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    Clinical Trial Results:
    An Evaluation of the Safety and Efficacy of On-Demand Treatment with BeneFIX (Nonacog Alfa, Recombinant Factor IX) in Chinese Subjects with Hemophilia B

    Summary
    EudraCT number
    2014-004156-65
    Trial protocol
    Outside EU/EEA  
    Global end of trial date
    24 Dec 2009

    Results information
    Results version number
    v1(current)
    This version publication date
    16 May 2016
    First version publication date
    01 Aug 2015
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    3090A1-3305
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT00866606
    WHO universal trial number (UTN)
    -
    Other trial identifiers
    alias: B1821004
    Sponsors
    Sponsor organisation name
    Pfizer Inc.
    Sponsor organisation address
    235 E 42nd Street, New York, United States, NY 10017
    Public contact
    Pfizer ClinicalTrials.gov Call Center, Pfizer, Inc., 001 800-718-1021, ClinicalTrials.gov_Inquiries@pfizer.com
    Scientific contact
    Pfizer ClinicalTrials.gov Call Center, Pfizer, Inc., 001 800-718-1021, ClinicalTrials.gov_Inquiries@pfizer.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
    19 Sep 2010
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    24 Dec 2009
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To describe the safety and clinical efficacy of BeneFIX in previously treated Chinese subjects with hemophilia B.
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and in compliance with all International Conference on Harmonization (ICH) Good Clinical Practice (GCP) Guidelines. All the local regulatory requirements pertinent to safety of trial subjects were followed.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    18 Sep 2008
    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
    China: 35
    Worldwide total number of subjects
    35
    EEA total number of subjects
    0
    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)
    4
    Adolescents (12-17 years)
    6
    Adults (18-64 years)
    25
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Subjects were enrolled in six centers in China.

    Pre-assignment
    Screening details
    Study was initiated on 18 September 2008 and completed on 24 December 2009. A total of 35 subjects were enrolled in the study.

    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
    BeneFactor IX (BeneFIX)
    Arm description
    Subjects received on-demand treatments with BeneFIX according to investigator’s prescription over a 6-month (calendar day) period. All BeneFIX administrations occurred in the clinic (hospital).
    Arm type
    Experimental

    Investigational medicinal product name
    BeneFIX
    Investigational medicinal product code
    Other name
    Nonacog Alfa, Recombinant Factor IX
    Pharmaceutical forms
    Powder and solvent for solution for injection
    Routes of administration
    Intravenous bolus use
    Dosage and administration details
    A single 75 International Unit (IU)/kilogram (kg) (±5 IU/kg) intravenous (IV) bolus infusion of BeneFIX was given for recovery assessments.

    Number of subjects in period 1
    BeneFactor IX (BeneFIX)
    Started
    35
    Completed
    31
    Not completed
    4
         Adverse Event
    1
         Lost to follow-up
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    BeneFactor IX (BeneFIX)
    Reporting group description
    Subjects received on-demand treatments with BeneFIX according to investigator’s prescription over a 6-month (calendar day) period. All BeneFIX administrations occurred in the clinic (hospital).

    Reporting group values
    BeneFactor IX (BeneFIX) Total
    Number of subjects
    35 35
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    25.7 ± 13.6 -
    Gender categorical
    Units: Subjects
        Female
    0 0
        Male
    35 35

    End points

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    End points reporting groups
    Reporting group title
    BeneFactor IX (BeneFIX)
    Reporting group description
    Subjects received on-demand treatments with BeneFIX according to investigator’s prescription over a 6-month (calendar day) period. All BeneFIX administrations occurred in the clinic (hospital).

    Primary: Investigator Hemostatic Efficacy Assessment of Subjects After 8 Hours Post Infusion

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    End point title
    Investigator Hemostatic Efficacy Assessment of Subjects After 8 Hours Post Infusion [1]
    End point description
    Investigator Hemostatic Efficacy Assessment was based on response of bleeding episodes to BeneFIX treatment on 4-point rating scale: Excellent(1): definite pain relief or improvement in signs of bleeding starting within 8 hours after infusion, with no additional infusion; Good(2): definite pain relief or improvement in signs of bleeding starting within 8 hrs or following infusion; Moderate(3): probable or slight improvement starting after 8 hours following infusion; No Response(4): no improvement at all between infusions or during 24 hour interval following an infusion, or condition worsens. Full Analysis set (FAS) population included all subjects who were treated and had at least 1 evaluable efficacy assessment after treatment.
    End point type
    Primary
    End point timeframe
    8 hours post infusion.
    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: Only descriptive analysis was planned to be reported for this end point.
    End point values
    BeneFactor IX (BeneFIX)
    Number of subjects analysed
    34
    Units: Units on a scale
        arithmetic mean (standard deviation)
    1.7 ± 0.72
    No statistical analyses for this end point

    Primary: Investigator Hemostatic Efficacy Assessment of Subjects After 24 Hours Post Infusion

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    End point title
    Investigator Hemostatic Efficacy Assessment of Subjects After 24 Hours Post Infusion [2]
    End point description
    Investigator Hemostatic Efficacy Assessment was based on response of bleeding episodes to BeneFIX treatment on 4-point rating scale: Excellent(1): definite pain relief or improvement in signs of bleeding starting within 8 hours after infusion, with no additional infusion; Good(2): definite pain relief or improvement in signs of bleeding starting within 8 hrs or following infusion; Moderate(3): probable or slight improvement starting after 8 hours following infusion; No Response(4): no improvement at all between infusions or during 24 hour interval following an infusion, or condition worsens. FAS population included all subjects who were treated and had at least 1 evaluable efficacy assessment after treatment.
    End point type
    Primary
    End point timeframe
    24 hours post infusion
    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: Only descriptive analysis was planned to be reported for this end point.
    End point values
    BeneFactor IX (BeneFIX)
    Number of subjects analysed
    34
    Units: Units on a scale
        arithmetic mean (standard deviation)
    1.58 ± 0.71
    No statistical analyses for this end point

    Primary: Percentage of Subjects With FIX Inhibitor Development

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    End point title
    Percentage of Subjects With FIX Inhibitor Development [3]
    End point description
    Incidence of FIX inhibitor was defined as any result determined as positive at local laboratory, and confirmed at central laboratory with Nijmegen assay result greater than or equal to (>=)0.6 Bethesda Unit (BU). Incidence was stratified by subject exposure history - Minimally Treated Patients (MTPs): those who had received at least one prior FIX infusion, and less than or equal to (<=) 100 documented Exposure Days (EDs); while Previously Treated Patients (PTPs): those who had received >100 documented prior EDs. When number of prior EDs for an individual was not known to be at least 100, subjects were included in the MTP population. Safety Set (SS) population included all enrolled subjects who had taken at least 1 dose of drug. The 'n' is signifying those subjects who received study drug and were evaluated for this measure at the timepoint for each visit respectively.
    End point type
    Primary
    End point timeframe
    Baseline up to 6 months
    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: Only descriptive analysis was planned to be reported for this end point.
    End point values
    BeneFactor IX (BeneFIX)
    Number of subjects analysed
    35
    Units: Percentage of Subjects
    number (not applicable)
        Total (n=35)
    2.86
        MTP (n=24)
    4.17
        PTP (n=11)
    0
    No statistical analyses for this end point

    Secondary: Number of Infusions Required to Treat Each Bleed

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    End point title
    Number of Infusions Required to Treat Each Bleed
    End point description
    The number of BeneFIX infusions required to treat each bleeding episode were analyzed. The average frequency of BeneFIX infusions per hemorrhage incidence to treat every hemorrhage was equal to the total number of injections throughout the study divided by total number of hemorrhagic events. FAS population included all subjects who were treated and had at least 1 evaluable efficacy assessment after treatment.
    End point type
    Secondary
    End point timeframe
    Baseline up to 6 months
    End point values
    BeneFactor IX (BeneFIX)
    Number of subjects analysed
    34
    Units: Infusions
        arithmetic mean (standard deviation)
    1.2 ± 0.86
    No statistical analyses for this end point

    Secondary: FIX Incremental Recovery

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    End point title
    FIX Incremental Recovery
    End point description
    FIX recovery was assessed by evaluating FIX:C after initial exposure and following 6 months of repeated exposures to BeneFIX. A modified FIX recovery study was performed at Day 1 (Visit 2) and Month 6/Final/Early Termination visits (Visit 4) and when clinically indicated at the applicable on-demand visits. Blood samples for determination of FIX:C were collected immediately before BeneFIX infusion and at 30 minutes (±5 minutes) after the start of infusion. Post-infusion blood samples were collected via venipuncture in arm contralateral to arm used for infusion. FAS population included all subjects who were treated and had at least 1 evaluable efficacy assessment after treatment. The 'n' is signifying those subjects who received study drug and were evaluated for this measure at the timepoint for each visit respectively.
    End point type
    Secondary
    End point timeframe
    Baseline (Visit 2) up to 6 months (Visit 4)
    End point values
    BeneFactor IX (BeneFIX)
    Number of subjects analysed
    34
    Units: IU/deciliter (dL) per IU/kg
    arithmetic mean (standard deviation)
        Visit 2 (n=30)
    0.76 ± 0.222
        Visit 4 (n=31)
    0.727 ± 0.275
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Less Than Expected Therapeutic Effect (LETE)

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    End point title
    Percentage of Subjects With Less Than Expected Therapeutic Effect (LETE)
    End point description
    The incidence of LETE for on-demand treatment was defined as no response after each of 2 successive infusions within 24 hours for the same bleeding event in the absence of confounding factors. FAS population included all subjects who were treated and had at least 1 evaluable efficacy assessment after treatment.
    End point type
    Secondary
    End point timeframe
    Baseline up to 6 months
    End point values
    BeneFactor IX (BeneFIX)
    Number of subjects analysed
    34
    Units: Percentage of Subjects
        number (not applicable)
    0
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Allergic-Type Allergic Reactions

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    End point title
    Percentage of Subjects With Allergic-Type Allergic Reactions
    End point description
    Hypersensitivity to undesirable (damaging, discomfort-producing and sometimes fatal) reactions produced by the normal immune system. Hypersensitivity reactions require a pre-sensitized (immune) state of the host. SS population included all enrolled subjects who had taken at least 1 dose of drug.
    End point type
    Secondary
    End point timeframe
    Baseline up to 6 months
    End point values
    BeneFactor IX (BeneFIX)
    Number of subjects analysed
    35
    Units: Percentage of Subjects
        number (not applicable)
    0
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Thrombosis

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    End point title
    Percentage of Subjects With Thrombosis
    End point description
    Thrombosis is the formation of a blood clot (thrombus) inside a blood vessel, obstructing the flow of blood through the circulatory system. When a blood vessel is injured, the body uses platelets and fibrin to form a blood clot to prevent blood loss. SS population included all enrolled subjects who had taken at least 1 dose of drug.
    End point type
    Secondary
    End point timeframe
    Baseline up to 6 months
    End point values
    BeneFactor IX (BeneFIX)
    Number of subjects analysed
    35
    Units: Percentage of Subjects
        number (not applicable)
    0
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Red Blood Cell (RBC) Agglutination

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    End point title
    Percentage of Subjects With Red Blood Cell (RBC) Agglutination
    End point description
    RBC Agglutination is the clumping of red blood cells in the presence of an antibody. The antibody or other molecule bonded multiple particles and joined them, creating a large complex. SS population included all enrolled subjects who had taken at least 1 dose of drug.
    End point type
    Secondary
    End point timeframe
    Baseline up to 6 months
    End point values
    BeneFactor IX (BeneFIX)
    Number of subjects analysed
    35
    Units: Percentage of Subjects
        number (not applicable)
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From screening until 30 days after the last visit (Month 6/Final/Early Termination visit)
    Adverse event reporting additional description
    The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as non-serious in another subject, or one subject may have experienced both a serious and non-serious event during the study.
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    17.1
    Reporting groups
    Reporting group title
    BeneFactor IX (BeneFIX)
    Reporting group description
    Subjects received on-demand treatments with BeneFIX according to investigator’s prescription over a 6-month (calendar day) period. A single 75 IU/kg (±5 IU/kg) IV bolus infusion of BeneFIX was given for recovery assessments. All BeneFIX administrations occurred in the clinic (hospital).

    Serious adverse events
    BeneFactor IX (BeneFIX)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 35 (5.71%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Surgical and medical procedures
    Synovectomy
         subjects affected / exposed
    1 / 35 (2.86%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorders
    Haemorrhage intracranial
         subjects affected / exposed
    1 / 35 (2.86%)
         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
    BeneFactor IX (BeneFIX)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    10 / 35 (28.57%)
    Vascular disorders
    Haemorrhage
         subjects affected / exposed
    1 / 35 (2.86%)
         occurrences all number
    1
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    1 / 35 (2.86%)
         occurrences all number
    1
    Ligament sprain
         subjects affected / exposed
    2 / 35 (5.71%)
         occurrences all number
    2
    Limb injury
         subjects affected / exposed
    2 / 35 (5.71%)
         occurrences all number
    2
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 35 (2.86%)
         occurrences all number
    1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 35 (2.86%)
         occurrences all number
    1
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    1 / 35 (2.86%)
         occurrences all number
    1
    Oedema peripheral
         subjects affected / exposed
    1 / 35 (2.86%)
         occurrences all number
    1
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    1 / 35 (2.86%)
         occurrences all number
    1
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 35 (2.86%)
         occurrences all number
    1
    Musculoskeletal and connective tissue disorders
    Arthritis
         subjects affected / exposed
    1 / 35 (2.86%)
         occurrences all number
    1
    Infections and infestations
    Infection
         subjects affected / exposed
    1 / 35 (2.86%)
         occurrences all number
    1

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? No

    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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