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    Clinical Trial Results:
    Paradigm 6: Safety and Efficacy of nonacog beta pegol (N9-GP) in Previously Untreated Patients with Haemophilia B - An Open-label Single-arm Multicentre Non-controlled Phase 3a Trial Investigating Safety and Efficacy of Nonacog Beta Pegol (N9-GP) in Prophylaxis and Treatment of Bleeding Episodes in Previously Untreated Patients With Haemophilia B (FIX Activity Below or Equal to 2 Percent)

    Summary
    EudraCT number
    		 2012-004867-38
    Trial protocol
    		 DE   AT   ES   RO   IT  
    Global end of trial date
    27 Oct 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    12 May 2023
    First version publication date
    12 May 2023
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    NN7999-3895
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02141074
    WHO universal trial number (UTN)
    		 U1111-1135-9557
    Sponsors
    Sponsor organisation name
    Novo Nordisk A/S
    Sponsor organisation address
    Novo Allé, Bagsvaerd, Denmark, 2880
    Public contact
    Clinical Reporting Office (2834), Novo Nordisk A/S, clinicaltrials@novonordisk.com
    Scientific contact
    Clinical Reporting Office (2834), Novo Nordisk A/S, clinicaltrials@novonordisk.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-000731-PIP01-09
    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
    08 Dec 2022
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    27 Oct 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate immunogenicity of N9-GP (nonacog beta pegol)
    Protection of trial subjects
    The trial was conducted in accordance with the Declaration of Helsinki 2010 and International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) Good Clinical Practice, including archiving of essential documents 1996 and United States Food and Drug Administration (FDA) 21 US Code of Federal Regulations (CFR) 312, 50, and 56 2013.
    Background therapy
    		 Not applicable
    Evidence for comparator
    		 Not applicable
    Actual start date of recruitment
    02 Jul 2014
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy
    Long term follow-up duration
    		 4 Years
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Australia: 2
    Country: Number of subjects enrolled
    Austria: 2
    Country: Number of subjects enrolled
    Canada: 1
    Country: Number of subjects enrolled
    Israel: 2
    Country: Number of subjects enrolled
    Japan: 1
    Country: Number of subjects enrolled
    Malaysia: 6
    Country: Number of subjects enrolled
    Spain: 4
    Country: Number of subjects enrolled
    Taiwan: 6
    Country: Number of subjects enrolled
    Thailand: 6
    Country: Number of subjects enrolled
    United Kingdom: 5
    Country: Number of subjects enrolled
    United States: 19
    Worldwide total number of subjects
    54
    EEA total number of subjects
    6
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    5
    Infants and toddlers (28 days-23 months)
    40
    Children (2-11 years)
    9
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The trial was conducted at 29 sites in 11 countries as follows (number of sites that screened subjects/ number of sites that randomised subjects): Australia (1/1), Austria (2/2), Canada (1/1), Israel (1/1), Japan (1/1), Malaysia (4/4), Spain (3/3), Taiwan (2/2), Thailand (2/2), United Kingdom (3/3), United States (9/9).

    Pre-assignment
    Screening details
    		 Trial consists of main phase including pre-prophylaxis & prophylaxis, extension phase & prophylaxis period until end of treatment. Pre-prophylaxis was optional and allowed subjects to receive treatment until 24 months of age/upon reaching 20EDs, whichever came first. Other subjects directly started on prophylaxis treatment at visit 1.

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

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 Pre-prophylaxis
    Arm description
    		 Subjects received nonacog beta pegol 40 international units/kilogram (IU/kg) intravenous injection at intervals longer than a week on-demand for bleeding episodes until they were 24 months of age or until 20 exposure days (ED), whichever came first, in the main phase. Subjects switched from pre-prophylaxis treatment to prophylaxis treatment no later than 24 months of age/20 ED, whichever came first.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Nonacog beta pegol
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Nonacog beta pegol 40 IU/kg intravenous injection at intervals longer than a week until subjects were 24 months of age or until 20 exposure days (ED), whichever came first in the main phase.

    Arm title
    		 Prophylaxis
    Arm description
    		 Subjects who started with pre-prophylaxis were switched to prophylaxis no later than 24 months of age or upon reaching 20EDs, whichever came first. Other subjects who started directly on prophylaxis since visit 1 received once weekly dosing of nonacog beta pegol 40 IU/kg intravenous injection in the main phase, extension phase, and until the end of treatment.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Nonacog beta pegol
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Nonacog beta pegol 40 IU/kg intravenous injection once weekly in the main phase, extension phase and until the end of treatment.

    Number of subjects in period 1
    		Pre-prophylaxis Prophylaxis
    Started
    34
    51
    Completed
    31
    41
    Not completed
    3
    10
         Consent withdrawn by subject
    -
    1
         Adverse event, non-fatal
    3
    4
         Other
    -
    3
         Withdrawal by parent/guardian
    -
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall Study
    Reporting group description
    		 Subjects received pre-prophylaxis treatment of nonacog beta pegol 40 IU/kg intravenous injection at intervals longer than a week on-demand for bleeding episodes until they were 24 months of age or until 20 exposure days (ED) whichever came first in the main phase. After which they switched to prophylaxis treatment. In prophylaxis, subjects received nonacog beta pegol 40 IU/kg intravenous injection once weekly in the main phase, extension phase and until end of treatment.

    Reporting group values
    		 Overall Study Total
    Number of subjects
    		 54 54
    Age Categorical
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 5 5
        Infants and toddlers (28 days-23 months)
    		 40 40
        Children (2-11 years)
    		 9 9
        Adolescents (12-17 years)
    		 0 0
        Adults (18-64 years)
    		 0 0
        From 65-84 years
    		 0 0
        85 years and over
    		 0 0
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 0.8 ± 1.1 -
    Gender Categorical
    Units: Subjects
        Female
    		 0 0
        Male
    		 54 54

    End points

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    End points reporting groups
    Reporting group title
    Pre-prophylaxis
    Reporting group description
    		 Subjects received nonacog beta pegol 40 international units/kilogram (IU/kg) intravenous injection at intervals longer than a week on-demand for bleeding episodes until they were 24 months of age or until 20 exposure days (ED), whichever came first, in the main phase. Subjects switched from pre-prophylaxis treatment to prophylaxis treatment no later than 24 months of age/20 ED, whichever came first.

    Reporting group title
    Prophylaxis
    Reporting group description
    		 Subjects who started with pre-prophylaxis were switched to prophylaxis no later than 24 months of age or upon reaching 20EDs, whichever came first. Other subjects who started directly on prophylaxis since visit 1 received once weekly dosing of nonacog beta pegol 40 IU/kg intravenous injection in the main phase, extension phase, and until the end of treatment.

    Primary: Incidence of Inhibitory Antibodies Against Coagulation Factor IX (FIX) (50 Exposure Days)

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    End point title
    		 Incidence of Inhibitory Antibodies Against Coagulation Factor IX (FIX) (50 Exposure Days) [1]
    End point description
    Incidence of inihibitory antibodies against FIX after 50 ED is presented. Incidence of inhibitory antibodies against FIX was defined as an inhibitory antibody titre greater than equal to 0.6 Bethesda unit (BU) at two consecutive tests performed at the central laboratory and also tested positive for nonacog beta pegol binding antibodies. Safety analysis set included all subjects exposed to nonacog beta pegol. Number of Subjects Analysed = Subjects with available data for this endpoint.
    End point type
    Primary
    End point timeframe
    When minimum 20 previously untreated patients (PUPs) have reached at least 50 exposure days (ED)
    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 comparative statistical analysis was performed between the reported groups.
    End point values
    		 Pre-prophylaxis Prophylaxis
    Number of subjects analysed
    20
    28
    Units: Subjects
    2
    0
    No statistical analyses for this end point

    Primary: Incidence of Inhibitory Antibodies Against FIX (100 ED)

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    End point title
    		 Incidence of Inhibitory Antibodies Against FIX (100 ED) [2]
    End point description
    Incidence of inihibitory antibodies against FIX after 100 ED is presented. Incidence of inhibitory antibodies against FIX was defined as an inhibitory antibody titre greater than equal to 0.6 Bethesda unit (BU) at two consecutive tests performed at the central laboratory and also tested positive for nonacog beta pegol binding antibodies. Safety analysis set included all subjects exposed to nonacog beta pegol. Number of Subjects Analysed = Subjects with available data for this endpoint.
    End point type
    Primary
    End point timeframe
    When minimum 40 PUPs have reached at least 100 ED
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No comparative statistical analysis was performed between the reported groups.
    End point values
    		 Pre-prophylaxis Prophylaxis
    Number of subjects analysed
    19
    47
    Units: Subjects
    2
    2
    No statistical analyses for this end point

    Primary: Incidence of Inhibitory Antibodies Against FIX (At End of Trial)

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    End point title
    		 Incidence of Inhibitory Antibodies Against FIX (At End of Trial) [3]
    End point description
    Incidence of inihibitory antibodies against FIX at end of trial is presented. Incidence of inhibitory antibodies against FIX was defined as an inhibitory antibody titre greater than equal to 0.6 Bethesda unit (BU) at two consecutive tests performed at the central laboratory and also tested positive for nonacog beta pegol binding antibodies. Safety analysis set included all subjects exposed to nonacog beta pegol. Number of Subjects Analysed = Subjects with available data for this endpoint.
    End point type
    Primary
    End point timeframe
    At end of trial
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No comparative statistical analysis was performed between the reported groups.
    End point values
    		 Pre-prophylaxis Prophylaxis
    Number of subjects analysed
    20
    51
    Units: Subjects
    2
    2
    No statistical analyses for this end point

    Secondary: Number of Adverse Events

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    End point title
    		 Number of Adverse Events
    End point description
    Number of adverse events after 50 ED, after 100 ED, and at end of trial is presented. An adverse event was defined as any untoward medical occurrence in a subject who was administered a product, and which does not necessarily have a causal relationship with this treatment. All presented adverse events are treatment emergent adverse events, defined as an event that occured while the subject was on treatment in the period from first dosing with nonacog beta pegol to the end of trial/discontinuation of treatment. Safety analysis set included all subjects exposed to nonacog beta pegol. n= Subjects evaluated for this endpoint at the given time point.
    End point type
    Secondary
    End point timeframe
    When minimum 20 PUPs have reached at least 50 ED; when minimum 40 PUPs have reached at least 100 ED; at end of trial
    End point values
    		 Pre-prophylaxis Prophylaxis
    Number of subjects analysed
    34
    51
    Units: Events
    number (not applicable)
        50 ED (n=24,28)
    86
    291
        100 ED (n=32,47)
    131
    610
        End of trial (n=34,51)
    134
    794
    No statistical analyses for this end point

    Secondary: Frequency of Adverse Events

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    End point title
    		 Frequency of Adverse Events
    End point description
    Frequency of adverse events after 50 ED, after 100 ED, and at end of trial is presented. An adverse event was defined as any untoward medical occurrence in a subject who was administered a product, and which does not necessarily have a causal relationship with this treatment. All presented adverse events are treatment emergent adverse events, defined as an event that occured while the subject was on treatment in the period from first dosing with nonacog beta pegol to the end of trial/discontinuation of treatment. Safety analysis set included all subjects exposed to nonacog beta pegol. n= Subjects evaluated for this endpoint at the given time point.
    End point type
    Secondary
    End point timeframe
    When minimum 20 PUPs have reached at least 50 ED; when minimum 40 PUPs have reached at least 100 ED; at end of trial
    End point values
    		 Pre-prophylaxis Prophylaxis
    Number of subjects analysed
    34
    51
    Units: Events per patient years of exposure
    number (not applicable)
        50 ED (n=24,28)
    5.59
    5.87
        100 ED (n=32,47)
    5.92
    5.08
        End of trial (n=34,51)
    5.52
    4.10
    No statistical analyses for this end point

    Secondary: Number of Serious Adverse Events

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    End point title
    		 Number of Serious Adverse Events
    End point description
    Number of serious adverse events after 50 ED, after 100 ED, and at end of trial is presented. A serious adverse event was an experience that at any dose resulted in: death; life-threatening experience; in-patient hospitalisation or prolongation of existing hospitalisation; a persistent or significant disability/incapacity; congenital anomaly/birth defect; important medical events that may not result in death, be life-threatening/require hospitalisation could be considered a serious adverse event based upon appropriate medical judgement. Safety analysis set included all subjects exposed to nonacog beta pegol. n= Subjects evaluated for this endpoint at the given time point.
    End point type
    Secondary
    End point timeframe
    When minimum 20 PUPs have reached at least 50 ED; when minimum 40 PUPs have reached at least 100 ED; at end of trial
    End point values
    		 Pre-prophylaxis Prophylaxis
    Number of subjects analysed
    34
    51
    Units: Events
    number (not applicable)
        50 ED (n=24,28)
    9
    14
        100 ED (n=32,47)
    13
    27
        End of trial (n=34,51)
    14
    30
    No statistical analyses for this end point

    Secondary: Frequency of Serious Adverse Events

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    End point title
    		 Frequency of Serious Adverse Events
    End point description
    Frequency of serious adverse events after 50 ED, after 100 ED, and at end of trial is presented. A serious adverse event was an experience that at any dose resulted in: death; life-threatening experience; in-patient hospitalisation or prolongation of existing hospitalisation; a persistent or significant disability/incapacity; congenital anomaly/birth defect; important medical events that may not result in death, be life-threatening/require hospitalisation could be considered a serious adverse event based upon appropriate medical judgement. Safety analysis set included all subjects exposed to nonacog beta pegol. n= Subjects evaluated for this endpoint at the given time point.
    End point type
    Secondary
    End point timeframe
    When minimum 20 PUPs have reached at least 50 ED; when minimum 40 PUPs have reached at least 100 ED; at end of trial
    End point values
    		 Pre-prophylaxis Prophylaxis
    Number of subjects analysed
    34
    51
    Units: Events per patient years of exposure
    number (not applicable)
        50 ED (n=24,28)
    0.59
    0.28
        100 ED (n=32,47)
    0.59
    0.22
        End of trial (n=34,51)
    0.58
    0.15
    No statistical analyses for this end point

    Secondary: Number of Medical Events of Special Interest

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    End point title
    		 Number of Medical Events of Special Interest
    End point description
    Number of medical events of special interest after 50 ED, after 100 ED, and at end of trial is presented. A medical event of special interest (MESI) was an event that, in the evaluation of safety, has a special focus. A MESI was an adverse event (serious or non-serious adverse event) that fulfils one or more of the MESI criteria. Safety analysis set included all subjects exposed to nonacog beta pegol. n= Subjects evaluated for this endpoint at the given time point.
    End point type
    Secondary
    End point timeframe
    When minimum 20 PUPs have reached at least 50 ED; when minimum 40 PUPs have reached at least 100 ED; at end of trial
    End point values
    		 Pre-prophylaxis Prophylaxis
    Number of subjects analysed
    34
    51
    Units: Events
    number (not applicable)
        50 ED (n=24,28)
    5
    9
        100 ED (n=32,47)
    6
    31
        End of trial (n=34,51)
    6
    38
    No statistical analyses for this end point

    Secondary: Frequency of Medical Events of Special Interest

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    End point title
    		 Frequency of Medical Events of Special Interest
    End point description
    Frequency of medical events of special interest after 50 ED, after 100 ED, and at end of trial is presented. A medical event of special interest (MESI) was an event that, in the evaluation of safety, has a special focus. A MESI was an adverse event (serious or non-serious adverse event) that fulfils one or more of the MESI criteria. Safety analysis set included all subjects exposed to nonacog beta pegol. n= Subjects evaluated for this endpoint at the given time point.
    End point type
    Secondary
    End point timeframe
    When minimum 20 PUPs have reached at least 50 ED; when minimum 40 PUPs have reached at least 100 ED; at end of trial
    End point values
    		 Pre-prophylaxis Prophylaxis
    Number of subjects analysed
    34
    51
    Units: Events per patient years of exposure
    number (not applicable)
        50 ED (n=24,28)
    0.33
    0.18
        100 ED (n=32,47)
    0.27
    0.26
        End of trial (n=34,51)
    0.25
    0.20
    No statistical analyses for this end point

    Secondary: Number of Breakthrough Bleeding Episodes During Prophylaxis (Annualised Bleeding Rate)

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    End point title
    		 Number of Breakthrough Bleeding Episodes During Prophylaxis (Annualised Bleeding Rate) [4]
    End point description
    Number of breakthrough bleeding episodes during prophylaxis (annualised bleeding rate) after 50 ED, after 100 ED, and at end of trial is presented. Annualised bleeding rate is the number of bleeding episodes per year. Full analysis set included all subjects exposed to nonacog beta pegol. n= Subjects evaluated for this endpoint at the given time point.
    End point type
    Secondary
    End point timeframe
    When minimum 20 PUPs have reached at least 50 ED; when minimum 40 PUPs have reached at least 100 ED; at end of trial
    Notes
    [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint is only for ABR during prophylaxis hence the pre-prophylaxis arm is not included.
    End point values
    		 Prophylaxis
    Number of subjects analysed
    47
    Units: bleeds/subject/year
    median (full range (min-max))
        50 ED (n=28)
    0.00 (0.00 to 2.60)
        100 ED (n=47)
    0.25 (0.00 to 17.39)
        End of trial (n=51)
    0.33 (0.00 to 17.39)
    No statistical analyses for this end point

    Secondary: Haemostatic Effect by 4-point Haemostatic Response Scale ("Excellent", "Good", "Moderate" and "Poor")

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    End point title
    		 Haemostatic Effect by 4-point Haemostatic Response Scale ("Excellent", "Good", "Moderate" and "Poor")
    End point description
    Haemostatic effect by 4-point haemostatic response scale after 50 ED, after 100 ED, and at end of trial is presented. The haemostatic response after treatment of a bleed with nonacog beta pegol was evaluated on a 4-point scale as excellent, good, moderate or poor. Excellent: abrupt pain relief and/or clear improvement in objective signs of bleeding; Good: noticeable pain relief and/or improvement in signs of bleeding; Moderate: probable or slight beneficial effect after the first injection; Poor: no improvement or worsening of symptoms. If the haemostatic response was rated as excellent or good, the treatment of the bleed was considered a success. If the haemostatic response was rated as moderate or poor, the treatment was considered a failure. Full analysis set included all subjects exposed to nonacog beta pegol. n= Subjects evaluated for this endpoint at the given time point.
    End point type
    Secondary
    End point timeframe
    When minimum 20 PUPs have reached at least 50 ED; when minimum 40 PUPs have reached at least 100 ED; at end of trial
    End point values
    		 Pre-prophylaxis Prophylaxis
    Number of subjects analysed
    34
    51
    Units: Number of bleeds
    number (not applicable)
        50 ED (n=24,28) Excellent
    23
    9
        50 ED (n=24,28) Good
    8
    5
        50 ED (n=24,28) Moderate
    2
    1
        50 ED (n=24,28) Poor
    0
    0
        100 ED (n=32,47) Excellent
    44
    44
        100 ED (n=32,47) Good
    17
    30
        100 ED (n=32,47) Moderate
    2
    3
        100 ED (n=32,47) Poor
    0
    0
        End of trial (n=34,51) Excellent
    45
    86
        End of trial (n=34,51) Good
    18
    45
        End of trial (n=34,51) Moderate
    2
    4
        End of trial (n=34,51) Poor
    0
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to Week 434
    Adverse event reporting additional description
    All presented adverse events are treatment emergent adverse events, defined as an event that occured while the subject was on treatment in the period from first dosing with nonacog beta pegol to the end of trial/discontinuation of treatment. Safety analysis set included all subjects exposed to nonacog beta pegol.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    25
    Reporting groups
    Reporting group title
    Prophylaxis
    Reporting group description
    		 Subjects who started with pre-prophylaxis were switched to prophylaxis no later than 24 months of age or upon reaching 20EDs, whichever came first. Other subjects who started directly on prophylaxis since visit 1 received once weekly dosing of nonacog beta pegol 40 IU/kg intravenous injection in the main phase, extension phase, and until the end of treatment.

    Reporting group title
    Pre-prophylaxis
    Reporting group description
    		 Subjects received nonacog beta pegol 40 international units/kilogram (IU/kg) intravenous injection at intervals longer than a week on-demand for bleeding episodes until they were 24 months of age or until 20 exposure days (ED), whichever came first, in the main phase. Subjects switched from pre-prophylaxis treatment to prophylaxis treatment no later than 24 months of age/20 ED, whichever came first.

    Serious adverse events
    		 Prophylaxis Pre-prophylaxis
    Total subjects affected by serious adverse events
         subjects affected / exposed
    19 / 51 (37.25%)
    9 / 34 (26.47%)
         number of deaths (all causes)
    1
    1
         number of deaths resulting from adverse events
    0
    0
    Investigations
    Catheterisation cardiac
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood culture positive
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 34 (2.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Head injury
         subjects affected / exposed
    1 / 51 (1.96%)
    1 / 34 (2.94%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Poor venous access
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Language disorder
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhage intracranial
         subjects affected / exposed
    1 / 51 (1.96%)
    2 / 34 (5.88%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Blood and lymphatic system disorders
    Factor IX inhibition
         subjects affected / exposed
    2 / 51 (3.92%)
    2 / 34 (5.88%)
         occurrences causally related to treatment / all
    2 / 2
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Platelet dysfunction
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Anaphylactic reaction
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 34 (2.94%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypersensitivity
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Dental caries
         subjects affected / exposed
    2 / 51 (3.92%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Tonsillar hypertrophy
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Henoch-Schonlein purpura
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Autism spectrum disorder
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Gastroenteritis viral
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 34 (2.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis salmonella
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 34 (2.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis of male external genital organ
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Catheter site infection
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 34 (2.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacteraemia
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchiolitis
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 34 (2.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pharyngitis
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Otitis media viral
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nasopharyngitis
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    1 / 51 (1.96%)
    1 / 34 (2.94%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 34 (2.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    4 / 51 (7.84%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Prophylaxis Pre-prophylaxis
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    46 / 51 (90.20%)
    22 / 34 (64.71%)
    Injury, poisoning and procedural complications
    Head injury
         subjects affected / exposed
    7 / 51 (13.73%)
    0 / 34 (0.00%)
         occurrences all number
    10
    0
    Fall
         subjects affected / exposed
    8 / 51 (15.69%)
    1 / 34 (2.94%)
         occurrences all number
    14
    1
    Contusion
         subjects affected / exposed
    6 / 51 (11.76%)
    0 / 34 (0.00%)
         occurrences all number
    16
    0
    Arthropod bite
         subjects affected / exposed
    6 / 51 (11.76%)
    0 / 34 (0.00%)
         occurrences all number
    7
    0
    Thermal burn
         subjects affected / exposed
    3 / 51 (5.88%)
    0 / 34 (0.00%)
         occurrences all number
    3
    0
    Skin laceration
         subjects affected / exposed
    4 / 51 (7.84%)
    1 / 34 (2.94%)
         occurrences all number
    9
    1
    Lip injury
         subjects affected / exposed
    3 / 51 (5.88%)
    0 / 34 (0.00%)
         occurrences all number
    3
    0
    Congenital, familial and genetic disorders
    Phimosis
         subjects affected / exposed
    3 / 51 (5.88%)
    0 / 34 (0.00%)
         occurrences all number
    3
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    3 / 51 (5.88%)
    0 / 34 (0.00%)
         occurrences all number
    11
    0
    Speech disorder developmental
         subjects affected / exposed
    5 / 51 (9.80%)
    0 / 34 (0.00%)
         occurrences all number
    5
    0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    27 / 51 (52.94%)
    11 / 34 (32.35%)
         occurrences all number
    74
    23
    Immune system disorders
    Drug hypersensitivity
         subjects affected / exposed
    4 / 51 (7.84%)
    1 / 34 (2.94%)
         occurrences all number
    5
    1
    Eye disorders
    Conjunctivitis allergic
         subjects affected / exposed
    3 / 51 (5.88%)
    0 / 34 (0.00%)
         occurrences all number
    4
    0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    5 / 51 (9.80%)
    0 / 34 (0.00%)
         occurrences all number
    6
    0
    Diarrhoea
         subjects affected / exposed
    11 / 51 (21.57%)
    3 / 34 (8.82%)
         occurrences all number
    13
    3
    Dental caries
         subjects affected / exposed
    5 / 51 (9.80%)
    0 / 34 (0.00%)
         occurrences all number
    7
    0
    Constipation
         subjects affected / exposed
    4 / 51 (7.84%)
    0 / 34 (0.00%)
         occurrences all number
    8
    0
    Vomiting
         subjects affected / exposed
    11 / 51 (21.57%)
    2 / 34 (5.88%)
         occurrences all number
    15
    2
    Teething
         subjects affected / exposed
    4 / 51 (7.84%)
    1 / 34 (2.94%)
         occurrences all number
    7
    3
    Respiratory, thoracic and mediastinal disorders
    Epistaxis
         subjects affected / exposed
    3 / 51 (5.88%)
    1 / 34 (2.94%)
         occurrences all number
    3
    1
    Cough
         subjects affected / exposed
    17 / 51 (33.33%)
    4 / 34 (11.76%)
         occurrences all number
    34
    5
    Rhinorrhoea
         subjects affected / exposed
    9 / 51 (17.65%)
    3 / 34 (8.82%)
         occurrences all number
    21
    5
    Rhinitis allergic
         subjects affected / exposed
    3 / 51 (5.88%)
    0 / 34 (0.00%)
         occurrences all number
    3
    0
    Oropharyngeal pain
         subjects affected / exposed
    4 / 51 (7.84%)
    0 / 34 (0.00%)
         occurrences all number
    8
    0
    Nasal congestion
         subjects affected / exposed
    4 / 51 (7.84%)
    1 / 34 (2.94%)
         occurrences all number
    16
    2
    Skin and subcutaneous tissue disorders
    Erythema
         subjects affected / exposed
    3 / 51 (5.88%)
    0 / 34 (0.00%)
         occurrences all number
    3
    0
    Eczema
         subjects affected / exposed
    3 / 51 (5.88%)
    0 / 34 (0.00%)
         occurrences all number
    5
    0
    Rash
         subjects affected / exposed
    6 / 51 (11.76%)
    3 / 34 (8.82%)
         occurrences all number
    14
    3
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    4 / 51 (7.84%)
    0 / 34 (0.00%)
         occurrences all number
    4
    0
    Infections and infestations
    Influenza
         subjects affected / exposed
    5 / 51 (9.80%)
    0 / 34 (0.00%)
         occurrences all number
    6
    0
    Hand-foot-and-mouth disease
         subjects affected / exposed
    4 / 51 (7.84%)
    0 / 34 (0.00%)
         occurrences all number
    4
    0
    Gastroenteritis
         subjects affected / exposed
    4 / 51 (7.84%)
    0 / 34 (0.00%)
         occurrences all number
    4
    0
    Ear infection
         subjects affected / exposed
    9 / 51 (17.65%)
    3 / 34 (8.82%)
         occurrences all number
    13
    4
    Conjunctivitis
         subjects affected / exposed
    4 / 51 (7.84%)
    1 / 34 (2.94%)
         occurrences all number
    6
    1
    COVID-19
         subjects affected / exposed
    6 / 51 (11.76%)
    0 / 34 (0.00%)
         occurrences all number
    7
    0
    Bronchitis
         subjects affected / exposed
    6 / 51 (11.76%)
    1 / 34 (2.94%)
         occurrences all number
    8
    1
    Viral infection
         subjects affected / exposed
    5 / 51 (9.80%)
    3 / 34 (8.82%)
         occurrences all number
    10
    3
    Tonsillitis
         subjects affected / exposed
    5 / 51 (9.80%)
    1 / 34 (2.94%)
         occurrences all number
    8
    1
    Sinusitis
         subjects affected / exposed
    3 / 51 (5.88%)
    0 / 34 (0.00%)
         occurrences all number
    5
    0
    Rhinitis
         subjects affected / exposed
    3 / 51 (5.88%)
    0 / 34 (0.00%)
         occurrences all number
    4
    0
    Pharyngitis
         subjects affected / exposed
    4 / 51 (7.84%)
    1 / 34 (2.94%)
         occurrences all number
    4
    1
    Otitis media acute
         subjects affected / exposed
    5 / 51 (9.80%)
    2 / 34 (5.88%)
         occurrences all number
    5
    4
    Otitis media
         subjects affected / exposed
    6 / 51 (11.76%)
    2 / 34 (5.88%)
         occurrences all number
    12
    2
    Nasopharyngitis
         subjects affected / exposed
    23 / 51 (45.10%)
    5 / 34 (14.71%)
         occurrences all number
    68
    12
    Upper respiratory tract infection
         subjects affected / exposed
    19 / 51 (37.25%)
    5 / 34 (14.71%)
         occurrences all number
    33
    6

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    17 Jun 2015
    This amendment allowed major surgery, specified requirements for major surgery and the data items to be recorded, ensured that genotyping of the haemophilia B mutation was collected, and minor clarifications and corrections to protocol version 1.0.
    15 Feb 2017
    This amendment specified the change in the colour of the reconstituted solution from “clear and colourless to slightly yellow solution” to “clear and colourless solution free from clearly visible particles”.
    30 Jan 2018
    This amendment included following parameters: neurological examination, biochemistry analysis, polyethylene glycol analysis and height to certain visits. Subject participation in the trial was also clarified. It was also specified that all central nervous system related adverse events (AEs) were to be categorised as medical event of special interest (MESI).
    11 Oct 2018
    This amendment included neurocognitive assessments and specified that all renal AEs were to be categorised as MESI.
    17 Dec 2019
    This amendment extended the recruitment period to increase the number of subjects on trial product to increase the number of baseline neurocognitive assessments collected in the trial.

    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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