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    Clinical Trial Results:
    Safety and Efficacy of turoctocog alfa pegol (N8-GP) in Prophylaxis and Treatment of Bleeds in Previously N8-GP Treated Patients with Severe Haemophilia A

    Summary
    EudraCT number
    		 2017-003788-36
    Trial protocol
    		 LT   GB   PT   GR   NO   DK   HU   FR   NL   DE   ES   HR   IT  
    Global end of trial date
    03 Dec 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    20 Jun 2021
    First version publication date
    20 Jun 2021
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    NN7088-4410
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03528551
    WHO universal trial number (UTN)
    		 U1111-1202-2780
    Other trial identifiers
    		 Japanese trial registration number: JapicCTI-183952
    Sponsors
    Sponsor organisation name
    Novo Nordisk A/S
    Sponsor organisation address
    Novo Allé, Bagsvaerd, Denmark, 2880
    Public contact
    Clinical Transparency Anchor and Disclosure (1452), Novo Nordisk A/S, clinicaltrials@novonordisk.com
    Scientific contact
    Clinical Transparency Anchor and Disclosure (1452), 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-001174-PIP02-12
    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
    30 Mar 2021
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    03 Dec 2020
    Global end of trial reached?
    Yes
    Global end of trial date
    03 Dec 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To investigate the safety of turoctocog alfa pegol during continuous use for prevention and treatment of bleeding episodes of previously turoctocog alfa pegol treated severe haemophilia A patients.
    Protection of trial subjects
    The trial was conducted in accordance with the Declaration of Helsinki (64th World Medical Association (WMA) 2013) and International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) Good Clinical Practice, including archiving of essential documents, (2016) and 21 CFR 312.120.
    Background therapy
    		 Not Applicable
    Evidence for comparator
    		 Not applicable
    Actual start date of recruitment
    30 Apr 2018
    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: 2
    Country: Number of subjects enrolled
    Brazil: 2
    Country: Number of subjects enrolled
    Canada: 2
    Country: Number of subjects enrolled
    Switzerland: 8
    Country: Number of subjects enrolled
    Germany: 4
    Country: Number of subjects enrolled
    Denmark: 5
    Country: Number of subjects enrolled
    Spain: 2
    Country: Number of subjects enrolled
    France: 7
    Country: Number of subjects enrolled
    United Kingdom: 16
    Country: Number of subjects enrolled
    Greece: 1
    Country: Number of subjects enrolled
    Croatia: 3
    Country: Number of subjects enrolled
    Hungary: 9
    Country: Number of subjects enrolled
    Israel: 6
    Country: Number of subjects enrolled
    Italy: 6
    Country: Number of subjects enrolled
    Japan: 6
    Country: Number of subjects enrolled
    Korea, Republic of: 4
    Country: Number of subjects enrolled
    Lithuania: 4
    Country: Number of subjects enrolled
    Malaysia: 5
    Country: Number of subjects enrolled
    Netherlands: 4
    Country: Number of subjects enrolled
    Norway: 1
    Country: Number of subjects enrolled
    Portugal: 2
    Country: Number of subjects enrolled
    Turkey: 13
    Country: Number of subjects enrolled
    Taiwan: 3
    Country: Number of subjects enrolled
    Ukraine: 5
    Country: Number of subjects enrolled
    United States: 40
    Worldwide total number of subjects
    160
    EEA total number of subjects
    48
    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)
    29
    Adolescents (12-17 years)
    29
    Adults (18-64 years)
    98
    From 65 to 84 years
    4
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The trial was conducted at 66 sites in 25 countries: Australia(2), Brazil(1), Canada(1), Croatia(1), Denmark(1), France(2), Germany(2), Greece(1), Hungary(2), Israel(1), Italy(2), Japan(3), Korea(1), Lithuania(1), Malaysia(1), Netherlands(2), Norway(1), Portugal(1), Spain(2), Switzerland(4), Taiwan(1), Turkey(5), Ukraine(1), UK(8), USA(19).

    Pre-assignment
    Screening details
    		 Out of 160 subjects enrolled in this study, 102 came from trial NN7088-3859 and 58 came from trial NN7088-3885. The subjects received turoctocog alfa pegol (N8-GP) injections either as once-weekly, twice weekly or thrice weekly during the 104 weeks treatment period.

    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
    		 N8-GP, Once weekly
    Arm description
    		 Subjects received once weekly (dosing every 7 day) prophylaxis doses of N8-GP, 75 IU/kg intravenous injections for 104 weeks. Subjects treated with N8-GP once weekly or were on the on demand regimen in the previous trial NN7088-3859 (pathfinder2) were included in this arm. At the investigator’s discretion an intensification of the dosing regimen to twice weekly was allowed if the subject experienced more than 2 bleeds within an 8 week period or experienced a severe bleed requiring hospitalization.
    Arm type
    		 Experimental

    Investigational medicinal product name
    N8-GP 3000 IU/vial
    Investigational medicinal product code
    Other name
    Turoctocog alfa pegol
    Pharmaceutical forms
    Powder and solvent for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    The recommended prophylaxis dose was 75 IU/kg BW. The individual dose levels were decided by the investigator based on recommendations from the World Federation of Haemophilia. For prevention of bleeding during surgery and for treatment of bleeding episodes, the recommended doses were 20-75 IU/kg BW, depending on the surgical procedure and location and severity of the bleed, respectively. Depending on the body weight of the subject at the last scheduled visit, the strength of the product was chosen and continued the same throughout the trial: for <80 kg BW - 2000 IU vials and for ≥ 80 kg BW - 3000 IU vials.

    Arm title
    		 N8-GP, Twice weekly
    Arm description
    		 Subjects received twice weekly (dosing every 3 and 4 days) prophylaxis doses of N8-GP intravenous injections for 104 weeks: N8-GP, 50 IU/kg for subjects aged ≥ 12 years and N8-GP, 60 IU/kg for subjects aged < 12 years. Subjects treated with N8-GP in the previous trials NN7088-3859 (pathfinder2) and NN7088-3885 (pathfinder5) were included in this arm. At the investigator’s discretion, an intensification of the dosing regimen to thrice weekly was allowed if the subject experienced spontaneous bleeding episodes. Subjects in this arm were permitted to switch to three times weekly at any time if clinically justified. Otherwise any treatment regimen was preferably be kept for a minimum of 6 months.
    Arm type
    		 Experimental

    Investigational medicinal product name
    N8-GP 3000 IU/vial
    Investigational medicinal product code
    Other name
    Turoctocog alfa pegol
    Pharmaceutical forms
    Powder and solvent for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    The recommended prophylaxis dose was 75 IU/kg BW. The individual dose levels were decided by the investigator based on recommendations from the World Federation of Haemophilia. For prevention of bleeding during surgery and for treatment of bleeding episodes, the recommended doses were 20-75 IU/kg BW, depending on the surgical procedure and location and severity of the bleed, respectively. Depending on the body weight of the subject at the last scheduled visit, the strength of the product was chosen and continued the same throughout the trial: for <80 kg BW - 2000 IU vials and for ≥ 80 kg BW - 3000 IU vials.

    Arm title
    		 N8-GP, Three times weekly
    Arm description
    		 Subjects received three times weekly (dosing every 2, 2 and 3 days) prophylaxis doses of N8-GP, 50 IU/kg as intravenous injections for a duration of 104 weeks. Subjects treated with N8-GP in the previous trials NN7088-3859 (pathfinder2) and NN7088-3885 (pathfinder5) were included in this arm. Subjects in this arm were permitted to switch to twice weekly at any time if clinically justified. Otherwise any treatment regimen was preferably be kept for a minimum of 6 months.
    Arm type
    		 Experimental

    Investigational medicinal product name
    N8-GP 3000 IU/vial
    Investigational medicinal product code
    Other name
    Turoctocog alfa pegol
    Pharmaceutical forms
    Powder and solvent for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    The recommended prophylaxis doses were 50 IU/kg BW. The individual dose levels were decided by the investigator based on recommendations from the World Federation of Haemophilia. For prevention of bleeding during surgery and for treatment of bleeding episodes, the recommended doses were 20-75 IU/kg BW, depending on the surgical procedure and location and severity of the bleed, respectively. Depending on the body weight of the subject at the last scheduled visit, the strength of the product was chosen and continued the same throughout the trial: for <80 kg - 2000 IU vials and for ≥80 kg 3000 IU vials.

    Number of subjects in period 1 [1]
    		N8-GP, Once weekly N8-GP, Twice weekly N8-GP, Three times weekly
    Started
    25
    133
    2
    Completed
    23
    114
    2
    Not completed
    2
    19
    0
         Consent withdrawn by subject
    -
    16
    -
         Transferred to other arm/group
    2
    3
    -
    Notes
    [1] - The number of subjects transferring in and out of the arms in the period are not the same. It is expected the net number of transfers in and out of the arms in a period, will be zero.
    Justification: Despite 133 and 2 subjects have started the trial with twice weekly and three times weekly regimen respectively, 2 subjects switched from once weekly to twice weekly and 5 subjects switched from twice weekly to three times weekly regimen. Due to the system limitation, the totals after subject switches are presented under 'Endpoints' section.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    N8-GP, Once weekly
    Reporting group description
    		 Subjects received once weekly (dosing every 7 day) prophylaxis doses of N8-GP, 75 IU/kg intravenous injections for 104 weeks. Subjects treated with N8-GP once weekly or were on the on demand regimen in the previous trial NN7088-3859 (pathfinder2) were included in this arm. At the investigator’s discretion an intensification of the dosing regimen to twice weekly was allowed if the subject experienced more than 2 bleeds within an 8 week period or experienced a severe bleed requiring hospitalization.

    Reporting group title
    N8-GP, Twice weekly
    Reporting group description
    		 Subjects received twice weekly (dosing every 3 and 4 days) prophylaxis doses of N8-GP intravenous injections for 104 weeks: N8-GP, 50 IU/kg for subjects aged ≥ 12 years and N8-GP, 60 IU/kg for subjects aged < 12 years. Subjects treated with N8-GP in the previous trials NN7088-3859 (pathfinder2) and NN7088-3885 (pathfinder5) were included in this arm. At the investigator’s discretion, an intensification of the dosing regimen to thrice weekly was allowed if the subject experienced spontaneous bleeding episodes. Subjects in this arm were permitted to switch to three times weekly at any time if clinically justified. Otherwise any treatment regimen was preferably be kept for a minimum of 6 months.

    Reporting group title
    N8-GP, Three times weekly
    Reporting group description
    		 Subjects received three times weekly (dosing every 2, 2 and 3 days) prophylaxis doses of N8-GP, 50 IU/kg as intravenous injections for a duration of 104 weeks. Subjects treated with N8-GP in the previous trials NN7088-3859 (pathfinder2) and NN7088-3885 (pathfinder5) were included in this arm. Subjects in this arm were permitted to switch to twice weekly at any time if clinically justified. Otherwise any treatment regimen was preferably be kept for a minimum of 6 months.

    Reporting group values
    		 N8-GP, Once weekly N8-GP, Twice weekly N8-GP, Three times weekly Total
    Number of subjects
    		 25 133 2
    Age Categorical
    Units: Subjects
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 35.1 ( 12.7 ) 27.3 ( 16.8 ) 25.3 ( 17.8 ) -
    Gender Categorical
    Units: Subjects
        Male
    		 25 133 2 160
        Female
    		 0 0 0 0

    End points

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    End points reporting groups
    Reporting group title
    N8-GP, Once weekly
    Reporting group description
    		 Subjects received once weekly (dosing every 7 day) prophylaxis doses of N8-GP, 75 IU/kg intravenous injections for 104 weeks. Subjects treated with N8-GP once weekly or were on the on demand regimen in the previous trial NN7088-3859 (pathfinder2) were included in this arm. At the investigator’s discretion an intensification of the dosing regimen to twice weekly was allowed if the subject experienced more than 2 bleeds within an 8 week period or experienced a severe bleed requiring hospitalization.

    Reporting group title
    N8-GP, Twice weekly
    Reporting group description
    		 Subjects received twice weekly (dosing every 3 and 4 days) prophylaxis doses of N8-GP intravenous injections for 104 weeks: N8-GP, 50 IU/kg for subjects aged ≥ 12 years and N8-GP, 60 IU/kg for subjects aged < 12 years. Subjects treated with N8-GP in the previous trials NN7088-3859 (pathfinder2) and NN7088-3885 (pathfinder5) were included in this arm. At the investigator’s discretion, an intensification of the dosing regimen to thrice weekly was allowed if the subject experienced spontaneous bleeding episodes. Subjects in this arm were permitted to switch to three times weekly at any time if clinically justified. Otherwise any treatment regimen was preferably be kept for a minimum of 6 months.

    Reporting group title
    N8-GP, Three times weekly
    Reporting group description
    		 Subjects received three times weekly (dosing every 2, 2 and 3 days) prophylaxis doses of N8-GP, 50 IU/kg as intravenous injections for a duration of 104 weeks. Subjects treated with N8-GP in the previous trials NN7088-3859 (pathfinder2) and NN7088-3885 (pathfinder5) were included in this arm. Subjects in this arm were permitted to switch to twice weekly at any time if clinically justified. Otherwise any treatment regimen was preferably be kept for a minimum of 6 months.

    Subject analysis set title
    N8-GP, Once weekly
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects received once weekly (dosing every 7 day) prophylaxis doses of N8-GP, 75 IU/kg intravenous injections for 104 weeks.

    Subject analysis set title
    N8-GP, Twice weekly (subjects transferred from other arm)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects received twice weekly (dosing every 3 and 4 days) prophylaxis doses of N8-GP intravenous injections for 104 weeks. During the trial, 2 subjects switched from once weekly to twice weekly regimen for treatment intensification. Thus, though 133 subjects have started the trial with twice weekly regimen, results of this arm is presented for 135 subjects in this arm (i.e. 133+2 = 135).

    Subject analysis set title
    N8-GP,Three times weekly (subjects transferred from other arm)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects received three times weekly (dosing every 2, 2 and 3 days) prophylaxis doses of N8-GP, 50 IU/kg as intravenous injections for a duration of 104 weeks. During the trial, 5 subjects switched from twice weekly to three times weekly regimen for treatment intensification. Thus, though 2 subjects have started the trial with three times regimen, results for this arm is presented for 7 subjects in this arm (i.e. 2+5 = 7).

    Primary: Number of adverse events reported

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    End point title
    		 Number of adverse events reported [1]
    End point description
    All presented adverse events are treatment emergent (TEAEs). The TEAEs were defined as the events reported after trial product administration (day 1) until the last patient last visit or end of the post-treatment follow-up period (i.e. 1 month). Results are based on the safety analysis set (SAS) which included all enrolled subjects as they were previously been exposed to trial product.
    End point type
    Primary
    End point timeframe
    Week 0 to week 104
    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: Since the primary endpoint is number of adverse events reported in the trial, the statistical analysis has not been done.
    End point values
    		 N8-GP, Once weekly N8-GP, Twice weekly (subjects transferred from other arm) N8-GP,Three times weekly (subjects transferred from other arm)
    Number of subjects analysed
    25
    135
    7
    Units: Events
    58
    444
    8
    No statistical analyses for this end point

    Secondary: Incidence of FVIII inhibitors ≥0.6 BU

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    End point title
    		 Incidence of FVIII inhibitors ≥0.6 BU
    End point description
    The Incidence of inhibitors against coagulation factor eight (FVIII) is defined as titre ≥0.6 Bethesda unit (BU). The inhibitor antibodies were measured using a heat modified Nijmegen FVIII Bethesda assay. The number of subjects who developed inhibitors against FVIII are reported. Results are based on Full analysis set (FAS), which included all subjects exposed to at least one dose of trial product in the current trial.
    End point type
    Secondary
    End point timeframe
    After 104 weeks
    End point values
    		 N8-GP, Once weekly N8-GP, Twice weekly (subjects transferred from other arm) N8-GP,Three times weekly (subjects transferred from other arm)
    Number of subjects analysed
    25
    135
    7
    Units: Subjects
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Number of bleeding episodes on prophylaxis

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    End point title
    		 Number of bleeding episodes on prophylaxis
    End point description
    Number of bleeding episodes per subject in the prophylaxis regimen was evaluated during 104 weeks. Results are based on FAS, which included all subjects exposed to at least one dose of trial product in the current trial.
    End point type
    Secondary
    End point timeframe
    After 104 weeks
    End point values
    		 N8-GP, Once weekly N8-GP, Twice weekly (subjects transferred from other arm) N8-GP,Three times weekly (subjects transferred from other arm)
    Number of subjects analysed
    25
    135
    7
    Units: Episodes
    123
    190
    14
    No statistical analyses for this end point

    Secondary: Number of spontaneous bleeding episodes on prophylaxis

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    End point title
    		 Number of spontaneous bleeding episodes on prophylaxis
    End point description
    Spontaneous bleeding referred as bleeding episodes that occurred without apparent cause. The number of spontaneous bleeding episodes was evaluated during 104 weeks. Results are based on FAS, which included all subjects exposed to at least one dose of trial product in the current trial.
    End point type
    Secondary
    End point timeframe
    After 104 weeks
    End point values
    		 N8-GP, Once weekly N8-GP, Twice weekly (subjects transferred from other arm) N8-GP,Three times weekly (subjects transferred from other arm)
    Number of subjects analysed
    25
    135
    7
    Units: Episodes
    98
    73
    8
    No statistical analyses for this end point

    Secondary: Haemostatic effect of N8-GP when used for treatment of bleeding episodes assessed as: Excellent, Good, Moderate, or None

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    End point title
    		 Haemostatic effect of N8-GP when used for treatment of bleeding episodes assessed as: Excellent, Good, Moderate, or None
    End point description
    The haemostatic effect after treatment of a bleed with turoctocog alfa pegol was assessed using a 4-point scale: ‘excellent’, ‘good’, ‘moderate’ or ‘none’. The evaluation was done as follows: 1. Excellent: Abrupt pain relief and/or unequivocal improvement in objective signs of bleeding within approximately 8 hours after a single injection. 2. Good: Definite pain relief and/or improvement in signs of bleeding within approximately 8 hours after an injection, but possibly requiring more than one injection for complete resolution. 3. Moderate: Probable or slight beneficial effect within approximately 8 hours after the first injection; usually requiring more than one injection 4. None: No improvement or worsening of symptoms. Results are based on FAS, which included all subjects exposed to at least one dose of trial product in the current trial.
    End point type
    Secondary
    End point timeframe
    After 104 weeks
    End point values
    		 N8-GP, Once weekly N8-GP, Twice weekly (subjects transferred from other arm) N8-GP,Three times weekly (subjects transferred from other arm)
    Number of subjects analysed
    25
    135
    7
    Units: Score on a scale
        Excellent
    114
    94
    8
        Good
    8
    80
    6
        Moderate
    0
    4
    0
        None
    0
    0
    0
        Missing
    0
    8
    0
    No statistical analyses for this end point

    Secondary: Number of turoctocog alfa pegol injections required per bleeding episode

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    End point title
    		 Number of turoctocog alfa pegol injections required per bleeding episode
    End point description
    The number of N8-GP injections required per bleeding episode was evaluated from week 0 to week 104. All bleeds including surgery bleeds are included. Results are based on FAS, which included all subjects exposed to at least one dose of trial product in the current trial.
    End point type
    Secondary
    End point timeframe
    After 104 weeks
    End point values
    		 N8-GP, Once weekly N8-GP, Twice weekly (subjects transferred from other arm) N8-GP,Three times weekly (subjects transferred from other arm)
    Number of subjects analysed
    25
    135
    7
    Units: Injections per bleed
        1 injection
    110
    136
    12
        2 injections
    10
    39
    2
        3 injections
    2
    5
    0
        4 injections
    0
    2
    0
        5 injections
    0
    3
    0
        6 injections
    1
    2
    0
        8 injections
    0
    1
    0
        9 injections
    0
    1
    0
        10 injections
    0
    1
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Week 0 to week 104 (treatment period) + 1 month (follow-up period).
    Adverse event reporting additional description
    All adverse events are treatment emergent (TEAEs). The TEAEs were defined as the events reported after trial product administration (day 1) until the last patient last visit or end of the post-treatment follow-up period (i.e. 1 month). SAS included all enrolled subjects as they were previously been exposed to trial product.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    23
    Reporting groups
    Reporting group title
    N8-GP, Once weekly
    Reporting group description
    		 Subjects received once weekly (dosing every 7 day) prophylaxis doses of N8-GP, 75 IU/kg intravenous injections for 104 weeks. Subjects treated with N8-GP once weekly or were on the on demand regimen in the previous trial NN7088-3859 (pathfinder2) were included in this arm. At the investigator’s discretion an intensification of the dosing regimen to twice weekly was allowed if the subject experienced more than 2 bleeds within an 8 week period or experienced a severe bleed requiring hospitalization. Otherwise any treatment regimen was preferably be kept for a minimum of 6 months.

    Reporting group title
    N8-GP, Twice weekly
    Reporting group description
    		 Subjects received twice weekly (dosing every 3 and 4 days) prophylaxis doses of N8-GP intravenous injections for 104 weeks: N8-GP, 50 IU/kg for subjects aged ≥ 12 years and N8-GP, 60 IU/kg for subjects aged < 12 years. Subjects treated with N8-GP in the previous trials NN7088-3859 (pathfinder2) and NN7088-3885 (pathfinder5) were included in this arm. At the investigator’s discretion, an intensification of the dosing regimen to thrice weekly was allowed if the subject experienced spontaneous bleeding episodes. Subjects in this arm were permitted to switch to three times weekly at any time if clinically justified. Otherwise any treatment regimen was preferably be kept for a minimum of 6 months. During the trial, 2 subjects switched from once weekly to twice weekly regimen for treatment intensification. Thus, though 133 subjects have started the trial with twice weekly regimen, AE data is presented for 135 subjects in this arm (i.e. 133+2 = 135).

    Reporting group title
    N8-GP, Three times weekly
    Reporting group description
    		 Subjects received three times weekly (dosing every 2, 2 and 3 days) prophylaxis doses of N8-GP, 50 IU/kg as intravenous injections for a duration of 104 weeks. Subjects treated with N8-GP in the previous trials NN7088-3859 (pathfinder2) and NN7088-3885 (pathfinder5) were included in this arm. Subjects in this arm were permitted to switch to twice weekly at any time if clinically justified. Otherwise any treatment regimen was preferably be kept for a minimum of 6 months. During the trial, 5 subjects switched from twice weekly to three times weekly regimen for treatment intensification. Thus, though 2 subjects have started the trial with three times regimen, AE data is presented for 7 subjects in this arm (i.e. 2+5 = 7).

    Reporting group title
    Total
    Reporting group description
    		 Total number of subjects from 3 arms

    Serious adverse events
    		 N8-GP, Once weekly N8-GP, Twice weekly N8-GP, Three times weekly Total
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 25 (16.00%)
    15 / 135 (11.11%)
    0 / 7 (0.00%)
    19 / 160 (11.88%)
         number of deaths (all causes)
    0
    1
    0
    1
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Malignant melanoma
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 135 (0.74%)
    0 / 7 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    Melanocytic naevus
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 135 (0.74%)
    0 / 7 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Squamous cell carcinoma of the tongue
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 135 (0.74%)
    0 / 7 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Humerus fracture
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 135 (0.74%)
    0 / 7 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Procedural haemorrhage
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 135 (0.00%)
    0 / 7 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Road traffic accident
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 135 (0.00%)
    0 / 7 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin laceration
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 135 (0.74%)
    0 / 7 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Traumatic haemorrhage
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 135 (0.74%)
    0 / 7 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Wound secretion
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 135 (0.74%)
    0 / 7 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Surgical and medical procedures
    Mole excision
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 135 (0.74%)
    0 / 7 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Cervical radiculopathy
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 135 (0.00%)
    0 / 7 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Presyncope
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 135 (0.74%)
    0 / 7 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    0 / 25 (0.00%)
    3 / 135 (2.22%)
    0 / 7 (0.00%)
    3 / 160 (1.88%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
    0 / 0
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 135 (0.00%)
    0 / 7 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Depression suicidal
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 135 (0.74%)
    0 / 7 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthropathy
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 135 (0.00%)
    0 / 7 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intervertebral disc protrusion
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 135 (0.00%)
    0 / 7 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 135 (0.74%)
    0 / 7 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Arthritis bacterial
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 135 (0.74%)
    0 / 7 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Subcutaneous abscess
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 135 (0.00%)
    0 / 7 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         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
    		 N8-GP, Once weekly N8-GP, Twice weekly N8-GP, Three times weekly Total
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    9 / 25 (36.00%)
    46 / 135 (34.07%)
    4 / 7 (57.14%)
    56 / 160 (35.00%)
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    0 / 25 (0.00%)
    3 / 135 (2.22%)
    1 / 7 (14.29%)
    3 / 160 (1.88%)
         occurrences all number
    0
    3
    1
    4
    Nervous system disorders
    Headache
         subjects affected / exposed
    0 / 25 (0.00%)
    10 / 135 (7.41%)
    0 / 7 (0.00%)
    10 / 160 (6.25%)
         occurrences all number
    0
    11
    0
    11
    Gastrointestinal disorders
    Dental caries
         subjects affected / exposed
    3 / 25 (12.00%)
    0 / 135 (0.00%)
    0 / 7 (0.00%)
    3 / 160 (1.88%)
         occurrences all number
    3
    0
    0
    3
    Psychiatric disorders
    Attention deficit hyperactivity disorder
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 135 (0.00%)
    1 / 7 (14.29%)
    1 / 160 (0.63%)
         occurrences all number
    0
    0
    1
    1
    Depression
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 135 (0.74%)
    2 / 7 (28.57%)
    3 / 160 (1.88%)
         occurrences all number
    0
    1
    2
    3
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    2 / 25 (8.00%)
    11 / 135 (8.15%)
    1 / 7 (14.29%)
    14 / 160 (8.75%)
         occurrences all number
    2
    12
    1
    15
    Limb discomfort
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 135 (0.00%)
    1 / 7 (14.29%)
    1 / 160 (0.63%)
         occurrences all number
    0
    0
    1
    1
    Infections and infestations
    Influenza
         subjects affected / exposed
    0 / 25 (0.00%)
    9 / 135 (6.67%)
    0 / 7 (0.00%)
    9 / 160 (5.63%)
         occurrences all number
    0
    9
    0
    9
    Nasopharyngitis
         subjects affected / exposed
    3 / 25 (12.00%)
    21 / 135 (15.56%)
    0 / 7 (0.00%)
    24 / 160 (15.00%)
         occurrences all number
    3
    23
    0
    26
    Upper respiratory tract infection
         subjects affected / exposed
    4 / 25 (16.00%)
    11 / 135 (8.15%)
    1 / 7 (14.29%)
    16 / 160 (10.00%)
         occurrences all number
    13
    18
    2
    33
    Metabolism and nutrition disorders
    Vitamin B12 deficiency
         subjects affected / exposed
    2 / 25 (8.00%)
    0 / 135 (0.00%)
    0 / 7 (0.00%)
    2 / 160 (1.25%)
         occurrences all number
    2
    0
    0
    2

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    31 Jul 2019
    - Visits 2, 4, 6 and 8 (weeks 13, 39, 65 and 91) could be conducted as phone visits for patients receiving trial drug at home as part of the Direct to Patient (DTP) programme. - The choice of vial strength for each patient was based on the body weight at the last scheduled visit conducted in trial NN7088-3859 or 3885 prior to the initial shipment of trial product in current trial NN7088-4410. This was to ensure availability of trial product at the start of trial. - Added that patients may be discontinued from the trial when commercial N8-GP becomes available in their respective country. Trial discontinuation will allow for patients to undertake commercial treatment instead of participating in a clinical trial. - Sentence in the haematology section deleted to clarify that only FVIII activity must be taken 30 min post dose, not haematology. - “Web-portal for document exchange” section added to appendix 3 – Trial governance considerations. - A few minor administrative changes performed.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
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