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    Clinical Trial Results:
    A Phase 3, Prospective, Multicenter Study to Evaluate Efficacy and Safety of Recombinant von Willebrand Factor (rVWF) with or without ADVATE in Elective Surgical Procedures in Subjects With Severe von Willebrand Disease

    Summary
    EudraCT number
    2014-003575-38
    Trial protocol
    AT   IT   CZ   GB   NL   ES   DE  
    Global end of trial date
    06 Jul 2016

    Results information
    Results version number
    v1(current)
    This version publication date
    19 Jul 2017
    First version publication date
    19 Jul 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    071101
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02283268
    WHO universal trial number (UTN)
    -
    Sponsors
    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
    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
    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
    06 Jul 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    06 Jul 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    06 Jul 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the hemostatic efficacy and safety of rVWF with or without ADVATE in subjects (≥18 years) diagnosed with hereditary severe VWD undergoing major or minor elective surgical procedures.
    Protection of trial subjects
    The study was conducted in accordance with the study protocol, the International Conference on Harmonization Guideline for Good Clinical Practice E6 (ICH GCP April 1996), Title 21 of the US Code of Federal Regulations (US CFR), the European Clinical Trial Directive (2001/20/EC and 2005/28/EC), and applicable national and local regulatory requirements.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    01 Apr 2015
    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: 2
    Country: Number of subjects enrolled
    Australia: 2
    Country: Number of subjects enrolled
    Taiwan: 3
    Country: Number of subjects enrolled
    Germany: 1
    Country: Number of subjects enrolled
    Russian Federation: 5
    Country: Number of subjects enrolled
    Spain: 2
    Country: Number of subjects enrolled
    Ukraine: 3
    Country: Number of subjects enrolled
    United Kingdom: 2
    Country: Number of subjects enrolled
    Italy: 3
    Country: Number of subjects enrolled
    Turkey: 1
    Worldwide total number of subjects
    24
    EEA total number of subjects
    8
    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)
    21
    From 65 to 84 years
    3
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Enrollment was conducted at 14 study sites in 10 countries (USA, Australia, Taiwan, Germany, Russia, Spain, Ukraine, United Kingdom, Italy, Turkey).

    Pre-assignment
    Screening details
    A total of 24 subjects were enrolled (signed informed consent) and screened. Of these, 15 participants were treated with investigational product.

    Pre-assignment period milestones
    Number of subjects started
    24
    Number of subjects completed
    15

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    Consent withdrawn by subject: 1
    Reason: Number of subjects
    Screen Failure: 8
    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
    Recombinant von Willebrand Factor (rVWF)
    Arm description
    Surgery participants treated with Recombinant von Willebrand Factor (rVWF)
    Arm type
    Experimental

    Investigational medicinal product name
    rVWF (Recombinant von Willebrand Factor)
    Investigational medicinal product code
    BAX111
    Other name
    Pharmaceutical forms
    Powder for solution for injection/infusion
    Routes of administration
    Intravenous bolus use
    Dosage and administration details
    The dose will be tailored to raise Von Willebrand factor: Ristocetin cofactor activity (VWF:RCo) concentration to 100% of normal for major surgeries and to 50-60% of normal for minor and oral surgeries. PK infusion (major surgeries) with 50±5 IU rVWF:RCo/kg will be given within 42 days prior surgery to guide the preoperative priming dose. Priming dose with rVWF will be administered (12-24 hours prior surgery). If FVIII levels prior to loading dose administration are not at least 30 IU/dL ADVATE will be administered in addition to rVWF in order to raise FVIII:C levels to recommended levels. A rVWF loading dose with or without ADVATE within 1 hour prior to surgery will be administered. The peri- and postoperative substitution regimen will be individualized according to the PK results, intensity and duration of the hemostatic challenge, and the institution’s standard of care.

    Number of subjects in period 1 [1]
    Recombinant von Willebrand Factor (rVWF)
    Started
    15
    Completed
    14
    Not completed
    1
         Consent withdrawn by subject
    1
    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: A total of 24 subjects were enrolled (signed informed consent) and screened. Of these, 15 subjects were treated with investigational product, 8 subjects were screen failures and 1 subject withdrew consent prior to treatment.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Recombinant von Willebrand Factor (rVWF)
    Reporting group description
    Surgery participants treated with Recombinant von Willebrand Factor (rVWF)

    Reporting group values
    Recombinant von Willebrand Factor (rVWF) Total
    Number of subjects
    15
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        median (full range (min-max))
    40 (20 to 70) -
    Gender categorical
    Units: Subjects
        Female
    8 8
        Male
    7 7

    End points

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    End points reporting groups
    Reporting group title
    Recombinant von Willebrand Factor (rVWF)
    Reporting group description
    Surgery participants treated with Recombinant von Willebrand Factor (rVWF)

    Subject analysis set title
    All Subjects Enrolled Set
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    All subjects who signed informed consent.

    Subject analysis set title
    Full Ananalysis Set
    Subject analysis set type
    Full analysis
    Subject analysis set description
    All subjects included in the Safety Analysis Set with at least one hemostatic assessment.

    Subject analysis set title
    Per Protocol Analysis Set
    Subject analysis set type
    Per protocol
    Subject analysis set description
    All subjects with available overall assessment of hemostatic efficacy assessed by the investigator 24 hours after last infusion of study drug or at completion visit who met all study entry criteria and who had no major protocol violations that might impact hemostatic efficacy.

    Subject analysis set title
    Pharmacokinetic Analysis Set
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    All subjects who underwent a PK assessment and have at least one post dose concentration without protocol deviations or events with potential to affect PK.

    Subject analysis set title
    Safety Analysis Set
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    All subjects included in the All Subjects Enrolled Set that received any amount of investigational product.

    Subject analysis set title
    Minor surgery
    Subject analysis set type
    Full analysis
    Subject analysis set description
    All subjects who underwent minor surgery.

    Subject analysis set title
    Major surgery
    Subject analysis set type
    Full analysis
    Subject analysis set description
    All subjects who underwent major surgery.

    Subject analysis set title
    Oral surgery
    Subject analysis set type
    Full analysis
    Subject analysis set description
    All subjects who underwent oral surgery.

    Subject analysis set title
    Von Willebrand Disease Type 1
    Subject analysis set type
    Full analysis
    Subject analysis set description
    All subjects with von Willebrand Disease Type 1.

    Subject analysis set title
    Von Willebrand Disease Type 2A
    Subject analysis set type
    Full analysis
    Subject analysis set description
    All subjects with von Willebrand Disease Type 2A.

    Subject analysis set title
    Von Willebrand Disease Type 2B
    Subject analysis set type
    Full analysis
    Subject analysis set description
    All subjects with von Willebrand Disease Type 2B.

    Subject analysis set title
    Von Willebrand Disease Type 2M
    Subject analysis set type
    Full analysis
    Subject analysis set description
    All subjects with von Willebrand Disease Type 2M.

    Subject analysis set title
    Von Willebrand Disease Type 3
    Subject analysis set type
    Full analysis
    Subject analysis set description
    All subjects with von Willebrand Disease Type 3.

    Primary: Overall hemostatic efficacy as assessed by the investigator (hemophilia physician)

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    End point title
    Overall hemostatic efficacy as assessed by the investigator (hemophilia physician) [1]
    End point description
    Hemostatic efficacy will be rated on a scale of excellent - good - moderate - none. Excellent: Intra-, and postoperative hemostasis achieved with rVWF with our without ADVATE was as good or better than that expected for the type of surgical procedure performed in a hemostatically normal subject. Good: Intra-, and postoperative hemostasis achieved with rVWF with or without ADVATE was probably as good as that expected for the type of surgical procedure performed in a hemostatically normal subject. Moderate: Intra-, and postoperative hemostasis with rVWF with or without ADVATE was clearly less than optimal for the type of procedure performed but was maintained without the need to change the rVWF concentrate. None: Participant experienced uncontrolled bleeding that was the result of inadequate therapeutic response despite proper dosing, necessitating a change of rVWF concentrate.
    End point type
    Primary
    End point timeframe
    24 hours after last peri-operative infusion or at completion of Day 14 visit, whichever occurs earlier
    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: Per protocol, only descriptive statistics were collected for this endpoint.
    End point values
    Recombinant von Willebrand Factor (rVWF) Minor surgery Major surgery Oral surgery Von Willebrand Disease Type 1 Von Willebrand Disease Type 2A Von Willebrand Disease Type 2B Von Willebrand Disease Type 2M Von Willebrand Disease Type 3
    Number of subjects analysed
    15
    4
    10
    1
    3
    2
    1
    1
    8
    Units: Subjects
        Excellent
    11
    4
    7
    0
    2
    1
    1
    0
    7
        Good
    4
    0
    3
    1
    1
    1
    0
    1
    1
        Moderate
    0
    0
    0
    0
    0
    0
    0
    0
    0
        None
    0
    0
    0
    0
    0
    0
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Intraoperative actual versus predicted blood loss as assessed by the operating surgeon

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    End point title
    Intraoperative actual versus predicted blood loss as assessed by the operating surgeon
    End point description
    The predicted blood loss will be estimated preoperatively by the operating surgeon based on a hemostatically normal individual of the same sex, age, stature and co-morbidities as the participant. The actual blood loss will be assessed consisting of the estimated blood loss, including into swabs, towels and suction during the procedure, per the anesthesiologist's record.
    End point type
    Secondary
    End point timeframe
    Day 0 (at completion of surgery)
    End point values
    Recombinant von Willebrand Factor (rVWF) Minor surgery Major surgery Oral surgery Von Willebrand Disease Type 1 Von Willebrand Disease Type 2A Von Willebrand Disease Type 2B Von Willebrand Disease Type 2M Von Willebrand Disease Type 3
    Number of subjects analysed
    15 [2]
    4
    10 [3]
    1 [4]
    3
    2 [5]
    1 [6]
    1 [7]
    8
    Units: mL
    arithmetic mean (standard deviation)
        Actual blood loss
    94.3 ± 177.88
    0 ± 0
    127 ± 209.27
    145 ± 9999
    115 ± 103.32
    42.5 ± 53.03
    50 ± 9999
    50 ± 9999
    110.6 ± 240.87
        Predicted blood loss
    106.1 ± 161.82
    2.5 ± 5
    152.8 ± 186.33
    100 ± 9999
    100 ± 100
    10 ± 9999
    50 ± 9999
    50 ± 9999
    134.4 ± 206.46
    Notes
    [2] - predicted blood loss: 14
    [3] - predicted blood loss: 9
    [4] - no dispersion possible as n=1, 9999 entered
    [5] - predicted blood loss=1; no dispersion possible as n=1, 9999 entered
    [6] - no dispersion possible as n=1, 9999 entered
    [7] - no dispersion possible as n=1, 9999 entered
    No statistical analyses for this end point

    Secondary: Intraoperative actual blood loss relative to predicted blood loss

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    End point title
    Intraoperative actual blood loss relative to predicted blood loss
    End point description
    Actual blood loss relative to predicted blood loss will be calculated as [Actual Blood loss (mL)] divided by [Predicted Blood Loss (mL)] multiplied by 100.
    End point type
    Secondary
    End point timeframe
    Day 0 (at completion of surgery)
    End point values
    Recombinant von Willebrand Factor (rVWF) Minor surgery Major surgery Oral surgery Von Willebrand Disease Type 1 Von Willebrand Disease Type 2A Von Willebrand Disease Type 2B Von Willebrand Disease Type 2M Von Willebrand Disease Type 3
    Number of subjects analysed
    11
    1 [8]
    9
    1 [9]
    2
    1 [10]
    1 [11]
    1 [12]
    6
    Units: Percent
        arithmetic mean (standard deviation)
    69.6 ± 44.77
    0 ± 9999
    68.9 ± 34.48
    145 ± 9999
    122.5 ± 31.82
    50 ± 9999
    100 ± 9999
    100 ± 9999
    45 ± 38.92
    Notes
    [8] - No standard deviation possible as only one participant was analyzed. 9999 was entered.
    [9] - No standard deviation possible as only one participant was analyzed. 9999 was entered.
    [10] - No standard deviation possible as only one participant was analyzed. 9999 was entered.
    [11] - No standard deviation possible as only one participant was analyzed. 9999 was entered.
    [12] - No standard deviation possible as only one participant was analyzed. 9999 was entered.
    No statistical analyses for this end point

    Secondary: Intraoperative actual versus predicted blood loss score as assessed by the operating surgeon

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    End point title
    Intraoperative actual versus predicted blood loss score as assessed by the operating surgeon
    End point description
    Hemostatic efficacy will be rated on a scale of excellent - good - moderate - none. Excellent: Intraoperative blood loss was less than or equal to the maximum blood loss expected for the type of procedure performed in a hemostatically normal subject (≤ 100%). Good: Intraoperative blood loss was up to 50% more than the maximum expected blood loss for the type of procedure performed in a hemostatically normal subject (101-150%) Moderate: Intraoperative blood loss was more than 50% of the maximum expected blood loss for the type of procedure performed in a hemostatically normal subject (>150%). None: Uncontrolled hemorrhage that was the result of inadequate therapeutic response despite proper dosing, necessitating a change of clotting factor replacement regimen.
    End point type
    Secondary
    End point timeframe
    Day 0 (at completion of surgery)
    End point values
    Recombinant von Willebrand Factor (rVWF) Minor surgery Major surgery Oral surgery Von Willebrand Disease Type 1 Von Willebrand Disease Type 2A Von Willebrand Disease Type 2B Von Willebrand Disease Type 2M Von Willebrand Disease Type 3
    Number of subjects analysed
    15
    4
    10
    1
    3
    2
    1
    1
    8
    Units: Subjects
        Excellent
    13
    4
    8
    1
    3
    1
    1
    1
    7
        Good
    2
    0
    2
    0
    0
    1
    0
    0
    1
        Moderate
    0
    0
    0
    0
    0
    0
    0
    0
    0
        None
    0
    0
    0
    0
    0
    0
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Intraoperative hemostatic efficacy score as assessed by the operating surgeon

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    End point title
    Intraoperative hemostatic efficacy score as assessed by the operating surgeon
    End point description
    Hemostatic efficacy will be rated on a scale of excellent - good - moderate - none. Excellent: Intraoperative hemostasis achieved with rVWF with our without ADVATE was as good or better than that expected for the type of surgical procedure performed in a hemostatically normal subject. Good: Intraoperative hemostasis achieved with rVWF with or without ADVATE was probably as good as that expected for the type of surgical procedure performed in a hemostatically normal subject. Moderate: Intraoperative hemostasis with rVWF with or without ADVATE was clearly less than optimal for the type of procedure performed but was maintained without the need to change the rVWF concentrate. None: Participant experienced uncontrolled bleeding that was the result of inadequate therapeutic response despite proper dosing, necessitating a change of rVWF concentrate.
    End point type
    Secondary
    End point timeframe
    Day 0 (at completion of surgery)
    End point values
    Recombinant von Willebrand Factor (rVWF) Minor surgery Major surgery Oral surgery Von Willebrand Disease Type 1 Von Willebrand Disease Type 2A Von Willebrand Disease Type 2B Von Willebrand Disease Type 2M Von Willebrand Disease Type 3
    Number of subjects analysed
    15
    4
    10
    1
    3
    2
    1
    1
    8
    Units: Subjects
        Excellent
    13
    4
    8
    1
    3
    1
    1
    1
    7
        Good
    2
    0
    2
    0
    0
    1
    0
    0
    1
        Moderate
    0
    0
    0
    0
    0
    0
    0
    0
    0
        None
    0
    0
    0
    0
    0
    0
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Daily intra- and postoperative weight-adjusted dose of rVWF with or without ADVATE

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    End point title
    Daily intra- and postoperative weight-adjusted dose of rVWF with or without ADVATE
    End point description
    End point type
    Secondary
    End point timeframe
    Daily, from day of surgery through postoperative Day 14
    End point values
    Recombinant von Willebrand Factor (rVWF)
    Number of subjects analysed
    15
    Units: IU/kg
    median (inter-quartile range (Q1-Q3))
        intraoperative (n=1)
    18.1 (18.1 to 18.1)
        postoperative day 1 (n=3)
    23.5 (16.9 to 47.2)
        postoperative day 2 (n=11)
    42.3 (23.2 to 50.6)
        postoperative day 3 (n=12)
    28.6 (20.6 to 48.9)
        postoperative day 4 (n=9)
    33.9 (23.2 to 44.3)
        postoperative day 5 (n=7)
    31.5 (18.8 to 47.2)
        postoperative day 6 (n=5)
    23.2 (18.8 to 23.6)
        postoperative day 7 (n=5)
    23.8 (23.6 to 50.8)
        postoperative day 8 (n=7)
    33.9 (23.6 to 53.6)
        postoperative day 9 (n=3)
    23.6 (16.3 to 53.6)
        postoperative day 10 (n=3)
    23.6 (16.3 to 34.8)
        postoperative day 11 (n=3)
    23.6 (16.3 to 53.6)
        postoperative day 12 (n=4)
    29.3 (20.1 to 44.2)
        postoperative day 13 (n=1)
    16.3 (16.3 to 16.3)
        postoperative day 14 (n=2)
    25.5 (16.3 to 34.8)
        postoperative day 15 (n=1)
    16.3 (16.3 to 16.3)
    No statistical analyses for this end point

    Secondary: Occurrence of adverse events

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    End point title
    Occurrence of adverse events
    End point description
    Treatment emergent adverse events (TEAEs) and treatment emergent serious adverse events (TESAEs) will be evaluated. The safety analysis data set, including all subjects who received any amount of investigational product, was used for analysis of this endpoint.
    End point type
    Secondary
    End point timeframe
    From first infusion of investigational product through study completion (ie, 14 days post surgery)
    End point values
    Recombinant von Willebrand Factor (rVWF)
    Number of subjects analysed
    15
    Units: Adverse Events
        Treatment emergent Adverse Events (TEAEs)
    12
        Severe TEAEs
    1
        TEAEs related to rVWF
    0
        TEAEs related to ADVATE
    0
        TEAEs related to both rVWF and ADVATE
    0
        Treatment emergent Serious Adverse Events (TESAEs)
    2
        TESAEs related to rVWF
    0
        TESAEs related to ADVATE
    0
        TESAEs related to both rVWF and ADVATE
    0
        TEAEs leading to discontinuation of rVWF
    0
        TEAEs leading to discontinuation of ADVATE
    0
        TEAEs leading to discontinuation of study
    0
        TEAEs leading to death
    0
        TEAEs related to study procedure
    0
        TESAEs related to study procedure
    0
    No statistical analyses for this end point

    Secondary: Occurrence of thrombotic events

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    End point title
    Occurrence of thrombotic events
    End point description
    Treatment emergent adverse events (TEAEs) and treatment emergent serious adverse events (TESAEs) will be evaluated. The safety analysis data set, including all subjects who received any amount of investigational product, was used for analysis of this endpoint.
    End point type
    Secondary
    End point timeframe
    From first infusion of investigational product through study completion (ie, 14 days post surgery)
    End point values
    Recombinant von Willebrand Factor (rVWF)
    Number of subjects analysed
    15
    Units: Adverse Events
        Thrombotic TEAEs
    2
        Thrombotic TESAEs
    1
    No statistical analyses for this end point

    Secondary: Occurrence of severe allergic reactions (eg, anaphylaxis)

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    End point title
    Occurrence of severe allergic reactions (eg, anaphylaxis)
    End point description
    Treatment emergent adverse events (TEAEs) and treatment emergent serious adverse events (TESAEs) will be evaluated. The safety analysis data set, including all subjects who received any amount of investigational product, was used for analysis of this endpoint.
    End point type
    Secondary
    End point timeframe
    From first infusion of investigational product through study completion (ie, 14 days post surgery)
    End point values
    Recombinant von Willebrand Factor (rVWF)
    Number of subjects analysed
    15
    Units: Adverse Events
        Severe allergic reaction TEAEs
    0
        Severe allergic reaction TESAEs
    0
    No statistical analyses for this end point

    Secondary: Number of subjects who developed inhibitory and total binding antibodies to von Willebrand Factor (VWF) and inhibitory antibodies to Factor VIII (FVIII)

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    End point title
    Number of subjects who developed inhibitory and total binding antibodies to von Willebrand Factor (VWF) and inhibitory antibodies to Factor VIII (FVIII)
    End point description
    Participants were treated with recombinant van Willebrand Factor (rVWF) with or without ADVATE. The safety analysis data set, including all subjects who received any amount of investigational product, was used for analysis of this endpoint.
    End point type
    Secondary
    End point timeframe
    Testing occurred throughout the study at screening, prior PK infusion, pre-surgery, post surgery in case of excessive bleeding or unexplained bleeding, at postoperative day 7 and at study completion visit (ie. 14 days post surgery).
    End point values
    Recombinant von Willebrand Factor (rVWF)
    Number of subjects analysed
    15
    Units: Subjects
        Development of inhibitory antibodies to VWF
    0
        Development of total binding antibodies to VWF
    1
        Development of inhibitory antibodies to FVIII
    0
    No statistical analyses for this end point

    Secondary: Development of antibodies to Chinese hamster ovary (CHO) proteins, mouse immunoglobulin G (IgG) or recombinant Furin (rFurin)

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    End point title
    Development of antibodies to Chinese hamster ovary (CHO) proteins, mouse immunoglobulin G (IgG) or recombinant Furin (rFurin)
    End point description
    Participants were treated with recombinant van Willebrand Factor (rVWF) with or without ADVATE. The safety analysis data set, including all subjects who received any amount of investigational product, was used for analysis of this endpoint.
    End point type
    Secondary
    End point timeframe
    Testing occurred throughout the study at screening, prior PK infusion, pre-surgery, post surgery in case of excessive bleeding or unexplained bleeding, at postoperative day 7 and at study completion visit (ie. 14 days post surgery).
    End point values
    Recombinant von Willebrand Factor (rVWF)
    Number of subjects analysed
    15
    Units: Subjects
    0
    No statistical analyses for this end point

    Secondary: Pharmacokinetics: Area under the plasma concentration versus time curve from 0 to 72 hours post-infusion (AUC 0-72 h/dose)

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    End point title
    Pharmacokinetics: Area under the plasma concentration versus time curve from 0 to 72 hours post-infusion (AUC 0-72 h/dose)
    End point description
    This assessment is only required for subjects undergoing major surgery. Subjects will receive a PK infusion at a dose of 50±5 IU/kg rVWF:RCo within 42 days prior to surgery. The area under the plasma concentration/time curve from 0 to 72 hours post-infusion will be computed using the linear trapezoidal rule. For the calculation of AUC(0-72h) the levels at 72 hours will be linearly interpolated/extrapolated from the 2 nearest sampling time points. PK analysis was performed for the following analytes: VWF Ristocetin Cofactor Activity (VWF:RCo), VWF Antigen Activity (VWF:Ag), VWF Collagen Binding Activity (VWF:CB), VWF Activity Measured INNOVANCE VWF Ac Assay (VWF:Ac), FVIII Coagulation Activity (FVIII:C)
    End point type
    Secondary
    End point timeframe
    PK measurements were done within 30 minutes pre-infusion, and post infusion at 30 (± 5) minutes, 60 (± 5) minutes, 6 (± 1) hours, 12 (± 1) hours, 24 (± 2) hours, 48 (± 2) hours and 72 (± 2) hours.
    End point values
    Pharmacokinetic Analysis Set
    Number of subjects analysed
    11 [13]
    Units: hours*IU/dL
    geometric mean (geometric coefficient of variation)
        VWF:RCo
    31.91 ± 37.5
        VWF:Ag
    57.08 ± 25.6
        VWF:CB
    63.91 ± 29.4
        VWF:Ac
    54.61 ± 28.1
        FVIII:C
    67.49 ± 31.1
    Notes
    [13] - For FVIII:C n=5
    No statistical analyses for this end point

    Secondary: Pharmacokinetics: Area under the plasma concentration versus time curve from time 0 to infinity (AUC 0-∞ /dose)

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    End point title
    Pharmacokinetics: Area under the plasma concentration versus time curve from time 0 to infinity (AUC 0-∞ /dose)
    End point description
    This assessment is only required for subjects undergoing major surgery. Subjects will receive a PK infusion at a dose of 50±5 IU/kg rVWF:RCo within 42 days prior to surgery. The area under the plasma concentration/time curve from time 0 to infinity and the area under the first moment curve from time 0 to infinity will be calculated as the sum of AUC or AUMC from time 0 to the time of last quantifiable concentration plus a tail area correction calculated as Ct/λz and Ct/λz(t+1/λz), respectively, where Ct is the last quantifiable concentration, t is the time of last quantifiable concentration and λz is the terminal or disposition rate constant. PK analysis was performed for the following analytes: VWF Ristocetin Cofactor Activity (VWF:RCo), VWF Antigen Activity (VWF:Ag), VWF Collagen Binding Activity (VWF:CB), VWF Activity Measured INNOVANCE VWF Ac Assay (VWF:Ac), FVIII Coagulation Activity (FVIII:C)
    End point type
    Secondary
    End point timeframe
    PK measurements were done within 30 minutes pre-infusion, and post infusion at 30 (± 5) minutes, 60 (± 5) minutes, 6 (± 1) hours, 12 (± 1) hours, 24 (± 2) hours, 48 (± 2) hours and 72 (± 2) hours.
    End point values
    Pharmacokinetic Analysis Set
    Number of subjects analysed
    11 [14]
    Units: hours*IU/dL
    geometric mean (geometric coefficient of variation)
        VWF:RCo
    34.43 ± 43.3
        VWF:Ag
    68.87 ± 31.5
        VWF:CB
    71.82 ± 34.1
        VWF:Ac
    61.9 ± 32.2
        FVIII:C
    75 ± 30.9
    Notes
    [14] - For FVIII:C n=3
    No statistical analyses for this end point

    Secondary: Pharmacokinetics: Mean residence time (MRT)

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    End point title
    Pharmacokinetics: Mean residence time (MRT)
    End point description
    This assessment is only required for subjects undergoing major surgery. Subjects will receive a PK infusion at a dose of 50±5 IU/kg rVWF:RCo within 42 days prior to surgery. Mean residence time will be calculated as area under the first moment curve from time 0 to infinity divided by the area under the curve time 0 to infinity minus T/2 where T is the duration of the infusion. PK analysis was performed for the following analytes: VWF Ristocetin Cofactor Activity (VWF:RCo), VWF Antigen Activity (VWF:Ag), VWF Collagen Binding Activity (VWF:CB), VWF Activity Measured INNOVANCE VWF Ac Assay (VWF:Ac)
    End point type
    Secondary
    End point timeframe
    PK measurements were done within 30 minutes pre-infusion, and post infusion at 30 (± 5) minutes, 60 (± 5) minutes, 6 (± 1) hours, 12 (± 1) hours, 24 (± 2) hours, 48 (± 2) hours and 72 (± 2) hours.
    End point values
    Pharmacokinetic Analysis Set
    Number of subjects analysed
    11
    Units: hours
    geometric mean (geometric coefficient of variation)
        VWF:RCo
    22.69 ± 41.3
        VWF:Ag
    37.92 ± 28.4
        VWF:CB
    29.35 ± 31.1
        VWF:Ac
    29.75 ± 28.6
    No statistical analyses for this end point

    Secondary: Pharmacokinetics: Clearance (CL)

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    End point title
    Pharmacokinetics: Clearance (CL)
    End point description
    This assessment is only required for subjects undergoing major surgery. Subjects will receive a PK infusion at a dose of 50±5 IU/kg rVWF:RCo within 42 days prior to surgery. Clearance will be calculated as dose (IU/kg) divided by the area under the curve time 0 to infinity. PK analysis was performed for the following analytes: VWF Ristocetin Cofactor Activity (VWF:RCo), VWF Antigen Activity (VWF:Ag), VWF Collagen Binding Activity (VWF:CB), VWF Activity Measured INNOVANCE VWF Ac Assay (VWF:Ac)
    End point type
    Secondary
    End point timeframe
    PK measurements were done within 30 minutes pre-infusion, and post infusion at 30 (± 5) minutes, 60 (± 5) minutes, 6 (± 1) hours, 12 (± 1) hours, 24 (± 2) hours, 48 (± 2) hours and 72 (± 2) hours.
    End point values
    Pharmacokinetic Analysis Set
    Number of subjects analysed
    11
    Units: dL/hour/kg
    geometric mean (geometric coefficient of variation)
        VWF:RCo
    0.02904 ± 43.3
        VWF:Ag
    0.01452 ± 31.5
        VWF:CB
    0.01392 ± 34.1
        VWF:Ac
    0.01616 ± 32.2
    No statistical analyses for this end point

    Secondary: Pharmacokinetics: Incremental recovery (IR)

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    End point title
    Pharmacokinetics: Incremental recovery (IR)
    End point description
    This assessment is only required for subjects undergoing major surgery. Subjects will receive a PK infusion at a dose of 50±5 IU/kg rVWF:RCo within 42 days prior to surgery. Incremental recovery will be calculated as (Cmax minus Cpreinfusion) divided by the dose (IU/kg) where kg refers to the body weight at the time of dosing and Cmax is the observed maximum concentration before correction for pre-infusion values. PK analysis was performed for the following analytes: VWF Ristocetin Cofactor Activity (VWF:RCo), VWF Antigen Activity (VWF:Ag), VWF Collagen Binding Activity (VWF:CB), VWF Activity Measured INNOVANCE VWF Ac Assay (VWF:Ac)
    End point type
    Secondary
    End point timeframe
    PK measurements were done within 30 minutes pre-infusion, and post infusion at 30 (± 5) minutes, 60 (± 5) minutes, 6 (± 1) hours, 12 (± 1) hours, 24 (± 2) hours, 48 (± 2) hours and 72 (± 2) hours.
    End point values
    Pharmacokinetic Analysis Set
    Number of subjects analysed
    11
    Units: IU/dL
    arithmetic mean (standard deviation)
        VWF:RCo
    1.961 ± 0.45445
        VWF:Ag
    1.991 ± 0.38395
        VWF:CB
    2.78 ± 0.5664
        VWF:Ac
    2.635 ± 0.3805
    No statistical analyses for this end point

    Secondary: Pharmacokinetics: Elimination phase half-life (T1/2)

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    End point title
    Pharmacokinetics: Elimination phase half-life (T1/2)
    End point description
    This assessment is only required for subjects undergoing major surgery. Subjects will receive a PK infusion at a dose of 50±5 IU/kg rVWF:RCo within 42 days prior to surgery. Terminal or disposition half-life (T1/2) will be calculated as ln2/λz where λz is the terminal elimination rate constant as calculated in WinNonlin NCA using at least three quantifiable concentrations. PK analysis was performed for the following analytes: VWF Ristocetin Cofactor Activity (VWF:RCo), VWF Antigen Activity (VWF:Ag), VWF Collagen Binding Activity (VWF:CB), VWF Activity Measured INNOVANCE VWF Ac Assay (VWF:Ac)
    End point type
    Secondary
    End point timeframe
    PK measurements were done within 30 minutes pre-infusion, and post infusion at 30 (± 5) minutes, 60 (± 5) minutes, 6 (± 1) hours, 12 (± 1) hours, 24 (± 2) hours, 48 (± 2) hours and 72 (± 2) hours.
    End point values
    Pharmacokinetic Analysis Set
    Number of subjects analysed
    11
    Units: hours
    geometric mean (geometric coefficient of variation)
        VWF:RCo
    16.52 ± 42.7
        VWF:Ag
    26.88 ± 26.5
        VWF:CB
    21.07 ± 33.2
        VWF:Ac
    22.19 ± 28.5
    No statistical analyses for this end point

    Secondary: Pharmacokinetics: Volume of distribution at steady state (Vss)

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    End point title
    Pharmacokinetics: Volume of distribution at steady state (Vss)
    End point description
    This assessment is only required for subjects undergoing major surgery. Subjects will receive a PK infusion at a dose of 50±5 IU/kg rVWF:RCo within 42 days prior to surgery. Vss will be calculated as the clearance multiplied with the mean residence time. PK analysis was performed for the following analytes: VWF Ristocetin Cofactor Activity (VWF:RCo), VWF Antigen Activity (VWF:Ag), VWF Collagen Binding Activity (VWF:CB), VWF Activity Measured INNOVANCE VWF Ac Assay (VWF:Ac)
    End point type
    Secondary
    End point timeframe
    PK measurements were done within 30 minutes pre-infusion, and post infusion at 30 (± 5) minutes, 60 (± 5) minutes, 6 (± 1) hours, 12 (± 1) hours, 24 (± 2) hours, 48 (± 2) hours and 72 (± 2) hours.
    End point values
    Pharmacokinetic Analysis Set
    Number of subjects analysed
    11
    Units: dL/kg
    geometric mean (geometric coefficient of variation)
        VWF:RCo
    0.6591 ± 28.8
        VWF:Ag
    0.5506 ± 18.4
        VWF:CB
    0.4086 ± 24
        VWF:Ac
    0.4806 ± 21.5
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Throughout the study period (from the first exposure to investigational product until study completion or discontinuation date). Total study duration: 1 year and 3 months. Per participant: up to 58 days.
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    19.0
    Reporting groups
    Reporting group title
    Recombinant von Willebrand Factor (rVWF)
    Reporting group description
    Surgery participants treated with Recombinant von Willebrand Factor (rVWF)

    Serious adverse events
    Recombinant von Willebrand Factor (rVWF)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 15 (13.33%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Diverticulitis
         subjects affected / exposed
    1 / 15 (6.67%)
         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
    Recombinant von Willebrand Factor (rVWF)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    6 / 15 (40.00%)
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Blood and lymphatic system disorders
    Iron deficiency anaemia
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Nervous system disorders
    Headache
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Dizziness
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    General disorders and administration site conditions
    Peripheral swelling
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Reproductive system and breast disorders
    Pelvic pain
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Skin and subcutaneous tissue disorders
    Acne
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Dry skin
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Musculoskeletal and connective tissue disorders
    Joint swelling
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    1 / 15 (6.67%)
         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
    30 Aug 2012
    The various types of severe VWD that are eligible for the study were clarified to include VWD with a history of requiring substitution therapy containing VWF to control bleeding; Type 1 (VWF:RCoF < 20 IU/dL); Type 2A (as verified by multimer pattern), Type 2B (as diagnosed by genotype), Type 2N (FVIII:C<10% and historically documented genetics), and Type 2M; or Type 3 (VWF:Ag ≤ 3 IU/dL). The option to give a priming dose of rVWF 12-24 hours before surgery was deleted to reduce the number of different dose regimens investigated. The primary efficacy endpoint was updated to include intra- and post-operative actual versus predicted blood loss; and overall assessment of clinical (hemostatic) efficacy at 24 hours after last infusion of IP. Furthermore, it was made mandatory that the surgeon documents predicted values with a source data document to strengthen the quality of the predicted average and maximum blood loss. Two options for administration of the combination of rVWF and rFVIII were added to ease reconstitution and mixing of study drugs. Option 1: Infusion of premixed drug, Option 2: Sequential infusion Treatment success was defined as a mean primary efficacy rating score of <2 for a subject’s IP-covered surgery, dental, or invasive procedure (Excellent = 1, Good = 2, Moderate = 3, None = 4).
    27 Nov 2013
    Throughout the protocol, wording on analysis of primary and secondary outcome measures was adjusted to reflect revised primary and secondary objectives. Primary hemostatic efficacy assessment rating scale was revised to reflect the authority’s feedback (inclusion of objective measure of cessation of bleeding). Completion visit was changed from 30 days (± 3 days) after the last IP infusion to 14 days (± 2 days) after surgery to standardize treatment duration and evaluation of primary efficacy endpoint. The priming dose VWF infusion 12-24 hours prior surgery included in the original protocol and deleted in Global Amendment 1 was reintroduced to improve the IP treatment scheme.
    19 Mar 2015
    The sponsor name/entity was changed.

    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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