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    Clinical Trial Results:
    A Phase 2/3, multicenter, open-label clinical study to assess the safety and efficacy of BAY86-6150 in subjects with hemophilia A or B with inhibitors, composed of 2 Parts (A & B). Part A: Sequential cohorts of four dose levels of the modified rFVIIa BAY86-6150 assessed in a non-controlled dose response design in acutely bleeding subjects and for PK/ PD in an intra-individual crossover design compared with one fixed dose of eptacog alfa (activated) in non-bleeding subjects. Part B: Confirmatory study to further investigate the efficacy and safety of BAY86-6150.

    Summary
    EudraCT number
    2011-000323-33
    Trial protocol
    DE   HU   PL   DK   IT  
    Global end of trial date
    24 Mar 2014

    Results information
    Results version number
    v1
    This version publication date
    12 Jul 2016
    First version publication date
    26 Jul 2015
    Other versions
    v2

    Trial information

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    Trial identification
    Sponsor protocol code
    BAY86-6150/15534
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01625390
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Bayer HealthCare AG
    Sponsor organisation address
    Kaiser-Wilhelm-Allee, D-51368, Leverkusen, Germany,
    Public contact
    Therapeutic Area Head, Bayer HealthCare AG, clinical-trials-contact@bayerhealthcare.com
    Scientific contact
    Therapeutic Area Head, Bayer HealthCare AG, clinical-trials-contact@bayerhealthcare.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
    24 Jul 2014
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    24 Mar 2014
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    Part A: - To identify the recommended dose by conducting a risk-benefit assessment of four different dose levels of BAY86-6150 based on safety and dose response assessments in acutely bleeding subjects with hemophilia A or B with inhibitors. Part B: - To further investigate the safety and efficacy of the recommended dose of BAY86-6150 in acutely bleeding subjects with hemophilia A or B with inhibitors.
    Protection of trial subjects
    The conduct of this clinical study met all local legal and regulatory requirements. The study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki and the International Conference on Harmonization guideline E6: Good Clinical Practice. Participating subjects signed informed consent form and could withdraw from the study at any time without any disadvantage and without having to provide a reason for this decision. Only investigators qualified by training and experience were selected as appropriate experts to investigate the study drug.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    21 Jun 2012
    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
    South Africa: 5
    Country: Number of subjects enrolled
    Bulgaria: 3
    Country: Number of subjects enrolled
    Singapore: 2
    Worldwide total number of subjects
    10
    EEA total number of subjects
    3
    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)
    1
    Adults (18-64 years)
    9
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    The study was conducted at 8 study centers in Bulgaria, Korea, Poland, Singapore, Turkey, Ukraine, and South Africa. Overall, subjects enrolled in 3 countries (Bulgaria, Singapore and South Africa) were assigned to treatment. The study was conducted between 21 June 2012 (first subject first visit) and 24 March 2014 (last subject last visit).

    Pre-assignment
    Screening details
    Study was composed of Part A: 4 dose levels were to be evaluated sequentially, Part B: subjects were to be treated with the recommended dose level of BAY86-6150. However, the study was prematurely discontinued due to safety reasons and only 10 out of 20 enrolled subjects were treated with an initial dose of 6.5 microgram per kilogram.

    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
    Experimental, modified rFVIIa (BAY86-6150)
    Arm description
    Subjects received targeted intravenous injection of modified recombinant human Factor VIIa (rFVIIa) (BAY86-6150) at an initial dose of 6.5 microgram per kilogram. Dose was escalated as per investigator’s discretion or until the highest dose level was completed.
    Arm type
    Experimental

    Investigational medicinal product name
    Modified recombinant human Factor VIIa (rFVIIa)
    Investigational medicinal product code
    BAY86-6150
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received targeted intravenous injection of modified rFVIIa (BAY86-6150) at an initial dose of 6.5 microgram per kilogram. Dose was escalated as per investigator’s discretion or until the highest dose level was completed.

    Number of subjects in period 1
    Experimental, modified rFVIIa (BAY86-6150)
    Started
    10
    Completed
    0
    Not completed
    10
         Study terminated by sponsor
    9
         Consent withdrawn by subject
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall Study
    Reporting group description
    Subjects received targeted intravenous injection of modified recombinant human Factor VIIa (rFVIIa) (BAY86-6150) at an initial dose of 6.5 microgram per kilogram. Dose was escalated as per investigator’s discretion or until the highest dose level was completed.

    Reporting group values
    Overall Study Total
    Number of subjects
    10 10
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    27.4 ± 8.2 -
    Gender categorical
    Units: Subjects
        Male
    10 10

    End points

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    End points reporting groups
    Reporting group title
    Experimental, modified rFVIIa (BAY86-6150)
    Reporting group description
    Subjects received targeted intravenous injection of modified recombinant human Factor VIIa (rFVIIa) (BAY86-6150) at an initial dose of 6.5 microgram per kilogram. Dose was escalated as per investigator’s discretion or until the highest dose level was completed.

    Primary: Number of Subjects with Successful Treatments of Bleeding Episodes

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    End point title
    Number of Subjects with Successful Treatments of Bleeding Episodes [1]
    End point description
    The successful treatment was defined by "No rescue medication administered".
    End point type
    Primary
    End point timeframe
    Baseline up to the last injection of BAY86-6150
    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: Data was not analysed as the study was terminated due to safety reasons and hence, statistical analysis was not performed.
    End point values
    Experimental, modified rFVIIa (BAY86-6150)
    Number of subjects analysed
    0 [2]
    Units: subjects
    Notes
    [2] - Data was not analysed as the study was terminated due to safety reasons.
    No statistical analyses for this end point

    Primary: Proportion of Successful Treatments of Bleeding Episodes on Subject Level

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    End point title
    Proportion of Successful Treatments of Bleeding Episodes on Subject Level [3]
    End point description
    The individual success rate was calculated as the number of bleeding episodes treated successfully (without rescue medication) divided by the total number of bleeding episodes experienced on a dose level. A responder was defined as at least 70% of bleeding episodes treated without rescue medication.
    End point type
    Primary
    End point timeframe
    Baseline up to the last injection of BAY86-6150
    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: Data was not analysed as the study was terminated due to safety reasons and hence, statistical analysis was not performed.
    End point values
    Experimental, modified rFVIIa (BAY86-6150)
    Number of subjects analysed
    0 [4]
    Units: percentage of successful treatment
        number (not applicable)
    Notes
    [4] - Data was not analysed as the study was terminated due to safety reasons.
    No statistical analyses for this end point

    Secondary: Number of Injections Needed to Stop the Bleeding Episode

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    End point title
    Number of Injections Needed to Stop the Bleeding Episode
    End point description
    The number of injections needed to stop the bleeding episodes were calculated as total number of injections given divided by the total number of bleeds. In case rescue medication was given, the number of injections was set to 3, regardless of how many applications of rescue medication were applied.
    End point type
    Secondary
    End point timeframe
    Baseline up to the last injection of BAY86-6150
    End point values
    Experimental, modified rFVIIa (BAY86-6150)
    Number of subjects analysed
    0 [5]
    Units: injections
    Notes
    [5] - Data was not analysed as the study was terminated due to safety reasons.
    No statistical analyses for this end point

    Secondary: Time to Stop the Bleed

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    End point title
    Time to Stop the Bleed
    End point description
    The time to stop a bleeding episode was assessed as the period between the onset of bleeding and the complete cessation of the bleeding episode as assessed by the subject. Analyses were decided to perform using life table methods. Subjects assessed the cessation of a bleeding episode based on their long-term experiences coping with bleeds since childhood.
    End point type
    Secondary
    End point timeframe
    Baseline up to the last injection of BAY86-6150
    End point values
    Experimental, modified rFVIIa (BAY86-6150)
    Number of subjects analysed
    0 [6]
    Units: hours
        arithmetic mean (standard deviation)
    ±
    Notes
    [6] - Data was not analysed as the study was terminated due to safety reasons.
    No statistical analyses for this end point

    Secondary: Subject’s Efficacy Assessment

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    End point title
    Subject’s Efficacy Assessment
    End point description
    The effective response to treatment as rated by the subject’s assessment was determined according to: “Please rate the effectiveness (for example, cessation of bleed, pain, tenderness, size of hemorrhage, swelling and joint mobility) of the treatment as per your assessment: Very effective; Effective; Partially effective; Not effective".
    End point type
    Secondary
    End point timeframe
    After every acute bleeding episode or every other week up to 14 days after last exposure to BAY 86-6150
    End point values
    Experimental, modified rFVIIa (BAY86-6150)
    Number of subjects analysed
    0 [7]
    Units: units on a scale
        number (not applicable)
    Notes
    [7] - Data was not analysed as the study was terminated due to safety reasons.
    No statistical analyses for this end point

    Secondary: Euro Quality of Life-5 Dimension (EQ-5D)

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    End point title
    Euro Quality of Life-5 Dimension (EQ-5D)
    End point description
    Health related quality of life (HRQoL) was assessed using the self administered Euro-QoL (EQ-5D). EQ-5D is a participant answered questionnaire scoring 5 dimensions - mobility, self-care, usual activities, pain/discomfort and anxiety/depression. The EQ-5D is a validated, generic preference based measure of health widely used in health economic calculations. Subjects rated their general health using the EQ-5D. The EQ-5D total score ranges from 0 (worst imaginable health state) to 100 (best imaginable health state which is also the best possible outcome).
    End point type
    Secondary
    End point timeframe
    Baseline up to 14 days after last exposure to BAY86-6150
    End point values
    Experimental, modified rFVIIa (BAY86-6150)
    Number of subjects analysed
    0 [8]
    Units: units on a scale
        number (not applicable)
    Notes
    [8] - Data was not analysed as the study was terminated due to safety reasons.
    No statistical analyses for this end point

    Secondary: Brief Pain Inventory (BPI) Score

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    End point title
    Brief Pain Inventory (BPI) Score
    End point description
    Brief Pain Inventory - Short Form (BPI-SF) allows subjects to rate the severity of their pain and the degree to which their pain interferes with common dimensions of feeling and function (e.g., general activity, walking, work, mood, enjoyment of life, relations with others, and sleep). BPI-SF was a 15-item, self-administered, clinically valid, reliable and responsive measure developed to assess pain. BPI-SF was typically scored by averaging the pain severity score and overall pain interference score. Scores range from 0-10 and a higher score indicates a higher level of pain/interference.
    End point type
    Secondary
    End point timeframe
    Baseline up to 14 days after last exposure to BAY86-6150
    End point values
    Experimental, modified rFVIIa (BAY86-6150)
    Number of subjects analysed
    0 [9]
    Units: units on a scale
        number (not applicable)
    Notes
    [9] - Data was not analysed as the study was terminated due to safety reasons.
    No statistical analyses for this end point

    Secondary: Brief Pain Inventory (BPI) Score: Item 3 and 6

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    End point title
    Brief Pain Inventory (BPI) Score: Item 3 and 6
    End point description
    The effectiveness of BAY 86-6150 in alleviating the subject's pain through bleed resolution was assessed by the subjects using Items 3 and 6 of the BPI-SF measure. Item 3: “Please rate your pain by circling the one number that best describes your pain at its worst in the last 24 hours.” Score range from 0-10 and a higher score indicates a higher level of pain. It was completed by the subject in an e-diary prior to the first injection of BAY 86-6150 and every night for 7 days following the start of the bleed that was treated with BAY 86-6150. Item 6: “Please rate your pain by circling the one number that tells how much pain you have right now.” Score range from 0-10 and a higher score indicates a higher level of pain. It was completed by the subject in an e-diary prior to the first injection of BAY 86-6150. Item 6 was then completed at every hour for 6 hours following an injection of BAY 86-6150 but before the use of rescue medication (that is, if rescue medication was required).
    End point type
    Secondary
    End point timeframe
    Pre-injection, every night for a week after any BAY86-6150 injection for Item 3 Pre-injection, 1, 2, 3, and 4 hours after administration of BAY86-6150 for Item 6
    End point values
    Experimental, modified rFVIIa (BAY86-6150)
    Number of subjects analysed
    0 [10]
    Units: units on a scale
        number (not applicable)
    Notes
    [10] - Data was not analysed as the study was terminated due to safety reasons.
    No statistical analyses for this end point

    Secondary: Work Productivity and Activity Impairment (WPAI) Questionnaire

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    End point title
    Work Productivity and Activity Impairment (WPAI) Questionnaire
    End point description
    The effect of hemophilia on the subject’s ability to work and perform regular activities was evaluated by determination of a WPAI in adult subjects only. Six-items that assess impairment in work productivity and daily activity during the 7 days before the assessment. It measures the percentage of overall impairment in work productivity and daily activity due to hemophilia. A WPAI score of 0% = no impairment and a score of 100% = total loss of work productivity or activity.
    End point type
    Secondary
    End point timeframe
    Baseline, within 24 to 48 hours after the 2nd treatment with BAY86-6150, after every 5th exposure day to BAY86-6150, 14 days after last exposure to BAY86-6150
    End point values
    Experimental, modified rFVIIa (BAY86-6150)
    Number of subjects analysed
    0 [11]
    Units: percent total impairment
        number (not applicable)
    Notes
    [11] - Data was not analysed as the study was terminated due to safety reasons.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline up to 14 days after last exposure to BAY86-6150
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    16.1
    Reporting groups
    Reporting group title
    Experimental, modified rFVIIa (BAY86-6150)
    Reporting group description
    Subjects received targeted intravenous injection of modified recombinant human Factor VIIa (rFVIIa)(BAY86-6150) at an initial dose of 6.5 microgram per kilogram. Dose was escalated as per investigator'sdiscretion or until the highest dose level was completed.

    Serious adverse events
    Experimental, modified rFVIIa (BAY86-6150)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 10 (40.00%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    Investigations
    Anti factor VII antibody positive
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal and connective tissue disorders
    Haemophilic arthropathy
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Acute hepatitis B
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Oral candidiasis
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 10 (10.00%)
         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
    Experimental, modified rFVIIa (BAY86-6150)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    7 / 10 (70.00%)
    Injury, poisoning and procedural complications
    Eye injury
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences all number
    1
    Investigations
    Blood creatine phosphokinase increased
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences all number
    1
    Cardiac disorders
    Tachycardia paroxysmal
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences all number
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences all number
    1
    Nervous system disorders
    Headache
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences all number
    1
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences all number
    1
    Gastritis
         subjects affected / exposed
    2 / 10 (20.00%)
         occurrences all number
    2
    Renal and urinary disorders
    Urine abnormality
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences all number
    1
    Infections and infestations
    Acute tonsillitis
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences all number
    1
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 10 (10.00%)
         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
    24 Aug 2012
    The amendment was prepared in response to the comments by the Medical and Healthcare Products Regualtory Agency (MHRA) in the United Kingdom. The required changes led to modifications of the stopping rules for subjects in the study who experienced drug related adverse events. - The Common Terminology Criteria for Adverse Events (CTCAE) grading has been removed and replaced with more specific description of relevant clinical conditions. - Exclusion criterion was modified to clarify that besides activated Prothrombin Complex Concentrates (“aPCC”) also non-activated Prothrombin Complex Concentrates (“PCC”) were allowed to be administered during the study period. - The text was added as, hypersensitivity adverse events that could occur with any injected protein under definition of serious adverse event. - The dose of study medication for a subject would be de-escalated to the next lower level or withdrawn from the study if two or more drug-related severe adverse events or or a single drug-related serious adverse event occurred in a subject.

    Interruptions (globally)

    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    30 Apr 2013
    The recruitment and sequential cohorts of four dose levels in an intra-individual crossover design of Part A and Part B of the study were prematurely terminated due to development of neutralizing and cross-reacting antibodies to eptacog alfa (activated) which was a pre-specified withdrawal criterion in the study protocol.
    -

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    Results for primary or secondary endpoints were not able to be reported as the study was prematurely terminated due to safety reasons.
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