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    Clinical Trial Results:
    Clinical Study to Investigate the Efficacy, Safety, and Immunogenicity of human-cl rhFVIII in Previously Treated Patients With Severe Haemophilia A

    Summary
    EudraCT number
    2009-011055-43
    Trial protocol
    DE   AT   GB  
    Global end of trial date
    31 Jan 2012

    Results information
    Results version number
    v1(current)
    This version publication date
    09 Oct 2016
    First version publication date
    09 Oct 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    GENA-08
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01125813
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Octapharma AG
    Sponsor organisation address
    Seidenstraße 2, Lachen, Switzerland, CH-8853
    Public contact
    Johann Bichler, Octapharma AG, +41 (0)554512177, johann.bichler@octapharma.ch
    Scientific contact
    Johann Bichler, Octapharma AG, +41 (0)554512177, johann.bichler@octapharma.ch
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    EMEA-001024-PIP01-10
    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
    19 Jul 2012
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    31 Jan 2012
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To determine in previously treated subjects suffering from severe haemophilia A the efficacy of human-cl rhFVIII during prophylactic treatment, in the treatment of bleeding episodes and in surgical prophylaxis.
    Protection of trial subjects
    This trial was conducted in accordance with the ethical principles laid down in the Declaration of Helsinki. It was submitted to an IEC and it was conducted in compliance with the protocol, GCP regulations and applicable regulatory requirements. Inclusion and exclusion criteria were carefully defined in order to protect subjects from contraindications, interactions with other medication and safety factors associated with the IMP. Thoughout the study safety was assessed such as occurrence of AEs, measuring vital signs and routine safety laboratory parameters at pre-defined time points. Also inhibitors against FVIII and anti-rhFVIII antibodies were determined at pre-determined time points.
    Background therapy
    NA
    Evidence for comparator
    NA
    Actual start date of recruitment
    22 Jun 2010
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 15
    Country: Number of subjects enrolled
    Austria: 1
    Country: Number of subjects enrolled
    Bulgaria: 8
    Country: Number of subjects enrolled
    Germany: 8
    Worldwide total number of subjects
    32
    EEA total number of subjects
    32
    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)
    31
    From 65 to 84 years
    1
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    All screened 36. All enrolled 32. Inclusion criteria: must have severe haemophilia A (FVIII:C ≤1%; historical value as documented in patient records), male patients 12 years of age or older, previously treated with FVIII concentrate, at least 150 EDs, immunocompetent (CD4+ count >200/μL), negative for anti-human HIV, freely given written ICF.

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    Not blinded

    Arms
    Arm title
    Human-cl rhFVIII
    Arm description
    IMP was administerd to all patients prophylactically and for in-vivo recovery assessment and if required for treatment of bleeding episodes or surgical prophylaxis.
    Arm type
    Experimental

    Investigational medicinal product name
    Human-cl rhFVIII
    Investigational medicinal product code
    Other name
    Nuwiq
    Pharmaceutical forms
    Concentrate and solvent for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    A dose of 50 IU/kg was administered at Visit 1 and at 3 and 6 month for the purpose of assessing IVR. Prophylactic treatment: patients received 30-40 IU FVIII/kg every other day until 6 months and at least 50 EDs had been reached. On-demand treatment and surgical prophylaxis: dosage recommendations were given in the protocol. The IMP was to be administered at a maximum speed of 4 mL/minute.

    Number of subjects in period 1
    Human-cl rhFVIII
    Started
    32
    Completed
    30
    Not completed
    2
         Adverse event, serious fatal
    1
         Consent withdrawn by subject
    1

    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
    32 32
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    31 31
        From 65-84 years
    1 1
    Gender categorical
    Units: Subjects
        Female
    0 0
        Male
    32 32
    Subject analysis sets

    Subject analysis set title
    ITT / Subjects on prophylactic treatment (PROPH)
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    All patients in the ITT population who received at least one prophylactic infusion.

    Subject analysis set title
    BLEED population
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    All documented bleeding episodes (BEs) of patients in the ITT population for which any amount of treatment with Human-cl rhFVIII was documented. A total of 30 BEs that were treated with Human-cl rhFVIII were recorded in 15 patients .

    Subject analysis set title
    SURG population
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    All documented surgical interventions of patients in the ITT population for which any amount of Human-cl rhFVIII prior to, during or after the surgery was documented and no other FVIII concentrate was documented within 24 hours prior to surgery.

    Subject analysis sets values
    ITT / Subjects on prophylactic treatment (PROPH) BLEED population SURG population
    Number of subjects
    32
    15
    5
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    31
    5
        From 65-84 years
    1
    0
    Age continuous
    Units:
        
    ( )
    ( )
    ( )
    Gender categorical
    Units: Subjects
        Female
    0
    0
        Male
    32
    5

    End points

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    End points reporting groups
    Reporting group title
    Human-cl rhFVIII
    Reporting group description
    IMP was administerd to all patients prophylactically and for in-vivo recovery assessment and if required for treatment of bleeding episodes or surgical prophylaxis.

    Subject analysis set title
    ITT / Subjects on prophylactic treatment (PROPH)
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    All patients in the ITT population who received at least one prophylactic infusion.

    Subject analysis set title
    BLEED population
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    All documented bleeding episodes (BEs) of patients in the ITT population for which any amount of treatment with Human-cl rhFVIII was documented. A total of 30 BEs that were treated with Human-cl rhFVIII were recorded in 15 patients .

    Subject analysis set title
    SURG population
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    All documented surgical interventions of patients in the ITT population for which any amount of Human-cl rhFVIII prior to, during or after the surgery was documented and no other FVIII concentrate was documented within 24 hours prior to surgery.

    Primary: Overall efficacy assessment of Prophylactic Treatment

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    End point title
    Overall efficacy assessment of Prophylactic Treatment [1]
    End point description
    For prophylactic treatment, primary efficacy variables were the overall efficacy assessment after a total of at least 50 EDs at the end of the study and consumption of IMP (FVIII IU/kg per month, per year) per patient and in total. Prophylactic efficacy is assessed by the monthly bleeding rate (excellent: <0.75, good: 0.75-1.0, moderate: >1.0-1.5; poor: >1.5) Includes all bleeding episodes between start of prophylactic treatment and last prophylactic treatment + 2 days or study completion, whichever comes first. Bleeding episodes between start of treatment for surgery and re-start of prophylactic treatment after surgery are excluded.
    End point type
    Primary
    End point timeframe
    6 month
    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: descriptive analysis - no statistical analysis for this endpoint available
    End point values
    Human-cl rhFVIII
    Number of subjects analysed
    32
    Units: Number of patients
        Excellent
    29
        Good
    2
        Moderate
    1
        Poor
    0
    No statistical analyses for this end point

    Primary: Amount of Human-cl rhFVIII (IU/kg) for prophylactic treatment per month

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    End point title
    Amount of Human-cl rhFVIII (IU/kg) for prophylactic treatment per month [2]
    End point description
    End point type
    Primary
    End point timeframe
    Study drug consumption data per month
    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: descriptive analysis - no statistical analysis for this endpoint available
    End point values
    ITT / Subjects on prophylactic treatment (PROPH)
    Number of subjects analysed
    32
    Units: Human-cl rhFVIII per month (IU/kg/month)
        arithmetic mean (standard deviation)
    466.1 ( 65.5 )
    No statistical analyses for this end point

    Primary: Personal efficacy assessment of treatment of bleeding episode

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    End point title
    Personal efficacy assessment of treatment of bleeding episode [3]
    End point description
    At the end of a BE, the following efficacy assessment was made: • Excellent: Abrupt pain relief and/or unequivocal improvement in objective signs of bleeding within approximately 8 hours after a single infusion • Good: Definite pain relief and/or improvement in signs of bleeding within approximately 8–12 hours after an infusion requiring up to 2 infusions for complete resolution • Moderate: Probable or slight beneficial effect within approximately 12 hours after the first infusion requiring more than two infusions for complete resolution • None: No improvement within 12 hours, or worsening of symptoms, requiring more than 2 infusions for complete resolution
    End point type
    Primary
    End point timeframe
    Any bleeding epsiode treated with Human-cl rhFVIII during the study
    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: descriptive analysis - no statistical analysis for this endpoint available
    End point values
    BLEED population
    Number of subjects analysed
    15 [4]
    Units: bleeding episodes
        Excellent
    20
        Good
    8
        Moderat
    0
        None
    0
    Notes
    [4] - Number of bleeding episodes: 28
    No statistical analyses for this end point

    Primary: Efficacy evaluation of the use of Human-cl rhFVIII in surgical procedures

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    End point title
    Efficacy evaluation of the use of Human-cl rhFVIII in surgical procedures [5]
    End point description
    four point scale
    End point type
    Primary
    End point timeframe
    Overall efficacy assessment after the end of the surgical prophylactic treatment phase by the surgeon and haematologist.
    Notes
    [5] - 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: descriptive analysis - no statistical analysis for this endpoint available
    End point values
    SURG population
    Number of subjects analysed
    5
    Units: Overall efficacy
        Excellent
    4
        Good
    1
        Moderate
    0
        None
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    The condition of the subject was monitored throughout the study. 24 hours SAE reporting requirement.
    Adverse event reporting additional description
    All SAEs, suspected to be related to study treatment or not, were reported by telephone, fax or e-mail immediately to the responsible CPM, CRA or to local CRO.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    13.1
    Reporting groups
    Reporting group title
    Human-cl rhFVIII
    Reporting group description
    all patients who received at least one dose of Human-cl rhFVIII

    Serious adverse events
    Human-cl rhFVIII
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 32 (6.25%)
         number of deaths (all causes)
    1
         number of deaths resulting from adverse events
    0
    Injury, poisoning and procedural complications
    Traumatic fracture
         subjects affected / exposed
    1 / 32 (3.13%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorders
    Status epilepticus
         subjects affected / exposed
    1 / 32 (3.13%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Human-cl rhFVIII
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    21 / 32 (65.63%)
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    2 / 32 (6.25%)
         occurrences all number
    2
    Nervous system disorders
    Headache
         subjects affected / exposed
    3 / 32 (9.38%)
         occurrences all number
    3
    Paraesthesia
         subjects affected / exposed
    2 / 32 (6.25%)
         occurrences all number
    2
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    2 / 32 (6.25%)
         occurrences all number
    2
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    2 / 32 (6.25%)
         occurrences all number
    2
    Diarrhea
         subjects affected / exposed
    2 / 32 (6.25%)
         occurrences all number
    2
    Nausea
         subjects affected / exposed
    2 / 32 (6.25%)
         occurrences all number
    3
    Respiratory, thoracic and mediastinal disorders
    Epistaxis
         subjects affected / exposed
    2 / 32 (6.25%)
         occurrences all number
    6
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    2 / 32 (6.25%)
         occurrences all number
    4
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    5 / 32 (15.63%)
         occurrences all number
    7

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    10 May 2011
    • As it became clear that the study would take longer than originally anticipated, the planned clinical end was updated from Q1 2011 to Q4 2011. • In addition to vials containing 500 IU of Human-cl rhFVIII concentrate, also vials containing 1000 IU and 2000 IU were expected to become available during the study. These were included in the description of the IMP. • In this study, it was allowed to enter certain source data (vital signs, body weight and dates/times of blood drawings) directly into the CRF without prior written or electronic record of source data, turning the CRF into source. This was clarified in the text. • The final change concerned the documentation of BEs that occurred simultaneously at several sites. It was clarified that if a patient experienced simultaneously BEs at several sites, they each had to be documented as separate BEs.

    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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