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    Clinical Trial Results:
    A multi-national trial evaluating safety and efficacy, including pharmacokinetics, of NNC 0129-0000-1003 when administered for treatment and prophylaxis of bleeding in patients with haemophilia A

    Summary
    EudraCT number
    		 2011-001142-15
    Trial protocol
    		 NL   DE   SE   NO   DK   ES   GB   HU   IT   BG  
    Global end of trial date
    10 Dec 2018

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

    Trial information

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    Trial identification
    Sponsor protocol code
    NN7088-3859
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01480180
    WHO universal trial number (UTN)
    		 U1111-1119-7416
    Other trial identifiers
    		 Japanese trial registration: JapicCTI-121749
    Sponsors
    Sponsor organisation name
    Novo Nordisk A/S
    Sponsor organisation address
    Novo Allé, Bagsværd, Denmark, 2880
    Public contact
    Clinical Reporting Anchor and Disclosure (1452), Novo Nordisk A/S, clinicaltrials@novonordisk.com
    Scientific contact
    Clinical Reporting Anchor and Disclosure (1452), Novo Nordisk A/S, clinicaltrials@novonordisk.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    10 Dec 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    10 Dec 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    10 Dec 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The two co-primary objectives for this trial were: To evaluate the immunogenicity of NNC 0129-0000-1003 (hereafter referred to as N8-GP) in previously treated subjects with haemophilia A; To evaluate the clinical efficacy of N8-GP in bleeding prophylaxis (number of bleeds during prophylaxis)
    Protection of trial subjects
    The trial was conducted in accordance with the Declaration of Helsinki (Seoul, October 2008) and ICH Good Clinical Practice (Geneva, May 1996) and 21 CFR 312.120.
    Background therapy
    		 Not applicable
    Evidence for comparator
    		 Not applicable
    Actual start date of recruitment
    30 Jan 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
    Australia: 4
    Country: Number of subjects enrolled
    Brazil: 4
    Country: Number of subjects enrolled
    Croatia: 3
    Country: Number of subjects enrolled
    Denmark: 6
    Country: Number of subjects enrolled
    France: 4
    Country: Number of subjects enrolled
    Germany: 13
    Country: Number of subjects enrolled
    Hungary: 10
    Country: Number of subjects enrolled
    Israel: 4
    Country: Number of subjects enrolled
    Italy: 7
    Country: Number of subjects enrolled
    Japan: 15
    Country: Number of subjects enrolled
    Korea, Republic of: 5
    Country: Number of subjects enrolled
    Malaysia: 5
    Country: Number of subjects enrolled
    Netherlands: 7
    Country: Number of subjects enrolled
    Norway: 2
    Country: Number of subjects enrolled
    Russian Federation: 5
    Country: Number of subjects enrolled
    Spain: 2
    Country: Number of subjects enrolled
    Sweden: 1
    Country: Number of subjects enrolled
    Switzerland: 6
    Country: Number of subjects enrolled
    Taiwan: 5
    Country: Number of subjects enrolled
    Turkey: 10
    Country: Number of subjects enrolled
    United Kingdom: 22
    Country: Number of subjects enrolled
    United States: 46
    Worldwide total number of subjects
    186
    EEA total number of subjects
    77
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    25
    Adults (18-64 years)
    158
    From 65 to 84 years
    3
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The trial was conducted at 77 sites in 22 countries as follows: Australia:3; Brazil:1; Croatia:1; Denmark:2; France:3; Germany:5; Hungary:2; Israel:1; Italy:2; Japan:8; Malaysia:2; Netherlands:2; Norway:1; Russian Federation:1; Korea, Republic of:1; Spain:2; Sweden:1; Switzerland:3; Taiwan:2; Turkey:3; United Kingdom:6; United States:25.

    Pre-assignment
    Screening details
    		 The trial had a main phase and an extension phase (part 1 and 2). Subjects completing the NN7088-3776 study were eligible to participate in this study. If the subjects needed a surgery during the present trial, they could switch into the NN7088-3860 surgery trial and on completion/withdrawal from it, they could return to the NN7088-3859 study.

    Period 1
    Period 1 title
    Main Phase (baseline period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded
    Blinding implementation details
    Not applicable

    Arms
    Arm title
    		 Overall Period
    Arm description
    		 There were two arms in this period - Prophylaxis arm and the On-demand arm. Subjects in the prophylaxis arm received N8-GP for approximately 7 to 19 months. Subjects in the on-demand arm received treatment with N8-GP in case of a bleeding episode.
    Arm type
    		 Experimental

    Investigational medicinal product name
    N8-GP rFVIII
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder and solvent for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    There were two arms in the main phase – 1) Prophylaxis - Subjects received one single bolus dose of 50 IU/kg body weight (BW) of N8-GP every 4th day (96 hours interval). During treatment a shortening of the dosing interval for prophylaxis to twice weekly might be undertaken at the investigator’s discretion, if deemed necessary for the individual subject. Extra doses of N8-GP were administered, if the subject experienced a treatment-requiring bleeding episode or in case of minor surgery. 2) On-demand – Subjects received treatment with N8-GP if they experienced a treatment-requiring bleed. All bleeds were to be treated with doses between 20-75 IU/kg BW according to the severity and location of the bleeding episode. In both the arms, N8-GP was administered as a slow bolus i.v. injection over approximately 2 minutes (from start to completion of injection).

    Number of subjects in period 1
    		Overall Period
    Started
    186
    Completed
    165
    Not completed
    21
         Withdrawal criteria
    13
         Non-compliance
    3
         Unclassified
    4
         Lack of efficacy
    1
    Period 2
    Period 2 title
    Extension phase, part-1
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded
    Blinding implementation details
    Not applicable

    Arms
    Arm title
    		 Overall period
    Arm description
    		 There were three arms in the extension phase part-1: 1) N8-GP 50 IU/kg prophylaxis Q4D (once in 4 days) 2) N8-GP 75 IU/kg prophylaxis Q7D (once in 7 days) and 3) N8-GP 20-75 IU/kg on-demand. Subjects who were on N8-GP Q4D prophylaxis treatment in the main phase and had 0-2 bleeding episodes in last 6 months were randomised to receive N8-GP Q4D or Q7D in this period. Subjects with 3 or more bleeding episodes within the last 6 months of the main phase and subjects with low bleeding rates who were unwilling to be randomised continued with N8-GP Q4D. Subjects who received N8-GP on-demand treatment throughout the main phase continued with the on-demand regimen in the extension phase.
    Arm type
    		 Experimental

    Investigational medicinal product name
    N8-GP rFVIII
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder and solvent for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    There were three arms in the extension phase, part-1: 1) N8-GP 50 IU/kg prophylaxis Q4D- single bolus dose; 2) N8-GP 75 IU/kg prophylaxis Q7D – single bolus dose and 3) N8-GP 20-75 IU/kg on-demand. In the first 2 arms, extra doses of N8-GP were given if the subject had a treatment requiring bleeding episode or in case of a minor surgery. Based on bleeding pattern, the investigator could change the dosing frequency from Q7D to Q4D but changing from Q4D to Q7D was not permitted. Subjects on Q7D having 2 or more bleeding episodes or 1 episode requiring hospitalisation were shifted back to Q4D regimen. The trial product in all arms was to be administered as a slow bolus i.v. injection over approximately 2 minutes (from start to completion of injection).

    Number of subjects in period 2 [1]
    		Overall period
    Started
    150
    Completed
    139
    Not completed
    11
         Adverse event, non-fatal
    5
         Withdrawal criteria
    5
         Unclassified
    1
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: Out of the patients that completed the main phase, 15 patients chose not to continue in the extension part of the study.
    Period 3
    Period 3 title
    Extension phase, part-2
    Is this the baseline period?
    		 No
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    Not applicable

    Arms
    Arm title
    		 Overall Period
    Arm description
    		 There were three arms in the extension phase, part-2: 1) N8-GP 50 IU/kg prophylaxis Q4D- single bolus dose; 2) N8-GP 75 IU/kg prophylaxis Q7D – single bolus dose and 3) N8-GP 20-75 IU/kg on-demand. In the first 2 arms, subjects could continue on the same prophylaxis dose as received in extension phase (part-1) but could change between Q4D and Q7D dosing. Subjects received treatment for up to approximately 1.5 years or until N8-GP became commercially available in the subject’s country. In the third arm, subjects who received N8-GP on-demand treatment throughout the main phase continued with the on-demand regimen in the extension phase part-2.
    Arm type
    		 Experimental

    Investigational medicinal product name
    N8-GP rFVIII
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder and solvent for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    There were three arms in the extension phase, part-2: 1) N8-GP 50 IU/kg prophylaxis Q4D- single bolus dose; 2) N8-GP 75 IU/kg prophylaxis Q7D – single bolus dose and 3) N8-GP 20-75 IU/kg on-demand. In the first 2 arms, extra doses of N8-GP were given if the subject had a treatment requiring bleeding episode or in case of a minor surgery. During this period, it was possible to change the prophylaxis treatment of subjects to Q4D or Q7D. Subjects with 0-2 bleeds in last 6 months could move to Q7D. Subjects on Q7D having 2 or more bleeding episodes were shifted back to Q4D regimen. The trial product in all arms was to be administered as a slow bolus i.v. injection over approximately 2 minutes (from start to completion of injection).

    Number of subjects in period 3
    		Overall Period
    Started
    139
    Completed
    113
    Not completed
    26
         Withdrawal criteria
    17
         Unclassified
    5
         Lack of efficacy
    4

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall Period
    Reporting group description
    		 There were two arms in this period - Prophylaxis arm and the On-demand arm. Subjects in the prophylaxis arm received N8-GP for approximately 7 to 19 months. Subjects in the on-demand arm received treatment with N8-GP in case of a bleeding episode.

    Reporting group values
    		 Overall Period Total
    Number of subjects
    		 186 186
    Age Categorical
    Units: Subjects
        Adolescents (12-17 years)
    		 25 25
        Adults (18-64 years)
    		 158 158
        Elderly (65-84 years)
    		 3 3
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 31.1 ± 12.6 -
    Gender Categorical
    Units: Subjects
        Female
    		 0 0
        Male
    		 186 186

    End points

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    End points reporting groups
    Reporting group title
    Overall Period
    Reporting group description
    		 There were two arms in this period - Prophylaxis arm and the On-demand arm. Subjects in the prophylaxis arm received N8-GP for approximately 7 to 19 months. Subjects in the on-demand arm received treatment with N8-GP in case of a bleeding episode.
    Reporting group title
    Overall period
    Reporting group description
    		 There were three arms in the extension phase part-1: 1) N8-GP 50 IU/kg prophylaxis Q4D (once in 4 days) 2) N8-GP 75 IU/kg prophylaxis Q7D (once in 7 days) and 3) N8-GP 20-75 IU/kg on-demand. Subjects who were on N8-GP Q4D prophylaxis treatment in the main phase and had 0-2 bleeding episodes in last 6 months were randomised to receive N8-GP Q4D or Q7D in this period. Subjects with 3 or more bleeding episodes within the last 6 months of the main phase and subjects with low bleeding rates who were unwilling to be randomised continued with N8-GP Q4D. Subjects who received N8-GP on-demand treatment throughout the main phase continued with the on-demand regimen in the extension phase.
    Reporting group title
    Overall Period
    Reporting group description
    		 There were three arms in the extension phase, part-2: 1) N8-GP 50 IU/kg prophylaxis Q4D- single bolus dose; 2) N8-GP 75 IU/kg prophylaxis Q7D – single bolus dose and 3) N8-GP 20-75 IU/kg on-demand. In the first 2 arms, subjects could continue on the same prophylaxis dose as received in extension phase (part-1) but could change between Q4D and Q7D dosing. Subjects received treatment for up to approximately 1.5 years or until N8-GP became commercially available in the subject’s country. In the third arm, subjects who received N8-GP on-demand treatment throughout the main phase continued with the on-demand regimen in the extension phase part-2.

    Subject analysis set title
    N8-GP 50 IU/kg Prophylaxis Q4D
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Subjects in this arm received one single bolus dose of 50 U/kg BW of N8-GP administered intravenously (IV) every 4th day (96 hours) or twice weekly (investigator's discretion). The dose was adjusted to ensure a trough level of >1% FVIII:C activity in this arm.

    Subject analysis set title
    N8-GP 75 IU/kg Prophylaxis Q7D
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Subjects in this arm received one single bolus dose of 75 IU/kg BW of N8-GP administered intravenously (IV) every 7th day. Based on the bleeding pattern, the investigator could change the dosing frequency from Q7D to Q4D, but not vice versa.

    Subject analysis set title
    N8-GP 20-75 IU/kg on-demand
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Subjects in this arm received treatment with N8-GP in case of a bleeding episode. All bleeds were to be treated with doses between 20-75 U/kg BW according to the severity and location of the bleeding episode. The dosage (N8-GP units) was calculated by multiplying the subject’s weight in kilograms by the desired factor level multiplied by 0.5.

    Subject analysis set title
    N8-GP prophylaxis
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Subjects in this arm includes subjects both from the 50 IU/kg Q4D and the 75 IU/kg Q7d prophylaxis arms

    Subject analysis set title
    Prophylaxis
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Subjects in this arm received one single bolus dose of 50 U/kg BW of N8-GP administered intravenously (IV) every 4th day (96 hours) or twice weekly (investigator's discretion). The dose was adjusted to ensure a trough level of >1% FVIII:C activity in this arm.

    Subject analysis set title
    On-demand
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Subjects in this arm received treatment with N8-GP in case of a bleeding episode. All bleeds were to be treated with doses between 20-75 U/kg BW according to the severity and location of the bleeding episode. The dosage (N8-GP units) was calculated by multiplying the subject’s weight in kilograms by the desired factor level multiplied by 0.5.

    Primary: The Incidence rate of FVIII-inhibitors ≥0.6 BU: After approximately 24 months

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    End point title
    		 The Incidence rate of FVIII-inhibitors ≥0.6 BU: After approximately 24 months [1]
    End point description
    All subjects with neutralizing antibodies were included in the numerator and any subject with a minimum 50 exposure days plus any subject with inhibitory inhibitors was included in the denominator. A positive inhibitor test was defined as ≥0.6 bethesda unit (BU). Results are based on the safety analysis set. The safety analysis set consisted of all subjects exposed to N8-GP in this trial. Estimates are based on exact calculations for a binomial distribution. End point 'time frame' should be read as 'After approximately 19 months'. Number of subjects analysed (n) = Number of subjects with available data for respective arm.
    End point type
    Primary
    End point timeframe
    After approximately 24 months
    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: Evaluation of ‘incidence rate of FVIII inhibitors ≥0.6 BU’ was based on descriptive statistics. Hence statistical analysis is not applicable for this endpoint.
    End point values
    		 N8-GP 50 IU/kg Prophylaxis Q4D N8-GP 20-75 IU/kg on-demand
    Number of subjects analysed
    175
    12
    Units: Rate of inhibitory antibodies
        number (not applicable)
    0.006
    0
    No statistical analyses for this end point

    Primary: Annualised bleeding rate in the prophylaxis arm: After approximately 24 months

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    End point title
    		 Annualised bleeding rate in the prophylaxis arm: After approximately 24 months [2]
    End point description
    Annualised bleeding rate (ABR) is the number of bleeding episodes per year reported during the prophylactic treatment with N8-GP. Results were based on the full analysis set (FAS) which included all subjects exposed to N8-GP in this trial. End point 'time frame' should be read as 'After approximately 19 months'. Number of subjects analysed (n) = Number of subjects with available data for respective arm.
    End point type
    Primary
    End point timeframe
    After approximately 24 months
    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: Statistical analysis data for the co-primary endpoint – Annualised bleeding rate is based on one arm only, and can therefore not be provided in the present EudraCT results set-up.
    End point values
    		 Prophylaxis
    Number of subjects analysed
    175
    Units: Bleeds/subject/year
        median (inter-quartile range (Q1-Q3))
    1.33 (0 to 4.61)
    No statistical analyses for this end point

    Primary: The Incidence rate of FVIII-inhibitors ≥0.6 BU: After approximately 36 months

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    End point title
    		 The Incidence rate of FVIII-inhibitors ≥0.6 BU: After approximately 36 months [3]
    End point description
    All subjects with neutralizing antibodies were included in the numerator and any subject with a minimum 50 exposure days plus any subject with inhibitory inhibitors was included in the denominator. A positive inhibitor test was defined as ≥0.6 bethesda unit (BU). Results are based on the safety analysis set. The safety analysis set consisted of all subjects exposed to N8-GP in this trial. Estimates are based on exact calculations for a binomial distribution. End point time frame should be read as 'After approximately 25 months' (including 19 months from the Main phase and 6 months from the Extension phase, part 1). Number of subjects analysed (n) = Number of subjects with available data for respective arm.
    End point type
    Primary
    End point timeframe
    After approximately 36 months
    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: Evaluation of ‘incidence rate of FVIII inhibitors ≥0.6 BU’ was based on descriptive statistics. Hence statistical analysis is not applicable for this endpoint.
    End point values
    		 N8-GP 50 IU/kg Prophylaxis Q4D N8-GP 75 IU/kg Prophylaxis Q7D N8-GP 20-75 IU/kg on-demand
    Number of subjects analysed
    175
    38
    12
    Units: Rate of inhibitory antibodies
        number (not applicable)
    0.006
    0
    0
    No statistical analyses for this end point

    Primary: Annualised bleeding rate in the prophylaxis arm: After approximately 36 months

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    End point title
    		 Annualised bleeding rate in the prophylaxis arm: After approximately 36 months [4]
    End point description
    ABR is the number of bleeding episodes per year reported during the prophylactic treatment with N8-GP. Results were based on the FAS which included all subjects exposed to N8-GP in this trial. End point time frame should be read as 'After approximately 25 months' (including 19 months from the Main phase and 6 months from the Extension phase, part 1). Number of subjects analysed (n) = Number of subjects with available data for respective arm.
    End point type
    Primary
    End point timeframe
    After approximately 36 months
    Notes
    [4] - 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: Statistical analysis data for the co-primary endpoint – Annualised bleeding rate is based on one arm only, and can therefore not be provided in the present EudraCT results set-up.
    End point values
    		 N8-GP 50 IU/kg Prophylaxis Q4D N8-GP 75 IU/kg Prophylaxis Q7D
    Number of subjects analysed
    175
    38
    Units: Bleeds/subject/year
        median (inter-quartile range (Q1-Q3))
    1.36 (0.00 to 4.00)
    0 (0.00 to 2.36)
    No statistical analyses for this end point

    Primary: Incidence rate of FVIII-inhibitors ≥0.6 BU: At the end of treatment (EOT) visit

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    End point title
    		 Incidence rate of FVIII-inhibitors ≥0.6 BU: At the end of treatment (EOT) visit [5]
    End point description
    All subjects with neutralizing antibodies were included in the numerator and any subject with a minimum 50 exposure days plus any subject with inhibitory inhibitors was included in the denominator. A positive inhibitor test was defined as ≥0.6 bethesda unit (BU). Results are based on the safety analysis set. The safety analysis set consisted of all subjects exposed to N8-GP in this trial. Estimates are based on exact calculations for a binomial distribution. Number of subjects analysed (n) = Number of subjects with available data for respective arm.
    End point type
    Primary
    End point timeframe
    At the end of treatment visit
    Notes
    [5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Evaluation of ‘incidence rate of FVIII inhibitors ≥0.6 BU’ was based on descriptive statistics. Hence statistical analysis is not applicable for this endpoint.
    End point values
    		 N8-GP 20-75 IU/kg on-demand N8-GP prophylaxis
    Number of subjects analysed
    12
    177
    Units: Rate of inhibitory antibodies
        number (not applicable)
    0
    0.006
    No statistical analyses for this end point

    Primary: Annualised bleeding rate in the prophylaxis arm: At the end of treatment (EOT) visit

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    End point title
    		 Annualised bleeding rate in the prophylaxis arm: At the end of treatment (EOT) visit [6]
    End point description
    Annualised bleeding rate (ABR) is the number of bleeding episodes per year reported during the prophylactic treatment with N8-GP. Results were based on the FAS which included all subjects exposed to N8-GP in this trial. Number of subjects analysed (n) = Number of subjects with available data for respective arm.
    End point type
    Primary
    End point timeframe
    At the end of treatment period
    Notes
    [6] - 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: Statistical analysis data for the co-primary endpoint – Annualised bleeding rate is based on one arm only, and can therefore not be provided in the present EudraCT results set-up.
    End point values
    		 N8-GP 50 IU/kg Prophylaxis Q4D N8-GP 75 IU/kg Prophylaxis Q7D
    Number of subjects analysed
    177
    61
    Units: Bleeds/subject/year
        median (inter-quartile range (Q1-Q3))
    0.99 (0.00 to 2.68)
    1.95 (0.43 to 6.52)
    No statistical analyses for this end point

    Secondary: Haemostatic effect of N8-GP when used for treatment of bleeds, assessed on a four-point scale for haemostatic response (excellent, good, moderate and none) - After approximately 24 months

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    End point title
    		 Haemostatic effect of N8-GP when used for treatment of bleeds, assessed on a four-point scale for haemostatic response (excellent, good, moderate and none) - After approximately 24 months
    End point description
    Haemostatic effect of N8-GP for treatment of bleeding episodes was assessed by 4-point response scale: none, moderate, good or excellent. Evaluation during trial was done by subject and/or parent(s)/caregiver within approximately 8 hours after a single injection as follows: Excellent: Abrupt pain relief and/or clear improvement in objective signs of bleeding within approximately 8 hrs after a single injection; Good: Definite pain relief and/or improvement in signs of bleeding within approximately 8 hrs after a single injection, but possibly requiring more than one injection for complete resolution; Moderate: Probable or slight beneficial effect within approximately 8 hours after the first injection, but usually requiring more than one injection; None: No improvement, or worsening of symptoms. Results were based on the FAS. 'Number of subjects analysed' should be read as 'Number of bleeds analysed'.
    End point type
    Secondary
    End point timeframe
    After approximately 24 months
    End point values
    		 N8-GP 50 IU/kg Prophylaxis Q4D N8-GP 20-75 IU/kg on-demand
    Number of subjects analysed
    436 [7]
    532 [8]
    Units: Bleeding episodes
        Excellent
    192
    320
        Good
    174
    170
        Moderate
    62
    41
        None
    4
    1
        Missing
    4
    0
    Notes
    [7] - Out of 175 exposed subjects, 105 had 436 bleeds.
    [8] - All 12 exposed subjects had a total of 532 bleeds.
    No statistical analyses for this end point

    Secondary: Haemostatic effect of N8-GP when used for treatment of bleeds, assessed on a four-point scale for haemostatic response (excellent, good, moderate and none) - After approximately 36 months

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    End point title
    		 Haemostatic effect of N8-GP when used for treatment of bleeds, assessed on a four-point scale for haemostatic response (excellent, good, moderate and none) - After approximately 36 months
    End point description
    Haemostatic effect of N8-GP for treatment of bleeding episodes was assessed by 4-point response scale: none, moderate, good or excellent. Evaluation during trial was done by subject and/or parent(s)/caregiver within approximately 8 hours after a single injection as follows: Excellent: Abrupt pain relief and/or clear improvement in objective signs of bleeding within approximately 8 hrs after a single injection; Good: Definite pain relief and/or improvement in signs of bleeding within approximately 8 hrs after a single injection, but possibly requiring more than one injection for complete resolution; Moderate: Probable or slight beneficial effect within approximately 8 hours after the first injection, but usually requiring more than one injection; None: No improvement, or worsening of symptoms. Results were based on the FAS. 'Number of subjects analysed' should be read as 'Number of bleeds analysed'.
    End point type
    Secondary
    End point timeframe
    After approximately 36 months
    End point values
    		 N8-GP 50 IU/kg Prophylaxis Q4D N8-GP 75 IU/kg Prophylaxis Q7D N8-GP 20-75 IU/kg on-demand
    Number of subjects analysed
    716 [9]
    25 [10]
    695 [11]
    Units: Bleeding episodes
        Excellent
    330
    9
    406
        Good
    270
    11
    233
        Moderate
    98
    3
    55
        None
    4
    0
    1
        Missing
    14
    2
    0
    Notes
    [9] - Out of 175 exposed subjects, 116 subjects had 716 bleeds
    [10] - Out of 38 exposed subjects16 subjects had 25 bleeds
    [11] - Out of 12 exposed subjects 12 subjects had 695 bleeds
    No statistical analyses for this end point

    Secondary: Haemostatic effect of N8-GP when used for treatment of bleeds, assessed on a four-point scale for haemostatic response (excellent, good, moderate and none) - At end of treatment (EOT) visit

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    End point title
    		 Haemostatic effect of N8-GP when used for treatment of bleeds, assessed on a four-point scale for haemostatic response (excellent, good, moderate and none) - At end of treatment (EOT) visit
    End point description
    Haemostatic effect of N8-GP for treatment of bleeding episodes was assessed by 4-point response scale: none, moderate, good or excellent. Evaluation during trial was done by subject and/or parent(s)/caregiver within approximately 8 hours after a single injection as follows: Excellent: Abrupt pain relief and/or clear improvement in objective signs of bleeding within approximately 8 hrs after a single injection; Good: Definite pain relief and/or improvement in signs of bleeding within approximately 8 hrs after a single injection, but possibly requiring more than one injection for complete resolution; Moderate: Probable or slight beneficial effect within approximately 8 hours after the first injection, but usually requiring more than one injection; None: No improvement, or worsening of symptoms. Results were based on the FAS. 'Number of subjects analysed' should be read as 'Number of bleeds analysed'.
    End point type
    Secondary
    End point timeframe
    At the end of treatment visit
    End point values
    		 N8-GP 50 IU/kg Prophylaxis Q4D N8-GP 75 IU/kg Prophylaxis Q7D N8-GP 20-75 IU/kg on-demand
    Number of subjects analysed
    1312 [12]
    176 [13]
    1270 [14]
    Units: Bleeding episodes
        Excellent
    600
    75
    859
        Good
    532
    65
    339
        Moderate
    153
    29
    71
        None
    6
    2
    1
        Missing
    21
    5
    0
    Notes
    [12] - Out of 177 exposed subjects 126 subjects had 1312 bleeds
    [13] - Out of 61 exposed subjects, 53 subjects had 176 bleeds
    [14] - Out of 12 exposed subjects, all 12 subjects had a toal of 1270 bleeds
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From first exposure to N8-GP (week 0) to follow up visit after end of treatment in extension phase part 2. (Main phase:19 months; Extension phase:approximately 2 years or until N8-GP becomes commercially available in the subject's country).
    Adverse event reporting additional description
    The results are based on the safety analysis set. 'Number of deaths causally related to treatment’ is the data considered to present under ‘total number of deaths resulting from adverse events (AE)’. All the presented AEs were treatment-emergent. A treatment-emergent AE was defined as an event with onset after first N8-GP administration.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21
    Reporting groups
    Reporting group title
    N8-GP 50 IU/kg Q4D prophylaxis
    Reporting group description
    		 The trial consisted of a Main phase and extension phase (part 1 and part 2). In the main phase, subjects received N8-GP 50 IU/kg Q4D as prophylaxis treatment for a period of 19 months. In the extension phase, subjects received N8-GP 50 IU/kg Q4D as prophylaxis treatment for an overall period of up to two years or until N8-GP becomes commercially available in the subject's country.

    Reporting group title
    N8-GP 20-75 U/kg on-demand
    Reporting group description
    		 The trial consisted of a Main phase and extension phase (part 1 and part 2). In the main phsae, subjects received N8-GP 20-75 IU/kg on-demand treatment for a period of 19 months. In the extension phase, subjects received N8-GP 20-75 IU/kg on-demand treatment for an overall period of two years or until N8-GP becomes commercially available in the subject's country.

    Reporting group title
    N8-GP 75 IU/kg Q7D prophylaxis
    Reporting group description
    		 The trial consisted of a Main phase and extension phase (part 1 and part 2). In the main phase, subjects received N8-GP 75 IU/kg Q7D as prophylaxis treatment for a period of 19 months. In the extension phase, subjects received N8-GP 50 IU/kg Q7D as prophylaxis treatment for an overall period of up to two years or until N8-GP becomes commercially available in the subject's country.

    Serious adverse events
    		 N8-GP 50 IU/kg Q4D prophylaxis N8-GP 20-75 U/kg on-demand N8-GP 75 IU/kg Q7D prophylaxis
    Total subjects affected by serious adverse events
         subjects affected / exposed
    24 / 177 (13.56%)
    3 / 12 (25.00%)
    7 / 61 (11.48%)
         number of deaths (all causes)
    1
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Hepatocellular carcinoma
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 12 (0.00%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neuroma
         subjects affected / exposed
    0 / 177 (0.00%)
    0 / 12 (0.00%)
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancreatic carcinoma metastatic
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 12 (0.00%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Vascular disorders
    Circulatory collapse
         subjects affected / exposed
    0 / 177 (0.00%)
    0 / 12 (0.00%)
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Complication associated with device
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 12 (0.00%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Depression
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 12 (0.00%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Product issues
    Device dislocation
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 12 (0.00%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Ankle fracture
         subjects affected / exposed
    0 / 177 (0.00%)
    0 / 12 (0.00%)
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chest injury
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 12 (8.33%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Clavicle fracture
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 12 (8.33%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Extradural haematoma
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 12 (8.33%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Face injury
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 12 (0.00%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 12 (8.33%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 12 (0.00%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Forearm fracture
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 12 (0.00%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 12 (0.00%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pelvic fracture
         subjects affected / exposed
    0 / 177 (0.00%)
    0 / 12 (0.00%)
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rib fracture
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 12 (8.33%)
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Road traffic accident
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 12 (0.00%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sternal fracture
         subjects affected / exposed
    0 / 177 (0.00%)
    0 / 12 (0.00%)
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Subdural haematoma
         subjects affected / exposed
    0 / 177 (0.00%)
    0 / 12 (0.00%)
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Toxicity to various agents
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 12 (0.00%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Hydrocele
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 12 (0.00%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypertrophic cardiomyopathy
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 12 (0.00%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Aortic valve stenosis
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 12 (0.00%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebral infarction
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 12 (0.00%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cerebral microhaemorrhage
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 12 (0.00%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 12 (0.00%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 12 (0.00%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Factor VIII inhibition
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 12 (0.00%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Cataract
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 12 (8.33%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 12 (0.00%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Duodenal ulcer
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 12 (0.00%)
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastric varices
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 12 (0.00%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastric varices haemorrhage
         subjects affected / exposed
    0 / 177 (0.00%)
    0 / 12 (0.00%)
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Mesenteric haemorrhage
         subjects affected / exposed
    0 / 177 (0.00%)
    0 / 12 (0.00%)
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    0 / 177 (0.00%)
    0 / 12 (0.00%)
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 12 (0.00%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 12 (0.00%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Calculus urinary
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 12 (8.33%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    IgA nephropathy
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 12 (0.00%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tubulointerstitial nephritis
         subjects affected / exposed
    0 / 177 (0.00%)
    0 / 12 (0.00%)
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ureterolithiasis
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 12 (8.33%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Pathological fracture
         subjects affected / exposed
    0 / 177 (0.00%)
    0 / 12 (0.00%)
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Synovitis
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 12 (0.00%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Anal abscess
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 12 (0.00%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bacterial sepsis
         subjects affected / exposed
    0 / 177 (0.00%)
    0 / 12 (0.00%)
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Catheter site infection
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 12 (0.00%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 12 (0.00%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 12 (0.00%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 12 (0.00%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Enteritis infectious
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 12 (0.00%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infective spondylitis
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 12 (0.00%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intervertebral discitis
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 12 (0.00%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Localised infection
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 12 (0.00%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Osteomyelitis
         subjects affected / exposed
    0 / 177 (0.00%)
    0 / 12 (0.00%)
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 12 (0.00%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin graft infection
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 12 (0.00%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Viral infection
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 12 (0.00%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 N8-GP 50 IU/kg Q4D prophylaxis N8-GP 20-75 U/kg on-demand N8-GP 75 IU/kg Q7D prophylaxis
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    144 / 177 (81.36%)
    10 / 12 (83.33%)
    50 / 61 (81.97%)
    Vascular disorders
    Essential hypertension
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 12 (8.33%)
    0 / 61 (0.00%)
         occurrences all number
    0
    1
    0
    Hypertension
         subjects affected / exposed
    17 / 177 (9.60%)
    0 / 12 (0.00%)
    4 / 61 (6.56%)
         occurrences all number
    18
    0
    5
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    2 / 177 (1.13%)
    1 / 12 (8.33%)
    2 / 61 (3.28%)
         occurrences all number
    2
    1
    2
    Fatigue
         subjects affected / exposed
    4 / 177 (2.26%)
    1 / 12 (8.33%)
    1 / 61 (1.64%)
         occurrences all number
    4
    1
    2
    Pyrexia
         subjects affected / exposed
    9 / 177 (5.08%)
    2 / 12 (16.67%)
    5 / 61 (8.20%)
         occurrences all number
    10
    2
    7
    Immune system disorders
    Seasonal allergy
         subjects affected / exposed
    11 / 177 (6.21%)
    0 / 12 (0.00%)
    2 / 61 (3.28%)
         occurrences all number
    14
    0
    3
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    16 / 177 (9.04%)
    1 / 12 (8.33%)
    4 / 61 (6.56%)
         occurrences all number
    20
    2
    5
    Haemothorax
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 12 (8.33%)
    0 / 61 (0.00%)
         occurrences all number
    0
    1
    0
    Nasal obstruction
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 12 (8.33%)
    0 / 61 (0.00%)
         occurrences all number
    0
    1
    0
    Oropharyngeal pain
         subjects affected / exposed
    16 / 177 (9.04%)
    1 / 12 (8.33%)
    4 / 61 (6.56%)
         occurrences all number
    20
    1
    5
    Pneumothorax
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 12 (8.33%)
    0 / 61 (0.00%)
         occurrences all number
    0
    1
    0
    Rhinorrhoea
         subjects affected / exposed
    9 / 177 (5.08%)
    0 / 12 (0.00%)
    1 / 61 (1.64%)
         occurrences all number
    12
    0
    1
    Psychiatric disorders
    Depressed mood
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 12 (8.33%)
    1 / 61 (1.64%)
         occurrences all number
    0
    1
    1
    Depression
         subjects affected / exposed
    9 / 177 (5.08%)
    0 / 12 (0.00%)
    1 / 61 (1.64%)
         occurrences all number
    9
    0
    1
    Mental status changes
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 12 (8.33%)
    0 / 61 (0.00%)
         occurrences all number
    0
    1
    0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    12 / 177 (6.78%)
    3 / 12 (25.00%)
    3 / 61 (4.92%)
         occurrences all number
    17
    6
    3
    Aspartate aminotransferase increased
         subjects affected / exposed
    10 / 177 (5.65%)
    3 / 12 (25.00%)
    3 / 61 (4.92%)
         occurrences all number
    11
    5
    5
    Blood bilirubin increased
         subjects affected / exposed
    1 / 177 (0.56%)
    2 / 12 (16.67%)
    0 / 61 (0.00%)
         occurrences all number
    1
    2
    0
    Blood pressure increased
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 12 (8.33%)
    0 / 61 (0.00%)
         occurrences all number
    0
    1
    0
    C-reactive protein increased
         subjects affected / exposed
    5 / 177 (2.82%)
    0 / 12 (0.00%)
    4 / 61 (6.56%)
         occurrences all number
    7
    0
    4
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    6 / 177 (3.39%)
    3 / 12 (25.00%)
    1 / 61 (1.64%)
         occurrences all number
    10
    5
    1
    Liver function test abnormal
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 12 (8.33%)
    0 / 61 (0.00%)
         occurrences all number
    0
    1
    0
    Sputum abnormal
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 12 (8.33%)
    0 / 61 (0.00%)
         occurrences all number
    0
    1
    0
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    11 / 177 (6.21%)
    2 / 12 (16.67%)
    3 / 61 (4.92%)
         occurrences all number
    15
    10
    3
    Fall
         subjects affected / exposed
    10 / 177 (5.65%)
    0 / 12 (0.00%)
    2 / 61 (3.28%)
         occurrences all number
    10
    0
    2
    Foot fracture
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 12 (8.33%)
    0 / 61 (0.00%)
         occurrences all number
    0
    1
    0
    Joint injury
         subjects affected / exposed
    5 / 177 (2.82%)
    1 / 12 (8.33%)
    0 / 61 (0.00%)
         occurrences all number
    5
    1
    0
    Limb injury
         subjects affected / exposed
    6 / 177 (3.39%)
    0 / 12 (0.00%)
    5 / 61 (8.20%)
         occurrences all number
    7
    0
    6
    Scratch
         subjects affected / exposed
    1 / 177 (0.56%)
    1 / 12 (8.33%)
    1 / 61 (1.64%)
         occurrences all number
    1
    1
    1
    Skin laceration
         subjects affected / exposed
    10 / 177 (5.65%)
    0 / 12 (0.00%)
    5 / 61 (8.20%)
         occurrences all number
    12
    0
    5
    Spinal fracture
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 12 (8.33%)
    0 / 61 (0.00%)
         occurrences all number
    0
    1
    0
    Cardiac disorders
    Atrioventricular block first degree
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 12 (8.33%)
    0 / 61 (0.00%)
         occurrences all number
    0
    1
    0
    Nervous system disorders
    Carpal tunnel syndrome
         subjects affected / exposed
    1 / 177 (0.56%)
    1 / 12 (8.33%)
    0 / 61 (0.00%)
         occurrences all number
    1
    1
    0
    Dizziness
         subjects affected / exposed
    6 / 177 (3.39%)
    1 / 12 (8.33%)
    0 / 61 (0.00%)
         occurrences all number
    7
    1
    0
    Headache
         subjects affected / exposed
    35 / 177 (19.77%)
    3 / 12 (25.00%)
    13 / 61 (21.31%)
         occurrences all number
    79
    4
    25
    Seizure
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 12 (8.33%)
    0 / 61 (0.00%)
         occurrences all number
    0
    1
    0
    Blood and lymphatic system disorders
    Lymphadenopathy
         subjects affected / exposed
    2 / 177 (1.13%)
    1 / 12 (8.33%)
    0 / 61 (0.00%)
         occurrences all number
    2
    1
    0
    Ear and labyrinth disorders
    Ear discomfort
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 12 (8.33%)
    0 / 61 (0.00%)
         occurrences all number
    0
    1
    0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    4 / 177 (2.26%)
    1 / 12 (8.33%)
    1 / 61 (1.64%)
         occurrences all number
    5
    1
    1
    Abdominal pain upper
         subjects affected / exposed
    9 / 177 (5.08%)
    0 / 12 (0.00%)
    3 / 61 (4.92%)
         occurrences all number
    12
    0
    3
    Dental caries
         subjects affected / exposed
    6 / 177 (3.39%)
    1 / 12 (8.33%)
    2 / 61 (3.28%)
         occurrences all number
    11
    1
    2
    Diarrhoea
         subjects affected / exposed
    17 / 177 (9.60%)
    2 / 12 (16.67%)
    5 / 61 (8.20%)
         occurrences all number
    22
    2
    6
    Dyspepsia
         subjects affected / exposed
    4 / 177 (2.26%)
    1 / 12 (8.33%)
    1 / 61 (1.64%)
         occurrences all number
    4
    1
    1
    Flatulence
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 12 (8.33%)
    0 / 61 (0.00%)
         occurrences all number
    0
    2
    0
    Haemorrhoids
         subjects affected / exposed
    1 / 177 (0.56%)
    1 / 12 (8.33%)
    0 / 61 (0.00%)
         occurrences all number
    1
    1
    0
    Irritable bowel syndrome
         subjects affected / exposed
    1 / 177 (0.56%)
    1 / 12 (8.33%)
    0 / 61 (0.00%)
         occurrences all number
    1
    2
    0
    Nausea
         subjects affected / exposed
    14 / 177 (7.91%)
    1 / 12 (8.33%)
    3 / 61 (4.92%)
         occurrences all number
    20
    1
    3
    Toothache
         subjects affected / exposed
    10 / 177 (5.65%)
    1 / 12 (8.33%)
    3 / 61 (4.92%)
         occurrences all number
    11
    1
    5
    Vomiting
         subjects affected / exposed
    9 / 177 (5.08%)
    1 / 12 (8.33%)
    4 / 61 (6.56%)
         occurrences all number
    11
    1
    4
    Hepatobiliary disorders
    Hepatic function abnormal
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 12 (8.33%)
    0 / 61 (0.00%)
         occurrences all number
    0
    1
    0
    Skin and subcutaneous tissue disorders
    Acne
         subjects affected / exposed
    3 / 177 (1.69%)
    0 / 12 (0.00%)
    4 / 61 (6.56%)
         occurrences all number
    4
    0
    4
    Blister
         subjects affected / exposed
    1 / 177 (0.56%)
    1 / 12 (8.33%)
    1 / 61 (1.64%)
         occurrences all number
    3
    1
    1
    Dry skin
         subjects affected / exposed
    2 / 177 (1.13%)
    1 / 12 (8.33%)
    0 / 61 (0.00%)
         occurrences all number
    2
    1
    0
    Eczema
         subjects affected / exposed
    5 / 177 (2.82%)
    1 / 12 (8.33%)
    2 / 61 (3.28%)
         occurrences all number
    8
    2
    2
    Eczema asteatotic
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 12 (8.33%)
    0 / 61 (0.00%)
         occurrences all number
    0
    1
    0
    Pruritus
         subjects affected / exposed
    2 / 177 (1.13%)
    1 / 12 (8.33%)
    0 / 61 (0.00%)
         occurrences all number
    2
    1
    0
    Rash
         subjects affected / exposed
    9 / 177 (5.08%)
    0 / 12 (0.00%)
    2 / 61 (3.28%)
         occurrences all number
    10
    0
    2
    Urticaria
         subjects affected / exposed
    2 / 177 (1.13%)
    1 / 12 (8.33%)
    2 / 61 (3.28%)
         occurrences all number
    2
    1
    2
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 12 (8.33%)
    1 / 61 (1.64%)
         occurrences all number
    0
    1
    1
    Urinary incontinence
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 12 (8.33%)
    0 / 61 (0.00%)
         occurrences all number
    0
    1
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    27 / 177 (15.25%)
    3 / 12 (25.00%)
    15 / 61 (24.59%)
         occurrences all number
    43
    4
    21
    Back pain
         subjects affected / exposed
    8 / 177 (4.52%)
    3 / 12 (25.00%)
    6 / 61 (9.84%)
         occurrences all number
    11
    3
    6
    Musculoskeletal chest pain
         subjects affected / exposed
    3 / 177 (1.69%)
    1 / 12 (8.33%)
    0 / 61 (0.00%)
         occurrences all number
    3
    1
    0
    Musculoskeletal pain
         subjects affected / exposed
    14 / 177 (7.91%)
    1 / 12 (8.33%)
    4 / 61 (6.56%)
         occurrences all number
    14
    1
    4
    Osteoarthritis
         subjects affected / exposed
    3 / 177 (1.69%)
    1 / 12 (8.33%)
    0 / 61 (0.00%)
         occurrences all number
    3
    1
    0
    Pain in extremity
         subjects affected / exposed
    12 / 177 (6.78%)
    0 / 12 (0.00%)
    1 / 61 (1.64%)
         occurrences all number
    14
    0
    1
    Rheumatic disorder
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 12 (8.33%)
    0 / 61 (0.00%)
         occurrences all number
    0
    2
    0
    Synovitis
         subjects affected / exposed
    3 / 177 (1.69%)
    0 / 12 (0.00%)
    5 / 61 (8.20%)
         occurrences all number
    5
    0
    5
    Tendonitis
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 12 (8.33%)
    6 / 61 (9.84%)
         occurrences all number
    0
    1
    6
    Tenosynovitis
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 12 (8.33%)
    0 / 61 (0.00%)
         occurrences all number
    0
    3
    0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    9 / 177 (5.08%)
    1 / 12 (8.33%)
    1 / 61 (1.64%)
         occurrences all number
    9
    1
    1
    Citrobacter infection
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 12 (8.33%)
    0 / 61 (0.00%)
         occurrences all number
    0
    1
    0
    Conjunctivitis
         subjects affected / exposed
    5 / 177 (2.82%)
    1 / 12 (8.33%)
    0 / 61 (0.00%)
         occurrences all number
    5
    1
    0
    Folliculitis
         subjects affected / exposed
    2 / 177 (1.13%)
    1 / 12 (8.33%)
    0 / 61 (0.00%)
         occurrences all number
    2
    2
    0
    Gastroenteritis
         subjects affected / exposed
    6 / 177 (3.39%)
    1 / 12 (8.33%)
    1 / 61 (1.64%)
         occurrences all number
    9
    1
    1
    Influenza
         subjects affected / exposed
    16 / 177 (9.04%)
    2 / 12 (16.67%)
    6 / 61 (9.84%)
         occurrences all number
    22
    2
    7
    Nasopharyngitis
         subjects affected / exposed
    48 / 177 (27.12%)
    5 / 12 (41.67%)
    12 / 61 (19.67%)
         occurrences all number
    78
    12
    16
    Periodontitis
         subjects affected / exposed
    1 / 177 (0.56%)
    2 / 12 (16.67%)
    1 / 61 (1.64%)
         occurrences all number
    1
    2
    1
    Tinea infection
         subjects affected / exposed
    1 / 177 (0.56%)
    1 / 12 (8.33%)
    1 / 61 (1.64%)
         occurrences all number
    1
    1
    1
    Tonsillitis
         subjects affected / exposed
    10 / 177 (5.65%)
    1 / 12 (8.33%)
    4 / 61 (6.56%)
         occurrences all number
    11
    2
    5
    Upper respiratory tract infection
         subjects affected / exposed
    37 / 177 (20.90%)
    0 / 12 (0.00%)
    9 / 61 (14.75%)
         occurrences all number
    59
    0
    14
    Metabolism and nutrition disorders
    Gout
         subjects affected / exposed
    1 / 177 (0.56%)
    1 / 12 (8.33%)
    1 / 61 (1.64%)
         occurrences all number
    1
    2
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    22 Dec 2011
    This global substantial amendment was issued primarily as a response to a voluntary harmonised procedure (VHP) assessment, which involve the clinical trial application (CTA) submission of the NN7088-3859 and NN7088- 3860 protocol in 8 European countries: VHP recommend a more detailed guidance on the treatment of bleeds. Therefore section 5.3.2 had been updated accordingly. VHP recommended a more clear guidance for the required observation period for adverse reactions in connection to administration of the two first doses of N8-GP. This had been added in the relevant sections. Anti-coagulants and heparin had been added in section 6.5 as prohibited medication to the protocols withdrawal criteria to make this more consistent.
    13 Apr 2012
    This global substantial protocol amendment was issued primarily as a response to a Special Protocol Assessment request sent to the US FDA in connection with submission of the NN7088-3859 protocol in the United States: 1) Annualised bleeding rate in prophylaxis arm. The calculation of annualised bleeding rate for withdrawals has been changed. Imputation will also be performed for withdrawals within the first month. An annualised bleeding rate of 24 will be used for imputation for all subjects withdrawing in the first month, including those with zero bleeds. 2) Sample size calculations have been changed. For the inhibitor test a true inhibitor rate of 0.5% instead of 1% is now assumed. This is based on the experience with clinical trials with turoctocog alfa. For the prophylaxis test, the impact on the power of the change in imputation rule for early withdrawals without bleeding episodes is accounted for. 3) An interim analysis has been added in order to evaluate the over-dispersion (only) once approximately 90 subjects have entered into the prophylaxis arm. If the estimated overdispersion is greater than 6 then the planned sample size will be adjusted up to include 160 prophylaxis subjects instead of 120 subjects. The planned sample size will not be increased without issuing a further amendment.
    21 Dec 2012
    This global substantial protocol amendment was issued in order to allow for an increase in sample size following the described interim analysis, should it be determined to be necessary.
    05 Apr 2013
    This global substantial amendment was issued in order to extend the maximum treatment period with 3 months, from 24 to 27 months, due to an extension of the recruitment period. Therefore additional visits 12a to visit 12j have been added. Subjects for the surgery trial, NN7088-3860, are recruited via this trial where they must have had at least 5 EDs before entering the surgery trial. This amendment will allow the continued recruitment of major surgery subjects after the recruitment of this trial has been completed. This is in order to ensure recruitment into the surgery trial and fulfilment of regulatory requirements regarding collection of major surgery data. The extension trial will not await these subjects to complete 50 EDs before it is initiated.
    04 Jul 2013
    This global amendment was issued to include the following: In version 6.0 of the NN7088-3859 protocol subjects could be transferred to the extension trial NN7088-3861 where they could continue treatment with N8-GP until it was commercially available. Instead of setting up a separate trial, the extension trial will be included in the current trial as an extension phase.
    17 Sep 2013
    This global amendment was issued primarily as a response to a VHP assessment, which involved a central EU CTA submission of the NN7088-3859 protocol version 7.0 in 8 European countries. Main changes were a description of rules for when a subject should be switched from Q7D to Q4D treatment regimen and deletion of every 5 and 6 day dosing regimens from the protocol.
    17 Sep 2013
    The VHP requested that subjects in the Q7D treatment arm receive the same visit schedule as subjects in the Q4D treatment arm of the main study phase i.e. monthly visits at the start of treatment, followed by visits every second month. In addition, it was agreed with the VHP to also implement this visit schedule for subjects randomised to Q4D in the extension phase part 1. This is to avoid any bias in the randomised arms. Part 1 of the extension is 6 months in duration, therefore monthly visits for the first 4 months have been introduced, followed by a visit 2 months later. The VHP stipulated that this visit schedule should apply for every switch to Q7D independent of the part of the extension phase. Therefore, this requirement has also been implemented for Q7D subjects in part 2 of the extension. In part 2, those switching to Q7D, will have visits every month for the first 4 months and subsequently every two months while on Q7D.
    23 Jan 2014
    The withdrawal criteria section 6.5 of the protocol was amended to allow subjects with a low titre inhibitor [≤5 Bethesda units (BU)], that does not result in clinically ineffective treatment with N8-GP, to continue in the trial. Text regarding adverse events was updated.
    19 Nov 2015
    This global amendment was issued to allow subjects to transfer to a separate pharmacokinetics (PK) trial NN7088-4033 and back again; to monitor antibody development against host cell protein; addition of interim analyses before submission; prolonged storage of leftover blood samples to enable further characterisation as new biomarkers related to the disease or related diseases and/or safety, efficacy or mechanism of action may evolve.
    21 Jun 2016
    The purpose of this amendment was to clarify when the subjects could complete the trial (to continue in another N8-GP trial, NN7088-4410).

    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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