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    Clinical Trial Results:
    Safety and Efficacy of NNC-0156-0000-0009 after Long-Term Exposure in Patients with Haemophilia B

    Summary
    EudraCT number
    		 2010-023072-17
    Trial protocol
    		 FR   GB   NL   DE   IT   ES   AT   GR  
    Global end of trial date
    31 Mar 2014

    Results information
    Results version number
    		 v1(current)
    This version publication date
    15 Mar 2016
    First version publication date
    30 Jul 2015
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    NN7999-3775
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01395810
    WHO universal trial number (UTN)
    		 U1111-1121-5408
    Sponsors
    Sponsor organisation name
    Novo Nordisk A/S
    Sponsor organisation address
    Novo Allé, Bagsvaerd, Denmark, 2880
    Public contact
    Global Clinical Registry (GCR, 1452), Novo Nordisk A/S, clinicaltrials@novonordisk.com
    Scientific contact
    Global Clinical Registry (GCR, 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?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    30 Sep 2014
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    31 Mar 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    31 Mar 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the immunogenicity of NNC-0156-0000-0009 (nonacog beta pegol)
    Protection of trial subjects
    The trial was conducted in accordance with the Declaration of Helsinki (Seoul, October 2008), the ICH Good Clinical Practice (Geneva, May 1996) and FDA 21 CFR 312.120.
    Background therapy
    		 Not applicable
    Evidence for comparator
    		 Not applicable
    Actual start date of recruitment
    16 Apr 2012
    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
    Netherlands: 3
    Country: Number of subjects enrolled
    United Kingdom: 8
    Country: Number of subjects enrolled
    France: 2
    Country: Number of subjects enrolled
    Germany: 4
    Country: Number of subjects enrolled
    Italy: 3
    Country: Number of subjects enrolled
    Japan: 6
    Country: Number of subjects enrolled
    Macedonia, the former Yugoslav Republic of: 4
    Country: Number of subjects enrolled
    Malaysia: 4
    Country: Number of subjects enrolled
    Romania: 1
    Country: Number of subjects enrolled
    Russian Federation: 3
    Country: Number of subjects enrolled
    South Africa: 4
    Country: Number of subjects enrolled
    Taiwan: 1
    Country: Number of subjects enrolled
    Thailand: 4
    Country: Number of subjects enrolled
    Turkey: 4
    Country: Number of subjects enrolled
    United States: 20
    Worldwide total number of subjects
    71
    EEA total number of subjects
    21
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    15
    Adults (18-64 years)
    55
    From 65 to 84 years
    1
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The trial was conducted at 41 sites in 15 countries as follows: France: 1 site; Germany: 3 sites; Italy: 2 sites; Japan: 4 sites; Macedonia: 2 sites; Malaysia: 1 site; Netherlands: 1 site; Romania: 1 site, Russia: 1 site; South Africa: 1 site; Taiwan: 1 site, Thailand: 2 sites; Turkey: 3 sites; United Kingdom: 5 sites; United States: 13 sites.

    Pre-assignment
    Screening details
    		 Not applicable

    Period 1
    Period 1 title
    Overall study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 Prophylaxis 10 IU/kg
    Arm description
    		 Subjects were given 10 IU/kg weekly nonacog beta pegol. Subjects were free to switch between treatment arms if agreed between the investigator and the subject.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Nonacog beta pegol
    Investigational medicinal product code
    Other name
    NNC-0156-0000-0009, N9-GP
    Pharmaceutical forms
    Powder and solvent for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Administration of the appropriate volume of nonacog beta pegol was given as an i.v. bolus injection. The maximum injection rate was 4 mL/min.

    Arm title
    		 Prophylaxis 40 IU/kg
    Arm description
    		 Subjects were dosed with 40 IU/kg weekly. Subjects were free to switch between treatment arms if agreed between the investigator and the subject.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Nonacog beta pegol
    Investigational medicinal product code
    Other name
    NNC-0156-0000-0009, N9-GP
    Pharmaceutical forms
    Powder and solvent for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Administration of the appropriate volume of nonacog beta pegol was given as an i.v. bolus injection. The maximum injection rate was 4 mL/min.

    Arm title
    		 Prophylaxis 80 IU/kg
    Arm description
    		 Subjects were dosed with 80 IU/kg every second week. Subjects were free to switch between treatment arms if agreed between the investigator and the subject.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Nonacog beta pegol
    Investigational medicinal product code
    Other name
    NNC-0156-0000-0009, N9-GP
    Pharmaceutical forms
    Powder and solvent for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Administration of the appropriate volume of nonacog beta pegol was given as an i.v. bolus injection. The maximum injection rate was 4 mL/min.

    Arm title
    		 On-demand
    Arm description
    		 The recommended dose for treatment of a mild or moderate bleeding episode, for example a joint bleed, was a single dose of 40 IU/kg nonacog beta pegol. If there was no observed effect of 40 IU/kg, the investigator was to be contacted prior to administration of the second dose of 40 IU/kg. The recommended dose for treatment of severe bleeds was 80 IU/kg nonacog beta pegol. Subjects were free to switch between treatment arms if agreed between the investigator and the subject.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Nonacog beta pegol
    Investigational medicinal product code
    Other name
    NNC-0156-0000-0009, N9-GP
    Pharmaceutical forms
    Powder and solvent for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Administration of the appropriate volume of nonacog beta pegol was given as an i.v. bolus injection. The maximum injection rate was 4 mL/min.

    Number of subjects in period 1
    		Prophylaxis 10 IU/kg Prophylaxis 40 IU/kg Prophylaxis 80 IU/kg On-demand
    Started
    21
    52
    2
    5
    Completed
    19
    48
    2
    5
    Not completed
    2
    4
    0
    0
         Adverse event, non-fatal
    -
    1
    -
    -
         Withdrawal criteria
    -
    2
    -
    -
         Unclassified
    2
    -
    -
    -
         Lack of efficacy
    -
    1
    -
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall study
    Reporting group description
    		 The trial included four different treatment (nonacog beta pegol) arms: three prophylaxis treatment arms with 10 IU/kg or 40 IU/kg weekly, or 80 IU/kg every second week, and one on-demand treatment with single dose of 40 IU/kg.

    Reporting group values
    		 Overall study Total
    Number of subjects
    		 71 71
    Age categorical
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 0 0
        Adolescents (12-17 years)
    		 15 15
        Adults (18-64 years)
    		 55 55
        From 65-84 years
    		 1 1
        85 years and over
    		 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 32 ( 14.2 ) -
    Gender categorical
    Units: Subjects
        Female
    		 0 0
        Male
    		 71 71

    End points

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    End points reporting groups
    Reporting group title
    Prophylaxis 10 IU/kg
    Reporting group description
    		 Subjects were given 10 IU/kg weekly nonacog beta pegol. Subjects were free to switch between treatment arms if agreed between the investigator and the subject.

    Reporting group title
    Prophylaxis 40 IU/kg
    Reporting group description
    		 Subjects were dosed with 40 IU/kg weekly. Subjects were free to switch between treatment arms if agreed between the investigator and the subject.

    Reporting group title
    Prophylaxis 80 IU/kg
    Reporting group description
    		 Subjects were dosed with 80 IU/kg every second week. Subjects were free to switch between treatment arms if agreed between the investigator and the subject.

    Reporting group title
    On-demand
    Reporting group description
    		 The recommended dose for treatment of a mild or moderate bleeding episode, for example a joint bleed, was a single dose of 40 IU/kg nonacog beta pegol. If there was no observed effect of 40 IU/kg, the investigator was to be contacted prior to administration of the second dose of 40 IU/kg. The recommended dose for treatment of severe bleeds was 80 IU/kg nonacog beta pegol. Subjects were free to switch between treatment arms if agreed between the investigator and the subject.

    Primary: Incidence of inhibitory antibodies against FIX defined as titre ≥0.6 BU

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    End point title
    		 Incidence of inhibitory antibodies against FIX defined as titre ≥0.6 BU [1]
    End point description
    The primary endpoint was incidence of inhibitors against coagulation factor nine (FIX) defined as titre ≥0.6 Bethesda unit (BU).
    End point type
    Primary
    End point timeframe
    This efficacy endpoint was evaluated based on all available information until the end of trial (EOT) visit.
    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: No statistical analysis was planned for the primary endpoint.
    End point values
    		 Prophylaxis 10 IU/kg Prophylaxis 40 IU/kg Prophylaxis 80 IU/kg On-demand
    Number of subjects analysed
    21
    52
    2
    5 [2]
    Units: patients with inhibitory antibodies
    0
    0
    0
    0
    Notes
    [2] - Patients who switched arms are represented in multiple columns.
    No statistical analyses for this end point

    Secondary: Haemostatic effect of nonacog beta pegol when used for treatment of bleeding episodes.

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    End point title
    		 Haemostatic effect of nonacog beta pegol when used for treatment of bleeding episodes.
    End point description
    The haemostatic effect was evaluated by a four-point scale where an "excellent" or "good" outcome translated into a successful treatment, and a "moderate" / "poor" outcome was considered a treatment failure.
    End point type
    Secondary
    End point timeframe
    Available information until the end of trial (EOT) visit.
    End point values
    		 Prophylaxis 10 IU/kg Prophylaxis 40 IU/kg Prophylaxis 80 IU/kg On-demand
    Number of subjects analysed
    21
    52
    2
    5
    Units: Number
        Number of bleeding episodes
    35
    98
    1
    73
        Excellent
    16
    37
    0
    5
        Good
    18
    54
    1
    63
        Moderate
    1
    4
    0
    4
        Poor
    0
    1
    0
    1
        Missing
    0
    2
    0
    0
    No statistical analyses for this end point

    Secondary: Number of bleeding episodes during routine prophylaxis.

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    End point title
    		 Number of bleeding episodes during routine prophylaxis.
    End point description
    End point type
    Secondary
    End point timeframe
    All available information until the end of trial (EOT) visit.
    End point values
    		 Prophylaxis 10 IU/kg Prophylaxis 40 IU/kg Prophylaxis 80 IU/kg On-demand
    Number of subjects analysed
    21
    52
    2
    5
    Units: Number
        Number of patients with bleeds
    14
    31
    1
    5
        Number of bleeding episodes
    35
    98
    1
    73
    No statistical analyses for this end point

    Secondary: FIX trough levels

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    End point title
    		 FIX trough levels [3]
    End point description
    During the trial, the mean pre-dose coagulation factor nine (FIX) levels were measured with a one-stage clotting assay.
    End point type
    Secondary
    End point timeframe
    All available information until the EOT visit.
    Notes
    [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint was analysed only for the prophylaxis arms (i.e., 10 IU/kg, 40 IU/kg and 80 IU/kg). No trough measurements were collected for patients on 80 IU/kg every second week prophylaxis.
    End point values
    		 Prophylaxis 10 IU/kg Prophylaxis 40 IU/kg
    Number of subjects analysed
    21
    52
    Units: U/mL
        arithmetic mean (confidence interval 95%)
    0.098 (0.08 to 0.119)
    0.213 (0.189 to 0.241)
    No statistical analyses for this end point

    Secondary: Adverse Events (AEs).

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    End point title
    		 Adverse Events (AEs).
    End point description
    End point type
    Secondary
    End point timeframe
    All available information until the last visit.
    End point values
    		 Prophylaxis 10 IU/kg Prophylaxis 40 IU/kg Prophylaxis 80 IU/kg On-demand
    Number of subjects analysed
    21
    52
    2
    5
    Units: Number
        Number of subjects with adverse events
    15
    32
    0
    5
        Number of adverse events
    46
    91
    0
    18
    No statistical analyses for this end point

    Secondary: Serious Adverse Events (SAEs)

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    End point title
    		 Serious Adverse Events (SAEs)
    End point description
    End point type
    Secondary
    End point timeframe
    All available information until the last visit.
    End point values
    		 Prophylaxis 10 IU/kg Prophylaxis 40 IU/kg Prophylaxis 80 IU/kg On-demand
    Number of subjects analysed
    21
    52
    2
    5
    Units: Number
        Number of subjects with serious adverse events
    1
    5
    0
    0
        Number of serious adverse events
    1
    5
    0
    0
    No statistical analyses for this end point

    Secondary: Laboratory parameter - haematology: Platelets (Visit 1- Baseline)

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    End point title
    		 Laboratory parameter - haematology: Platelets (Visit 1- Baseline)
    End point description
    End point type
    Secondary
    End point timeframe
    All available information until the last visit.
    End point values
    		 Prophylaxis 10 IU/kg Prophylaxis 40 IU/kg Prophylaxis 80 IU/kg On-demand
    Number of subjects analysed
    18
    47
    0 [4]
    5
    Units: x10^9/L
        arithmetic mean (standard deviation)
    224.7 ( 55.9 )
    240.5 ( 84.2 )
    ( )
    240 ( 54.1 )
    Notes
    [4] - For this endpoint (at Visit 1), no subjects were analysed in prophylaxis 80 IU/kg treatment arm.
    No statistical analyses for this end point

    Secondary: Laboratory parameter - haematology: Platelets (End of Trial)

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    End point title
    		 Laboratory parameter - haematology: Platelets (End of Trial)
    End point description
    End point type
    Secondary
    End point timeframe
    All available information until the last visit.
    End point values
    		 Prophylaxis 10 IU/kg Prophylaxis 40 IU/kg Prophylaxis 80 IU/kg On-demand
    Number of subjects analysed
    16
    44
    2
    4
    Units: x10^9/L
        arithmetic mean (standard deviation)
    230.7 ( 75 )
    235.3 ( 63.3 )
    247.3 ( 26.4 )
    256 ( 78.5 )
    No statistical analyses for this end point

    Secondary: Laboratory parameter - haematology: Haemoglobin (Visit 1- Baseline)

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    End point title
    		 Laboratory parameter - haematology: Haemoglobin (Visit 1- Baseline)
    End point description
    End point type
    Secondary
    End point timeframe
    All available information until the last visit.
    End point values
    		 Prophylaxis 10 IU/kg Prophylaxis 40 IU/kg Prophylaxis 80 IU/kg On-demand
    Number of subjects analysed
    18
    48
    0 [5]
    5
    Units: mmol/L
        arithmetic mean (standard deviation)
    9.45 ( 0.61 )
    8.98 ( 1.06 )
    ( )
    9.22 ( 0.66 )
    Notes
    [5] - For this endpoint (at Visit 1), no subjects were analysed in prophylaxis 80 IU/kg treatment arm.
    No statistical analyses for this end point

    Secondary: Laboratory parameter - haematology: Haemoglobin (End of Trial)

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    End point title
    		 Laboratory parameter - haematology: Haemoglobin (End of Trial)
    End point description
    End point type
    Secondary
    End point timeframe
    All available information until the last visit.
    End point values
    		 Prophylaxis 10 IU/kg Prophylaxis 40 IU/kg Prophylaxis 80 IU/kg On-demand
    Number of subjects analysed
    16
    44
    2
    4
    Units: mmol/L
        arithmetic mean (standard deviation)
    9.58 ( 0.6 )
    9.22 ( 0.73 )
    10 ( 1.7 )
    9.65 ( 0.84 )
    No statistical analyses for this end point

    Secondary: Laboratory parameter - haematology: Red blood cell count (Visit 1- Baseline)

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    End point title
    		 Laboratory parameter - haematology: Red blood cell count (Visit 1- Baseline)
    End point description
    End point type
    Secondary
    End point timeframe
    All available information until the last visit.
    End point values
    		 Prophylaxis 10 IU/kg Prophylaxis 40 IU/kg Prophylaxis 80 IU/kg On-demand
    Number of subjects analysed
    18
    48
    0 [6]
    5
    Units: 10^12/L
        arithmetic mean (standard deviation)
    5.18 ( 0.41 )
    4.96 ( 0.64 )
    ( )
    4.9 ( 0.5 )
    Notes
    [6] - For this endpoint (at Visit 1), no subjects were analysed in prophylaxis 80 IU/kg treatment arm.
    No statistical analyses for this end point

    Secondary: Laboratory parameter - haematology: Red blood cell count (End of Trial)

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    End point title
    		 Laboratory parameter - haematology: Red blood cell count (End of Trial)
    End point description
    End point type
    Secondary
    End point timeframe
    All available information until the last visit.
    End point values
    		 Prophylaxis 10 IU/kg Prophylaxis 40 IU/kg Prophylaxis 80 IU/kg On-demand
    Number of subjects analysed
    16
    44
    2
    4
    Units: 10^12/L
        arithmetic mean (standard deviation)
    5.2 ( 0.33 )
    5.1 ( 0.52 )
    5.57 ( 0.41 )
    5.09 ( 0.26 )
    No statistical analyses for this end point

    Secondary: Laboratory parameter - haematology: Mean corpuscular volume (Visit 1- Baseline)

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    End point title
    		 Laboratory parameter - haematology: Mean corpuscular volume (Visit 1- Baseline)
    End point description
    End point type
    Secondary
    End point timeframe
    All available information until the last visit.
    End point values
    		 Prophylaxis 10 IU/kg Prophylaxis 40 IU/kg Prophylaxis 80 IU/kg On-demand
    Number of subjects analysed
    18
    48
    0 [7]
    5
    Units: fL
        arithmetic mean (standard deviation)
    87 ( 4.7 )
    87.5 ( 7.3 )
    ( )
    89.7 ( 11.3 )
    Notes
    [7] - For this endpoint (at Visit 1), no subjects were analysed in prophylaxis 80 IU/kg treatment arm.
    No statistical analyses for this end point

    Secondary: Laboratory parameter - haematology: Mean corpuscular volume (End of Trial)

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    End point title
    		 Laboratory parameter - haematology: Mean corpuscular volume (End of Trial)
    End point description
    End point type
    Secondary
    End point timeframe
    All available information until the last visit.
    End point values
    		 Prophylaxis 10 IU/kg Prophylaxis 40 IU/kg Prophylaxis 80 IU/kg On-demand
    Number of subjects analysed
    16
    44
    2
    4
    Units: fL
        arithmetic mean (standard deviation)
    86.8 ( 4.9 )
    87.6 ( 6.6 )
    84.9 ( 5.8 )
    89.2 ( 6.5 )
    No statistical analyses for this end point

    Secondary: Laboratory parameter - haematology: Haematocrit (Visit 1- Baseline)

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    End point title
    		 Laboratory parameter - haematology: Haematocrit (Visit 1- Baseline)
    End point description
    End point type
    Secondary
    End point timeframe
    All available information until the last visit.
    End point values
    		 Prophylaxis 10 IU/kg Prophylaxis 40 IU/kg Prophylaxis 80 IU/kg On-demand
    Number of subjects analysed
    18
    48
    0 [8]
    5
    Units: Percentage (%)
        arithmetic mean (standard deviation)
    44.8 ( 2.7 )
    43.2 ( 4.6 )
    ( )
    43.6 ( 3 )
    Notes
    [8] - For this endpoint (at Visit 1), no subjects were analysed in prophylaxis 80 IU/kg treatment arm.
    No statistical analyses for this end point

    Secondary: Laboratory parameter - haematology: Haematocrit (End of Trial)

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    End point title
    		 Laboratory parameter - haematology: Haematocrit (End of Trial)
    End point description
    End point type
    Secondary
    End point timeframe
    All available information until the last visit.
    End point values
    		 Prophylaxis 10 IU/kg Prophylaxis 40 IU/kg Prophylaxis 80 IU/kg On-demand
    Number of subjects analysed
    16
    44
    2
    4
    Units: Percentage (%)
        arithmetic mean (standard deviation)
    45 ( 1.7 )
    44.4 ( 3.2 )
    47.4 ( 6.7 )
    45.3 ( 3.8 )
    No statistical analyses for this end point

    Secondary: Laboratory parameter - haematology: Mean corpuscular haemoglobin (Visit 1- Baseline)

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    End point title
    		 Laboratory parameter - haematology: Mean corpuscular haemoglobin (Visit 1- Baseline)
    End point description
    End point type
    Secondary
    End point timeframe
    All available information until the last visit.
    End point values
    		 Prophylaxis 10 IU/kg Prophylaxis 40 IU/kg Prophylaxis 80 IU/kg On-demand
    Number of subjects analysed
    18
    48
    0 [9]
    5
    Units: fmol
        arithmetic mean (standard deviation)
    1.83 ( 0.11 )
    1.82 ( 0.18 )
    ( )
    1.89 ( 0.26 )
    Notes
    [9] - For this endpoint (at Visit 1), no subjects were analysed in prophylaxis 80 IU/kg treatment arm.
    No statistical analyses for this end point

    Secondary: Laboratory parameter - haematology: Mean corpuscular haemoglobin (End of Trial)

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    End point title
    		 Laboratory parameter - haematology: Mean corpuscular haemoglobin (End of Trial)
    End point description
    End point type
    Secondary
    End point timeframe
    All available information until the last visit.
    End point values
    		 Prophylaxis 10 IU/kg Prophylaxis 40 IU/kg Prophylaxis 80 IU/kg On-demand
    Number of subjects analysed
    16
    44
    2
    4
    Units: fmol
        arithmetic mean (standard deviation)
    1.85 ( 0.13 )
    1.82 ( 0.16 )
    1.79 ( 0.17 )
    1.9 ( 0.17 )
    No statistical analyses for this end point

    Secondary: Laboratory parameter - haematology: White blood cell count (Visit 1- Baseline)

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    End point title
    		 Laboratory parameter - haematology: White blood cell count (Visit 1- Baseline)
    End point description
    End point type
    Secondary
    End point timeframe
    All available information until the last visit.
    End point values
    		 Prophylaxis 10 IU/kg Prophylaxis 40 IU/kg Prophylaxis 80 IU/kg On-demand
    Number of subjects analysed
    18
    48
    0 [10]
    5
    Units: 10^9/L
        arithmetic mean (standard deviation)
    6.64 ( 1.75 )
    6.33 ( 1.54 )
    ( )
    6.02 ( 0.86 )
    Notes
    [10] - For this endpoint (at Visit 1), no subjects were analysed in prophylaxis 80 IU/kg treatment arm.
    No statistical analyses for this end point

    Secondary: Laboratory parameter - haematology: White blood cell count (End of Trial)

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    End point title
    		 Laboratory parameter - haematology: White blood cell count (End of Trial)
    End point description
    End point type
    Secondary
    End point timeframe
    All available information until the last visit.
    End point values
    		 Prophylaxis 10 IU/kg Prophylaxis 40 IU/kg Prophylaxis 80 IU/kg On-demand
    Number of subjects analysed
    16
    44
    2
    4
    Units: 10^9/L
        arithmetic mean (standard deviation)
    6.73 ( 1.67 )
    6.6 ( 1.74 )
    6.25 ( 0.63 )
    6.44 ( 1.59 )
    No statistical analyses for this end point

    Secondary: Laboratory parameter - haematology: Lymphocytes (Visit 1- Baseline)

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    End point title
    		 Laboratory parameter - haematology: Lymphocytes (Visit 1- Baseline)
    End point description
    End point type
    Secondary
    End point timeframe
    All available information until the last visit.
    End point values
    		 Prophylaxis 10 IU/kg Prophylaxis 40 IU/kg Prophylaxis 80 IU/kg On-demand
    Number of subjects analysed
    18
    48
    0 [11]
    5
    Units: Percentage (%)
        arithmetic mean (standard deviation)
    29.8 ( 8 )
    33.2 ( 7.4 )
    ( )
    30.1 ( 7.1 )
    Notes
    [11] - For this endpoint (at Visit 1), no subjects were analysed in prophylaxis 80 IU/kg treatment arm.
    No statistical analyses for this end point

    Secondary: Laboratory parameter - haematology: Lymphocytes (End of Trial)

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    End point title
    		 Laboratory parameter - haematology: Lymphocytes (End of Trial)
    End point description
    End point type
    Secondary
    End point timeframe
    All available information until the last visit.
    End point values
    		 Prophylaxis 10 IU/kg Prophylaxis 40 IU/kg Prophylaxis 80 IU/kg On-demand
    Number of subjects analysed
    16
    43
    2
    4
    Units: Percentage (%)
        arithmetic mean (standard deviation)
    33.3 ( 9.5 )
    30.7 ( 7.3 )
    34 ( 5 )
    31.1 ( 4.6 )
    No statistical analyses for this end point

    Secondary: Laboratory parameter - haematology: Monocytes (Visit 1- Baseline)

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    End point title
    		 Laboratory parameter - haematology: Monocytes (Visit 1- Baseline)
    End point description
    End point type
    Secondary
    End point timeframe
    All available information until the last visit.
    End point values
    		 Prophylaxis 10 IU/kg Prophylaxis 40 IU/kg Prophylaxis 80 IU/kg On-demand
    Number of subjects analysed
    18
    48
    0 [12]
    5
    Units: Percentage (%)
        arithmetic mean (standard deviation)
    6.88 ( 2.66 )
    8.2 ( 3.02 )
    ( )
    6.9 ( 1.88 )
    Notes
    [12] - For this endpoint (at Visit 1), no subjects were analysed in prophylaxis 80 IU/kg treatment arm.
    No statistical analyses for this end point

    Secondary: Laboratory parameter - haematology: Monocytes (End of Trial)

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    End point title
    		 Laboratory parameter - haematology: Monocytes (End of Trial)
    End point description
    End point type
    Secondary
    End point timeframe
    All available information until the last visit.
    End point values
    		 Prophylaxis 10 IU/kg Prophylaxis 40 IU/kg Prophylaxis 80 IU/kg On-demand
    Number of subjects analysed
    16
    43
    2
    4
    Units: Percentage (%)
        arithmetic mean (standard deviation)
    7.14 ( 1.92 )
    8.33 ( 2.61 )
    6.79 ( 3.95 )
    7.18 ( 1.89 )
    No statistical analyses for this end point

    Secondary: Laboratory parameter - haematology: Neutrophils (Visit 1- Baseline)

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    End point title
    		 Laboratory parameter - haematology: Neutrophils (Visit 1- Baseline)
    End point description
    End point type
    Secondary
    End point timeframe
    All available information until the last visit.
    End point values
    		 Prophylaxis 10 IU/kg Prophylaxis 40 IU/kg Prophylaxis 80 IU/kg On-demand
    Number of subjects analysed
    18
    48
    0 [13]
    5
    Units: Percentage (%)
        arithmetic mean (standard deviation)
    60.9 ( 10.6 )
    55.1 ( 7.4 )
    ( )
    60.3 ( 7.2 )
    Notes
    [13] - For this endpoint (at Visit 1), no subjects were analysed in prophylaxis 80 IU/kg treatment arm.
    No statistical analyses for this end point

    Secondary: Laboratory parameter - haematology: Neutrophils (End of Trial)

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    End point title
    		 Laboratory parameter - haematology: Neutrophils (End of Trial)
    End point description
    End point type
    Secondary
    End point timeframe
    All available information until the last visit.
    End point values
    		 Prophylaxis 10 IU/kg Prophylaxis 40 IU/kg Prophylaxis 80 IU/kg On-demand
    Number of subjects analysed
    16
    43
    2
    4
    Units: Percentage (%)
        arithmetic mean (standard deviation)
    56.5 ( 11 )
    57.7 ( 8.9 )
    56.7 ( 8.1 )
    59.1 ( 6.9 )
    No statistical analyses for this end point

    Secondary: Laboratory parameter - haematology: Eosinophils (Visit 1- Baseline)

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    End point title
    		 Laboratory parameter - haematology: Eosinophils (Visit 1- Baseline)
    End point description
    End point type
    Secondary
    End point timeframe
    All available information until the last visit.
    End point values
    		 Prophylaxis 10 IU/kg Prophylaxis 40 IU/kg Prophylaxis 80 IU/kg On-demand
    Number of subjects analysed
    18
    48
    0 [14]
    5
    Units: Percentage (%)
        arithmetic mean (standard deviation)
    2.26 ( 2.16 )
    2.91 ( 1.71 )
    ( )
    2.02 ( 0.71 )
    Notes
    [14] - For this endpoint (at Visit 1), no subjects were analysed in prophylaxis 80 IU/kg treatment arm.
    No statistical analyses for this end point

    Secondary: Laboratory parameter - haematology: Eosinophils (End of Trial)

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    End point title
    		 Laboratory parameter - haematology: Eosinophils (End of Trial)
    End point description
    End point type
    Secondary
    End point timeframe
    All available information until the last visit.
    End point values
    		 Prophylaxis 10 IU/kg Prophylaxis 40 IU/kg Prophylaxis 80 IU/kg On-demand
    Number of subjects analysed
    16
    43
    2
    4
    Units: Percentage (%)
        arithmetic mean (standard deviation)
    2.46 ( 1.62 )
    2.78 ( 1.99 )
    1.21 ( 0.44 )
    1.8 ( 1.18 )
    No statistical analyses for this end point

    Secondary: Laboratory parameter - haematology: Basophils (Visit 1- Baseline)

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    End point title
    		 Laboratory parameter - haematology: Basophils (Visit 1- Baseline)
    End point description
    End point type
    Secondary
    End point timeframe
    All available information until the last visit.
    End point values
    		 Prophylaxis 10 IU/kg Prophylaxis 40 IU/kg Prophylaxis 80 IU/kg On-demand
    Number of subjects analysed
    18
    48
    0 [15]
    5
    Units: Percentage (%)
        arithmetic mean (standard deviation)
    0.54 ( 0.57 )
    0.56 ( 0.37 )
    ( )
    0.44 ( 0.52 )
    Notes
    [15] - For this endpoint (at Visit 1), no subjects were analysed in prophylaxis 80 IU/kg treatment arm.
    No statistical analyses for this end point

    Secondary: Laboratory parameter - haematology: Basophils (End of Trial)

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    End point title
    		 Laboratory parameter - haematology: Basophils (End of Trial)
    End point description
    End point type
    Secondary
    End point timeframe
    All available information until the last visit.
    End point values
    		 Prophylaxis 10 IU/kg Prophylaxis 40 IU/kg Prophylaxis 80 IU/kg On-demand
    Number of subjects analysed
    16
    43
    2
    4
    Units: Percentage (%)
        arithmetic mean (standard deviation)
    0.58 ( 0.48 )
    0.47 ( 0.39 )
    0.46 ( 0.06 )
    0.4 ( 0.49 )
    No statistical analyses for this end point

    Secondary: Laboratory parameter - biochemistry: Sodium (Visit 1- Baseline)

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    End point title
    		 Laboratory parameter - biochemistry: Sodium (Visit 1- Baseline)
    End point description
    End point type
    Secondary
    End point timeframe
    All available information until the last visit.
    End point values
    		 Prophylaxis 10 IU/kg Prophylaxis 40 IU/kg Prophylaxis 80 IU/kg On-demand
    Number of subjects analysed
    18
    45
    0 [16]
    5
    Units: mmol/L
        arithmetic mean (standard deviation)
    141.8 ( 2.3 )
    141.7 ( 2.6 )
    ( )
    142.6 ( 3.4 )
    Notes
    [16] - For this endpoint (at Visit 1), no subjects were analysed in prophylaxis 80 IU/kg treatment arm.
    No statistical analyses for this end point

    Secondary: Laboratory parameter - biochemistry: Sodium (End of Trial)

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    End point title
    		 Laboratory parameter - biochemistry: Sodium (End of Trial)
    End point description
    End point type
    Secondary
    End point timeframe
    All available information until the last visit.
    End point values
    		 Prophylaxis 10 IU/kg Prophylaxis 40 IU/kg Prophylaxis 80 IU/kg On-demand
    Number of subjects analysed
    16
    45
    2
    4
    Units: mmol/L
        arithmetic mean (standard deviation)
    141.9 ( 2 )
    141.8 ( 2.9 )
    142.5 ( 2.1 )
    143.5 ( 2.6 )
    No statistical analyses for this end point

    Secondary: Laboratory parameter - biochemistry: Potassium (Visit 1- Baseline)

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    End point title
    		 Laboratory parameter - biochemistry: Potassium (Visit 1- Baseline)
    End point description
    End point type
    Secondary
    End point timeframe
    All available information until the last visit.
    End point values
    		 Prophylaxis 10 IU/kg Prophylaxis 40 IU/kg Prophylaxis 80 IU/kg On-demand
    Number of subjects analysed
    18
    45
    0 [17]
    5
    Units: mmol/L
        arithmetic mean (standard deviation)
    4.2 ( 0.39 )
    4.25 ( 0.31 )
    ( )
    4.06 ( 0.36 )
    Notes
    [17] - For this endpoint (at Visit 1), no subjects were analysed in prophylaxis 80 IU/kg treatment arm.
    No statistical analyses for this end point

    Secondary: Laboratory parameter - biochemistry: Potassium (End of Trial)

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    End point title
    		 Laboratory parameter - biochemistry: Potassium (End of Trial)
    End point description
    End point type
    Secondary
    End point timeframe
    All available information until the last visit.
    End point values
    		 Prophylaxis 10 IU/kg Prophylaxis 40 IU/kg Prophylaxis 80 IU/kg On-demand
    Number of subjects analysed
    16
    44
    2
    4
    Units: mmol/L
        arithmetic mean (standard deviation)
    4.25 ( 0.35 )
    4.29 ( 0.26 )
    4.25 ( 0.21 )
    4.08 ( 0.43 )
    No statistical analyses for this end point

    Secondary: Laboratory parameter - biochemistry: Creatinine (Visit 1- Baseline)

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    End point title
    		 Laboratory parameter - biochemistry: Creatinine (Visit 1- Baseline)
    End point description
    End point type
    Secondary
    End point timeframe
    All available information until the last visit.
    End point values
    		 Prophylaxis 10 IU/kg Prophylaxis 40 IU/kg Prophylaxis 80 IU/kg On-demand
    Number of subjects analysed
    18
    45
    0 [18]
    5
    Units: µmol/L
        arithmetic mean (standard deviation)
    73.2 ( 8.8 )
    74.2 ( 17 )
    ( )
    74 ( 6.5 )
    Notes
    [18] - For this endpoint (at Visit 1), no subjects were analysed in prophylaxis 80 IU/kg treatment arm.
    No statistical analyses for this end point

    Secondary: Laboratory parameter - biochemistry: Creatinine (End of Trial)

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    End point title
    		 Laboratory parameter - biochemistry: Creatinine (End of Trial)
    End point description
    End point type
    Secondary
    End point timeframe
    All available information until the last visit.
    End point values
    		 Prophylaxis 10 IU/kg Prophylaxis 40 IU/kg Prophylaxis 80 IU/kg On-demand
    Number of subjects analysed
    16
    45
    2
    4
    Units: µmol/L
        arithmetic mean (standard deviation)
    76.8 ( 13.7 )
    80.6 ( 19.6 )
    68.5 ( 16.3 )
    71.5 ( 13.5 )
    No statistical analyses for this end point

    Secondary: Laboratory parameter - biochemistry: Albumin (Visit 1- Baseline)

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    End point title
    		 Laboratory parameter - biochemistry: Albumin (Visit 1- Baseline)
    End point description
    End point type
    Secondary
    End point timeframe
    All available information until the last visit.
    End point values
    		 Prophylaxis 10 IU/kg Prophylaxis 40 IU/kg Prophylaxis 80 IU/kg On-demand
    Number of subjects analysed
    18
    45
    0 [19]
    5
    Units: g/L
        arithmetic mean (standard deviation)
    47.8 ( 2.8 )
    46.2 ( 4.7 )
    ( )
    47.4 ( 1.8 )
    Notes
    [19] - For this endpoint (at Visit 1), no subjects were analysed in prophylaxis 80 IU/kg treatment arm.
    No statistical analyses for this end point

    Secondary: Laboratory parameter - biochemistry: Albumin (End of Trial)

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    End point title
    		 Laboratory parameter - biochemistry: Albumin (End of Trial)
    End point description
    End point type
    Secondary
    End point timeframe
    All available information until the last visit.
    End point values
    		 Prophylaxis 10 IU/kg Prophylaxis 40 IU/kg Prophylaxis 80 IU/kg On-demand
    Number of subjects analysed
    16
    45
    2
    4
    Units: g/L
        arithmetic mean (standard deviation)
    45.6 ( 2.8 )
    46.5 ( 2.9 )
    48 ( 0 )
    47.3 ( 3 )
    No statistical analyses for this end point

    Secondary: Laboratory parameter - biochemistry: Total bilirubin (Visit 1- Baseline)

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    End point title
    		 Laboratory parameter - biochemistry: Total bilirubin (Visit 1- Baseline)
    End point description
    End point type
    Secondary
    End point timeframe
    All available information until the last visit.
    End point values
    		 Prophylaxis 10 IU/kg Prophylaxis 40 IU/kg Prophylaxis 80 IU/kg On-demand
    Number of subjects analysed
    18
    45
    0 [20]
    5
    Units: µmol/L
        arithmetic mean (standard deviation)
    9.8 ( 5.9 )
    10.8 ( 11.3 )
    ( )
    11.2 ( 1.8 )
    Notes
    [20] - For this endpoint (at Visit 1), no subjects were analysed in prophylaxis 80 IU/kg treatment arm.
    No statistical analyses for this end point

    Secondary: Laboratory parameter - biochemistry: Total bilirubin (End of Trial)

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    End point title
    		 Laboratory parameter - biochemistry: Total bilirubin (End of Trial)
    End point description
    End point type
    Secondary
    End point timeframe
    All available information until the last visit.
    End point values
    		 Prophylaxis 10 IU/kg Prophylaxis 40 IU/kg Prophylaxis 80 IU/kg On-demand
    Number of subjects analysed
    16
    45
    2
    4
    Units: µmol/L
        arithmetic mean (standard deviation)
    9.8 ( 6.2 )
    9.5 ( 5.5 )
    8 ( 1.4 )
    8.3 ( 1.5 )
    No statistical analyses for this end point

    Secondary: Laboratory parameter - biochemistry: Aspartate aminotransferase (ASAT) (Visit 1- Baseline)

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    End point title
    		 Laboratory parameter - biochemistry: Aspartate aminotransferase (ASAT) (Visit 1- Baseline)
    End point description
    End point type
    Secondary
    End point timeframe
    All available information until the last visit.
    End point values
    		 Prophylaxis 10 IU/kg Prophylaxis 40 IU/kg Prophylaxis 80 IU/kg On-demand
    Number of subjects analysed
    18
    45
    0 [21]
    5
    Units: IU/L
        arithmetic mean (standard deviation)
    24.4 ( 7.8 )
    32.3 ( 27.8 )
    ( )
    25.8 ( 9.1 )
    Notes
    [21] - For this endpoint (at Visit 1), no subjects were analysed in prophylaxis 80 IU/kg treatment arm.
    No statistical analyses for this end point

    Secondary: Laboratory parameter - biochemistry: Aspartate aminotransferase (ASAT) (End of Trial)

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    End point title
    		 Laboratory parameter - biochemistry: Aspartate aminotransferase (ASAT) (End of Trial)
    End point description
    End point type
    Secondary
    End point timeframe
    All available information until the last visit.
    End point values
    		 Prophylaxis 10 IU/kg Prophylaxis 40 IU/kg Prophylaxis 80 IU/kg On-demand
    Number of subjects analysed
    15
    44
    2
    4
    Units: IU/L
        arithmetic mean (standard deviation)
    25.5 ( 12.3 )
    30.6 ( 30.8 )
    17.5 ( 0.7 )
    24.8 ( 6.8 )
    No statistical analyses for this end point

    Secondary: Laboratory parameter - biochemistry: Alanine aminotransferase (ALAT) (Visit 1- Baseline)

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    End point title
    		 Laboratory parameter - biochemistry: Alanine aminotransferase (ALAT) (Visit 1- Baseline)
    End point description
    End point type
    Secondary
    End point timeframe
    All available information until the last visit.
    End point values
    		 Prophylaxis 10 IU/kg Prophylaxis 40 IU/kg Prophylaxis 80 IU/kg On-demand
    Number of subjects analysed
    18
    45
    0 [22]
    5
    Units: IU/L
        arithmetic mean (standard deviation)
    25.3 ( 15.1 )
    36.8 ( 45.7 )
    ( )
    25.6 ( 14.7 )
    Notes
    [22] - For this endpoint (at Visit 1), no subjects were analysed in prophylaxis 80 IU/kg treatment arm.
    No statistical analyses for this end point

    Secondary: Laboratory parameter - biochemistry: Alanine aminotransferase (ALAT) (End of Trial)

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    End point title
    		 Laboratory parameter - biochemistry: Alanine aminotransferase (ALAT) (End of Trial)
    End point description
    End point type
    Secondary
    End point timeframe
    All available information until the last visit.
    End point values
    		 Prophylaxis 10 IU/kg Prophylaxis 40 IU/kg Prophylaxis 80 IU/kg On-demand
    Number of subjects analysed
    15
    45
    2
    4
    Units: IU/L
        arithmetic mean (standard deviation)
    27.3 ( 19 )
    31.9 ( 33.1 )
    14.5 ( 4.9 )
    32.8 ( 11.9 )
    No statistical analyses for this end point

    Secondary: Laboratory parameter - biochemistry: Gamma glutamyltransferase (GGT) (Visit 1- Baseline)

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    End point title
    		 Laboratory parameter - biochemistry: Gamma glutamyltransferase (GGT) (Visit 1- Baseline)
    End point description
    End point type
    Secondary
    End point timeframe
    All available information until the last visit.
    End point values
    		 Prophylaxis 10 IU/kg Prophylaxis 40 IU/kg Prophylaxis 80 IU/kg On-demand
    Number of subjects analysed
    18
    45
    0 [23]
    5
    Units: IU/L
        arithmetic mean (standard deviation)
    28.9 ( 19.1 )
    46.2 ( 58.3 )
    ( )
    39.8 ( 44.2 )
    Notes
    [23] - For this endpoint (at Visit 1), no subjects were analysed in prophylaxis 80 IU/kg treatment arm.
    No statistical analyses for this end point

    Secondary: Laboratory parameter - biochemistry: Gamma glutamyltransferase (GGT) (End of Trial)

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    End point title
    		 Laboratory parameter - biochemistry: Gamma glutamyltransferase (GGT) (End of Trial)
    End point description
    End point type
    Secondary
    End point timeframe
    All available information until the last visit.
    End point values
    		 Prophylaxis 10 IU/kg Prophylaxis 40 IU/kg Prophylaxis 80 IU/kg On-demand
    Number of subjects analysed
    16
    45
    2
    4
    Units: IU/L
        arithmetic mean (standard deviation)
    44.1 ( 48.2 )
    38 ( 51.6 )
    26 ( 21.2 )
    33 ( 16 )
    No statistical analyses for this end point

    Secondary: Laboratory parameter - biochemistry: Alkaline phosphatase (Visit 1- Baseline)

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    End point title
    		 Laboratory parameter - biochemistry: Alkaline phosphatase (Visit 1- Baseline)
    End point description
    End point type
    Secondary
    End point timeframe
    All available information until the last visit.
    End point values
    		 Prophylaxis 10 IU/kg Prophylaxis 40 IU/kg Prophylaxis 80 IU/kg On-demand
    Number of subjects analysed
    18
    45
    0 [24]
    5
    Units: IU/L
        arithmetic mean (standard deviation)
    82.2 ( 30.8 )
    101 ( 55 )
    ( )
    79.2 ( 16 )
    Notes
    [24] - For this endpoint (at Visit 1), no subjects were analysed in prophylaxis 80 IU/kg treatment arm.
    No statistical analyses for this end point

    Secondary: Laboratory parameter - biochemistry: Alkaline phosphatase (End of Trial)

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    End point title
    		 Laboratory parameter - biochemistry: Alkaline phosphatase (End of Trial)
    End point description
    End point type
    Secondary
    End point timeframe
    All available information until the last visit.
    End point values
    		 Prophylaxis 10 IU/kg Prophylaxis 40 IU/kg Prophylaxis 80 IU/kg On-demand
    Number of subjects analysed
    16
    44
    2
    4
    Units: IU/L
        arithmetic mean (standard deviation)
    77.3 ( 25.1 )
    89.6 ( 33.2 )
    106 ( 52.3 )
    75.3 ( 17.1 )
    No statistical analyses for this end point

    Secondary: Laboratory parameter - biochemistry: C-reactive protein (Visit 1- Baseline)

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    End point title
    		 Laboratory parameter - biochemistry: C-reactive protein (Visit 1- Baseline)
    End point description
    End point type
    Secondary
    End point timeframe
    All available information until the last visit.
    End point values
    		 Prophylaxis 10 IU/kg Prophylaxis 40 IU/kg Prophylaxis 80 IU/kg On-demand
    Number of subjects analysed
    18
    45
    0 [25]
    5
    Units: mg/L
        arithmetic mean (standard deviation)
    3.14 ( 5.22 )
    5.52 ( 19.01 )
    ( )
    2.7 ( 2.77 )
    Notes
    [25] - For this endpoint (at Visit 1), no subjects were analysed in prophylaxis 80 IU/kg treatment arm.
    No statistical analyses for this end point

    Secondary: Laboratory parameter - biochemistry: C-reactive protein (End of Trial)

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    End point title
    		 Laboratory parameter - biochemistry: C-reactive protein (End of Trial)
    End point description
    End point type
    Secondary
    End point timeframe
    All available information until the last visit.
    End point values
    		 Prophylaxis 10 IU/kg Prophylaxis 40 IU/kg Prophylaxis 80 IU/kg On-demand
    Number of subjects analysed
    16
    45
    2
    4
    Units: mg/L
        arithmetic mean (standard deviation)
    2.75 ( 4.76 )
    2.47 ( 3.4 )
    2.75 ( 3.18 )
    2.5 ( 1.29 )
    No statistical analyses for this end point

    Secondary: Physical examination - deterioration of pre-existing condition or new finding (Visit 2)

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    End point title
    		 Physical examination - deterioration of pre-existing condition or new finding (Visit 2)
    End point description
    End point type
    Secondary
    End point timeframe
    All available information until the last visit.
    End point values
    		 Prophylaxis 10 IU/kg Prophylaxis 40 IU/kg Prophylaxis 80 IU/kg On-demand
    Number of subjects analysed
    3
    14
    0 [26]
    1
    Units: Number
        New Finding: Yes
    0
    1
    1
        New Finding: No
    0
    9
    0
        Not applicable
    2
    1
    0
        Not done
    1
    3
    0
    Notes
    [26] - For this endpoint (at Visit 2), no subjects were analysed in prophylaxis 80 IU/kg treatment arm.
    No statistical analyses for this end point

    Secondary: Physical examination - deterioration of pre-existing condition or new finding (End of Trial)

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    End point title
    		 Physical examination - deterioration of pre-existing condition or new finding (End of Trial)
    End point description
    End point type
    Secondary
    End point timeframe
    All available information until the last visit.
    End point values
    		 Prophylaxis 10 IU/kg Prophylaxis 40 IU/kg Prophylaxis 80 IU/kg On-demand
    Number of subjects analysed
    16
    46
    2
    4
    Units: Number
        New Finding: Yes
    0
    2
    0
    1
        New Finding: No
    16
    44
    2
    3
    No statistical analyses for this end point

    Secondary: Vital signs: Systolic blood pressure (Visit 1- Baseline)

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    End point title
    		 Vital signs: Systolic blood pressure (Visit 1- Baseline)
    End point description
    End point type
    Secondary
    End point timeframe
    All available information until the last visit.
    End point values
    		 Prophylaxis 10 IU/kg Prophylaxis 40 IU/kg Prophylaxis 80 IU/kg On-demand
    Number of subjects analysed
    18
    48
    0 [27]
    5
    Units: mmHg
        arithmetic mean (standard deviation)
    125.8 ( 8.4 )
    118.3 ( 9.4 )
    ( )
    124 ( 23 )
    Notes
    [27] - For this endpoint (at Visit 1), no subjects were analysed in prophylaxis 80 IU/kg treatment arm.
    No statistical analyses for this end point

    Secondary: Vital signs: Systolic blood pressure (End of Trial)

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    End point title
    		 Vital signs: Systolic blood pressure (End of Trial)
    End point description
    End point type
    Secondary
    End point timeframe
    All available information until the last visit.
    End point values
    		 Prophylaxis 10 IU/kg Prophylaxis 40 IU/kg Prophylaxis 80 IU/kg On-demand
    Number of subjects analysed
    16
    46
    2
    4
    Units: mmHg
        arithmetic mean (standard deviation)
    129.3 ( 13 )
    123.5 ( 8.8 )
    105 ( 7.1 )
    130 ( 23 )
    No statistical analyses for this end point

    Secondary: Vital signs: Diastolic blood pressure (Visit 1- Baseline)

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    End point title
    		 Vital signs: Diastolic blood pressure (Visit 1- Baseline)
    End point description
    End point type
    Secondary
    End point timeframe
    All available information until the last visit.
    End point values
    		 Prophylaxis 10 IU/kg Prophylaxis 40 IU/kg Prophylaxis 80 IU/kg On-demand
    Number of subjects analysed
    18
    48
    0 [28]
    5
    Units: mmHg
        arithmetic mean (standard deviation)
    77.8 ( 10 )
    74.1 ( 9.8 )
    ( )
    75.4 ( 14 )
    Notes
    [28] - For this endpoint (at Visit 1), no subjects were analysed in prophylaxis 80 IU/kg treatment arm.
    No statistical analyses for this end point

    Secondary: Vital signs: Diastolic blood pressure (End of Trial)

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    End point title
    		 Vital signs: Diastolic blood pressure (End of Trial)
    End point description
    End point type
    Secondary
    End point timeframe
    All available information until the last visit.
    End point values
    		 Prophylaxis 10 IU/kg Prophylaxis 40 IU/kg Prophylaxis 80 IU/kg On-demand
    Number of subjects analysed
    16
    46
    2
    4
    Units: mmHg
        arithmetic mean (standard deviation)
    78.1 ( 12 )
    74.5 ( 11 )
    70 ( 14 )
    84.8 ( 12 )
    No statistical analyses for this end point

    Secondary: Vital signs: Pulse (Visit 1- Baseline)

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    End point title
    		 Vital signs: Pulse (Visit 1- Baseline)
    End point description
    End point type
    Secondary
    End point timeframe
    All available information until the last visit.
    End point values
    		 Prophylaxis 10 IU/kg Prophylaxis 40 IU/kg Prophylaxis 80 IU/kg On-demand
    Number of subjects analysed
    18
    48
    0 [29]
    5
    Units: beats/min
        arithmetic mean (standard deviation)
    76.2 ( 10 )
    73.1 ( 10 )
    ( )
    67.2 ( 11 )
    Notes
    [29] - For this endpoint (at Visit 1), no subjects were analysed in prophylaxis 80 IU/kg treatment arm.
    No statistical analyses for this end point

    Secondary: Vital signs: Pulse (End of Trial)

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    End point title
    		 Vital signs: Pulse (End of Trial)
    End point description
    End point type
    Secondary
    End point timeframe
    All available information until the last visit.
    End point values
    		 Prophylaxis 10 IU/kg Prophylaxis 40 IU/kg Prophylaxis 80 IU/kg On-demand
    Number of subjects analysed
    16
    46
    2
    4
    Units: beats/min
        arithmetic mean (standard deviation)
    75 ( 11 )
    77.2 ( 13 )
    71 ( 1.4 )
    70.8 ( 7 )
    No statistical analyses for this end point

    Secondary: Vital signs: Respiratory rate (Visit 1- Baseline)

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    End point title
    		 Vital signs: Respiratory rate (Visit 1- Baseline)
    End point description
    End point type
    Secondary
    End point timeframe
    All available information until the last visit.
    End point values
    		 Prophylaxis 10 IU/kg Prophylaxis 40 IU/kg Prophylaxis 80 IU/kg On-demand
    Number of subjects analysed
    18
    48
    0 [30]
    5
    Units: breaths/min
        arithmetic mean (standard deviation)
    16.7 ( 3.2 )
    17 ( 2.4 )
    ( )
    19.2 ( 1.8 )
    Notes
    [30] - For this endpoint (at Visit 1), no subjects were analysed in prophylaxis 80 IU/kg treatment arm.
    No statistical analyses for this end point

    Secondary: Vital signs: Respiratory rate (End of Trial)

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    End point title
    		 Vital signs: Respiratory rate (End of Trial)
    End point description
    End point type
    Secondary
    End point timeframe
    All available information until the last visit.
    End point values
    		 Prophylaxis 10 IU/kg Prophylaxis 40 IU/kg Prophylaxis 80 IU/kg On-demand
    Number of subjects analysed
    16
    46
    2
    4
    Units: breaths/min
        arithmetic mean (standard deviation)
    17 ( 2.3 )
    16.8 ( 2.4 )
    19 ( 4.2 )
    18 ( 2.8 )
    No statistical analyses for this end point

    Secondary: Vital signs: Body temperature (Visit 1- Baseline)

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    End point title
    		 Vital signs: Body temperature (Visit 1- Baseline)
    End point description
    End point type
    Secondary
    End point timeframe
    All available information until the last visit.
    End point values
    		 Prophylaxis 10 IU/kg Prophylaxis 40 IU/kg Prophylaxis 80 IU/kg On-demand
    Number of subjects analysed
    18
    48
    0 [31]
    5
    Units: Celsius (C)
        arithmetic mean (standard deviation)
    36.6 ( 0.4 )
    36.5 ( 0.4 )
    ( )
    36.6 ( 0.5 )
    Notes
    [31] - For this endpoint (at Visit 1), no subjects were analysed in prophylaxis 80 IU/kg treatment arm.
    No statistical analyses for this end point

    Secondary: Vital signs: Body temperature (End of Trial)

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    End point title
    		 Vital signs: Body temperature (End of Trial)
    End point description
    End point type
    Secondary
    End point timeframe
    All available information until the last visit.
    End point values
    		 Prophylaxis 10 IU/kg Prophylaxis 40 IU/kg Prophylaxis 80 IU/kg On-demand
    Number of subjects analysed
    16
    46
    2
    4
    Units: Celsius (C)
        arithmetic mean (standard deviation)
    36.6 ( 0.4 )
    36.5 ( 0.4 )
    36.1 ( 0.1 )
    36.7 ( 0.5 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    AEs from baseline visit (visit 1) and until one week after last treatment with nonacog beta pegol (±2 days)
    Adverse event reporting additional description
    The safety analysis set consists of all patients exposed to nonacog beta pegol.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    16.1
    Reporting groups
    Reporting group title
    Prophylaxis 10 IU/kg
    Reporting group description
    		 Patients were given 10 IU/kg weekly nonacog beta pegol.

    Reporting group title
    Prophylaxis 40 IU/kg
    Reporting group description
    		 Patients were dosed with 40 IU/kg weekly nonacog beta pegol.

    Reporting group title
    Prophylaxis 80 IU/kg
    Reporting group description
    		 Patients were dosed with 80 IU/kg every second week.

    Reporting group title
    On-demand
    Reporting group description
    		 The recommended dose for treatment of a mild or moderate bleeding episode, for example a joint bleed, was a single dose of 40 IU/kg nonacog beta pegol. If there was no observed effect of 40 IU/kg, the investigator was to be contacted prior to administration of the second dose of 40 IU/kg. The recommended dose for treatment of severe bleeds was 80 IU/kg nonacog beta pegol.

    Serious adverse events
    		 Prophylaxis 10 IU/kg Prophylaxis 40 IU/kg Prophylaxis 80 IU/kg On-demand
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 21 (4.76%)
    5 / 52 (9.62%)
    0 / 2 (0.00%)
    0 / 5 (0.00%)
         number of deaths (all causes)
    0
    1
    0
    0
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Hepatocellular carcinoma
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 52 (1.92%)
    0 / 2 (0.00%)
    0 / 5 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Femur fracture
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 52 (1.92%)
    0 / 2 (0.00%)
    0 / 5 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Road traffic accident
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 52 (1.92%)
    0 / 2 (0.00%)
    0 / 5 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Local swelling
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 52 (1.92%)
    0 / 2 (0.00%)
    0 / 5 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Faecaloma
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 52 (0.00%)
    0 / 2 (0.00%)
    0 / 5 (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
    Infections and infestations
    Gastroenteritis
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 52 (1.92%)
    0 / 2 (0.00%)
    0 / 5 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Post procedural infection
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 52 (1.92%)
    0 / 2 (0.00%)
    0 / 5 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    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
    		 Prophylaxis 10 IU/kg Prophylaxis 40 IU/kg Prophylaxis 80 IU/kg On-demand
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    8 / 21 (38.10%)
    8 / 52 (15.38%)
    0 / 2 (0.00%)
    5 / 5 (100.00%)
    Injury, poisoning and procedural complications
    Ligament sprain
         subjects affected / exposed
    0 / 21 (0.00%)
    3 / 52 (5.77%)
    0 / 2 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    0
    5
    0
    0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 52 (0.00%)
    0 / 2 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    0
    0
    1
    Nervous system disorders
    Headache
         subjects affected / exposed
    2 / 21 (9.52%)
    1 / 52 (1.92%)
    0 / 2 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    2
    2
    0
    0
    General disorders and administration site conditions
    Influenza like illness
         subjects affected / exposed
    1 / 21 (4.76%)
    1 / 52 (1.92%)
    0 / 2 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    1
    1
    0
    1
    Pain
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 52 (1.92%)
    0 / 2 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    1
    0
    3
    Chest discomfort
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 52 (0.00%)
    0 / 2 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    0
    0
    1
    Swelling
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 52 (0.00%)
    0 / 2 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    0
    0
    1
    Eye disorders
    Asthenopia
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 52 (0.00%)
    0 / 2 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    0
    0
    1
    Gastrointestinal disorders
    Dental caries
         subjects affected / exposed
    2 / 21 (9.52%)
    0 / 52 (0.00%)
    0 / 2 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    2 / 21 (9.52%)
    1 / 52 (1.92%)
    0 / 2 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    2
    1
    0
    1
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 52 (0.00%)
    0 / 2 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    0
    0
    1
    Psychiatric disorders
    Libido decreased
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 52 (0.00%)
    0 / 2 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    0
    0
    1
    Musculoskeletal and connective tissue disorders
    Joint range of motion decreased
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 52 (0.00%)
    0 / 2 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    0
    0
    1
    Muscle spasms
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 52 (0.00%)
    0 / 2 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    0
    0
    1
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    3 / 21 (14.29%)
    4 / 52 (7.69%)
    0 / 2 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    5
    5
    0
    0
    Influenza
         subjects affected / exposed
    4 / 21 (19.05%)
    0 / 52 (0.00%)
    0 / 2 (0.00%)
    0 / 5 (0.00%)
         occurrences all number
    6
    0
    0
    0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 52 (0.00%)
    0 / 2 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    0
    0
    3
    Bronchitis
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 52 (0.00%)
    0 / 2 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    0
    0
    1
    Urinary tract infection
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 52 (0.00%)
    0 / 2 (0.00%)
    1 / 5 (20.00%)
         occurrences all number
    0
    0
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    29 Dec 2011
    Linguistic revision to one of the stopping rules. Protocol updated on a few operational issues and inconsistencies.
    11 May 2012
    Changes in the visual appearance of the trial product. Information on stop time of bleeding episode. Information on number of months on on-demand treatment.
    05 Apr 2013
    Austria, Greece, Latvia, Lithuania and Romania were added to the trial.
    05 Apr 2013
    Implementation of a fourth treatment option (80 IU/kg every second week).
    23 Jul 2013
    The protocol was updated due to temporary trial product treatment arm restrictions.
    27 Sep 2013
    The protocol was updated due to shortening of trial and temporary restrictions had been permanent.

    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.
    Not applicable
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