years)
    Reporting group description
    		 Participants were to receive turoctocog alfa for 6 months in the main phase and up to approximately 18 months in the extension phase of this study.

    Serious adverse events
    		 Small children (0 to <6 years) Older children (6 to <12 years) Adolescents (12 to <18 years) Adults (>=18 years)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 33 (0.00%)
    2 / 11 (18.18%)
    0 / 15 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Injury, poisoning and procedural complications
    Femur fracture
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 33 (0.00%)
    1 / 11 (9.09%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 33 (0.00%)
    1 / 11 (9.09%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Hand-foot-and-mouth disease
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 33 (0.00%)
    0 / 11 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 33 (0.00%)
    1 / 11 (9.09%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Small children (0 to <6 years) Older children (6 to <12 years) Adolescents (12 to <18 years) Adults (>=18 years)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    8 / 9 (88.89%)
    18 / 33 (54.55%)
    7 / 11 (63.64%)
    10 / 15 (66.67%)
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 33 (0.00%)
    0 / 11 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    1
    Puncture site reaction
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 33 (0.00%)
    1 / 11 (9.09%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Pyrexia
         subjects affected / exposed
    4 / 9 (44.44%)
    2 / 33 (6.06%)
    0 / 11 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    7
    2
    0
    0
    Immune system disorders
    Drug hypersensitivity
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 33 (0.00%)
    0 / 11 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    1
    Reproductive system and breast disorders
    Balanoposthitis
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 33 (0.00%)
    0 / 11 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    1 / 9 (11.11%)
    1 / 33 (3.03%)
    1 / 11 (9.09%)
    0 / 15 (0.00%)
         occurrences all number
    2
    1
    1
    0
    Oropharyngeal pain
         subjects affected / exposed
    0 / 9 (0.00%)
    2 / 33 (6.06%)
    0 / 11 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    2
    0
    1
    Rhinorrhoea
         subjects affected / exposed
    0 / 9 (0.00%)
    3 / 33 (9.09%)
    0 / 11 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    3
    0
    0
    Investigations
    Antiphospholipid antibodies positive
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 33 (0.00%)
    1 / 11 (9.09%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Platelet count increased
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 33 (0.00%)
    1 / 11 (9.09%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 33 (0.00%)
    1 / 11 (9.09%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 33 (0.00%)
    1 / 11 (9.09%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Injury, poisoning and procedural complications
    Wound
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 33 (0.00%)
    0 / 11 (0.00%)
    2 / 15 (13.33%)
         occurrences all number
    0
    0
    0
    2
    Nervous system disorders
    Neuralgia
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 33 (0.00%)
    0 / 11 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    1
    Eye disorders
    Xerophthalmia
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 33 (0.00%)
    0 / 11 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    1
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 33 (3.03%)
    0 / 11 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    0
    1
    Constipation
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 33 (0.00%)
    0 / 11 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Dental caries
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 33 (0.00%)
    0 / 11 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Diarrhoea
         subjects affected / exposed
    1 / 9 (11.11%)
    2 / 33 (6.06%)
    1 / 11 (9.09%)
    1 / 15 (6.67%)
         occurrences all number
    1
    2
    1
    1
    Gastritis
         subjects affected / exposed
    1 / 9 (11.11%)
    1 / 33 (3.03%)
    0 / 11 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Loose tooth
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 33 (0.00%)
    0 / 11 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    1
    Tooth development disorder
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 33 (0.00%)
    0 / 11 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Gastrointestinal disorder
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 33 (0.00%)
    0 / 11 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Nausea
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 33 (0.00%)
    1 / 11 (9.09%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Toothache
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 33 (0.00%)
    0 / 11 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    1
    Vomiting
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 33 (0.00%)
    0 / 11 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Hepatobiliary disorders
    Hepatic function abnormal
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 33 (0.00%)
    0 / 11 (0.00%)
    2 / 15 (13.33%)
         occurrences all number
    0
    0
    0
    2
    Skin and subcutaneous tissue disorders
    Dermatitis allergic
         subjects affected / exposed
    1 / 9 (11.11%)
    1 / 33 (3.03%)
    0 / 11 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Urticaria papular
         subjects affected / exposed
    1 / 9 (11.11%)
    1 / 33 (3.03%)
    0 / 11 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Urticaria
         subjects affected / exposed
    0 / 9 (0.00%)
    2 / 33 (6.06%)
    0 / 11 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Renal and urinary disorders
    Urethral disorder
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 33 (0.00%)
    0 / 11 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Musculoskeletal and connective tissue disorders
    Muscle spasms
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 33 (0.00%)
    1 / 11 (9.09%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Infections and infestations
    Conjunctivitis
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 33 (0.00%)
    0 / 11 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Fungal skin infection
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 33 (0.00%)
    0 / 11 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    1
    Gastroenteritis
         subjects affected / exposed
    1 / 9 (11.11%)
    1 / 33 (3.03%)
    0 / 11 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Gastrointestinal fungal infection
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 33 (0.00%)
    1 / 11 (9.09%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Nasopharyngitis
         subjects affected / exposed
    1 / 9 (11.11%)
    6 / 33 (18.18%)
    2 / 11 (18.18%)
    1 / 15 (6.67%)
         occurrences all number
    1
    7
    2
    1
    Oral herpes
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 33 (0.00%)
    0 / 11 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Otitis externa
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 33 (0.00%)
    0 / 11 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    1
    Pharyngitis
         subjects affected / exposed
    1 / 9 (11.11%)
    1 / 33 (3.03%)
    0 / 11 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Pneumonia
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 33 (0.00%)
    0 / 11 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Respiratory tract infection
         subjects affected / exposed
    0 / 9 (0.00%)
    2 / 33 (6.06%)
    0 / 11 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    3
    0
    0
    Tonsillitis
         subjects affected / exposed
    1 / 9 (11.11%)
    2 / 33 (6.06%)
    0 / 11 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    2
    6
    0
    0
    Upper respiratory tract infection
         subjects affected / exposed
    7 / 9 (77.78%)
    7 / 33 (21.21%)
    2 / 11 (18.18%)
    3 / 15 (20.00%)
         occurrences all number
    12
    9
    3
    3
    Viral rash
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 33 (0.00%)
    1 / 11 (9.09%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Bronchitis
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 33 (0.00%)
    0 / 11 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Gastrointestinal infection
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 33 (0.00%)
    0 / 11 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Laryngitis
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 33 (0.00%)
    0 / 11 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    1
    Mumps
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 33 (0.00%)
    0 / 11 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Rhinitis
         subjects affected / exposed
    0 / 9 (0.00%)
    2 / 33 (6.06%)
    0 / 11 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    3
    0
    0
    Tinea manuum
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 33 (0.00%)
    0 / 11 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Metabolism and nutrition disorders
    Malnutrition
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 33 (3.03%)
    1 / 11 (9.09%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    1
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    28 Jun 2016
    Update to the trial timelines as the trial was on hold for about 1.5 years. Furthermore, changes in Novo Nordisk standard operating procedures and haemophilia standards during the hold were added to the protocol, such as clinical data interchange standards and request from the Chinese Food and Drug Administration regarding more frequent human immunodeficiency virus and hepatitis testing.
    30 Sep 2016
    1) Clarification of the clinical trial insurance coverage in case of inhibitor development during the trial. Previously, it was described in general terms and was changed in order to describe inhibitor development and taking into consideration the Chinese law. 2) The switch between on demand and prophylaxis treatment regimen was also clarified. 3) Addition of height measurements for paediatric patients during the trial. 4) Added that the remaining samples for FVIII were shipped out of China in order to perform chromogenic testing in a centralized lab. 5) Section related to ‘adverse events and technical complaints’ and ‘case report forms’ have been updated to reflect current mandatory text and clarifying use of electronic case report form (eCRF)/ paper CRF in safety reporting. 6) Minor grammatical changes.

    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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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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