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    Clinical Trial Results:
    International clinical study to investigate the efficacy and safety of Wiloctin in patients with inherited von willebrand disease (vWD)

    Summary
    EudraCT number
    		 2006-002857-54
    Trial protocol
    		 DE  
    Global end of trial date
    02 Mar 2007

    Results information
    Results version number
    		 v1(current)
    This version publication date
    23 Nov 2017
    First version publication date
    23 Nov 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    TMAE-104
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Octapharma AG
    Sponsor organisation address
    Seidenstrasse 2, Lachen, Switzerland, CH-8853
    Public contact
    Clinical Research and Develpment, Octapharma Pharmazeutika Produktionsgesellschaft mbH, 0043 1610320,
    Scientific contact
    Clinical Research and Develpment, Octapharma Pharmazeutika Produktionsgesellschaft mbH, 0043 1610320, clinical.department@octapharma.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
    11 Jul 2007
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    02 Mar 2007
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study is to confirm the clinical efficacy of WILOCTIN using surrogate markers, i.e. the plasma levels of FVIII:C, vWF:Ag, vWF:CBA and vWF:RCoF before and after administration.
    Protection of trial subjects
    This trial was conducted in accordance to the principles of GCP, ensuring that the rights, safety and well-being of patients are protected and in consistency with the Declaration of Helsinki. Inclusion and exclusion criteria were carefully defined in order to protect subjects from contraindications, interactions with other medication and risk factors associated with the investigational medicinal product. Throughout the study safety was assessed, such as occurrence of AEs, safety labs, assessment of viral markers, vital signs and physical examinations.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    02 Jan 2002
    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
    Poland: 23
    Country: Number of subjects enrolled
    Portugal: 3
    Country: Number of subjects enrolled
    Sweden: 5
    Country: Number of subjects enrolled
    United Kingdom: 5
    Country: Number of subjects enrolled
    Finland: 2
    Country: Number of subjects enrolled
    Austria: 2
    Country: Number of subjects enrolled
    Norway: 1
    Worldwide total number of subjects
    41
    EEA total number of subjects
    41
    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)
    7
    Adolescents (12-17 years)
    3
    Adults (18-64 years)
    27
    From 65 to 84 years
    4
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Defined inherited VWD, types 1 to 3; aged > 6 and < 85 years; not sufficiently responding to DDAVP treatment; written informed consent freely given.

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

    Arms
    Arm title
    		 WILATE (formerly called Wiloctin)
    Arm description
    		 Dosing of WILATE (formerly called Wiloctin) and frequency of treatment was determined according to the clinical needs of the subjects and the opinion of the treating physician. WILATE was administered intravenously. Twenty eight different WILATE batches were used during the study.
    Arm type
    		 Experimental

    Investigational medicinal product name
    WILATE, plasma derived VWF: FVIII concentrate
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    WILATE was to be injected intravenously at a speed of 2-3 mL per minute, using aseptic technique. At the end of the infusion, the injection line was to be flushed with 0.9 % sodium chloride. WILATE could also be administered by continuous infusion

    Number of subjects in period 1
    		WILATE (formerly called Wiloctin)
    Started
    41
    Completed
    41

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall Trial
    Reporting group description
    		 -

    Reporting group values
    		 Overall Trial Total
    Number of subjects
    		 41 41
    Age categorical
    Units: Subjects
        Age total
    		 41 41
    Age continuous
    Units: years
        arithmetic mean (full range (min-max))
    		 36.2 (5 to 73) -
    Gender categorical
    Units: Subjects
        Female
    		 23 23
        Male
    		 18 18

    End points

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    End points reporting groups
    Reporting group title
    WILATE (formerly called Wiloctin)
    Reporting group description
    		 Dosing of WILATE (formerly called Wiloctin) and frequency of treatment was determined according to the clinical needs of the subjects and the opinion of the treating physician. WILATE was administered intravenously. Twenty eight different WILATE batches were used during the study.

    Subject analysis set title
    VWD Type 3 PK Analysis Baseline
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    surrogate markers, i.e. plasma levels of FVIII:C, FVIII:C chromo, VWF:Ag, VWF:CB and VWF:RCo at Baseline

    Subject analysis set title
    VWD Type 3 PK Analysis > 6M
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    surrogate markers, i.e. plasma levels of FVIII:C, FVIII:C chromo, VWF:Ag, VWF:CB and VWF:RCo t > 6M

    Subject analysis set title
    VWD Type 3 Recovery (nominal) Analysis Baseline
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    surrogate markers, i.e. plasma levels of FVIII:C, FVIII:C chromo, VWF:Ag and VWF:RCo at Baseline

    Subject analysis set title
    VWD Type 3 Recovery (nominal) Analysis >6M
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    surrogate markers, i.e. plasma levels of FVIII:C, FVIII:C chromo, VWF:Ag and VWF:RCo at Baseline

    Subject analysis set title
    VWD Type 3 Recovery (actual) Analysis Baseline
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    surrogate markers, i.e. plasma levels of FVIII:C, FVIII:C chromo and VWF:RCo at Baseline

    Subject analysis set title
    VWD Type 3 Recovery (actual) Analysis >6M
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    surrogate markers, i.e. plasma levels of FVIII:C, FVIII:C chromo and VWF:RCo at Baseline

    Primary: Median Half Life

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    End point title
    		 Median Half Life [1]
    End point description
    surrogate markers, i.e. plasma levels of FVIII:C, FVIII:C chromo, VWF:Ag, VWF:CB and VWF:RCo at Baseline and >6M
    End point type
    Primary
    End point timeframe
    Baseline and >6M.
    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: Primarily descriptive statistical methods were used to analyse the data. Statistical tests of hypotheses and confidence intervals were of explanatory nature only.
    End point values
    		 VWD Type 3 PK Analysis Baseline VWD Type 3 PK Analysis > 6M
    Number of subjects analysed
    6
    6
    Units: hours
    number (not applicable)
        VWF: RCo
    18.96
    15.75
        VWF: Ag
    9.44
    9.66
        VWF:CB
    12.46
    13.42
        FVIII: C chromo
    16.84
    16.35
        FVIII:C
    24.21
    18.57
    No statistical analyses for this end point

    Primary: Median Recovery (nominal)

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    End point title
    		 Median Recovery (nominal) [2]
    End point description
    surrogate markers, i.e. plasma levels of FVIII:C, FVIII:C chromo, VWF:Ag and VWF:RCo at Baseline and >6M
    End point type
    Primary
    End point timeframe
    Baseline and >6M
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Primarily descriptive statistical methods were used to analyse data. Statistical tests of hypotheses and confidence intervals were of explanatory nature only.
    End point values
    		 VWD Type 3 Recovery (nominal) Analysis Baseline VWD Type 3 Recovery (nominal) Analysis >6M
    Number of subjects analysed
    6
    6
    Units: %/IU/kg
    number (not applicable)
        VWF: RCo
    1.47
    1.41
        VWF: Ag
    1.35
    1.63
        FVIII: C chromo
    1.72
    1.61
        FVIII:C
    1.76
    1.67
    No statistical analyses for this end point

    Primary: Median Recovery (actual)

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    End point title
    		 Median Recovery (actual) [3]
    End point description
    surrogate markers, i.e. plasma levels of FVIII:C, FVIII:C chromo and VWF:RCo at Baseline and >6M
    End point type
    Primary
    End point timeframe
    Baseline and >6M
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Primarily descriptive statistical methods were used to analyse the data. Statistical tests of hypotheses and confidence intervals were of explanatory nature only.
    End point values
    		 VWD Type 3 Recovery (actual) Analysis Baseline VWD Type 3 Recovery (actual) Analysis >6M
    Number of subjects analysed
    6
    6
    Units: %/IU/kg
    number (not applicable)
        VWF: RCo
    1.85
    1.75
        FVIII: C chromo
    1.76
    1.67
        FVIII:C
    1.8
    1.74
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    throughout the study period
    Adverse event reporting additional description
    AEs were to be categorised according to intensity, duration, frequency and time of occurrence
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    9.0
    Reporting groups
    Reporting group title
    Safety Set
    Reporting group description
    		 All subjects who had received at least one treatment with WILATE

    Serious adverse events
    		 Safety Set
    Total subjects affected by serious adverse events
         subjects affected / exposed
    12 / 41 (29.27%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Investigations
    Parvovirus B19 serology positive
         subjects affected / exposed
    3 / 41 (7.32%)
         occurrences causally related to treatment / all
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    Injury, poisoning and procedural complications
    Scratch
         subjects affected / exposed
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Surgical and medical procedures
    Tooth extraction
         subjects affected / exposed
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorders
    Syncope
         subjects affected / exposed
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Catheter site haemorrhage
         subjects affected / exposed
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Chest pain
         subjects affected / exposed
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    multi-organ failure
         subjects affected / exposed
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Gastrointestinal haemorrhage
         subjects affected / exposed
    5 / 41 (12.20%)
         occurrences causally related to treatment / all
    0 / 30
         deaths causally related to treatment / all
    0 / 0
    Melaena
         subjects affected / exposed
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Mouth haemorrhage
         subjects affected / exposed
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Epistaxis
         subjects affected / exposed
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal and connective tissue disorders
    Haemarthrosis
         subjects affected / exposed
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Synovitis
         subjects affected / exposed
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    catheter related infection
         subjects affected / exposed
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Parotitis
         subjects affected / exposed
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Safety Set
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    25 / 41 (60.98%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    3 / 41 (7.32%)
         occurrences all number
    4
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    5 / 41 (12.20%)
         occurrences all number
    10
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    3 / 41 (7.32%)
         occurrences all number
    6
    Gastrointestinal disorders
    Gastrointestinal haemorrhage
         subjects affected / exposed
    5 / 41 (12.20%)
         occurrences all number
    30
    Infections and infestations
    Pharyngitis
         subjects affected / exposed
    9 / 41 (21.95%)
         occurrences all number
    18
    Nasopharyngitis
         subjects affected / exposed
    4 / 41 (9.76%)
         occurrences all number
    10

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    14 Nov 2001
    Amendment I : In order to confirm the available information on the pharmacokinetic properties of Wiloctin, it has been proposed to include a pharmacokinetic evaluation of Wiloctin in some patients (e.g. before the patients have to undergo a planned surgery). Therefore, Octapharma decided to amend the study protocol, and to include a pharmacokinetic assessment in around 10 patients.
    16 Oct 2006
    Amendment VI: Due to the submission of the study in Germany, it is necessary to amend the individual duration of the study.

    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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