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    Clinical Trial Results:
    A Multicentre, Interventional, Non-randomized, Open-label, Single-group Phase III Study to Evaluate Plasma-Derived Antihaemophilic Factor/von Willebrand Factor Concentrate (Biostate®) for Immune Tolerance Induction in Male Paediatric Subjects With Haemophilia A (</=2%) Who Have Developed High-titre Antibodies to Factor VIII (Factor VIII Inhibitors)

    Summary
    EudraCT number
    2010-020113-85
    Trial protocol
    DE   FR   AT   GR   IT  
    Global end of trial date
    10 Dec 2013

    Results information
    Results version number
    v1(current)
    This version publication date
    13 Jul 2016
    First version publication date
    06 Aug 2015
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CSLCT-BIO-10-67
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01445197
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    CSL Behring GmbH
    Sponsor organisation address
    Emil-von-Behring-Str. 76, Marburg, Germany, 35041
    Public contact
    Clinical Trial Disclosure Manager, CSL Behring, clinicaltrials@cslbehring.com
    Scientific contact
    Clinical Trial Disclosure Manager, CSL Behring, clinicaltrials@cslbehring.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?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    16 Apr 2014
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    10 Dec 2013
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The primary objective of this study was to determine the proportion of subjects who achieve a complete response (success) following immune tolerance induction (ITI) treatment with Biostate.
    Protection of trial subjects
    This study was carried out in accordance with the International Conference on Harmonisation (ICH) Good Clinical Practice guidelines, and standard operating procedures for clinical research and development at CSL Behring (CSLB). The study protocol and all amendments were approved by the Independent Ethics Committee(s) (IECs) / Institutional Review Board(s) (IRBs) of the participating centers. Before undergoing screening procedures for possible enrollment into the study, subjects were informed, in an understandable form, about the nature, scope, and possible consequences of the study. The investigator was responsible for obtaining a subject’s written informed consent to participate in the study. The investigator may cease study treatment and withdraw the subject, or the subject may withdraw himself from participation in the study at any time. If a subject is withdrawn from the study or further participation is declined, the subject will continue to have access to medical care and will be treated according to routine medical practice, but will no longer receive the investigational medicinal product (IMP).
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    07 Dec 2012
    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)
    1
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    The study included a Screening period of up to 28 days (plus an optional waiting period of up to 11 months). If the waiting period of up to 11 months was added at the discretion of the investigator to allow the subject’s inhibitor titre to decrease prior to the start of ITI treatment, the screening period duration was up to 12 months in total.

    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
    Biostate
    Arm description
    During ITI treatment, Biostate was administered intravenously at a daily dose of approximately 200 international units (IU)/kg body weight (b.w.), preferably split into 2 doses of 100 IU/kg b.w. per day.
    Arm type
    Experimental

    Investigational medicinal product name
    Human coagulation Factor VIII / von Willebrand Factor
    Investigational medicinal product code
    Other name
    Biostate®, Voncento®
    Pharmaceutical forms
    Powder and solvent for solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Doses were administered as bolus intravenous injections at a rate not exceeding 6 mL/min.

    Number of subjects in period 1
    Biostate
    Started
    1
    Completed Treatment Period
    1
    Completed
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Biostate
    Reporting group description
    During ITI treatment, Biostate was administered intravenously at a daily dose of approximately 200 international units (IU)/kg body weight (b.w.), preferably split into 2 doses of 100 IU/kg b.w. per day.

    Reporting group values
    Biostate Total
    Number of subjects
    1 1
    Age categorical
    Units: Subjects
        In utero
    0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0
        Newborns (0-27 days)
    0 0
        Infants and toddlers (28 days-23 months)
    1 1
        Children (2-11 years)
    0 0
        Adolescents (12-17 years)
    0 0
        Adults (18-64 years)
    0 0
        From 65-84 years
    0 0
        85 years and over
    0 0
    Gender categorical
    Units: Subjects
        Female
    0 0
        Male
    1 1

    End points

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    End points reporting groups
    Reporting group title
    Biostate
    Reporting group description
    During ITI treatment, Biostate was administered intravenously at a daily dose of approximately 200 international units (IU)/kg body weight (b.w.), preferably split into 2 doses of 100 IU/kg b.w. per day.

    Primary: Number of Subjects Who Achieve Complete, Partial, and No Response (ITI Failure) to Treatment

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    End point title
    Number of Subjects Who Achieve Complete, Partial, and No Response (ITI Failure) to Treatment [1]
    End point description
    Complete Response = The following criteria were met in the given order: 1. An undetectable inhibitor titre (<0.6 BU/mL) at 2 consecutive assessments, tested at intervals of 2 weeks (±3 days); 2. After the subject was placed on prophylaxis and after a 48-hour wash-out period, FVIII plasma recovery of ≥66% of predicted and FVIII half-life of ≥6 hours based on blood samples taken prior to and at 10 min, 30 min, 2, 8, 12 (optional), and 24 hrs after administration of 50 IU/kg b.w. Biostate. ITI Failure = One of the following 2 conditions was fulfilled: 1. For a non-overlapping 6-month period, a reduction in the inhibitor titre of ≥20% based on 2 measurements taken 2 weeks (±3 days) apart was not achieved; 2. after 30 months of ITI treatment, the inhibitor titre was >5.0 BU/mL. Partial Response = If subject at the end of ITI treatment met neither the criteria for complete response nor those for ITI failure, the outcome for that subject was to be regarded as partial response.
    End point type
    Primary
    End point timeframe
    Up to approximately 9 months
    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: Because the study was terminated and only 1 subject was enrolled into the study, the primary objective could not be assessed with any further statistical analysis.
    End point values
    Biostate
    Number of subjects analysed
    1
    Units: Subjects
        Complete Response
    0
        Partial Response
    0
        No Response (ITI Failure)
    1
    No statistical analyses for this end point

    Secondary: Summary of Overall Treatment-Emergent Adverse Events (AEs) and Serious AEs

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    End point title
    Summary of Overall Treatment-Emergent Adverse Events (AEs) and Serious AEs
    End point description
    An AE was defined as any untoward medical occurrence in a subject administered an IMP (whether it is the study or any reference product[s]), which does not necessarily have a causal relationship with the IMP. An SAE was defined as any untoward medical occurrence that at any dose: results in death; is life-threatening; requires in-patient hospitalisation or prolongation of existing hospitalization; results in persistent or significant disability or incapacity; is a congenital anomaly or birth defect; is medically significant. Treatment-emergent events were defined as those occurring after the first dose of IMP.
    End point type
    Secondary
    End point timeframe
    From first IMP dose through Final Visit (3 months [±2 weeks]) after complete response or the final dose of IMP (total study duration was up to approximately 9 months). AE/SAEs considered related to a study procedure were recorded from informed consent.
    End point values
    Biostate
    Number of subjects analysed
    1
    Units: subjects
        Overall TESAEs
    5
        Overall Unrelated TESAEs
    2
        Overall Possibly Related TESAEs
    3
        Overall Related TESAEs
    0
        Overall Non-serious TEAEs
    5
        Overall Unrelated Non-serious TEAEs
    5
        Overall Possibly Related Non-serious TEAEs
    0
        Overall Related Non-serious TEAEs
    0
    No statistical analyses for this end point

    Secondary: Number of Subjects With Clinically Significant Markers of Activation of Coagulation

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    End point title
    Number of Subjects With Clinically Significant Markers of Activation of Coagulation
    End point description
    Thrombogenic risk was assessed by reporting the number of subjects with clinical symptoms or increased markers of activation of coagulation (eg, fibrin fragments, thrombin-antithrombin complex [TAT]).
    End point type
    Secondary
    End point timeframe
    Up to approximately 9 months
    End point values
    Biostate
    Number of subjects analysed
    1
    Units: subjects
    1
    No statistical analyses for this end point

    Secondary: Summary of Bleeding Events

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    End point title
    Summary of Bleeding Events
    End point description
    The frequency, nature and location of bleeding events were recorded in the subject’s e-diary and/or the electronic case report form (eCRF). A major bleeding event was classified as one for which a subject was required to visit the Hemophilia Treatment Center to seek treatment recommendations from the treating physician. Major bleeding events may include: cerebral bleeding, severe bleeding into muscle or mucosal bleeding of the gastrointestinal tract (excluding nasal or oral bleeding) and bleeding events in target joints or those associated with swelling, pain, a decreased range of motion and an intensified treatment (use of bypassing agents for > 3 days). All other bleeding events were classified as minor unless the Investigator assessment noted otherwise.
    End point type
    Secondary
    End point timeframe
    Up to approximately 9 months
    End point values
    Biostate
    Number of subjects analysed
    1
    Units: bleeding events
        Overall
    10
        Major
    0
        Minor
    9
        Unspecified
    1
    No statistical analyses for this end point

    Secondary: Number of Catheter-related Complications

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    End point title
    Number of Catheter-related Complications
    End point description
    Occurrence of catheter-related complications (eg, line infections) were recorded in the subject’s e-diary.
    End point type
    Secondary
    End point timeframe
    up to approximately 9 months
    End point values
    Biostate
    Number of subjects analysed
    1
    Units: complications
    1
    No statistical analyses for this end point

    Secondary: Time to Complete Response (Success)

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    End point title
    Time to Complete Response (Success)
    End point description
    The time point for complete response (success) was defined as the time when recovery is ≥ 66% of predicted, FVIII half-life is ≥ 6 hours, and a titre of < 0.6 BU/mL is confirmed, after the subject had been placed in prophylaxis.
    End point type
    Secondary
    End point timeframe
    Up to approximately 38 months (30-month treatment period plus approximately 8 months for establishing complete response)
    End point values
    Biostate
    Number of subjects analysed
    0 [2]
    Units: days
    Notes
    [2] - The subject in this study did not achieve a complete response.
    No statistical analyses for this end point

    Secondary: Time to Inhibitor Titre <0.6 BU/mL for the First Time

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    End point title
    Time to Inhibitor Titre <0.6 BU/mL for the First Time
    End point description
    Time to the first instance of an inhibitor titre of <0.6 BU/mL, as assessed by the central laboratory.
    End point type
    Secondary
    End point timeframe
    30 months
    End point values
    Biostate
    Number of subjects analysed
    0 [3]
    Units: days
    Notes
    [3] - The subject in this study did not reach an inhibitor titre of <0.6 BU/mL.
    No statistical analyses for this end point

    Secondary: FVIII Inhibition Titres

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    End point title
    FVIII Inhibition Titres
    End point description
    End point type
    Secondary
    End point timeframe
    Screening through End-of-study (EOS; total study duration was up to approximately 9 months)
    End point values
    Biostate
    Number of subjects analysed
    1
    Units: Bethesda units (BU)/mL
    number (not applicable)
        Screening
    128
        Day 1
    101
        Day 3
    66
        Day 7
    83
        Day 14
    44
        Month 1
    32.96
        Month 2
    26.88
        Month 3
    32.96
        Month 4
    64
        Month 5
    103.7
        Unscheduled visit (between Months 5 and 6)
    135.7
        Month 6
    111.36
        Month 7
    118
        Month 8
    66
        Unscheduled visit (between Month 8 and EOS) 1
    169
        Unscheduled visit (between Month 8 and EOS) 2
    159
        EOS
    143
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From first IMP dose through Final Visit (3 months [±2 weeks]) after complete response or the final dose of IMP (total study duration was up to approximately 9 months). AE/SAEs considered related to a study procedure were recorded from informed consent.
    Adverse event reporting additional description
    All events presented were treatment-emergent (defined as those occurring after the first dose of IMP).
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    13.1
    Reporting groups
    Reporting group title
    Biostate
    Reporting group description
    During ITI treatment, Biostate was administered intravenously at a daily dose of approximately 200 international units (IU)/kg body weight (b.w.), preferably split into 2 doses of 100 IU/kg b.w. per day.

    Serious adverse events
    Biostate
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 1 (100.00%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Nervous system disorders
    Hydrocephalus
         subjects affected / exposed
    1 / 1 (100.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    1 / 1 (100.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Carotid artery stenosis
         subjects affected / exposed
    1 / 1 (100.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Mouth haemorrhage
         subjects affected / exposed
    1 / 1 (100.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Device related infection
         subjects affected / exposed
    1 / 1 (100.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    Biostate
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    1 / 1 (100.00%)
    Nervous system disorders
    Convulsion
         subjects affected / exposed
    1 / 1 (100.00%)
         occurrences all number
    1
    General disorders and administration site conditions
    Face oedema
         subjects affected / exposed
    1 / 1 (100.00%)
         occurrences all number
    1
    Gastrointestinal disorders
    Gastroenteritis
         subjects affected / exposed
    1 / 1 (100.00%)
         occurrences all number
    1
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    1 / 1 (100.00%)
         occurrences all number
    1
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 1 (100.00%)
         occurrences all number
    1

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    23 Sep 2011
    Following discussion with External Expert and comments from competent authorities: - Recalculation of sample size - Dosing range introduced - Day 14 Visit introduced - Dose reduction scheme clarified - Definition major bleedings added - Orthopedic score (Gilbert Score) added - Editorial changes: consistent use of terms, consistent use of American English vs British English - Change of study team members

    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.
    Because the study was terminated due to lack of enrolment and overall feasibility, and only 1 subject was enrolled into the study, the primary objective could not be assessed and no conclusions about the efficacy of Biostate in ITI can be drawn.
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