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    Clinical Trial Results:
    Antihemophilic Factor (Recombinant) Plasma/Albumin-Free Method (rAHF PFM): A Phase 3/4, Prospective, Controlled, Randomized, Multi-Center Study to Compare the Efficacy and Safety of Continuous Infusion (CI) versus Intermittent Bolus Infusion (BI) in Subjects with Severe or Moderately Severe Hemophilia A Undergoing Major Orthopedic Surgery

    Summary
    EudraCT number
    2005-005697-71
    Trial protocol
    AT   SE   BE   PT   ES   HU   NL   GB   IT   PL  
    Global end of trial date
    09 Dec 2015

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

    Trial information

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    Trial identification
    Sponsor protocol code
    060402
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT00357656
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Baxalta US Inc.
    Sponsor organisation address
    One Baxter Way, Westlake Village, United States, CA 91362
    Public contact
    Clinical Trial Registries and Results Disclosure, Baxalta US Inc., ClinicalTrialsDisclosure@baxalta.com
    Scientific contact
    Clinical Trial Registries and Results Disclosure, Baxalta US Inc., ClinicalTrialsDisclosure@baxalta.com
    Sponsor organisation name
    Baxalta Innovations GmbH
    Sponsor organisation address
    Industriestrasse 67, Vienna, Austria, 1221
    Public contact
    Clinical Trial Registries and Results Disclosure, Baxalta Innovations GmbH, ClinicalTrialsDisclosure@baxalta.com
    Scientific contact
    Clinical Trial Registries and Results Disclosure, Baxalta Innovations GmbH, ClinicalTrialsDisclosure@baxalta.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
    09 Dec 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    09 Dec 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this trial is to compare the hemostatic efficacy of continuous infusion versus intermittent bolus infusion in the peri- and post-operative setting employing ADVATE (rAHF-PFM) in previously treated patients (PTPs) with severe or moderately severe hemophilia A (baseline FVIII level less or equal to 2% of normal) undergoing elective unilateral major orthopedic surgery that requires drain placement by assessing the cumulative packed red blood cell (PRBC) volume in the drainage fluid during the first 24 hours following surgery.
    Protection of trial subjects
    This study was conducted in accordance with the standards of Good Clinical Practice (GCP) in effect at the time of the study.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    29 May 2006
    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 States: 4
    Country: Number of subjects enrolled
    Austria: 5
    Country: Number of subjects enrolled
    Norway: 1
    Country: Number of subjects enrolled
    France: 1
    Country: Number of subjects enrolled
    Portugal: 5
    Country: Number of subjects enrolled
    Netherlands: 1
    Country: Number of subjects enrolled
    Spain: 4
    Country: Number of subjects enrolled
    Russian Federation: 27
    Country: Number of subjects enrolled
    Romania: 5
    Country: Number of subjects enrolled
    Hungary: 6
    Country: Number of subjects enrolled
    Poland: 13
    Worldwide total number of subjects
    72
    EEA total number of subjects
    41
    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)
    72
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Enrollment was conducted at 22 clinical sites in 12 countries (Austria, France, Hungary, Italy, Norway, Poland, Portugal, Romania, Russia, Spain, The Netherlands, USA). Of 85 subjects enrolled, 72 subjects participated in a PK study in the preoperative period; 63 subjects were then randomized to treatment by continuous or bolus infusion.

    Pre-assignment
    Screening details
    Of 85 subjects enrolled, 15 were screen failures, 4 were discontinued on the basis of the PK study in the preoperative period, 1 subject died, 1 was discontinued by physician decision (imprisonment), and 1 was discontinued per sponsor decision. Eventually, 63 subjects were randomized to treatment by continuous (n=32) or bolus infusion (n=31).

    Pre-assignment period milestones
    Number of subjects started
    72
    Intermediate milestone: Number of subjects
    PK infusion: 72
    Number of subjects completed
    63

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    PK results: 4
    Reason: Number of subjects
    Physician decision (imprisonment): 1
    Reason: Number of subjects
    Sponsor decision: 1
    Reason: Number of subjects
    Death: 1
    Reason: Number of subjects
    Screen failure: 2
    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Treatment by Continuous infusion
    Arm description
    This reporting group comprises all 32 subjects in the Full Analysis Set who were randomized to receive ADVATE (rAHF-PFM) by continuous infusion (CI).
    Arm type
    Experimental

    Investigational medicinal product name
    Advate
    Investigational medicinal product code
    Other name
    rAHF-PFM (Antihemophilic Factor (Recombinant) - Plasma/Albumin Free Method)
    Pharmaceutical forms
    Powder and solvent for solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects initially underwent a pharmacokinetic (PK) evaluation with ADVATE (dose: 50 IU ± 5 IU/kg). Prior to surgery, subjects received a loading dose with ADVATE (based on subject´s PK profile), to maintain a minimum target FVIII level of at least 80% of normal. After the loading dose(s), subjects received ADVATE either as intermittent bolus infusion (BI) or as continuous infusion (CI). The dose recommendations were provided by the sponsor and were based on the subject´s PK profile. For safety reasons, all subjects were to receive a rebolus in the recovery room to compensate for perioperative blood loss and increased FVIII consumption. The following minimum FVIII levels were to be targeted for both CI and BI treatment: at least 80% of normal for the first 72 hours after the initial loading dose, then at least 50% of normal until postoperative Day 7. For CI, ADVATE was to be administered with a syringe pump (infusion rate according to dosing regimen).

    Arm title
    Treatment by Bolus infusion
    Arm description
    This reporting group comprises all 31 subjects in the Full Analysis Set who were randomized to receive ADVATE (rAHF-PFM) by intermittent bolus infusion (BI).
    Arm type
    Experimental

    Investigational medicinal product name
    Advate
    Investigational medicinal product code
    Other name
    rAHF-PFM (Antihemophilic Factor (Recombinant) - Plasma/Albumin Free Method)
    Pharmaceutical forms
    Powder and solvent for solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects initially underwent a pharmacokinetic (PK) evaluation with ADVATE (dose: 50 IU ± 5 IU/kg). Prior to surgery, subjects received a loading dose with ADVATE (based on subject´s PK profile), to maintain a minimum target FVIII level of at least 80% of normal. After the loading dose(s), subjects received ADVATE either as intermittent bolus infusion (BI) or as continuous infusion (CI). The dose recommendations were provided by the sponsor and were based on the subject´s PK profile. For safety reasons, all subjects were to receive a rebolus in the recovery room to compensate for perioperative blood loss and increased FVIII consumption. The following minimum FVIII levels were to be targeted for both CI and BI treatment: at least 80% of normal for the first 72 hours after the initial loading dose, then at least 50% of normal until postoperative Day 7. For CI, ADVATE was to be administered with a syringe pump (infusion rate according to dosing regimen).

    Number of subjects in period 1 [1]
    Treatment by Continuous infusion Treatment by Bolus infusion
    Started
    32
    31
    Completed
    29
    31
    Not completed
    3
    0
         No surgery performed
             3
             -
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: Of 85 subjects enrolled, 72 subjects participated in a PK evaluation in the preoperative period; 63 subjects were then randomized to treatment by continuous or bolus infusion.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Treatment by Continuous infusion
    Reporting group description
    This reporting group comprises all 32 subjects in the Full Analysis Set who were randomized to receive ADVATE (rAHF-PFM) by continuous infusion (CI).

    Reporting group title
    Treatment by Bolus infusion
    Reporting group description
    This reporting group comprises all 31 subjects in the Full Analysis Set who were randomized to receive ADVATE (rAHF-PFM) by intermittent bolus infusion (BI).

    Reporting group values
    Treatment by Continuous infusion Treatment by Bolus infusion Total
    Number of subjects
    32 31 63
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    32 31 63
    Age continuous
    Units: years
        log mean (standard deviation)
    39 ± 11.52 38.6 ± 9.76 -
    Gender categorical
    Units:
        Male
    32 31 63
        Female
    0 0 0
    Subject analysis sets

    Subject analysis set title
    Full Analysis Set
    Subject analysis set type
    Full analysis
    Subject analysis set description
    The Full Analysis Set (FAS) comprises all subjects who were randomized to receive bolus infusion (BI) or continuous infusion (CI) of ADVATE (rAHF-PFM).

    Subject analysis set title
    Full Analysis Set - Continuous Infusion (CI)
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    This analysis set comprises all subjects in the Full Analysis Set (FAS) who were randomized to receive continuous infusion (CI) of ADVATE (rAHF-PFM). This analysis set is identical to Reporting Group 1 (Treatment by Continuous Infusion).

    Subject analysis set title
    Full Analysis Set - Bolus Infusion (BI)
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    This analysis set comprises all subjects in the FAS who were randomized to receive bolus infusion (BI) of ADVATE (rAHF-PFM). This analysis set is identical to Reporting Group 2 (Treatment by Bolus Infusion).

    Subject analysis set title
    Safety Analysis Set
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    The Safety Analysis Set (SAS) comprises all subjects treated with at least one ADVATE (rAHF-PFM) dose. All safety analyses were performed on the SAS.

    Subject analysis set title
    Per Protocol Analysis Set
    Subject analysis set type
    Per protocol
    Subject analysis set description
    The Per Protocol Analysis Set (PPAS) comprises all subjects who were randomized to receive BI or CI of ADVATE (rAHF-PFM) and have observed drainage volumes up to 24 hours including hematocrit results for these drainage fluids.

    Subject analysis set title
    Per Protocol Analysis Set - CI
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    This analysis set comprises all subjects in the PPAS who were randomized to receive CI of ADVATE (rAHF-PFM) and have observed drainage volumes up to 24 hours including hematocrit results for these drainage fluids.

    Subject analysis set title
    Per Protocol Analysis Set - BI
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    This analysis set comprises all subjects in the PPAS who were randomized to receive BI of ADVATE (rAHF-PFM) and have observed drainage volumes up to 24 hours including hematocrit results for these drainage fluids.

    Subject analysis set title
    Pharmacokinetic (PK) Full Analysis Set
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    The PK Full Analysis Set (PKFAS) consists of all subjects who had a PK evaluation. If a subject had a repeat PK, the PK parameters of all evaluations were to be listed, but only the last value was to be used for summary statistics. This analysis set is identical to the Full Analysis Set (FAS).

    Subject analysis set title
    PKFAS - CI
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    This analysis set comprises all subjects in the PKFAS who had a PK evaluation and were randomized to CI. This analysis set is identical to the FAS - CI.

    Subject analysis set title
    PKFAS - BI
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    This analysis set comprises all subjects in the PKFAS who had a PK evaluation and were randomized to BI. This analysis set is identical to the FAS - BI.

    Subject analysis set title
    Stratum A - CI
    Subject analysis set type
    Per protocol
    Subject analysis set description
    Stratum A (CI) includes subjects in the per-protocol analysis set who underwent unilateral knee replacement and were treated by continuous infusion.

    Subject analysis set title
    Stratum B - CI
    Subject analysis set type
    Per protocol
    Subject analysis set description
    Stratum B (CI) includes subjects in the per-protocol analysis set who underwent hip surgery and were treated by continuous infusion.

    Subject analysis set title
    Stratum C - CI
    Subject analysis set type
    Per protocol
    Subject analysis set description
    Stratum C (CI) includes subjects in the per-protocol analysis set who underwent shoulder/elbow/ankle/knee (except knee replacement) surgery and were treated by continuous infusion.

    Subject analysis set title
    Stratum A - BI
    Subject analysis set type
    Per protocol
    Subject analysis set description
    Stratum A (BI) includes subjects in the per-protocol analysis set who underwent unilateral knee replacement and were treated by bolus infusion.

    Subject analysis set title
    Stratum B - BI
    Subject analysis set type
    Per protocol
    Subject analysis set description
    Stratum B (BI) includes subjects in the per-protocol analysis set who underwent hip surgery and were treated by bolus infusion.

    Subject analysis set title
    Stratum C - BI
    Subject analysis set type
    Per protocol
    Subject analysis set description
    Stratum C (BI) includes subjects in the per-protocol analysis set who underwent shoulder/elbow/ankle/knee (except knee replacement) surgery and were treated by bolus infusion.

    Subject analysis sets values
    Full Analysis Set Full Analysis Set - Continuous Infusion (CI) Full Analysis Set - Bolus Infusion (BI) Safety Analysis Set Per Protocol Analysis Set Per Protocol Analysis Set - CI Per Protocol Analysis Set - BI Pharmacokinetic (PK) Full Analysis Set PKFAS - CI PKFAS - BI Stratum A - CI Stratum B - CI Stratum C - CI Stratum A - BI Stratum B - BI Stratum C - BI
    Number of subjects
    63
    32
    31
    72
    60
    29
    31
    63
    32
    31
    24
    2
    3
    24
    2
    5
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    63
    32
    31
    72
    60
    29
    31
    63
    32
    31
    24
    2
    3
    24
    2
    5
    Age continuous
    Units: years
        log mean (standard deviation)
    38.8 ± 10.61
    39 ± 11.52
    38.6 ± 9.76
    38.6 ± 10.49
    38.7 ± 10.69
    38.8 ± 11.77
    38.6 ± 9.76
    38.8 ± 10.61
    39 ± 11.52
    38.6 ± 9.76
    38.4 ± 10.95
    47 ± 14.14
    36.3 ± 19.6
    37.5 ± 9.06
    55.5 ± 3.54
    37.2 ± 9.34
    Gender categorical
    Units:
        Male
    63
    32
    31
    72
    60
    29
    31
    63
    32
    31
    24
    2
    3
    24
    2
    5
        Female
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0

    End points

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    End points reporting groups
    Reporting group title
    Treatment by Continuous infusion
    Reporting group description
    This reporting group comprises all 32 subjects in the Full Analysis Set who were randomized to receive ADVATE (rAHF-PFM) by continuous infusion (CI).

    Reporting group title
    Treatment by Bolus infusion
    Reporting group description
    This reporting group comprises all 31 subjects in the Full Analysis Set who were randomized to receive ADVATE (rAHF-PFM) by intermittent bolus infusion (BI).

    Subject analysis set title
    Full Analysis Set
    Subject analysis set type
    Full analysis
    Subject analysis set description
    The Full Analysis Set (FAS) comprises all subjects who were randomized to receive bolus infusion (BI) or continuous infusion (CI) of ADVATE (rAHF-PFM).

    Subject analysis set title
    Full Analysis Set - Continuous Infusion (CI)
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    This analysis set comprises all subjects in the Full Analysis Set (FAS) who were randomized to receive continuous infusion (CI) of ADVATE (rAHF-PFM). This analysis set is identical to Reporting Group 1 (Treatment by Continuous Infusion).

    Subject analysis set title
    Full Analysis Set - Bolus Infusion (BI)
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    This analysis set comprises all subjects in the FAS who were randomized to receive bolus infusion (BI) of ADVATE (rAHF-PFM). This analysis set is identical to Reporting Group 2 (Treatment by Bolus Infusion).

    Subject analysis set title
    Safety Analysis Set
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    The Safety Analysis Set (SAS) comprises all subjects treated with at least one ADVATE (rAHF-PFM) dose. All safety analyses were performed on the SAS.

    Subject analysis set title
    Per Protocol Analysis Set
    Subject analysis set type
    Per protocol
    Subject analysis set description
    The Per Protocol Analysis Set (PPAS) comprises all subjects who were randomized to receive BI or CI of ADVATE (rAHF-PFM) and have observed drainage volumes up to 24 hours including hematocrit results for these drainage fluids.

    Subject analysis set title
    Per Protocol Analysis Set - CI
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    This analysis set comprises all subjects in the PPAS who were randomized to receive CI of ADVATE (rAHF-PFM) and have observed drainage volumes up to 24 hours including hematocrit results for these drainage fluids.

    Subject analysis set title
    Per Protocol Analysis Set - BI
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    This analysis set comprises all subjects in the PPAS who were randomized to receive BI of ADVATE (rAHF-PFM) and have observed drainage volumes up to 24 hours including hematocrit results for these drainage fluids.

    Subject analysis set title
    Pharmacokinetic (PK) Full Analysis Set
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    The PK Full Analysis Set (PKFAS) consists of all subjects who had a PK evaluation. If a subject had a repeat PK, the PK parameters of all evaluations were to be listed, but only the last value was to be used for summary statistics. This analysis set is identical to the Full Analysis Set (FAS).

    Subject analysis set title
    PKFAS - CI
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    This analysis set comprises all subjects in the PKFAS who had a PK evaluation and were randomized to CI. This analysis set is identical to the FAS - CI.

    Subject analysis set title
    PKFAS - BI
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    This analysis set comprises all subjects in the PKFAS who had a PK evaluation and were randomized to BI. This analysis set is identical to the FAS - BI.

    Subject analysis set title
    Stratum A - CI
    Subject analysis set type
    Per protocol
    Subject analysis set description
    Stratum A (CI) includes subjects in the per-protocol analysis set who underwent unilateral knee replacement and were treated by continuous infusion.

    Subject analysis set title
    Stratum B - CI
    Subject analysis set type
    Per protocol
    Subject analysis set description
    Stratum B (CI) includes subjects in the per-protocol analysis set who underwent hip surgery and were treated by continuous infusion.

    Subject analysis set title
    Stratum C - CI
    Subject analysis set type
    Per protocol
    Subject analysis set description
    Stratum C (CI) includes subjects in the per-protocol analysis set who underwent shoulder/elbow/ankle/knee (except knee replacement) surgery and were treated by continuous infusion.

    Subject analysis set title
    Stratum A - BI
    Subject analysis set type
    Per protocol
    Subject analysis set description
    Stratum A (BI) includes subjects in the per-protocol analysis set who underwent unilateral knee replacement and were treated by bolus infusion.

    Subject analysis set title
    Stratum B - BI
    Subject analysis set type
    Per protocol
    Subject analysis set description
    Stratum B (BI) includes subjects in the per-protocol analysis set who underwent hip surgery and were treated by bolus infusion.

    Subject analysis set title
    Stratum C - BI
    Subject analysis set type
    Per protocol
    Subject analysis set description
    Stratum C (BI) includes subjects in the per-protocol analysis set who underwent shoulder/elbow/ankle/knee (except knee replacement) surgery and were treated by bolus infusion.

    Primary: Cumulative packed red blood cell (PRBC) volume in the drainage fluid during the first 24 hours following surgery in subjects receiving ADVATE (rAHF-PFM) by bolus (BI) or continuous infusion (CI)

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    End point title
    Cumulative packed red blood cell (PRBC) volume in the drainage fluid during the first 24 hours following surgery in subjects receiving ADVATE (rAHF-PFM) by bolus (BI) or continuous infusion (CI)
    End point description
    Drainage fluid volume was to be measured cumulatively and recorded every 8 hours +/- 30 minutes during the first 24 hours following surgery.
    End point type
    Primary
    End point timeframe
    During the first 24 postoperative hours
    End point values
    Treatment by Continuous infusion Treatment by Bolus infusion Per Protocol Analysis Set - CI Per Protocol Analysis Set - BI Stratum A - CI Stratum B - CI Stratum C - CI Stratum A - BI Stratum B - BI Stratum C - BI
    Number of subjects analysed
    26
    28
    26
    28
    23
    1
    2
    22
    2
    4
    Units: T/L
        arithmetic mean (standard deviation)
    3.383 ± 0.632
    3.632 ± 0.971
    3.383 ± 0.632
    3.632 ± 0.971
    3.345 ± 0.616
    3.4 ± 0
    3.82 ± 1.103
    3.718 ± 0.978
    2.855 ± 1.732
    3.548 ± 0.577
    Statistical analysis title
    Non-inferiority of CI to BI
    Statistical analysis description
    The main analysis used a point estimate and a two-sided 95% confidence interval for ratio of the primary outcome measure of CI over BI combined over the three strata: stratum A: unilateral knee replacement, stratum B: hip surgery, stratum C: shoulder/elbow/ankle/knee (except knee replacement) surgery. Non-inferiority by the 200% margin of non-inferiority was demonstrated if the upper confidence limit of a 95% 2-sided confidence interval for the ratio of means did not exceed 200%.
    Comparison groups
    Treatment by Bolus infusion v Treatment by Continuous infusion
    Number of subjects included in analysis
    54
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    < 0.001 [1]
    Method
    Hypothesis test
    Parameter type
    Mean ratio CI/BI
    Point estimate
    0.924
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.816
         upper limit
    1.046
    Notes
    [1] - one-sided p-value against the null hypothesis of ratio >=200%

    Secondary: Actual postoperative blood loss during the first 24 hours compared with the average blood loss as predicted preoperatively by the operating surgeon

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    End point title
    Actual postoperative blood loss during the first 24 hours compared with the average blood loss as predicted preoperatively by the operating surgeon
    End point description
    Drainage fluid volume was to be measured cumulatively and recorded every 8 hours +/- 30 minutes during the first 24 hours following surgery. Prior to surgery, the operating surgeon was to predict the estimated duration of surgery and the volume (mL) of the estimated expected blood loss for the surgery in a hemostatically normal individual of the same sex, age, and stature as the study subject 1) for the intraoperative procedure (defined as the time period from incision to application of compressive dressing and release of tourniquet, if applicable), 2) for the first 24 hours postoperatively, and 3) for the postoperative period until drain removal, if drainage continued beyond 24 hours.
    End point type
    Secondary
    End point timeframe
    During the first 24 postoperative hours
    End point values
    Treatment by Continuous infusion Treatment by Bolus infusion Per Protocol Analysis Set - CI Per Protocol Analysis Set - BI Stratum A - CI Stratum B - CI Stratum C - CI Stratum A - BI Stratum B - BI Stratum C - BI
    Number of subjects analysed
    29
    31
    29
    31
    24
    2
    3
    24
    2
    5
    Units: millilitre (mL)
        arithmetic mean (standard deviation)
    811.11 ± 79.511
    709.28 ± 150.103
    811.11 ± 79.511
    709.28 ± 150.103
    819.22 ± 66.992
    713.49 ± 0
    811.25 ± 163.027
    724.48 ± 66.367
    265 ± 49.497
    814.03 ± 171.019
    No statistical analyses for this end point

    Secondary: Actual postoperative blood loss compared to the expected average blood loss until drain removal as predicted preoperatively by the surgeon

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    End point title
    Actual postoperative blood loss compared to the expected average blood loss until drain removal as predicted preoperatively by the surgeon
    End point description
    If drainage continued beyond 24 hours, the PRBC volume and hemoglobin was to be measured cumulatively every 24 hours or whenever the drainage bottle was emptied and at the time of drain removal. Prior to surgery, the operating surgeon was to predict the estimated duration of surgery and the volume (mL) of the estimated expected blood loss for the surgery in a hemostatically normal individual of the same sex, age, and stature as the study subject 1) for the intraoperative procedure (defined as the time period from incision to application of compressive dressing and release of tourniquet, if applicable), 2) for the first 24 hours postoperatively, and 3) for the postoperative period until drain removal, if drainage continued beyond 24 hours.
    End point type
    Secondary
    End point timeframe
    Postoperatively until drain removal
    End point values
    Treatment by Continuous infusion Treatment by Bolus infusion Per Protocol Analysis Set - CI Per Protocol Analysis Set - BI Stratum A - CI Stratum B - CI Stratum C - CI Stratum A - BI Stratum B - BI Stratum C - BI
    Number of subjects analysed
    28
    30
    28
    30
    23
    2
    3
    23
    2
    5
    Units: mL
        arithmetic mean (standard deviation)
    929.49 ± 167.662
    766.73 ± 182.463
    929.49 ± 167.662
    766.73 ± 182.463
    899.83 ± 45.459
    921.1 ± 42.906
    1162.48 ± 514.033
    752.91 ± 42.343
    341.5 ± 135.075
    1000.37 ± 259.239
    No statistical analyses for this end point

    Secondary: Number of bleeding episodes during treatment with continuous or bolus infusion (through postoperative Day 7)

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    End point title
    Number of bleeding episodes during treatment with continuous or bolus infusion (through postoperative Day 7)
    End point description
    To simplify the results below: Bleeding episodes were reported for 4 subjects (3 subjects on bolus infusion: 2 in Stratum A and 1 in Stratum B, and 1 subject on continuous infusion/Stratum B). The 4 subjects had 1 bleeding episode each. No bleeding episodes were reported for Stratum C.
    End point type
    Secondary
    End point timeframe
    Postoperative Day 7
    End point values
    Treatment by Continuous infusion Treatment by Bolus infusion Per Protocol Analysis Set - CI Per Protocol Analysis Set - BI Stratum A - CI Stratum B - CI Stratum C - CI Stratum A - BI Stratum B - BI Stratum C - BI
    Number of subjects analysed
    29
    31
    29
    31
    24
    2
    3
    24
    2
    5
    Units: Bleeding episodes
        arithmetic mean (standard deviation)
    0.03 ± 0.186
    0.1 ± 0.301
    0.03 ± 0.186
    0.1 ± 0.301
    0 ± 0
    0.5 ± 0.707
    0 ± 0
    0.08 ± 0.282
    0.5 ± 0.707
    0 ± 0
    No statistical analyses for this end point

    Secondary: Number of units of packed red blood cells (PRBC) transfused

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    End point title
    Number of units of packed red blood cells (PRBC) transfused
    End point description
    End point type
    Secondary
    End point timeframe
    During the first postoperative 24 hours
    End point values
    Treatment by Continuous infusion Treatment by Bolus infusion Per Protocol Analysis Set - CI Per Protocol Analysis Set - BI Stratum A - CI Stratum B - CI Stratum C - CI Stratum A - BI Stratum B - BI Stratum C - BI
    Number of subjects analysed
    29
    31
    29
    31
    24
    2
    3
    24
    2
    5
    Units: PRBC units
        arithmetic mean (standard deviation)
    1.3 ± 1.4
    0.9 ± 1.2
    1.3 ± 1.4
    0.9 ± 1.2
    1.2 ± 1.3
    3.5 ± 2.1
    0.7 ± 1.2
    1 ± 1.3
    1.5 ± 2.1
    0.2 ± 0.4
    No statistical analyses for this end point

    Secondary: Number of adverse events (AEs) related to the administration of the study product

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    End point title
    Number of adverse events (AEs) related to the administration of the study product
    End point description
    All AEs from the first study drug exposure until the study completion/ discontinuation date were to be recorded. Each AE was to be evaluated by the investigator for “seriousness”, “severity” and “causal relationship to the investigational product exposure or study procedure”.
    End point type
    Secondary
    End point timeframe
    From first study drug exposure until study completion/discontinuation (approx. 9-26 weeks per subject)
    End point values
    Treatment by Continuous infusion Treatment by Bolus infusion Safety Analysis Set
    Number of subjects analysed
    5
    5
    10
    Units: adverse events (AEs)
    8
    6
    14
    No statistical analyses for this end point

    Secondary: Incidence of Factor VIII inhibitory antibody (≥0.4 Bethesda Units using the Nijmegen modification of the Bethesda assay) formation

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    End point title
    Incidence of Factor VIII inhibitory antibody (≥0.4 Bethesda Units using the Nijmegen modification of the Bethesda assay) formation
    End point description
    End point type
    Secondary
    End point timeframe
    Until study completion (approx. 9-26 weeks per subject)
    End point values
    Treatment by Continuous infusion Treatment by Bolus infusion Safety Analysis Set
    Number of subjects analysed
    2
    2
    4
    Units: subjects
    2
    2
    4
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Overall: 9 years and 6 months Per subject: 9-26 weeks
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    18.1
    Reporting groups
    Reporting group title
    Safety Analysis Set (n=72)
    Reporting group description
    The Safety Analysis Set (SAS) comprises all 72 subjects treated with at least one ADVATE (rAHF-PFM) dose. A total of 72 subjects received ADVATE (rAHF-PFM) for the pharmacokinetic evaluation in the preoperative period. Of these, 32 subjects were subsequently randomized to treatment with continous infusion, and 31 subjects were randomized to treatment with intermittent bolus infusion.

    Serious adverse events
    Safety Analysis Set (n=72)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    10 / 72 (13.89%)
         number of deaths (all causes)
    1
         number of deaths resulting from adverse events
    0
    Blood and lymphatic system disorders
    Factor VIII inhibition
         subjects affected / exposed
    4 / 72 (5.56%)
         occurrences causally related to treatment / all
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Multi-organ failure
         subjects affected / exposed
    1 / 72 (1.39%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal and connective tissue disorders
    Hemarthrosis
         subjects affected / exposed
    1 / 72 (1.39%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Joint swelling
         subjects affected / exposed
    1 / 72 (1.39%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Muscle hemorrhage
         subjects affected / exposed
    1 / 72 (1.39%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Febrile infection
         subjects affected / exposed
    1 / 72 (1.39%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pseudomembranous colitis
         subjects affected / exposed
    1 / 72 (1.39%)
         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 Analysis Set (n=72)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    43 / 72 (59.72%)
    Injury, poisoning and procedural complications
    Procedural pain
         subjects affected / exposed
    26 / 72 (36.11%)
         occurrences all number
    32
    Cardiac disorders
    Tachycardia
         subjects affected / exposed
    4 / 72 (5.56%)
         occurrences all number
    4
    Blood and lymphatic system disorders
    Anemia
         subjects affected / exposed
    18 / 72 (25.00%)
         occurrences all number
    21
    Thrombocytosis
         subjects affected / exposed
    4 / 72 (5.56%)
         occurrences all number
    4
    Nervous system disorders
    Headache
         subjects affected / exposed
    4 / 72 (5.56%)
         occurrences all number
    5
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    15 / 72 (20.83%)
         occurrences all number
    21
    Pain
         subjects affected / exposed
    8 / 72 (11.11%)
         occurrences all number
    8
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    4 / 72 (5.56%)
         occurrences all number
    4
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    5 / 72 (6.94%)
         occurrences all number
    5
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    7 / 72 (9.72%)
         occurrences all number
    30

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    14 Nov 2007
    Amendment 4: - Maximum subject age was raised from previously 65 to 70 years to allow the inclusion of subjects older than 65 years provided that their health status corresponds to NYHA classification less than or equal to II as defined by the New York Heart Association (NYHA) - The exclusion threshold for history of FVIII inhibitors in the Bethesda assay was raised from equal to or greater than 0.4 BU to equal to or greater than 0.5 BU.
    02 Sep 2011
    Amendment 5: Prior to Protocol Amendment 5 (version 02Sep2011), the study was performed in subjects undergoing unilateral primary total knee replacement. In Protocol Amendment 5, the surgeries were expanded to major orthopedic surgeries to increase the enrollment rate.

    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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