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    Clinical Trial Results:
    Clinical Study in Previously Treated Children with Severe Haemophilia A to Investigate the Long-Term Immunogenicity, Tolerability and Efficacy of Human-cl rhFVIII

    Summary
    EudraCT number
    2011-001785-17
    Trial protocol
    GB   FR   CZ   PL   RO  
    Global end of trial date
    13 May 2016

    Results information
    Results version number
    v1(current)
    This version publication date
    18 Dec 2016
    First version publication date
    18 Dec 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    GENA-13
    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
    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)
    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
    22 Nov 2016
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    13 May 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary endpoints of this study were to assess the long-term immunogenicity and tolerability of Human-cl rhFVIII. Long-term immunogenicity was assessed on the basis of inhibitor activity, determined using the modified Bethesda assay (Nijmegen modification) and anti-rhFVIII antibody measurements. Long-term clinical tolerability was assessed by monitoring adverse events (AEs) throughout the study duration.
    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 occurence 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
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    25 Oct 2011
    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: 10
    Country: Number of subjects enrolled
    Czech Republic: 1
    Country: Number of subjects enrolled
    France: 2
    Country: Number of subjects enrolled
    Poland: 24
    Country: Number of subjects enrolled
    Romania: 3
    Country: Number of subjects enrolled
    Russian Federation: 9
    Worldwide total number of subjects
    49
    EEA total number of subjects
    40
    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)
    43
    Adolescents (12-17 years)
    6
    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
    Participation in GENA-13 was open to all evaluable patients who had completed study GENA-03 with a study participation period of at least 6 months. The screening visit for GENA-13 coincided with the study completion visit of GENA-03.

    Pre-assignment
    Screening details
    Inclusion criteria: Completion of study GENA-03 by having a study participation period of at least 6 months, provided that prophylaxis with Human-cl rhFVIII continued without intermediate interruption. Voluntarily given, fully informed written and signed consent obtained from the parents (or legal guardians)

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

    Arms
    Arm title
    Human-cl rhFVIII
    Arm description
    Prophylactic and on-demand treatment with Human-cl rhFVIII Participation in GENA-13 was open to all evaluable patients who had completed study GENA-03 with a study participation period of 6 months. The mean duration of prophylactic treatment in GENA-03 had been 6.6 ± 1.4 months (median: 6.3 months, range 1.3–9.8). The screening visit for GENA-13 coincided with the study completion visit of GENA-03.
    Arm type
    Experimental

    Investigational medicinal product name
    Human-cl rhFVIII
    Investigational medicinal product code
    Other name
    Nuwiq
    Pharmaceutical forms
    Powder and solvent for solution for injection in pre-filled syringe
    Routes of administration
    Intravenous use
    Dosage and administration details
    The dosing recommendations in GENA-13 were the same as in its predecessor study GENA-03. For prophylactic treatment, an every-other-day or a 3-times-a-week dosage regimen was available for selection. Regardless of the selected regimen, the prophylactic dose was 30–40 IU FVIII/kg BW. Two dose escalations of approximately +5 IU FVIII/kg BW each were recommended if two or more spontaneous BEs within one month were reported. For the treatment of Bleeding Episodes (BE), the dosage and duration depended on the location and extent of bleeding as well as on the clinical situation of the patient.

    Number of subjects in period 1
    Human-cl rhFVIII
    Started
    49
    Completed
    44
    Not completed
    5
         Protocol deviation
    1
         Adverse event, serious fatal
    1
         Consent withdrawn by subject
    3

    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
    49 49
    Age categorical
    Units: Subjects
        Children (2-11 years)
    43 43
        Adolescents (12-17 years)
    6 6
    Gender categorical
    Units: Subjects
        Male
    49 49
        Female
    0 0
    Subject analysis sets

    Subject analysis set title
    Safety population (SAF)
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    All subjects who received at least one dose of Human-cl rhFVIII

    Subject analysis sets values
    Safety population (SAF)
    Number of subjects
    49
    Age categorical
    Units: Subjects
        Children (2-11 years)
    43
        Adolescents (12-17 years)
    6
    Age continuous
    Units:
        
    ±
    Gender categorical
    Units: Subjects
        Male
    49
        Female

    End points

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    End points reporting groups
    Reporting group title
    Human-cl rhFVIII
    Reporting group description
    Prophylactic and on-demand treatment with Human-cl rhFVIII Participation in GENA-13 was open to all evaluable patients who had completed study GENA-03 with a study participation period of 6 months. The mean duration of prophylactic treatment in GENA-03 had been 6.6 ± 1.4 months (median: 6.3 months, range 1.3–9.8). The screening visit for GENA-13 coincided with the study completion visit of GENA-03.

    Subject analysis set title
    Safety population (SAF)
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    All subjects who received at least one dose of Human-cl rhFVIII

    Primary: Long-term immunogenicity of Human-cl rhFVIII[

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    End point title
    Long-term immunogenicity of Human-cl rhFVIII[ [1]
    End point description
    Immunogenicity was to be assessed on the basis of FVIII inhibitors and anti-rhFVIII antibodies determined by central laboratories at predefined time points and whenever inhibitor development was suspected. An inhibitor test was considered to be negative if the titer was <0.6 BU.
    End point type
    Primary
    End point timeframe
    throughout the study
    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 this was an uncontrolled study, no inferential analysis involving formal testing and, consequently, no formal sample size estimation were performed. The statistical analysis of all endpoints was performed descriptively.
    End point values
    Safety population (SAF)
    Number of subjects analysed
    49
    Units: Occurrence of Inhibitor
        Occurrence of Inhibitor >0.6 BU/mL
    0
    No statistical analyses for this end point

    Primary: Long-term Tolerability of Human-cl rhFVIII

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    End point title
    Long-term Tolerability of Human-cl rhFVIII [2]
    End point description
    Monitoring of adverse events (AEs) and serious adverse events (SAEs), vital signs, laboratory parameters (haematology and clinical chemistry), and physical examinations (including the Haemophilia Joint Health Score, HJHS) throughout the study duration. Temporally related AEs: within 24 hours after the end of infusion AEs related to surgical procedures: AEs occurring between the start of surgical prophylaxis and the return to routine prophylaxis.
    End point type
    Primary
    End point timeframe
    Throughout the study
    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: Because this was an uncontrolled study, no inferential analysis involving formal testing and, consequently, no formal sample size estimation were performed. The statistical analysis of all endpoints was performed descriptively.
    End point values
    Safety population (SAF)
    Number of subjects analysed
    49
    Units: Occurrence of Adverse Events
        Adverse events (AEs)
    317
        Serious Adverse events (SAEs)
    30
        Severe AEs
    8
        Possibly/probably related AEs (ADRs)
    2
        Temporally related AEs
    127
        AEs related to surgical procedures
    2
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Timeframe for reporting AEs: AE were reported throughout the whole study. 24 hours SAE reporting requirement. Waiver from 24 hours SAE reporting: hospitalization for the treatment of a (disease-related) BE assessed as unrelated to IMP treatment.
    Adverse event reporting additional description
    All SAEs, whether suspected to be related to study treatment or not, are reported by telephone, fax or e-mail immediately to the responsible Clinical Project Manager, study Monitor, or to the responsible local CRO. AEs were evaluated at each patient visit.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    15.0
    Reporting groups
    Reporting group title
    Safety anaylsis population SAF
    Reporting group description
    all patients exposed to treatment

    Serious adverse events
    Safety anaylsis population SAF
    Total subjects affected by serious adverse events
         subjects affected / exposed
    21 / 49 (42.86%)
         number of deaths (all causes)
    1
         number of deaths resulting from adverse events
    0
    Injury, poisoning and procedural complications
    Head injury
         subjects affected / exposed
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Vascular disorders
    Haematoma
         subjects affected / exposed
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Surgical and medical procedures
    Synoviorthesis
         subjects affected / exposed
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Osteoma
         subjects affected / exposed
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorders
    Headache
         subjects affected / exposed
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Application site erosion
         subjects affected / exposed
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hernia
         subjects affected / exposed
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Device occlusion
         subjects affected / exposed
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Device damage
         subjects affected / exposed
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Multi-organ failure
         subjects affected / exposed
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Abdominal pain
         subjects affected / exposed
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    2 / 49 (4.08%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Renal colic
         subjects affected / exposed
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Skin and subcutaneous tissue disorders
    Ingrowing nail
         subjects affected / exposed
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal and connective tissue disorders
    Haemarthrosis
         subjects affected / exposed
    1 / 49 (2.04%)
         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
    3 / 49 (6.12%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Catheter site infection
         subjects affected / exposed
    2 / 49 (4.08%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Appendicitis
         subjects affected / exposed
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pharyngitis
         subjects affected / exposed
    1 / 49 (2.04%)
         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 anaylsis population SAF
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    45 / 49 (91.84%)
    Injury, poisoning and procedural complications
    Head injury
         subjects affected / exposed
    3 / 49 (6.12%)
         occurrences all number
    3
    Investigations
    Haemoglobin decreased
         subjects affected / exposed
    3 / 49 (6.12%)
         occurrences all number
    4
    Blood and lymphatic system disorders
    Haematuria
         subjects affected / exposed
    3 / 49 (6.12%)
         occurrences all number
    3
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    9 / 49 (18.37%)
         occurrences all number
    11
    Nervous system disorders
    Headache
         subjects affected / exposed
    6 / 49 (12.24%)
         occurrences all number
    19
    General disorders and administration site conditions
    Chills
         subjects affected / exposed
    6 / 49 (12.24%)
         occurrences all number
    10
    Pyrexia
         subjects affected / exposed
    6 / 49 (12.24%)
         occurrences all number
    11
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    3 / 49 (6.12%)
         occurrences all number
    3
    Vomiting
         subjects affected / exposed
    4 / 49 (8.16%)
         occurrences all number
    4
    Abdominal pain upper
         subjects affected / exposed
    3 / 49 (6.12%)
         occurrences all number
    4
    Musculoskeletal and connective tissue disorders
    Pain in extremity
         subjects affected / exposed
    5 / 49 (10.20%)
         occurrences all number
    6
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    10 / 49 (20.41%)
         occurrences all number
    15
    Nasopharyngitis
         subjects affected / exposed
    17 / 49 (34.69%)
         occurrences all number
    28
    Pharyngitis
         subjects affected / exposed
    7 / 49 (14.29%)
         occurrences all number
    11
    Rhinitis
         subjects affected / exposed
    8 / 49 (16.33%)
         occurrences all number
    14
    Tooth abscess
         subjects affected / exposed
    4 / 49 (8.16%)
         occurrences all number
    4
    Upper respiratory tract infection
         subjects affected / exposed
    9 / 49 (18.37%)
         occurrences all number
    17
    Varicella
         subjects affected / exposed
    5 / 49 (10.20%)
         occurrences all number
    5

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    19 Aug 2011
    Amendment 1: only applied to UK Limitation of the individual study duration for each participating patient to 2 years +/- 1 month.
    21 Aug 2013
    Amendment 2:  The planned clinical end of the study was moved from Q1 2014 to 15-Sep-2014 (± 2 weeks) or until the launch of Human-cl rhFVIII in the country where the study was being performed, whichever came earlier.  The countries and the number of sites participating in the study was updated from about 18 centres in UK, Austria, Czech Republic, Poland, Russia, Turkey and France to 10 centres in UK, Czech Republic, Poland, Russia, France and Romania.  The maximum number of patients enrolled in the study was changed from 60 to 50.  Some time windows and time points of assessment were clarified.  The dosing schedule was adapted to that used in the preceding GENA-03 study, i.e., the 3-times-weekly treatment schedule was added to the every-other-day treatment schedule.  The name of a central laboratory in Englewood, CO, was changed from ‘Esoterix Inc.’ to ‘LabCorp Clinical Trials.’  It was clarified that not only spontaneous BEs but BEs of any cause were going to be included in the efficacy analyses.  The cut-off for severe haemophilia was changed from FVIII ≤1% to FVIII <1%.
    16 Dec 2013
    Amendment 3: only applied to France The planned clinical end of the study was moved from Q1 2014 to the time when Human-cl rhFVIII became commercially available in France, approximately by QIII 2015. All other changes included in this amendment were the same as those listed for Amendment no. 2.
    23 May 2014
    Amendment 4: only applied to UK Prolongation of the study duration in the UK by 3 months because by then Human-cl rhFVIII was expected to be commercially available, avoiding a switch of FVIII concentrates in this vulnerable patient population.
    23 May 2014
    Amendment 5: only applied to France Planned clinical end of the study was moved from QIII 2015 to the time Human-cl rhFVIII was expected to be commercially available in France, approximately by QII 2016.

    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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