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    Clinical Trial Results:
    Safety and efficacy of turoctocog alfa pegol (N8-GP) in previously untreated patients with haemophilia A

    Summary
    EudraCT number
    		 2013-004025-88
    Trial protocol
    		 DE   AT   ES   PT   GR   BG   RO   IT   FR  
    Global end of trial date
    07 Jun 2023

    Results information
    Results version number
    		 v1(current)
    This version publication date
    22 Dec 2023
    First version publication date
    22 Dec 2023
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    NN7088-3908
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02137850
    WHO universal trial number (UTN)
    		 U1111-1148-1897
    Other trial identifiers
    		 Japanese trial registration: JapicCTI-142577
    Sponsors
    Sponsor organisation name
    Novo Nordisk A/S
    Sponsor organisation address
    Novo Allé, Bagsvaerd, Denmark, 2880
    Public contact
    Clinical Reporting Office (2834), Novo Nordisk A/S, clinicaltrials@novonordisk.com
    Scientific contact
    Clinical Reporting Office (2834), Novo Nordisk A/S, clinicaltrials@novonordisk.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    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 Jan 2022
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    11 Nov 2021
    Global end of trial reached?
    Yes
    Global end of trial date
    07 Jun 2023
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate immunogenicity of N8-GP (turoctocog alfa pegol) in previously untreated patients (PUPs) with severe haemophilia A
    Protection of trial subjects
    The trial was conducted in accordance with the Declaration of Helsinki, International Council for Harmonisation (ICH) Good Clinical Practice, including archiving of essential documents, and Food and Drug Administration (FDA) 21 Code of Federal Regulations (CFR) 312.12.
    Background therapy
    		 Not applicable
    Evidence for comparator
    		 Not applicable
    Actual start date of recruitment
    26 Jun 2014
    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: 5
    Country: Number of subjects enrolled
    Austria: 5
    Country: Number of subjects enrolled
    Bulgaria: 3
    Country: Number of subjects enrolled
    Canada: 1
    Country: Number of subjects enrolled
    Germany: 1
    Country: Number of subjects enrolled
    Greece: 4
    Country: Number of subjects enrolled
    Israel: 9
    Country: Number of subjects enrolled
    Italy: 1
    Country: Number of subjects enrolled
    Japan: 3
    Country: Number of subjects enrolled
    Malaysia: 11
    Country: Number of subjects enrolled
    Spain: 6
    Country: Number of subjects enrolled
    Taiwan: 2
    Country: Number of subjects enrolled
    Thailand: 12
    Country: Number of subjects enrolled
    United States: 18
    Worldwide total number of subjects
    81
    EEA total number of subjects
    20
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    12
    Infants and toddlers (28 days-23 months)
    61
    Children (2-11 years)
    8
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 The trial was conducted in 14 countries as follows: Australia (2), Austria (2), Bulgaria (1), Canada (1), Germany (1), Greece (2), Israel (1), Italy (1), Japan (3), Malaysia (3), Spain (2), Taiwan (1), Thailand (3), United States (8).

    Pre-assignment
    Screening details
    		 44 subjects were switched from pre-prophylaxis to other two groups during main phase (42 subjects were switched to prophylaxis group and 2 subjects were switched to immune tolerance induction (ITI) group). Out of 2 subjects in immune tolerance induction (ITI) group, 1 subject was again switched from the ITI group to the prophylaxis group.

    Period 1
    Period 1 title
    Main Phase
    Is this the baseline period?
    		 Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 Pre-prophylaxis
    Arm description
    		 At the beginning of the main phase of the trial, slow start prophylaxis and on-demand treatment of bleeding episodes with trial product (N8-GP) were allowed at the discretion of the investigator and Subject’s parent(s)/ legally acceptable representative (LAR). The N8-GP dose for pre-prophylaxis treatment (except for bleeding episodes) was 60 International unit per kilogram (IU/kg) body weight (within the range of 50-75 IU/kg) to be administered as a single bolus dose intravenously (i.v.) with more than one week between doses (at the discretion of the investigator).
    Arm type
    		 Experimental

    Investigational medicinal product name
    turoctocog alfa pegol (N8-GP)
    Investigational medicinal product code
    Other name
    Esperoct
    Pharmaceutical forms
    Powder and solvent for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    The N8-GP dose for pre-prophylaxis treatment (except for bleeding episodes) was 60 International unit per kilogram (IU/kg) body weight (within the range of 50-75 IU/kg) to be administered as a single bolus dose intravenously (i.v.) with more than one week between doses (at the discretion of the investigator).

    Arm title
    		 Prophylaxis
    Arm description
    		 For prophylaxis treatment, regular N8-GP administration was initiated no later than at the subject’s age of 24 months, or after 20 EDs on pre-prophylaxis, whatever came first. During the main phase of the trial, subjects received prophylaxis with i.v. injections of N8-GP preferably twice weekly, with doses separated by at least 3, and no more than 4, calendar days. Furthermore, it was permissible to start prophylaxis in the main phase with an every 3rd day or once-weekly dosing regimen. The N8-GP dose for prophylaxis treatment was 60 IU/kg (within the range of 50-75 IU/kg) to be administered as a single bolus dose i.v. on each administration day.
    Arm type
    		 Experimental

    Investigational medicinal product name
    turoctocog alfa pegol (N8-GP)
    Investigational medicinal product code
    Other name
    Esperoct
    Pharmaceutical forms
    Powder and solvent for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    The N8-GP dose for prophylaxis treatment was 60 IU/kg (within the range of 50-75 IU/kg) to be administered as a single bolus dose i.v. on each administration day.

    Arm title
    		 Immune tolerance induction (ITI)
    Arm description
    		 Subjects who developed FVIII inhibitors in the trial were offered ITI treatment with N8-GP. If a newly diagnosed inhibitor subject still responded well to treatment with N8-GP, initiation of ITI could be postponed with up to 6 months, or ITI could be cancelled if the inhibitors had resolved during the 6 months. N8-GP treatment could continue in case of low titre FVIII inhibitor (lesser than or equal (≤) 5 Bethesda Units). In case of high titre FVIII inhibitor (greater than (>) 5 Bethesda Units), the investigator had to decide how to proceed with treatment. ITI with N8-GP had to be initiated within 6 months of the confirmatory inhibitor test. The N8-GP dose for ITI treatment was according to local standard. Maximum of 75 IU/kg as single dose, maximum of 200 IU/kg over 24 hours.
    Arm type
    		 Experimental

    Investigational medicinal product name
    turoctocog alfa pegol (N8-GP)
    Investigational medicinal product code
    Other name
    Esperoct
    Pharmaceutical forms
    Powder and solvent for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    The N8-GP dose for ITI treatment was according to local standard. Maximum of 75 IU/kg as single dose, maximum of 200 IU/kg over 24 hours.

    Number of subjects in period 1
    		Pre-prophylaxis Prophylaxis Immune tolerance induction (ITI)
    Started
    55
    69
    8
    Completed
    44
    59
    6
    Not completed
    11
    10
    2
         Consent withdrawn by subject
    2
    -
    -
         Adverse event, non-fatal
    3
    4
    -
         Unspecified
    3
    1
    -
         Lost to follow-up
    -
    1
    -
         Withdrawal by parent/guardian
    1
    2
    1
         Protocol deviation
    1
    1
    -
         Lack of efficacy
    1
    1
    1
    Period 2
    Period 2 title
    Extension phase
    Is this the baseline period?
    		 No
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Prophylaxis
    Arm description
    		 For prophylaxis treatment, regular N8-GP administration was initiated no later than at the subject’s age of 24 months, or after 20 EDs on pre-prophylaxis, whatever came first. In the extension phase, subjects were to continue the prophylaxis dosing regimen as prescribed at the end of the main phase. Based on the subjects individual bleeding patterns, modification of N8-GP dose and/or frequency was permitted at the investigator’s discretion.
    Arm type
    		 Experimental

    Investigational medicinal product name
    turoctocog alfa pegol (N8-GP)
    Investigational medicinal product code
    Other name
    Esperoct
    Pharmaceutical forms
    Powder and solvent for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    The N8-GP dose for prophylaxis treatment was 60 IU/kg (within the range of 50-75 IU/kg) to be administered as a single bolus dose i.v. on each administration day.

    Number of subjects in period 2
    		Prophylaxis
    Started
    55
    Completed
    48
    Not completed
    7
         Adverse event, non-fatal
    1
         Other
    4
         Withdrawal by parent/guardian
    1
         Protocol deviation
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Main Phase
    Reporting group description
    		 In the main phase of the trial, Subjects received treatment with N8-GP until they reached a minimum of 50 exposure days (EDs) each. An ED was defined as any day during which the subject exposed to N8-GP, including doses given for treatment of bleeding episodes, prophylaxis, surgery, and for the purpose of PK assessment. When at least 50 Subjects had reached a minimum of 50 EDs each in the main phase, the analysis and evaluation for the main trial report was performed.

    Reporting group values
    		 Main Phase Total
    Number of subjects
    		 81 81
    Age Categorical
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 12 12
        Infants and toddlers (28 days-23 months)
    		 61 61
        Children (2-11 years)
    		 8 8
        Adolescents (12-17 years)
    		 0 0
        Adults (18-64 years)
    		 0 0
        From 65-84 years
    		 0 0
        85 years and over
    		 0 0
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 10.2 ( 11.0 ) -
    Gender Categorical
    Units: Subjects
        Female
    		 0 0
        Male
    		 81 81

    End points

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    End points reporting groups
    Reporting group title
    Pre-prophylaxis
    Reporting group description
    		 At the beginning of the main phase of the trial, slow start prophylaxis and on-demand treatment of bleeding episodes with trial product (N8-GP) were allowed at the discretion of the investigator and Subject’s parent(s)/ legally acceptable representative (LAR). The N8-GP dose for pre-prophylaxis treatment (except for bleeding episodes) was 60 International unit per kilogram (IU/kg) body weight (within the range of 50-75 IU/kg) to be administered as a single bolus dose intravenously (i.v.) with more than one week between doses (at the discretion of the investigator).

    Reporting group title
    Prophylaxis
    Reporting group description
    		 For prophylaxis treatment, regular N8-GP administration was initiated no later than at the subject’s age of 24 months, or after 20 EDs on pre-prophylaxis, whatever came first. During the main phase of the trial, subjects received prophylaxis with i.v. injections of N8-GP preferably twice weekly, with doses separated by at least 3, and no more than 4, calendar days. Furthermore, it was permissible to start prophylaxis in the main phase with an every 3rd day or once-weekly dosing regimen. The N8-GP dose for prophylaxis treatment was 60 IU/kg (within the range of 50-75 IU/kg) to be administered as a single bolus dose i.v. on each administration day.

    Reporting group title
    Immune tolerance induction (ITI)
    Reporting group description
    		 Subjects who developed FVIII inhibitors in the trial were offered ITI treatment with N8-GP. If a newly diagnosed inhibitor subject still responded well to treatment with N8-GP, initiation of ITI could be postponed with up to 6 months, or ITI could be cancelled if the inhibitors had resolved during the 6 months. N8-GP treatment could continue in case of low titre FVIII inhibitor (lesser than or equal (≤) 5 Bethesda Units). In case of high titre FVIII inhibitor (greater than (>) 5 Bethesda Units), the investigator had to decide how to proceed with treatment. ITI with N8-GP had to be initiated within 6 months of the confirmatory inhibitor test. The N8-GP dose for ITI treatment was according to local standard. Maximum of 75 IU/kg as single dose, maximum of 200 IU/kg over 24 hours.
    Reporting group title
    Prophylaxis
    Reporting group description
    		 For prophylaxis treatment, regular N8-GP administration was initiated no later than at the subject’s age of 24 months, or after 20 EDs on pre-prophylaxis, whatever came first. In the extension phase, subjects were to continue the prophylaxis dosing regimen as prescribed at the end of the main phase. Based on the subjects individual bleeding patterns, modification of N8-GP dose and/or frequency was permitted at the investigator’s discretion.

    Subject analysis set title
    Main + extension phase: pre-prophylaxis
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    At the beginning of the main phase of the trial, slow start prophylaxis and on-demand treatment of bleeding episodes with trial product (N8-GP) were allowed at the discretion of the investigator and Subject’s parent(s)/ legally acceptable representative (LAR).

    Subject analysis set title
    Main + extension phase: prophylaxis
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    For prophylaxis treatment, regular N8-GP administration was initiated no later than at the subject’s age of 24 months, or after 20 EDs on pre-prophylaxis, whatever came first. During the main phase of the trial, subjects received prophylaxis with i.v. injections of N8-GP preferably twice weekly, with doses separated by at least 3, and no more than 4, calendar days. Furthermore, it was permissible to start prophylaxis in the main phase with an every 3rd day or once-weekly dosing regimen. In the extension phase, subjects were to continue the prophylaxis dosing regimen as prescribed at the end of the main phase. Based on the subjects individual bleeding patterns, modification of N8-GP dose and/or frequency was permitted at the investigator’s discretion.

    Subject analysis set title
    Main + extension phase: immune tolerance induction (ITI)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Subjects who developed FVIII inhibitors in the trial were offered ITI treatment with N8-GP. If a newly diagnosed inhibitor subject still responded well to treatment with N8-GP, initiation of ITI could be postponed with up to 6 months, or ITI could be cancelled if the inhibitors had resolved during the 6 months. N8-GP treatment could continue in case of low titre FVIII inhibitor (lesser than or equal (≤) 5 Bethesda Units). In case of high titre FVIII inhibitor (greater than (>) 5 Bethesda Units), the investigator had to decide how to proceed with treatment. ITI with N8-GP had to be initiated within 6 months of the confirmatory inhibitor test.

    Primary: Incidence of inhibitory antibodies against coagulation factor VIII (FVIII)

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    End point title
    		 Incidence of inhibitory antibodies against coagulation factor VIII (FVIII)
    End point description
    The incidence of inhibitory antibodies was reported during the main and extension phase of the trial. Results were based on safety analysis set (SAS). The SAS consist of all subjects exposed to N8-GP. Number of subjects analyzed=subjects with available data for this endpoint.
    End point type
    Primary
    End point timeframe
    When the first 50 PUPs have reached at least 50 exposure days and at end of trial. End of trial will be up to 4 years after the first patient has reached 100 exposure days
    End point values
    		 Main + extension phase: pre-prophylaxis Main + extension phase: prophylaxis
    Number of subjects analysed
    55
    68
    Units: Subjects
    11
    10
    Statistical analysis title
    		 Statistical analysis 1
    Statistical analysis description
    A one-sided, upper 97.5% confidence limit was provided based on an exact calculation in the binomial distribution.
    Comparison groups
    Main + extension phase: pre-prophylaxis v Main + extension phase: prophylaxis
    Number of subjects included in analysis
    123
    Analysis specification
    Pre-specified
    Analysis type
    		 other [1]
    Method
    Parameter type
    		 Incidence rate
    Point estimate
    0.3
    Confidence interval
         level
    		 97.5%
         sides
    1-sided
         lower limit
    		 -
         upper limit
    		 0.421
    Notes
    [1] - Total number of subjects included in statistical analysis is 80. The number given here is auto-calculated by the system.

    Secondary: Frequency of adverse events including serious adverse events and medical events of special interest

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    End point title
    		 Frequency of adverse events including serious adverse events and medical events of special interest
    End point description
    The frequency of adverse events including serious adverse events and medical events of special interest reported during the main and extension phase of the trial. An adverse event (AE) is any untoward medical occurrence in a patient administered a product, and which does not necessarily have a causal relationship with this treatment. Serious adverse event (SAE) is an experience that at any dose results in any of the following: Death, a life-threatening experience, in-patient hospitalisation or prolongation of existing hospitalisation, persistent or significant disability or incapacity, congenital anomaly or birth defect and important medical events that may not result in death, be life threatening or require hospitalisation. Medical event of special interest (MESI) is an event which, in the evaluation of safety, has a special focus. Results were based on SAS. The SAS consists of all subjects exposed to N8-GP.
    End point type
    Secondary
    End point timeframe
    When the first 50 PUPs have reached at least 50 exposure days and at end of trial. End of trial will be up to 4 years after the first patient has reached 100 exposure days
    End point values
    		 Main + extension phase: pre-prophylaxis Main + extension phase: prophylaxis Main + extension phase: immune tolerance induction (ITI)
    Number of subjects analysed
    55
    69
    8
    Units: Events
    number (not applicable)
        Adverse events
    116
    644
    30
        Serious adverse events
    24
    56
    3
        Medical events of special interest
    17
    47
    0
    No statistical analyses for this end point

    Secondary: Number of breakthrough bleeding episodes during prophylaxis with turoctocog alfa pegol (N8-GP) (annualised bleeding rate)

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    End point title
    		 Number of breakthrough bleeding episodes during prophylaxis with turoctocog alfa pegol (N8-GP) (annualised bleeding rate)
    End point description
    The number of bleeding episodes per year reported during the prophylactic treatment with N8-GP. Results were based on full analysis set (FAS). The FAS consists of all subjects exposed to N8-GP. The endpoint is applicable for only reported group.
    End point type
    Secondary
    End point timeframe
    When the first 50 PUPs have reached at least 50 exposure days and at end of trial. End of trial will be up to 4 years after the first patient has reached 100 exposure days
    End point values
    		 Main + extension phase: prophylaxis
    Number of subjects analysed
    69
    Units: bleeds/patient/year
        median (inter-quartile range (Q1-Q3))
    1.35 (0.60 to 3.50)
    No statistical analyses for this end point

    Secondary: Incidence of confirmed high titre inhibitors (defined as inhibitor titre above 5 Bethesda Units (BU)

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    End point title
    		 Incidence of confirmed high titre inhibitors (defined as inhibitor titre above 5 Bethesda Units (BU)
    End point description
    The incidence of confirmed high titre inhibitors (defined as inhibitor titre above 5 Bethesda Units (BU) was reported during the main and extension phase of the trial. Results were based on safety analysis set (SAS). The SAS consist of all subjects exposed to N8-GP. Number of subjects analyzed=subjects with available data for this endpoint.
    End point type
    Secondary
    End point timeframe
    When the first 50 PUPs have reached at least 50 exposure days and at end of trial. End of trial will be up to 4 years after the first patient has reached 100 exposure days
    End point values
    		 Main + extension phase: pre-prophylaxis Main + extension phase: prophylaxis
    Number of subjects analysed
    55
    68
    Units: Subjects
    3
    8
    No statistical analyses for this end point

    Secondary: Haemostatic effect of N8-GP in treatment of bleeding episodes, assessed by a predefined 4-point haemostatic response scale (“excellent”, “good”, “moderate” and “none”)

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    End point title
    		 Haemostatic effect of N8-GP in treatment of bleeding episodes, assessed by a predefined 4-point haemostatic response scale (“excellent”, “good”, “moderate” and “none”)
    End point description
    Haemostatic effect of turoctocog alfa pegol for treatment of bleeding episodes was assessed by 4-point response scale: none, moderate, good or excellent. Excellent: Abrupt pain relief and/or clear improvement in objective signs of bleeding within approximately 8 hours after a single injection; Good: Definite pain relief and/or improvement in signs of bleeding within approximately 8 hours 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 full analysis set (FAS). The FAS consists of all subjects exposed to N8-GP. Number of subjects analyzed = number of bleeds in subjects.
    End point type
    Secondary
    End point timeframe
    When the first 50 PUPs have reached at least 50 exposure days and at end of trial. End of trial will be up to 4 years after the first patient has reached 100 exposure days
    End point values
    		 Main + extension phase: pre-prophylaxis Main + extension phase: prophylaxis Main + extension phase: immune tolerance induction (ITI)
    Number of subjects analysed
    48
    59
    4
    Units: Bleeding episodes
    number (not applicable)
        Excellent
    69
    227
    2
        Good
    62
    92
    3
        Moderate
    18
    18
    3
        None
    3
    6
    0
        Missing
    8
    2
    0
    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 of main phase to end of extension phase
    Adverse event reporting additional description
    All the presented adverse events (AEs) are treatment emergent adverse events (TEAEs). AEs occurring in a patient before being exposed to N8-GP. Safety analysis set included all patients exposed to N8-GP.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22
    Reporting groups
    Reporting group title
    Pre-prophylaxis
    Reporting group description
    		 At the beginning of the main phase of the trial, slow start prophylaxis and on-demand treatment of bleeding episodes with trial product (N8-GP) were allowed at the discretion of the investigator and Subject’s parent(s)/ legally acceptable representative (LAR). The N8-GP dose for pre-prophylaxis treatment was 60 IU/kg body weight (within the range of 50-75 IU/kg) to be administered as a single bolus dose intravenously (i.v.) with more than one week between doses (at the discretion of the investigator).

    Reporting group title
    Immune tolerance induction (ITI)
    Reporting group description
    		 Patients who developed FVIII inhibitors in the trial were offered ITI treatment with N8-GP. If a newly diagnosed inhibitor patient still responded well to treatment with N8-GP, initiation of ITI could be postponed with up to 6 months, or ITI could be cancelled if the inhibitors had resolved during the 6 months. N8-GP treatment could continue in case of low titre FVIII inhibitor (lesser than or equal (≤) 5 Bethesda Units). In case of high titre FVIII inhibitor (greater than (>) 5 Bethesda Units), the investigator had to decide how to proceed with treatment. ITI with N8-GP had to be initiated within 6 months of the confirmatory inhibitor test.

    Reporting group title
    Prophylaxis
    Reporting group description
    		 For prophylaxis treatment, regular N8-GP administration was initiated no later than at the subject’s age of 24 months, or after 20 EDs on pre-prophylaxis, whatever came first. The N8-GP dose for prophylaxis treatment was 60 IU/kg (within the range of 50-75 IU/kg) to be administered as a single bolus dose intravenously (i.v.) on each administration day.

    Serious adverse events
    		 Pre-prophylaxis Immune tolerance induction (ITI) Prophylaxis
    Total subjects affected by serious adverse events
         subjects affected / exposed
    18 / 55 (32.73%)
    1 / 8 (12.50%)
    34 / 69 (49.28%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Vascular disorders
    Haematoma
         subjects affected / exposed
    1 / 55 (1.82%)
    0 / 8 (0.00%)
    0 / 69 (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
    Surgical and medical procedures
    Arteriovenous fistula operation
         subjects affected / exposed
    0 / 55 (0.00%)
    0 / 8 (0.00%)
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tooth extraction
         subjects affected / exposed
    0 / 55 (0.00%)
    0 / 8 (0.00%)
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urogenital fistula repair
         subjects affected / exposed
    0 / 55 (0.00%)
    0 / 8 (0.00%)
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urethral repair
         subjects affected / exposed
    0 / 55 (0.00%)
    0 / 8 (0.00%)
    1 / 69 (1.45%)
         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
    Therapy non-responder
         subjects affected / exposed
    0 / 55 (0.00%)
    0 / 8 (0.00%)
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 55 (0.00%)
    0 / 8 (0.00%)
    2 / 69 (2.90%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vaccination site haemorrhage
         subjects affected / exposed
    1 / 55 (1.82%)
    0 / 8 (0.00%)
    0 / 69 (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
    Respiratory, thoracic and mediastinal disorders
    Respiratory failure
         subjects affected / exposed
    0 / 55 (0.00%)
    0 / 8 (0.00%)
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Delirium
         subjects affected / exposed
    0 / 55 (0.00%)
    0 / 8 (0.00%)
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Product issues
    Device issue
         subjects affected / exposed
    0 / 55 (0.00%)
    1 / 8 (12.50%)
    0 / 69 (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
    Investigations
    Anti factor VIII antibody positive
         subjects affected / exposed
    0 / 55 (0.00%)
    0 / 8 (0.00%)
    2 / 69 (2.90%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Heart rate increased
         subjects affected / exposed
    1 / 55 (1.82%)
    0 / 8 (0.00%)
    0 / 69 (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
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    0 / 55 (0.00%)
    0 / 8 (0.00%)
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    1 / 55 (1.82%)
    0 / 8 (0.00%)
    0 / 69 (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
    Head injury
         subjects affected / exposed
    2 / 55 (3.64%)
    0 / 8 (0.00%)
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tongue injury
         subjects affected / exposed
    0 / 55 (0.00%)
    0 / 8 (0.00%)
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Post procedural fistula
         subjects affected / exposed
    0 / 55 (0.00%)
    0 / 8 (0.00%)
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Traumatic haematoma
         subjects affected / exposed
    0 / 55 (0.00%)
    0 / 8 (0.00%)
    1 / 69 (1.45%)
         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
    0 / 55 (0.00%)
    0 / 8 (0.00%)
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tooth injury
         subjects affected / exposed
    0 / 55 (0.00%)
    0 / 8 (0.00%)
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tooth fracture
         subjects affected / exposed
    0 / 55 (0.00%)
    0 / 8 (0.00%)
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Wound
         subjects affected / exposed
    0 / 55 (0.00%)
    0 / 8 (0.00%)
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Wound haemorrhage
         subjects affected / exposed
    0 / 55 (0.00%)
    0 / 8 (0.00%)
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebral haemorrhage
         subjects affected / exposed
    1 / 55 (1.82%)
    0 / 8 (0.00%)
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Febrile convulsion
         subjects affected / exposed
    1 / 55 (1.82%)
    0 / 8 (0.00%)
    0 / 69 (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
    Spinal epidural haematoma
         subjects affected / exposed
    1 / 55 (1.82%)
    0 / 8 (0.00%)
    0 / 69 (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
    0 / 55 (0.00%)
    0 / 8 (0.00%)
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 55 (0.00%)
    0 / 8 (0.00%)
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Factor VIII inhibition
         subjects affected / exposed
    10 / 55 (18.18%)
    0 / 8 (0.00%)
    12 / 69 (17.39%)
         occurrences causally related to treatment / all
    10 / 10
    0 / 0
    12 / 13
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Mouth haemorrhage
         subjects affected / exposed
    1 / 55 (1.82%)
    0 / 8 (0.00%)
    0 / 69 (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 and subcutaneous tissue disorders
    Angioedema
         subjects affected / exposed
    0 / 55 (0.00%)
    0 / 8 (0.00%)
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rash erythematous
         subjects affected / exposed
    0 / 55 (0.00%)
    0 / 8 (0.00%)
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Haemarthrosis
         subjects affected / exposed
    1 / 55 (1.82%)
    0 / 8 (0.00%)
    0 / 69 (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
    Device related infection
         subjects affected / exposed
    0 / 55 (0.00%)
    1 / 8 (12.50%)
    0 / 69 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Enterobacter infection
         subjects affected / exposed
    0 / 55 (0.00%)
    0 / 8 (0.00%)
    1 / 69 (1.45%)
         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
    0 / 55 (0.00%)
    0 / 8 (0.00%)
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchiolitis
         subjects affected / exposed
    1 / 55 (1.82%)
    0 / 8 (0.00%)
    0 / 69 (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
    Gastroenteritis
         subjects affected / exposed
    0 / 55 (0.00%)
    0 / 8 (0.00%)
    1 / 69 (1.45%)
         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 / 55 (1.82%)
    0 / 8 (0.00%)
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    0 / 55 (0.00%)
    0 / 8 (0.00%)
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pharyngitis
         subjects affected / exposed
    0 / 55 (0.00%)
    0 / 8 (0.00%)
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pharyngotonsillitis
         subjects affected / exposed
    0 / 55 (0.00%)
    0 / 8 (0.00%)
    1 / 69 (1.45%)
         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 haemophilus
         subjects affected / exposed
    0 / 55 (0.00%)
    0 / 8 (0.00%)
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tonsillitis
         subjects affected / exposed
    0 / 55 (0.00%)
    0 / 8 (0.00%)
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 55 (0.00%)
    0 / 8 (0.00%)
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory syncytial virus infection
         subjects affected / exposed
    0 / 55 (0.00%)
    0 / 8 (0.00%)
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory syncytial virus bronchiolitis
         subjects affected / exposed
    1 / 55 (1.82%)
    0 / 8 (0.00%)
    0 / 69 (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
    Vascular device infection
         subjects affected / exposed
    0 / 55 (0.00%)
    0 / 8 (0.00%)
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Varicella zoster virus infection
         subjects affected / exposed
    0 / 55 (0.00%)
    0 / 8 (0.00%)
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tracheobronchitis
         subjects affected / exposed
    0 / 55 (0.00%)
    0 / 8 (0.00%)
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tracheitis
         subjects affected / exposed
    0 / 55 (0.00%)
    0 / 8 (0.00%)
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         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
    		 Pre-prophylaxis Immune tolerance induction (ITI) Prophylaxis
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    28 / 55 (50.91%)
    7 / 8 (87.50%)
    51 / 69 (73.91%)
    Investigations
    Anti factor VIII antibody positive
         subjects affected / exposed
    3 / 55 (5.45%)
    0 / 8 (0.00%)
    1 / 69 (1.45%)
         occurrences all number
    3
    0
    1
    Injury, poisoning and procedural complications
    Anaesthetic complication
         subjects affected / exposed
    0 / 55 (0.00%)
    1 / 8 (12.50%)
    0 / 69 (0.00%)
         occurrences all number
    0
    1
    0
    Contusion
         subjects affected / exposed
    3 / 55 (5.45%)
    1 / 8 (12.50%)
    5 / 69 (7.25%)
         occurrences all number
    5
    2
    72
    Cardiac disorders
    Cyanosis
         subjects affected / exposed
    4 / 55 (7.27%)
    0 / 8 (0.00%)
    0 / 69 (0.00%)
         occurrences all number
    4
    0
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    2 / 55 (3.64%)
    1 / 8 (12.50%)
    0 / 69 (0.00%)
         occurrences all number
    3
    2
    0
    Factor VIII inhibition
         subjects affected / exposed
    0 / 55 (0.00%)
    0 / 8 (0.00%)
    4 / 69 (5.80%)
         occurrences all number
    0
    0
    6
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    5 / 55 (9.09%)
    2 / 8 (25.00%)
    26 / 69 (37.68%)
         occurrences all number
    6
    2
    75
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    1 / 55 (1.82%)
    1 / 8 (12.50%)
    6 / 69 (8.70%)
         occurrences all number
    1
    1
    9
    Vomiting
         subjects affected / exposed
    1 / 55 (1.82%)
    1 / 8 (12.50%)
    5 / 69 (7.25%)
         occurrences all number
    1
    1
    10
    Tooth loss
         subjects affected / exposed
    0 / 55 (0.00%)
    1 / 8 (12.50%)
    1 / 69 (1.45%)
         occurrences all number
    0
    3
    2
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    3 / 55 (5.45%)
    0 / 8 (0.00%)
    9 / 69 (13.04%)
         occurrences all number
    3
    0
    13
    Tonsillar hypertrophy
         subjects affected / exposed
    0 / 55 (0.00%)
    1 / 8 (12.50%)
    1 / 69 (1.45%)
         occurrences all number
    0
    1
    1
    Rhinorrhoea
         subjects affected / exposed
    0 / 55 (0.00%)
    1 / 8 (12.50%)
    7 / 69 (10.14%)
         occurrences all number
    0
    1
    13
    Skin and subcutaneous tissue disorders
    Dermatitis diaper
         subjects affected / exposed
    1 / 55 (1.82%)
    1 / 8 (12.50%)
    1 / 69 (1.45%)
         occurrences all number
    1
    1
    2
    Infections and infestations
    Hand-foot-and-mouth disease
         subjects affected / exposed
    0 / 55 (0.00%)
    1 / 8 (12.50%)
    3 / 69 (4.35%)
         occurrences all number
    0
    1
    3
    Gastroenteritis
         subjects affected / exposed
    1 / 55 (1.82%)
    0 / 8 (0.00%)
    9 / 69 (13.04%)
         occurrences all number
    1
    0
    10
    Ear infection
         subjects affected / exposed
    3 / 55 (5.45%)
    0 / 8 (0.00%)
    9 / 69 (13.04%)
         occurrences all number
    7
    0
    13
    Conjunctivitis
         subjects affected / exposed
    0 / 55 (0.00%)
    0 / 8 (0.00%)
    5 / 69 (7.25%)
         occurrences all number
    0
    0
    6
    Cellulitis
         subjects affected / exposed
    0 / 55 (0.00%)
    1 / 8 (12.50%)
    1 / 69 (1.45%)
         occurrences all number
    0
    1
    1
    Bronchitis
         subjects affected / exposed
    1 / 55 (1.82%)
    1 / 8 (12.50%)
    6 / 69 (8.70%)
         occurrences all number
    1
    1
    6
    Influenza
         subjects affected / exposed
    0 / 55 (0.00%)
    0 / 8 (0.00%)
    6 / 69 (8.70%)
         occurrences all number
    0
    0
    7
    Varicella
         subjects affected / exposed
    1 / 55 (1.82%)
    1 / 8 (12.50%)
    2 / 69 (2.90%)
         occurrences all number
    1
    1
    2
    Upper respiratory tract infection
         subjects affected / exposed
    7 / 55 (12.73%)
    2 / 8 (25.00%)
    16 / 69 (23.19%)
         occurrences all number
    8
    3
    35
    Tonsillitis
         subjects affected / exposed
    2 / 55 (3.64%)
    0 / 8 (0.00%)
    6 / 69 (8.70%)
         occurrences all number
    2
    0
    8
    Rhinitis
         subjects affected / exposed
    0 / 55 (0.00%)
    0 / 8 (0.00%)
    5 / 69 (7.25%)
         occurrences all number
    0
    0
    10
    Pharyngotonsillitis
         subjects affected / exposed
    0 / 55 (0.00%)
    0 / 8 (0.00%)
    4 / 69 (5.80%)
         occurrences all number
    0
    0
    4
    Pharyngitis
         subjects affected / exposed
    1 / 55 (1.82%)
    0 / 8 (0.00%)
    5 / 69 (7.25%)
         occurrences all number
    1
    0
    8
    Otitis media
         subjects affected / exposed
    2 / 55 (3.64%)
    1 / 8 (12.50%)
    4 / 69 (5.80%)
         occurrences all number
    2
    1
    6
    Nasopharyngitis
         subjects affected / exposed
    6 / 55 (10.91%)
    1 / 8 (12.50%)
    22 / 69 (31.88%)
         occurrences all number
    7
    4
    80
    Viral infection
         subjects affected / exposed
    1 / 55 (1.82%)
    0 / 8 (0.00%)
    5 / 69 (7.25%)
         occurrences all number
    1
    0
    5

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    20 Mar 2015
    Detailed information on major surgery and ITI, extended trial timelines.
    01 Nov 2016
    This protocol amendment included a new secondary endpoint to assess the ITI treatment outcome and included monitoring of antibody development against Host Cell Protein (HCP).
    13 Jun 2019
    This protocol amendment specified interim analysis when approximately 45 subjects had reached 50 EDs each, and additional administrative changes.
    15 Jun 2020
    This protocol amendment specified the closure of recruitment to the trial, and that more than 50 but less than 100 subjects would complete the trial. LPLV date 13 November 2021 was kept. Due to the observations of non-inhibitor subjects with low IR, anti-PEG IgG and additional IgM antibody analyses were added to the assessments.

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

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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