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    Clinical Trial Results:
    A multi-centre, comparative, double blind, randomised cross-over trial investigating single dose pharmacokinetics and safety of turoctocog alfa pegol from the pivotal process and turoctocog alfa pegol from the commercial process in patients with severe haemophilia A

    Summary
    EudraCT number
    2015-005327-63
    Trial protocol
    NL   DK   DE   ES   FR  
    Global end of trial date
    07 Apr 2017

    Results information
    Results version number
    v1(current)
    This version publication date
    12 Apr 2018
    First version publication date
    12 Apr 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    NN7088-4033
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02920398
    WHO universal trial number (UTN)
    U1111-1176-9253
    Sponsors
    Sponsor organisation name
    Novo Nordisk A/S
    Sponsor organisation address
    Novo Allé, Bagsvaerd, 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
    28 Nov 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    07 Apr 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    07 Apr 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate and compare the single-dose pharmacokinetic of N8-GP (turoctocog alfa pegol) from the pivotal process with N8-GP from the commercial process, each given as intravenous administrations of 50 U/kg to patients with severe haemophilia A.
    Protection of trial subjects
    The trial was conducted in accordance with the Declaration of Helsinki (2008), International Conference on Harmonisation (ICH) Good Clinical Practice (1996) and United States Food and Drug Administration (FDA) 21 Code of Federal Regulations (CFR) 312.120.
    Background therapy
    Not applicable.
    Evidence for comparator
    Not applicable.
    Actual start date of recruitment
    04 Oct 2016
    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
    Denmark: 3
    Country: Number of subjects enrolled
    France: 1
    Country: Number of subjects enrolled
    Germany: 2
    Country: Number of subjects enrolled
    Netherlands: 2
    Country: Number of subjects enrolled
    Spain: 2
    Country: Number of subjects enrolled
    United States: 11
    Worldwide total number of subjects
    21
    EEA total number of subjects
    10
    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)
    0
    Adults (18-64 years)
    19
    From 65 to 84 years
    2
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    The trial was conducted at 11 sites in 6 countries, as follows: Denmark: 1 site; France: 1 site; Germany: 1 site; Netherlands: 1 site; Spain: 2 sites; United States: 5 sites.

    Pre-assignment
    Screening details
    Study Design: Subjects were recruited from trial NN7088-3859 (EudraCT number: 2011-001142-15) and returned to trial NN7088-3859 upon completion of this trial. This cross over trial included two identical pharmacokinetic (PK) visits (each consisting of 5 days) with a wash-out period of at least 7 days prior to each PK visit.

    Period 1
    Period 1 title
    Overall study (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator
    Blinding implementation details
    N8-GP was packed blinded and allocated via the interactive web response system (IWRS) to ensure the blinding of the trial product. The N8-GP from the pivotal manufacturing process and N8-GP from the commercial manufacturing process were visually identical.

    Arms
    Arm title
    Overall population
    Arm description
    This was a two period cross-over study. All subjects were randomised in a 1:1 manner to receive one of the two possible treatment sequences of trial products, turoctocog alfa pegol (N8-GP) from the commercial process and N8-GP from the pivotal process. Subjects, who received N8-GP from the commercial process in treatment period 1, received N8-GP from the pivotal process in treatment period 2. And subjects, who received N8-GP from the pivotal process in treatment period 1, received N8-GP from the commercial process in treatment period 2. There was a wash-out period of at least 7 days prior to dosing in both the periods.
    Arm type
    Cross-over

    Investigational medicinal product name
    Turoctocog alfa pegol
    Investigational medicinal product code
    Other name
    N8-GP
    Pharmaceutical forms
    Powder and solvent for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects were administered with a single-dose of N8-GP 50±5 IU/kg from the commercial process on day 1 of both the treatment periods. N8-GP was supplied as a sterile, freeze-dried powder in a 2–8°C (36–46°F) stable formulation single use vial with a nominal content of 2000 IU/vial was reconstituted with 4.3 mL 0.9% isotonic sodium chloride solution for intravenous (i.v.) injection. After reconstitution each vial contained 500 IU/mL N8-GP.

    Investigational medicinal product name
    Turoctocog alfa pegol
    Investigational medicinal product code
    Other name
    N8-GP
    Pharmaceutical forms
    Powder and solvent for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects were administered with a single-dose of N8-GP 50±5 IU/kg from the pivotal process on day 1 of both the treatment periods. N8-GP was supplied as a sterile, freeze-dried powder in a 2–8°C (36–46°F) stable formulation single use vial with a nominal content of 2000 IU/vial was reconstituted with 4.3 mL 0.9% isotonic sodium chloride solution for i.v. injection. After reconstitution each vial contained 500 IU/mL N8-GP.

    Number of subjects in period 1
    Overall population
    Started
    21
    Completed
    21

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall population
    Reporting group description
    This was a two period cross-over study. All subjects were randomised in a 1:1 manner to receive one of the two possible treatment sequences of trial products, turoctocog alfa pegol (N8-GP) from the commercial process and N8-GP from the pivotal process. Subjects, who received N8-GP from the commercial process in treatment period 1, received N8-GP from the pivotal process in treatment period 2. And subjects, who received N8-GP from the pivotal process in treatment period 1, received N8-GP from the commercial process in treatment period 2. There was a wash-out period of at least 7 days prior to dosing in both the periods.

    Reporting group values
    Overall population Total
    Number of subjects
    21 21
    Age Categorical
    Units: Subjects
        Adults (18-64 years)
    19 19
        From 65-84 years
    2 2
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    42.4 ( 14.2 ) -
    Gender Categorical
    Units: Subjects
        Male
    21 21
    Subject analysis sets

    Subject analysis set title
    Turoctocog alfa pegol commercial process
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Subjects received N8-GP from the commercial process in treatment period 1 (from treatment sequence, N8-GP commercial process/N8-GP pivotal process) and in treatment period 2 (from treatment sequence, N8-GP pivotal process/N8-GP commercial process).

    Subject analysis set title
    Turoctocog alfa pegol pivotal process
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Subjects received N8-GP from the pivotal process in treatment period 1 (from treatment sequence, N8-GP pivotal process/N8-GP commercial process) and in treatment period 2 (from treatment sequence, N8-GP commercial process/N8-GP pivotal process).

    Subject analysis sets values
    Turoctocog alfa pegol commercial process Turoctocog alfa pegol pivotal process
    Number of subjects
    21
    21
    Age Categorical
    Units: Subjects
        Adults (18-64 years)
    19
    19
        From 65-84 years
    2
    2
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    42.4 ( 14.2 )
    42.4 ( 14.2 )
    Gender Categorical
    Units: Subjects
        Male
    21
    21

    End points

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    End points reporting groups
    Reporting group title
    Overall population
    Reporting group description
    This was a two period cross-over study. All subjects were randomised in a 1:1 manner to receive one of the two possible treatment sequences of trial products, turoctocog alfa pegol (N8-GP) from the commercial process and N8-GP from the pivotal process. Subjects, who received N8-GP from the commercial process in treatment period 1, received N8-GP from the pivotal process in treatment period 2. And subjects, who received N8-GP from the pivotal process in treatment period 1, received N8-GP from the commercial process in treatment period 2. There was a wash-out period of at least 7 days prior to dosing in both the periods.

    Subject analysis set title
    Turoctocog alfa pegol commercial process
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Subjects received N8-GP from the commercial process in treatment period 1 (from treatment sequence, N8-GP commercial process/N8-GP pivotal process) and in treatment period 2 (from treatment sequence, N8-GP pivotal process/N8-GP commercial process).

    Subject analysis set title
    Turoctocog alfa pegol pivotal process
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Subjects received N8-GP from the pivotal process in treatment period 1 (from treatment sequence, N8-GP pivotal process/N8-GP commercial process) and in treatment period 2 (from treatment sequence, N8-GP commercial process/N8-GP pivotal process).

    Primary: Area under the FVIII activity-time curve - dose normalised to 50 U/kg (AUC0-96h, norm)

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    End point title
    Area under the FVIII activity-time curve - dose normalised to 50 U/kg (AUC0-96h, norm)
    End point description
    Area under the FVIII plasma activity versus time profile from time zero to 96h normalised to 50 U/kg (AUC0-96h, norm). i.e., Measure of FVIII plasma exposure in the time interval 0 to 96h. Blood samples were analysed using both chromogenic and one-stage clotting assays. The results are based on the full analysis set (FAS), which included all subjects with at least one evaluable PK profile. Number of subjects analysed = number of subjects contributed to the analysis. The following mentioned ‘Measure Type’ should be read as ‘Geometric Mean (Coefficient of Variation in Percentage)’.
    End point type
    Primary
    End point timeframe
    From 0 to 96 h post injection
    End point values
    Turoctocog alfa pegol commercial process Turoctocog alfa pegol pivotal process
    Number of subjects analysed
    20
    20
    Units: IU*h/mL
    geometric mean (geometric coefficient of variation)
        Chromogenic assay
    34.250 ( 32.091 )
    34.064 ( 28.715 )
        One-stage clotting assay
    40.965 ( 29.241 )
    41.731 ( 19.964 )
    Statistical analysis title
    N8-GP commercial process vs N8-GP pivotal process
    Statistical analysis description
    The primary endpoint was log-transformed and analysed using an analysis of variance (ANOVA) model with product, period, sequence and patient within sequence as factors. The following ‘comparison groups’ should be read as 'N8-GP commercial process versus (vs) N8-GP pivotal process'. Due to cross-over design of the trial, the following ‘number of subjects included in analysis’ is being erroneously displayed as 40. Actual ‘number of subjects included in analysis’ is 20.
    Comparison groups
    Turoctocog alfa pegol commercial process v Turoctocog alfa pegol pivotal process
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    Treatment ratio
    Point estimate
    1.01
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    0.97
         upper limit
    1.04

    Secondary: FVIII activity 30 min post administration - dose normalised to 50 U/kg

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    End point title
    FVIII activity 30 min post administration - dose normalised to 50 U/kg
    End point description
    The FVIII activity recorded 30 minutes after end of injection normalised to 50 U/kg. Blood samples were analysed using both chromogenic and one-stage clotting assays. The following timeframe should be read as ‘from time of trial product administration to 30 minutes post-dose’. The results are based on the FAS. Number of subjects analysed = number of subjects contributed to the analysis. The following mentioned ‘Measure Type’ should be read as ‘Geometric Mean (Coefficient of Variation in Percentage)’.
    End point type
    Secondary
    End point timeframe
    From time of trial product administration to 96 hours post-dose
    End point values
    Turoctocog alfa pegol commercial process Turoctocog alfa pegol pivotal process
    Number of subjects analysed
    20
    20
    Units: IU/mL
    geometric mean (geometric coefficient of variation)
        Chromogenic assay
    1.183 ( 16.568 )
    1.157 ( 18.982 )
        One-stage clotting assay
    1.420 ( 22.105 )
    1.320 ( 19.032 )
    No statistical analyses for this end point

    Secondary: Area under the FVIII activity-time curve from 0 to infinity

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    End point title
    Area under the FVIII activity-time curve from 0 to infinity
    End point description
    Area under the FVIII activity versus time profile from time zero to infinity (AUC0-inf). i.e., Measure of total FVIII plasma exposure. Blood samples were analysed using both chromogenic and one-stage clotting assays. The following timeframe should be read as ‘from time of trial product administration to infinity’. The results are based on the FAS. Number of subjects analysed = number of subjects contributed to the analysis. The following mentioned ‘Measure Type’ should be read as ‘Geometric Mean (Coefficient of Variation in Percentage)’.
    End point type
    Secondary
    End point timeframe
    From time of trial product administration to 96 hours post-dose
    End point values
    Turoctocog alfa pegol commercial process Turoctocog alfa pegol pivotal process
    Number of subjects analysed
    18
    18
    Units: IU*h/mL
    geometric mean (geometric coefficient of variation)
        Chromogenic assay
    40.305 ( 32.112 )
    40.987 ( 27.532 )
        One-stage clotting assay
    49.598 ( 28.704 )
    50.594 ( 22.384 )
    No statistical analyses for this end point

    Secondary: Clearance

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    End point title
    Clearance
    End point description
    Total plasma clearance (CL) of drug after intravenous administration. Blood samples were analysed using both chromogenic and one-stage clotting assays. The following timeframe should be read as ‘from time of trial product administration to infinity’. The results are based on the FAS. Number of subjects analysed = number of subjects contributed to the analysis. The following mentioned ‘Measure Type’ should be read as ‘Geometric Mean (Coefficient of Variation in Percentage)’.
    End point type
    Secondary
    End point timeframe
    From time of trial product administration to 96 hours post-dose
    End point values
    Turoctocog alfa pegol commercial process Turoctocog alfa pegol pivotal process
    Number of subjects analysed
    18
    18
    Units: mL/h/kg
    geometric mean (geometric coefficient of variation)
        Chromogenic assay
    1.340 ( 31.753 )
    1.340 ( 27.141 )
        One-stage clotting assay
    1.089 ( 28.218 )
    1.085 ( 22.120 )
    No statistical analyses for this end point

    Secondary: Incremental recovery

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    End point title
    Incremental recovery
    End point description
    Dose-normalised FVIII activity recorded 30 min after end of injection and reported as [U/mL]/[U/kg]. Expected to be the highest dose-normalised activity observed. Blood samples were analysed using both chromogenic and one-stage clotting assays. The following timeframe should be read as ‘from time of trial product administration to 30 min post-dose’. The results are based on the FAS. Number of subjects analysed = number of subjects contributed to the analysis. The following mentioned ‘Measure Type’ should be read as ‘Geometric Mean (Coefficient of Variation in Percentage)’.
    End point type
    Secondary
    End point timeframe
    From time of trial product administration to 96 hours post-dose
    End point values
    Turoctocog alfa pegol commercial process Turoctocog alfa pegol pivotal process
    Number of subjects analysed
    18
    18
    Units: (IU/mL) / (U/kg)
    geometric mean (geometric coefficient of variation)
        Chromogenic assay
    0.023 ( 17.284 )
    0.023 ( 19.909 )
        One-stage clotting assay
    0.028 ( 24.325 )
    0.026 ( 20.728 )
    No statistical analyses for this end point

    Secondary: Terminal half-life

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    End point title
    Terminal half-life
    End point description
    Terminal half-life (t½) = ln(2) / λz, where λz was the terminal elimination rate estimated using linear regression on the terminal part of the log(activity) versus time profile. Blood samples were analysed using both chromogenic and one-stage clotting assays. The following timeframe should be read as ‘from 24 hours post-dose to 96 hours post-dose’. The results are based on the FAS. Number of subjects analysed = number of subjects contributed to the analysis. The following mentioned ‘Measure Type’ should be read as ‘Geometric Mean (Coefficient of Variation in Percentage)’.
    End point type
    Secondary
    End point timeframe
    From time of trial product administration to 96 hours post-dose
    End point values
    Turoctocog alfa pegol commercial process Turoctocog alfa pegol pivotal process
    Number of subjects analysed
    18
    18
    Units: hour (h)
    geometric mean (geometric coefficient of variation)
        Chromogenic assay
    19.469 ( 37.648 )
    20.648 ( 30.984 )
        One-stage clotting assay
    22.908 ( 37.168 )
    23.405 ( 35.313 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    All AEs reported after exposed to N8-GP were defined as TEAEs. Since all patients were transferred from trial NN7088-3859, all AEs reported in this trial were considered as treatment emergent even if the AE occurred prior to the first dosing in this trial
    Adverse event reporting additional description
    Analysis population: Safety analysis set, which included all subjects transferring from trial NN7088-3859 into this trial. All reported adverse events in this trial were treatment emergent adverse events (TEAEs).
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    20.0
    Frequency threshold for reporting non-serious adverse events: 5%
    Notes
    [1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported.
    Justification: No non-serious adverse events with a prevalence of 5% are available for this trial. In total, 2 subjects in the turoctocog alfa pegol pivotal process arm had non-serious adverse events and no subject in the turoctocog alfa pegol commercial process arm had non-serious adverse events. Additionally 3 AEs were reported outside the PK visits

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    04 Nov 2016
    Changes were done in exclusion criteria. A criterion on hypersensitivity was added. The wording of the criterion is identical to the exclusion criterion in trial NN7088-3859’s protocol from where all patients were recruited.
    23 Mar 2017
    This protocol amendment was prepared to clarify the assays used for assessment of coagulation factor VIII (FVIII) activity in trial NN7088-4033 in order to align with updates in the assay strategy for all pathfinder™ trials.

    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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