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    Clinical Trial Results:
    Safety, Efficacy and Pharmacokinetics of NNC-0156-0000-0009 (N9-GP) in Previously Treated Children with Haemophilia B

    Summary
    EudraCT number
    		 2011-000826-31
    Trial protocol
    		 DE   GB   IT  
    Global end of trial date
    17 Nov 2023

    Results information
    Results version number
    		 v1(current)
    This version publication date
    01 Jun 2024
    First version publication date
    01 Jun 2024
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    NN7999-3774
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01467427
    WHO universal trial number (UTN)
    		 U1111-1119-5013
    Other trial identifiers
    		 Japanese trial registration: JapicCTI-121877
    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-PIP09-03
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    03 Sep 2021
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    17 Nov 2023
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate immunogenicity of glycopegylated recombinant coagulation factor IX (NNC-0156-0000-0009; hereafter referred to as nonacog beta pegol [N9-GP])
    Protection of trial subjects
    The trial was conducted in accordance with the Declaration of Helsinki 2013 and International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) Good Clinical Practice, including archiving of essential documents 1996 and 21 US Code of Federal Regulations (CFR) 312.120.50 and 56.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    16 May 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
    Canada: 4
    Country: Number of subjects enrolled
    Germany: 1
    Country: Number of subjects enrolled
    Italy: 1
    Country: Number of subjects enrolled
    Japan: 3
    Country: Number of subjects enrolled
    Malaysia: 2
    Country: Number of subjects enrolled
    Taiwan: 2
    Country: Number of subjects enrolled
    United Kingdom: 3
    Country: Number of subjects enrolled
    United States: 9
    Worldwide total number of subjects
    25
    EEA total number of subjects
    2
    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)
    3
    Children (2-11 years)
    20
    Adolescents (12-17 years)
    2
    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 19 sites in 8 countries as follows (number of sites that screened subjects/ number of sites that randomised subjects): Canada (1/ 1); Germany (1/ 1); Italy (1/ 1); Japan (3/ 3); Malaysia (1/ 1); Taiwan (1/ 1); United Kingdom (3/ 3); United States (8/ 6).

    Pre-assignment
    Screening details
    		 The trial consisted of a main phase/core study (Visit 1 – Visit 11) and an extension phase (Visit 12 – end of trial).

    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
    Yes

    Arm title
    		 Younger children (0-6 years)
    Arm description
    		 Subjects (0-6 years) received nonacog beta pegol 40 international units per kilogram (IU/kg) intravenous (i.v.) injection once weekly and as on-demand treatment for bleeds for the main and extension phases.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Nonacog beta pegol
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder and solvent for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Nonacog beta pegol 40 IU/kg intravenous (i.v.) injection was administered once weekly and as on-demand treatment for bleeds for the main and extension phases.

    Arm title
    		 Older children (7-12 years)
    Arm description
    		 Subjects (7-12 years) received nonacog beta pegol 40 IU/kg i.v. injection once weekly and as on-demand treatment for bleeds for the main and extension phases.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Nonacog beta pegol
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder and solvent for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Nonacog beta pegol 40 IU/kg i.v. injection was administered once weekly and as on-demand treatment for bleeds for the main and extension phases.

    Number of subjects in period 1
    		Younger children (0-6 years) Older children (7-12 years)
    Started
    12
    13
    Full analysis set
    12
    13
    Safety analysis set
    12
    13
    Completed main phase
    11
    13
    Entered extension phase
    11
    11
    Completed
    6
    4
    Not completed
    6
    9
         Consent withdrawn by subject
    3
    1
         Subject moved out of province
    -
    1
         Subject's caregiver decision
    1
    -
         Discontinuation of PI at site
    1
    -
         Study closed due to staff
    1
    -
         Withdrawal criteria
    -
    4
         Non-compliance
    -
    1
         Lost to follow-up
    -
    1
         Consent withdrawn by parent
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Younger children (0-6 years)
    Reporting group description
    		 Subjects (0-6 years) received nonacog beta pegol 40 international units per kilogram (IU/kg) intravenous (i.v.) injection once weekly and as on-demand treatment for bleeds for the main and extension phases.

    Reporting group title
    Older children (7-12 years)
    Reporting group description
    		 Subjects (7-12 years) received nonacog beta pegol 40 IU/kg i.v. injection once weekly and as on-demand treatment for bleeds for the main and extension phases.

    Reporting group values
    		 Younger children (0-6 years) Older children (7-12 years) Total
    Number of subjects
    		 12 13 25
    Age Categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 3 0 3
        Children (2-11 years)
    		 9 11 20
        Adolescents (12-17 years)
    		 0 2 2
        Adults (18-64 years)
    		 0 0 0
        From 65-84 years
    		 0 0 0
        85 years and over
    		 0 0 0
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 3.1 ( 1.7 ) 9.6 ( 1.6 ) -
    Gender Categorical
    Units: Subjects
        Female
    		 0 0 0
        Male
    		 12 13 25

    End points

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    End points reporting groups
    Reporting group title
    Younger children (0-6 years)
    Reporting group description
    		 Subjects (0-6 years) received nonacog beta pegol 40 international units per kilogram (IU/kg) intravenous (i.v.) injection once weekly and as on-demand treatment for bleeds for the main and extension phases.

    Reporting group title
    Older children (7-12 years)
    Reporting group description
    		 Subjects (7-12 years) received nonacog beta pegol 40 IU/kg i.v. injection once weekly and as on-demand treatment for bleeds for the main and extension phases.

    Primary: Incidence of Inhibitory Antibodies Against Coagulation Factor IX (FIX) Defined as Titre Greater Than or Equal To (≥) 0.6 Bethesda Unit (BU)

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    End point title
    		 Incidence of Inhibitory Antibodies Against Coagulation Factor IX (FIX) Defined as Titre Greater Than or Equal To (≥) 0.6 Bethesda Unit (BU) [1]
    End point description
    Number of subjects who developed inhibitory antibodies against factor IX are reported. Inhibitors were analysed with either the Nijmegen modified factor IX Bethesda assay or a heat/cold Nijmegen modified factor IX Bethesda assay. Safety analysis set included all subjects exposed to nonacog beta pegol.
    End point type
    Primary
    End point timeframe
    Week 52
    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
    		 Younger children (0-6 years) Older children (7-12 years)
    Number of subjects analysed
    12
    13
    Units: Subjects
    0
    0
    No statistical analyses for this end point

    Secondary: Number of Bleeding Episodes During Prophylaxis

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    End point title
    		 Number of Bleeding Episodes During Prophylaxis
    End point description
    Number of bleeding episodes per subject during routine prophylaxis was assessed using the individual annualised bleeding rates (bleeding episodes per subject per year). Full analysis set (FAS) included all subjects with efficacy data after exposure to nonacog beta pegol.
    End point type
    Secondary
    End point timeframe
    Week 52
    End point values
    		 Younger children (0-6 years) Older children (7-12 years)
    Number of subjects analysed
    12
    13
    Units: bleeds/subject/year
        median (inter-quartile range (Q1-Q3))
    0.00 (0.00 to 1.78)
    2.00 (0.68 to 2.89)
    No statistical analyses for this end point

    Secondary: Haemostatic Effect of N9-GP in Treatment of Bleeding Episodes by 4-point Categorical Scale for Haemostatic Response (Excellent, Good, Moderate and Poor)

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    End point title
    		 Haemostatic Effect of N9-GP in Treatment of Bleeding Episodes by 4-point Categorical Scale for Haemostatic Response (Excellent, Good, Moderate and Poor)
    End point description
    Haemostatic effect of nonacog beta pegol when used for treatment of bleeding episodes was measured and listed according to the four-point scale for haemostatic response as: Excellent – abrupt pain relief and/or clear improvement in objective signs of bleeding within 8 hours after a single infusion; Good – noticeable pain relief and/or improvement in signs of bleeding within 8 hours after a single injection; Moderate – probable or slight beneficial effect within the first 8 hours after the first injection but requiring more than one infusion within 8 hours; Poor – no improvement, or worsening of symptoms within 8 hours after two injections. FAS included all subjects with efficacy data after exposure to nonacog beta pegol.
    End point type
    Secondary
    End point timeframe
    Week 52
    End point values
    		 Younger children (0-6 years) Older children (7-12 years)
    Number of subjects analysed
    12
    13
    Units: Bleeding episodes
    number (not applicable)
        Excellent
    7
    15
        Good
    3
    14
        Moderate
    0
    2
        Poor
    1
    0
    No statistical analyses for this end point

    Secondary: Incremental Recovery at 30 Minutes (IR30min)

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    End point title
    		 Incremental Recovery at 30 Minutes (IR30min)
    End point description
    Incremental recovery at 30 min was calculated by dividing the factor IX activity units per millilitre (U/mL) measured in plasma 30 min after dosing by the dose injected at time 0 expressed as units per kilogram (U/kg) body weight. FAS included all subjects with efficacy data after exposure to nonacog beta pegol. Number of Subjects Analyzed = subjects who were evaluated for this endpoint.
    End point type
    Secondary
    End point timeframe
    Week 0
    End point values
    		 Younger children (0-6 years) Older children (7-12 years)
    Number of subjects analysed
    11
    13
    Units: (U/mL)/(U/kg)
        geometric mean (geometric coefficient of variation)
    0.015 ( 7.31 )
    0.016 ( 16.18 )
    No statistical analyses for this end point

    Secondary: Trough Level Single-dose

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    End point title
    		 Trough Level Single-dose
    End point description
    The lowest activity of factor IX recorded at week 0, 168 hours post-dose (immediately before next dose was given) is reported. FAS included all subjects with efficacy data after exposure to nonacog beta pegol. Number of Subjects Analyzed = subjects who were evaluated for this endpoint.
    End point type
    Secondary
    End point timeframe
    Week 0
    End point values
    		 Younger children (0-6 years) Older children (7-12 years)
    Number of subjects analysed
    11
    12
    Units: Units per millitre (U/mL)
        geometric mean (geometric coefficient of variation)
    0.084 ( 16.28 )
    0.109 ( 18.89 )
    No statistical analyses for this end point

    Secondary: Terminal Half-life (t1/2)

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    End point title
    		 Terminal Half-life (t1/2)
    End point description
    Terminal half-life was calculated as natural log [ln](2)/λz, where λz is the terminal elimination rate. The terminal elimination rate was estimated using linear regression on the terminal part of the log(activity) versus time profile. FAS included all subjects with efficacy data after exposure to nonacog beta pegol.
    End point type
    Secondary
    End point timeframe
    Week 0
    End point values
    		 Younger children (0-6 years) Older children (7-12 years)
    Number of subjects analysed
    12
    13
    Units: hours
        geometric mean (geometric coefficient of variation)
    69.576 ( 15.79 )
    76.323 ( 25.48 )
    No statistical analyses for this end point

    Secondary: Trough Level Steady State

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    End point title
    		 Trough Level Steady State
    End point description
    The lowest activity recorded immediately before next dose was given after week 1 i.e. from week 4 to week 52. The analysis is based on a mixed model on the log-transformed plasma concentrations with subject as a random effect. The mean trough level is presented back-transformed to the natural scale. FAS included all subjects with efficacy data after exposure to nonacog beta pegol.
    End point type
    Secondary
    End point timeframe
    Week 4 to Week 52
    End point values
    		 Younger children (0-6 years) Older children (7-12 years)
    Number of subjects analysed
    12
    13
    Units: Units per millitre (U/mL)
        arithmetic mean (confidence interval 95%)
    0.154 (0.127 to 0.186)
    0.190 (0.159 to 0.228)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to year 12
    Adverse event reporting additional description
    All presented adverse events are treatment emergent adverse events, defined as as adverse event occurring after dosing with trial product. 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
    26
    Reporting groups
    Reporting group title
    Younger children (0 - 6 years)
    Reporting group description
    		 Subjects received nonacog beta pegol 40 international units per kilogram (IU/kg) intravenous (i.v.) injection once weekly and as on-demand treatment for bleeds for the main and extension phases.

    Reporting group title
    Older children (7 - 12 years)
    Reporting group description
    		 Subjects received nonacog beta pegol 40 international units per kilogram (IU/kg) intravenous (i.v.) injection once weekly and as on-demand treatment for bleeds for the main and extension phases.

    Reporting group title
    Adolescents (13 - 17 years)
    Reporting group description
    		 Subjects received nonacog beta pegol 40 international units per kilogram (IU/kg) intravenous (i.v.) injection once weekly and as on-demand treatment for bleeds for the main and extension phases.

    Reporting group title
    Adults (18 - 70 years)
    Reporting group description
    		 Subjects received nonacog beta pegol 40 international units per kilogram (IU/kg) intravenous (i.v.) injection once weekly and as on-demand treatment for bleeds for the main and extension phases.

    Serious adverse events
    		 Younger children (0 - 6 years) Older children (7 - 12 years) Adolescents (13 - 17 years) Adults (18 - 70 years)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 12 (16.67%)
    5 / 23 (21.74%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Injury, poisoning and procedural complications
    Radius fracture
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 23 (4.35%)
    0 / 14 (0.00%)
    0 / 6 (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
    Vascular disorders
    Arteriovenous fistula
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 23 (4.35%)
    0 / 14 (0.00%)
    0 / 6 (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
    Congenital, familial and genetic disorders
    Cryptorchism
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 23 (4.35%)
    0 / 14 (0.00%)
    0 / 6 (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
    Tourette's disorder
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 23 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (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
    Nervous system disorders
    Migraine
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 23 (4.35%)
    0 / 14 (0.00%)
    0 / 6 (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
    Food poisoning
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 23 (4.35%)
    0 / 14 (0.00%)
    0 / 6 (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
    Respiratory, thoracic and mediastinal disorders
    Haemoptysis
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 23 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Wheezing
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 23 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (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
    Catheter site infection
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 23 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (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
    Gastroenteritis viral
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 23 (4.35%)
    0 / 14 (0.00%)
    0 / 6 (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
    Otitis media
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 23 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (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
    Viral upper respiratory tract infection
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 23 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (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
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Younger children (0 - 6 years) Older children (7 - 12 years) Adolescents (13 - 17 years) Adults (18 - 70 years)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    11 / 12 (91.67%)
    20 / 23 (86.96%)
    12 / 14 (85.71%)
    4 / 6 (66.67%)
    Vascular disorders
    Hypotension
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 23 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    General disorders and administration site conditions
    Application site irritation
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 23 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Gait disturbance
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 23 (4.35%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Pain
         subjects affected / exposed
    0 / 12 (0.00%)
    2 / 23 (8.70%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    7
    0
    0
    Pyrexia
         subjects affected / exposed
    7 / 12 (58.33%)
    6 / 23 (26.09%)
    2 / 14 (14.29%)
    0 / 6 (0.00%)
         occurrences all number
    18
    14
    2
    0
    Immune system disorders
    Allergy to arthropod bite
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 23 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Seasonal allergy
         subjects affected / exposed
    3 / 12 (25.00%)
    1 / 23 (4.35%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    3
    2
    0
    0
    Reproductive system and breast disorders
    Penile pain
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 23 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Penile discharge
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 23 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Nipple disorder
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 23 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    10 / 12 (83.33%)
    6 / 23 (26.09%)
    1 / 14 (7.14%)
    1 / 6 (16.67%)
         occurrences all number
    23
    8
    1
    1
    Catarrh
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 23 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Asthma
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 23 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Epistaxis
         subjects affected / exposed
    2 / 12 (16.67%)
    1 / 23 (4.35%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    4
    1
    0
    0
    Nasal congestion
         subjects affected / exposed
    2 / 12 (16.67%)
    2 / 23 (8.70%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    6
    2
    0
    0
    Oropharyngeal pain
         subjects affected / exposed
    3 / 12 (25.00%)
    3 / 23 (13.04%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    5
    5
    0
    0
    Rhinorrhoea
         subjects affected / exposed
    2 / 12 (16.67%)
    1 / 23 (4.35%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    11
    1
    1
    0
    Rhinitis allergic
         subjects affected / exposed
    1 / 12 (8.33%)
    1 / 23 (4.35%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    6
    1
    1
    0
    Wheezing
         subjects affected / exposed
    1 / 12 (8.33%)
    1 / 23 (4.35%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Psychiatric disorders
    Attention deficit hyperactivity disorder
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 23 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Sleep terror
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 23 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Product issues
    Device occlusion
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 23 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Investigations
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 23 (0.00%)
    0 / 14 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    1
    Cardiac murmur
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 23 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Varicella virus test positive
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 23 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Injury, poisoning and procedural complications
    Abdominal injury
         subjects affected / exposed
    1 / 12 (8.33%)
    1 / 23 (4.35%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Arthropod bite
         subjects affected / exposed
    2 / 12 (16.67%)
    1 / 23 (4.35%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    2
    1
    0
    0
    Accident
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 23 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Contusion
         subjects affected / exposed
    3 / 12 (25.00%)
    7 / 23 (30.43%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    12
    16
    1
    0
    Clavicle fracture
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 23 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Fall
         subjects affected / exposed
    3 / 12 (25.00%)
    4 / 23 (17.39%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    4
    5
    0
    0
    Ear injury
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 23 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Head injury
         subjects affected / exposed
    2 / 12 (16.67%)
    6 / 23 (26.09%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    9
    9
    1
    0
    Hand fracture
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 23 (4.35%)
    2 / 14 (14.29%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    2
    0
    Immunisation reaction
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 23 (4.35%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    5
    0
    Injury
         subjects affected / exposed
    1 / 12 (8.33%)
    3 / 23 (13.04%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    7
    0
    0
    Joint dislocation
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 23 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    3
    0
    0
    0
    Joint injury
         subjects affected / exposed
    1 / 12 (8.33%)
    3 / 23 (13.04%)
    2 / 14 (14.29%)
    0 / 6 (0.00%)
         occurrences all number
    1
    16
    2
    0
    Ligament sprain
         subjects affected / exposed
    2 / 12 (16.67%)
    5 / 23 (21.74%)
    3 / 14 (21.43%)
    1 / 6 (16.67%)
         occurrences all number
    2
    9
    8
    1
    Limb injury
         subjects affected / exposed
    2 / 12 (16.67%)
    4 / 23 (17.39%)
    2 / 14 (14.29%)
    0 / 6 (0.00%)
         occurrences all number
    2
    11
    3
    0
    Lip injury
         subjects affected / exposed
    2 / 12 (16.67%)
    0 / 23 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    3
    0
    0
    0
    Lumbar vertebral fracture
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 23 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Nasal injury
         subjects affected / exposed
    1 / 12 (8.33%)
    1 / 23 (4.35%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    1
    2
    1
    0
    Muscle strain
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 23 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Post procedural swelling
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 23 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Neck injury
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 23 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Product administration error
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 23 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Procedural pain
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 23 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Post-traumatic pain
         subjects affected / exposed
    2 / 12 (16.67%)
    1 / 23 (4.35%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    3
    7
    0
    0
    Skin laceration
         subjects affected / exposed
    1 / 12 (8.33%)
    2 / 23 (8.70%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    1
    3
    1
    0
    Skin injury
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 23 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Skin abrasion
         subjects affected / exposed
    4 / 12 (33.33%)
    3 / 23 (13.04%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    5
    7
    0
    0
    Road traffic accident
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 23 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Radius fracture
         subjects affected / exposed
    1 / 12 (8.33%)
    1 / 23 (4.35%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    1
    1
    1
    0
    Traumatic haematoma
         subjects affected / exposed
    1 / 12 (8.33%)
    1 / 23 (4.35%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    2
    0
    0
    Thermal burn
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 23 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Traumatic haemorrhage
         subjects affected / exposed
    1 / 12 (8.33%)
    2 / 23 (8.70%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    4
    2
    0
    0
    Wound
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 23 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    0 / 12 (0.00%)
    4 / 23 (17.39%)
    3 / 14 (21.43%)
    1 / 6 (16.67%)
         occurrences all number
    0
    12
    4
    1
    Hypoaesthesia
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 23 (0.00%)
    0 / 14 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    1
    Migraine
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 23 (0.00%)
    0 / 14 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    1
    Ear and labyrinth disorders
    Hypoacusis
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 23 (0.00%)
    0 / 14 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    1
    Eye disorders
    Eye irritation
         subjects affected / exposed
    1 / 12 (8.33%)
    1 / 23 (4.35%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Myopia
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 23 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Visual acuity reduced
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 23 (4.35%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    0 / 12 (0.00%)
    2 / 23 (8.70%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Abdominal pain upper
         subjects affected / exposed
    1 / 12 (8.33%)
    1 / 23 (4.35%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Abdominal pain
         subjects affected / exposed
    1 / 12 (8.33%)
    1 / 23 (4.35%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    3
    1
    0
    0
    Dental caries
         subjects affected / exposed
    0 / 12 (0.00%)
    2 / 23 (8.70%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Enteritis
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 23 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Dyspepsia
         subjects affected / exposed
    0 / 12 (0.00%)
    2 / 23 (8.70%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Diarrhoea
         subjects affected / exposed
    3 / 12 (25.00%)
    2 / 23 (8.70%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    5
    2
    0
    0
    Haematochezia
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 23 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Gastrointestinal disorder
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 23 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Gastritis
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 23 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Lip swelling
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 23 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Nausea
         subjects affected / exposed
    1 / 12 (8.33%)
    1 / 23 (4.35%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Vomiting
         subjects affected / exposed
    3 / 12 (25.00%)
    4 / 23 (17.39%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    8
    7
    0
    0
    Skin and subcutaneous tissue disorders
    Dermatitis allergic
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 23 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Dermatitis contact
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 23 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Erythema
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 23 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Haemorrhage subcutaneous
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 23 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Ingrowing nail
         subjects affected / exposed
    0 / 12 (0.00%)
    2 / 23 (8.70%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Nail disorder
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 23 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Rash
         subjects affected / exposed
    1 / 12 (8.33%)
    2 / 23 (8.70%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    2
    0
    0
    Urticaria
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 23 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    4
    0
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 23 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Renal impairment
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 23 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 12 (0.00%)
    5 / 23 (21.74%)
    3 / 14 (21.43%)
    1 / 6 (16.67%)
         occurrences all number
    0
    16
    4
    1
    Groin pain
         subjects affected / exposed
    0 / 12 (0.00%)
    2 / 23 (8.70%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Growing pains
         subjects affected / exposed
    1 / 12 (8.33%)
    1 / 23 (4.35%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Joint swelling
         subjects affected / exposed
    1 / 12 (8.33%)
    1 / 23 (4.35%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    1
    2
    1
    0
    Myalgia
         subjects affected / exposed
    0 / 12 (0.00%)
    3 / 23 (13.04%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    4
    0
    0
    Pain in extremity
         subjects affected / exposed
    1 / 12 (8.33%)
    6 / 23 (26.09%)
    2 / 14 (14.29%)
    0 / 6 (0.00%)
         occurrences all number
    3
    13
    2
    0
    Neck pain
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 23 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Synovitis
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 23 (4.35%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Infections and infestations
    Conjunctivitis
         subjects affected / exposed
    1 / 12 (8.33%)
    2 / 23 (8.70%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    2
    3
    1
    0
    COVID-19
         subjects affected / exposed
    0 / 12 (0.00%)
    3 / 23 (13.04%)
    2 / 14 (14.29%)
    0 / 6 (0.00%)
         occurrences all number
    0
    4
    2
    0
    Bronchitis
         subjects affected / exposed
    1 / 12 (8.33%)
    2 / 23 (8.70%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    3
    2
    1
    0
    Bronchiolitis
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 23 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Croup infectious
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 23 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Ear infection
         subjects affected / exposed
    3 / 12 (25.00%)
    2 / 23 (8.70%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    4
    2
    0
    0
    Diarrhoea infectious
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 23 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Gastroenteritis viral
         subjects affected / exposed
    2 / 12 (16.67%)
    0 / 23 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Gastroenteritis
         subjects affected / exposed
    1 / 12 (8.33%)
    2 / 23 (8.70%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    2
    2
    0
    0
    Influenza
         subjects affected / exposed
    1 / 12 (8.33%)
    2 / 23 (8.70%)
    3 / 14 (21.43%)
    0 / 6 (0.00%)
         occurrences all number
    1
    5
    5
    0
    Keratouveitis
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 23 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Localised infection
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 23 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 23 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    3
    0
    0
    0
    Nasopharyngitis
         subjects affected / exposed
    5 / 12 (41.67%)
    4 / 23 (17.39%)
    2 / 14 (14.29%)
    0 / 6 (0.00%)
         occurrences all number
    14
    17
    2
    0
    Myringitis
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 23 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Pharyngitis
         subjects affected / exposed
    2 / 12 (16.67%)
    3 / 23 (13.04%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    2
    3
    0
    0
    Pharyngitis streptococcal
         subjects affected / exposed
    3 / 12 (25.00%)
    3 / 23 (13.04%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    6
    6
    0
    0
    Pneumonia
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 23 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    4
    0
    0
    0
    Otitis media acute
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 23 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Otitis media
         subjects affected / exposed
    3 / 12 (25.00%)
    0 / 23 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    5
    0
    0
    0
    Pulpitis dental
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 23 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Rhinitis
         subjects affected / exposed
    1 / 12 (8.33%)
    1 / 23 (4.35%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    2
    1
    0
    0
    Streptococcal infection
         subjects affected / exposed
    1 / 12 (8.33%)
    1 / 23 (4.35%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Tooth abscess
         subjects affected / exposed
    0 / 12 (0.00%)
    2 / 23 (8.70%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Tonsillitis
         subjects affected / exposed
    0 / 12 (0.00%)
    2 / 23 (8.70%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    3
    0
    0
    Viral infection
         subjects affected / exposed
    0 / 12 (0.00%)
    2 / 23 (8.70%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    0
    2
    1
    0
    Varicella zoster virus infection
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 23 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Varicella
         subjects affected / exposed
    1 / 12 (8.33%)
    1 / 23 (4.35%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Upper respiratory tract infection
         subjects affected / exposed
    2 / 12 (16.67%)
    3 / 23 (13.04%)
    1 / 14 (7.14%)
    1 / 6 (16.67%)
         occurrences all number
    6
    4
    4
    2

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    07 Jun 2012
    Protocol was updated based on changes in the description of the visual appearance of the investigational medicinal product and information on stop time of bleeds.
    22 Sep 2013
    Protocol was updated based on change of the planned subject tailored nonacog beta pegol dose in the extension phase to a fixed dose of 40 IU/kg once weekly and some minor changes.
    26 Sep 2014
    Protocol was updated based on the following: major surgery could be performed as part of the trial; all subjects were switched from the current nonacog beta pegol to nonacog beta pegol intended for commercial use; optional blood samples for potential future assessments were drawn to address safety or efficacy, anti-drug antibody assessments and to improve the understanding of the mechanisms of action.
    26 Feb 2015
    Protocol was updated based on: total blood volume drawn at each visit in the extension phase was corrected; bio specimen for storage for genotype was added to flowchart; clarification on the dispensing visits, patient reported outcomes (PRO) questionnaires and other changes; timelines changed.
    23 Jan 2017
    Protocol was updated based on update in the colour of the nonacog beta pegol drug product; elaboration to the allergic reaction testing to align with the already described procedure in the flowchart.
    27 Feb 2018
    Protocol was updated based on: measurement of polyethylene glycol were added at every prospective visit; last subject last visit of the trial was extended to 2023 to allow the subjects to continue up to visit 32 and the youngest child to reach up to 12 years of age; new (and additional) age-appropriate PRO introduced at visit 17 and repeated at end of trial; monitoring visit frequency was prolonged to every 28 weeks and a phone call or other contact between parents and site staff was allowed; definition of incremental recovery was clarified and other minor changes to text.
    29 Sep 2018
    Protocol was updated based on: addition of neurocognitive assessments in the protocol; renal adverse events were categorised as medical events of special interest; PRO were added at the relevant visit where neurocognitive assessments were performed for the first time in each subject and at end of trial visit; chromogenic assay was no longer used by the central laboratory.

    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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