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    Clinical Trial Results:
    Evaluation of safety following Immune Tolerance Induction treatment with turoctocog alfa in patients with haemophilia A following inhibitor development in NN7170-4213 trial

    Summary
    EudraCT number
    		 2016-003821-40
    Trial protocol
    		 GB   AT   BG   DE  
    Global end of trial date
    19 Jun 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    27 Dec 2019
    First version publication date
    27 Dec 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    NN7170-4345
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03588741
    WHO universal trial number (UTN)
    		 U1111-1187-7323
    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, +1 866 8677178, clinicaltrials@novonordisk.com
    Scientific contact
    Clinical Reporting Anchor and Disclosure (1452), Novo Nordisk A/S, +1 866 8677178, 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
    31 Oct 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    19 Jun 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    19 Jun 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate safety of immune tolerance induction treatment with turoctocog alfa in patients who have developed neutralising antibodies against coagulation factor VIII (FVIII) after exposure to subcutaneous turoctocog alfa pegol during participation in NN7170-4213.
    Protection of trial subjects
    The trial was conducted in accordance with the Declaration of Helsinki (October 2013), ICH Good Clinical Practice, including archiving of essential documents (June 1996), and 21 CFR 312.120.
    Background therapy
    		 Not applicable.
    Evidence for comparator
    		 Not applicable.
    Actual start date of recruitment
    12 Jun 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
    Germany: 1
    Worldwide total number of subjects
    1
    EEA total number of subjects
    1
    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)
    1
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The trial was conducted at 1 trial site in Germany.

    Pre-assignment
    Screening details
    		 Previously treated subjects with severe haemophilia A (FVIII activity <1% according to medical records) who had developed clinically relevant FVIII inhibitors in trial NN7170-4213 were offered immune tolerance induction (ITI) treatment with turoctocog alfa.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Turoctocog alfa
    Arm description
    		 The subject received intravenous (i.v.) injection of 65 international units per kilogram (IU/kg) turoctocog alfa 3 times per week.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Turoctocog alfa
    Investigational medicinal product code
    Other name
    NovoEight
    Pharmaceutical forms
    Powder and solvent for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    The subject received i.v. injection of 65 IU/kg turoctocog alfa 3 times per week. The total consumption of turoctocog alfa comprised of a total of 8 administrations of between 63 and 65 IU/kg each.

    Number of subjects in period 1
    		Turoctocog alfa
    Started
    1
    Completed
    0
    Not completed
    1
         Withdrawal by subject
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Turoctocog alfa
    Reporting group description
    		 The subject received intravenous (i.v.) injection of 65 international units per kilogram (IU/kg) turoctocog alfa 3 times per week.

    Reporting group values
    		 Turoctocog alfa Total
    Number of subjects
    		 1 1
    Age Categorical
    Units: Subjects
        Adults (18-64 years)
    		 1 1
    Age Continuous
    Since the study enrolled a single subject, the age continuous data is not provided as this could be against General Data Protection Regulation (EU) 2016/679 (GDPR).
    Units: years
        arithmetic mean (standard deviation)
    		 0 ± 0 -
    Gender Categorical
    Units: Subjects
        Male
    		 1 1

    End points

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    End points reporting groups
    Reporting group title
    Turoctocog alfa
    Reporting group description
    		 The subject received intravenous (i.v.) injection of 65 international units per kilogram (IU/kg) turoctocog alfa 3 times per week.

    Subject analysis set title
    Full analysis set
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Full analysis set (FAS) comprised of all subjects who initiated ITI treatment with turoctocog alfa.

    Subject analysis set title
    Safety analysis set
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Safety analysis set (SAS) comprised of all subjects who initiated ITI treatment with turoctocog alfa.

    Primary: Number of adverse events

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    End point title
    		 Number of adverse events [1]
    End point description
    An adverse event (AE) was any untoward medical occurrence in a subject administered a medicinal product, and which does not necessarily have a causal relationship with this treatment. SAS comprised of all subjects who initiated ITI treatment with turoctocog alfa.
    End point type
    Primary
    End point timeframe
    During immune tolerance induction treatment with turoctocog alfa.
    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: The primary endpoint investigated safety and was analysed using descriptive statistics, and thus no statistical analysis was performed.
    End point values
    		 Turoctocog alfa
    Number of subjects analysed
    1 [2]
    Units: Events
    6
    Notes
    [2] - SAS.
    No statistical analyses for this end point

    Secondary: Response to immune tolerance induction treatment (success, partial success, failure, other)

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    End point title
    		 Response to immune tolerance induction treatment (success, partial success, failure, other)
    End point description
    ITI treatment response was categorized as: 1. Success: Undetectable inhibitor titre <0.6 bethesda units (BU) (or lower limit of quantification [LLoQ] if above 0.6 BU); Normalised FVIII in vivo recovery, defined as ≥0.013 international units (IU) per milliliter per IU per kilogram ((IU/ml)/(IU/kg)) (66% of expected incremental recovery); turoctocog alfa half-life ≥7 hours (based on FVIII activity) after 72 hours treatment-free washout period. 2. Partial success: Inhibitor titre ≤5 BU; Clinical effect of turoctocog alfa therapy as judged by the investigator. 3. Failure (one criterion had to be fulfilled): Failure to attain defined success or partial success after 24 months of ITI treatment with turoctocog alfa; Decrease in inhibitor titre after 12 months of ITI treatment <20% compared to peak titre. 4. Other: Subjects not fulfilling the above criteria e.g. early withdrawal from ITI treatment, lack of adherence to recommended ITI protocol etc. FAS.
    End point type
    Secondary
    End point timeframe
    Within a maximum immune tolerance induction treatment duration of 24 months.
    End point values
    		 Turoctocog alfa
    Number of subjects analysed
    1 [3]
    Units: Subjects
        Success
    0
        Partial success
    0
        Failure
    0
        Other
    1
    Notes
    [3] - FAS.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    up to 31 months
    Adverse event reporting additional description
    Evaluation of safety was based on SAS which comprised of all subjects who initiated ITI treatment with turoctocog alfa. ‘Number of deaths causally related to treatment’ is the data considered to present under ‘total number of deaths resulting from adverse events’.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22.0
    Reporting groups
    Reporting group title
    Turoctocog alfa
    Reporting group description
    		 Subjects received intravenous (i.v.) injection of 65 international units per kilogram (IU/kg) turoctocog alfa 3 times per week. The total consumption of turoctocog alfa comprised of a total of 8 administrations of between 63 and 65 IU/kg each.

    Serious adverse events
    		 Turoctocog alfa
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 1 (0.00%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Turoctocog alfa
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    1 / 1 (100.00%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    1 / 1 (100.00%)
         occurrences all number
    1
    Musculoskeletal and connective tissue disorders
    Muscle disorder
         subjects affected / exposed
    1 / 1 (100.00%)
         occurrences all number
    2
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    1 / 1 (100.00%)
         occurrences all number
    3

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    28 Jan 2019
    1) To align with new internal procedures in Novo Nordisk. Summary of Product Characteristics will no longer be the source of the Reference Safety Information (RSI) for assessment of AE expectedness. 2) Change in treatment of patient section, in order to allow investigators to treat the patients as deemed relevant and according to local guidelines. 3) Testing for non-neutralising antibodies will only be performed if deemed relevant or for safety reasons, e.g. in case of adverse events suspected of being related to antibodies.

    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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