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    Clinical Trial Results:
    BAX 326 (recombinant factor IX): A Phase 3 Prospective, Multicenter Study Evaluating Efficacy and Safety in Previously Treated Patients With Severe (FIX level < 1%) or Moderately Severe (FIX level 1-2%) Hemophilia B Undergoing Surgical or Other Invasive Procedures

    Due to the EudraCT – Results system being out of service between 31 July 2015 and 12 January 2016, these results have been published in compliance with revised timelines.
    Summary
    EudraCT number
    2011-000413-39
    Trial protocol
    GB   CZ   SE   BG   PL  
    Global end of trial date
    15 May 2014

    Results information
    Results version number
    v1(current)
    This version publication date
    27 Feb 2016
    First version publication date
    27 Feb 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    251002
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01507896
    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)
    Yes
    EMA paediatric investigation plan number(s)
    EMEA-001139-PIP01-11
    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
    14 Oct 2014
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    15 May 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    15 May 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the haemostatic efficacy and safety of BAX326 in the peri- and postoperative setting in subjects with severe (FIX level < 1%) or moderately severe (FIX level 1-2%) haemophilia B undergoing major or minor elective or emergency surgical, dental or other invasive procedures.
    Protection of trial subjects
    This study was conducted in accordance with the clinical protocol, the International Conference on Harmonisation 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
    19 Dec 2011
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Bulgaria: 6
    Country: Number of subjects enrolled
    Czech Republic: 1
    Country: Number of subjects enrolled
    Poland: 8
    Country: Number of subjects enrolled
    Romania: 1
    Country: Number of subjects enrolled
    Russian Federation: 17
    Country: Number of subjects enrolled
    Ukraine: 3
    Country: Number of subjects enrolled
    Chile: 4
    Country: Number of subjects enrolled
    Colombia: 1
    Worldwide total number of subjects
    41
    EEA total number of subjects
    16
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    1
    Adults (18-64 years)
    40
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Enrollment was conducted at 10 clinical sites in 8 countries (Bulgaria, Czech Republic, Poland, Romania, Russia, Ukraine, Chile, Colombia). A total of 30 subjects were enrolled in the study; 38 surgical procedures were performed with BAX326.

    Pre-assignment
    Screening details
    Of 30 subjects enrolled, one discontinued prior to receiving BAX326; however, this subject was re-enrolled later and received treatment with BAX326. 28 subjects underwent 38 surgical procedures (7 subjects had at least 2 surgeries and were re-enrolled for each new surgical procedure); another 2 subjects discontinued after PK assessment with BAX326.

    Pre-assignment period milestones
    Number of subjects started
    41
    Number of subjects completed
    40

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    Consent withdrawn by subject: 1
    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Arm title
    Overall trial
    Arm description
    Treatment with BAX326 (38 subjects underwent surgery, another 2 subjects only had a pharmacokinetic evaluation)
    Arm type
    Experimental

    Investigational medicinal product name
    BAX326 (recombinant factor IX)
    Investigational medicinal product code
    Other name
    Rixubis
    Pharmaceutical forms
    Powder and solvent for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects undergoing major surgery initially underwent a pharmacokinetic (PK) evaluation with BAX326, if PK parameters were not already available from the predecessor pivotal study (1 infusion). Following the loading dose(s) with BAX326 prior to surgery, subjects received BAX326 as a bolus infusion. The regimen was to be determined by the intensity and duration of the haemostatic challenge. The dose was to be tailored to raise FIX concentration to 80%-100% of normal for major surgeries and to 30%-60% of normal for minor surgeries to ensure that the recommended pre-infusion FIX activity levels were maintained in the perioperative period.

    Number of subjects in period 1 [1]
    Overall trial
    Started
    40
    Underwent surgery
    38
    Underwent PK assessment
    12 [2]
    Completed
    38
    Not completed
    2
         Surgery denied by sponsor
             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: Total of enrolled subjects (including re-enrolled subjects) = 41. One subject discontinued before treatment; two subjects discontinued after treatment.
    [2] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Subjects undergoing major surgery initially underwent a pharmacokinetic (PK) evaluation with BAX326, if PK parameters were not already available from the predecessor pivotal study (1 infusion).

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall trial
    Reporting group description
    Overall trial

    Reporting group values
    Overall trial Total
    Number of subjects
    40 40
    Age categorical
    Units: Subjects
        85 years and over
    0 0
        From 65-84 years
    0 0
        Adults (18-64 years)
    39 39
        Adolescents (12-17 years)
    1 1
        Children (2-11 years)
    0 0
        Infants and toddlers (28 days-23 months)
    0 0
        Newborns (0-27 days)
    0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0
        In utero
    0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    39.7 ± 11.2 -
    Gender categorical
    Units:
        Female
    0 0
        Male
    40 40
    Subject analysis sets

    Subject analysis set title
    Full Analysis Set
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Comprises all subjects (incl. re-enrolled subjects) who were exposed to investigational product (IP) during the study who provide data suitable for the hemostatic efficacy analysis

    Subject analysis set title
    Safety Analysis Set
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Comprises all subjects (incl. re-enrolled subjects) exposed to IP during the study

    Subject analysis set title
    Per-Protocol Analysis Set
    Subject analysis set type
    Per protocol
    Subject analysis set description
    Comprises subjects in the Full Analysis Set who do not have major protocol deviations that are associated with efficacy endpoints or serious breaches of protocol; there was 1 major protocol deviation among the 21 subjects who underwent major surgery, which brings the number of subjects undergoing major surgery in the per-protocol analaysis set to 20.

    Subject analysis set title
    PK Analysis Set
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Comprises subjects in the Full Analysis Set who had a presurgical PK assessment

    Subject analysis set title
    Subjects undergoing major surgery
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    The 21 major surgeries in the Full Analysis Set comprised 14 major, orthopedic surgeries (eg, joint replacement) and 7 non-orthopedic surgeries (3 abdominal, 3 dental, 1 excision of tumor from soft tissue).

    Subject analysis set title
    Subjects undergoing minor surgery
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    The 17 minor surgeries in the Full/Per-Protocol Analysis Set comprised 5 orthopedic surgeries (4 intraarticular infiltration, 1 synoviorthesis) and 12 non-orthopedic surgeries (11 dental, 1 intra-articular injection).

    Subject analysis sets values
    Full Analysis Set Safety Analysis Set Per-Protocol Analysis Set PK Analysis Set Subjects undergoing major surgery Subjects undergoing minor surgery
    Number of subjects
    40
    40
    39
    12
    21
    17
    Age categorical
    Units: Subjects
        85 years and over
    0
    0
    0
    0
    0
    0
        From 65-84 years
    0
    0
    0
    0
    0
    0
        Adults (18-64 years)
    39
    39
    38
    12
    21
    16
        Adolescents (12-17 years)
    1
    1
    1
    0
    0
    1
        Children (2-11 years)
    0
    0
    0
    0
    0
    0
        Infants and toddlers (28 days-23 months)
    0
    0
    0
    0
    0
    0
        Newborns (0-27 days)
    0
    0
    0
    0
    0
    0
        Preterm newborn infants (gestational age < 37 wks)
    0
    0
    0
    0
    0
    0
        In utero
    0
    0
    0
    0
    0
    0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    39.7 ± 11.2
    39.7 ± 11.2
    39.8 ± 11.3
    ±
    ±
    ±
    Gender categorical
    Units:
        Female
    0
    0
    0
    0
    0
    0
        Male
    40
    40
    39
    12
    21
    17

    End points

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    End points reporting groups
    Reporting group title
    Overall trial
    Reporting group description
    Treatment with BAX326 (38 subjects underwent surgery, another 2 subjects only had a pharmacokinetic evaluation)

    Subject analysis set title
    Full Analysis Set
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Comprises all subjects (incl. re-enrolled subjects) who were exposed to investigational product (IP) during the study who provide data suitable for the hemostatic efficacy analysis

    Subject analysis set title
    Safety Analysis Set
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Comprises all subjects (incl. re-enrolled subjects) exposed to IP during the study

    Subject analysis set title
    Per-Protocol Analysis Set
    Subject analysis set type
    Per protocol
    Subject analysis set description
    Comprises subjects in the Full Analysis Set who do not have major protocol deviations that are associated with efficacy endpoints or serious breaches of protocol; there was 1 major protocol deviation among the 21 subjects who underwent major surgery, which brings the number of subjects undergoing major surgery in the per-protocol analaysis set to 20.

    Subject analysis set title
    PK Analysis Set
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Comprises subjects in the Full Analysis Set who had a presurgical PK assessment

    Subject analysis set title
    Subjects undergoing major surgery
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    The 21 major surgeries in the Full Analysis Set comprised 14 major, orthopedic surgeries (eg, joint replacement) and 7 non-orthopedic surgeries (3 abdominal, 3 dental, 1 excision of tumor from soft tissue).

    Subject analysis set title
    Subjects undergoing minor surgery
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    The 17 minor surgeries in the Full/Per-Protocol Analysis Set comprised 5 orthopedic surgeries (4 intraarticular infiltration, 1 synoviorthesis) and 12 non-orthopedic surgeries (11 dental, 1 intra-articular injection).

    Primary: Intraoperative hemostatic efficacy

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    End point title
    Intraoperative hemostatic efficacy [1]
    End point description
    The intraoperative hemostatic efficacy was to be assessed by the operating surgeon according to the following criteria (4-point ordinal scale): - Excellent: Intraoperative blood loss was less than or equal to that expected for the type of procedure performed in a hemostatically normal subject (≤ 100% ) - Good: Intraoperative blood loss was up to 50% more than expected for the type of procedure performed in a hemostatically normal subject (101 – 150%) - Fair: Intraoperative blood loss was more than 50% of that expected 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 FIX concentrate Descriptive statistics: The intraoperative (at the end of surgery) hemostatic efficacy assessments were summarized by percentage of subjects in each efficacy categories (“excellent”, “good”, “fair” and “none”).
    End point type
    Primary
    End point timeframe
    At completion of surgery
    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, descriptive statistics were collected for this endpoint.
    End point values
    Full Analysis Set Per-Protocol Analysis Set Subjects undergoing major surgery Subjects undergoing minor surgery
    Number of subjects analysed
    38
    37
    21
    17
    Units: subjects
        Excellent
    37
    36
    20
    17
        Good
    1
    1
    1
    0
        Fair
    0
    0
    0
    0
        None
    0
    0
    0
    0
    No statistical analyses for this end point

    Primary: Actual intraoperative blood loss

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    End point title
    Actual intraoperative blood loss [2]
    End point description
    Actual intraoperative blood loss was summarized using descriptive statistics including median and range.
    End point type
    Primary
    End point timeframe
    At completion of surgery
    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: Per protocol, descriptive statistics were collected for this endpoint.
    End point values
    Full Analysis Set Per-Protocol Analysis Set Subjects undergoing major surgery Subjects undergoing minor surgery
    Number of subjects analysed
    38
    37
    21
    17
    Units: mL
        arithmetic mean (standard deviation)
    191.1 ± 354.1
    177.4 ± 348.5
    344.9 ± 420.1
    1.2 ± 1.1
    No statistical analyses for this end point

    Primary: Actual intraoperative blood loss compared to average and maximum blood loss predicted preoperatively by the operating surgeon

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    End point title
    Actual intraoperative blood loss compared to average and maximum blood loss predicted preoperatively by the operating surgeon [3]
    End point description
    Predicted average/maximum blood loss minus actual blood loss. The differences from the expected average and maximum blood loss was summarized using descriptive statistics including median and range.
    End point type
    Primary
    End point timeframe
    At completion of surgery
    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: Per protocol, descriptive statistics were collected for this endpoint.
    End point values
    Full Analysis Set Per-Protocol Analysis Set Subjects undergoing major surgery Subjects undergoing minor surgery
    Number of subjects analysed
    38
    37
    21
    17
    Units: mL
    arithmetic mean (standard deviation)
        Difference from predicted average blood loss
    -27 ± 158.9
    -22.4 ± 158.4
    -50.9 ± 213
    2.4 ± 4.9
        Difference from predicted maximum blood loss
    128.3 ± 260.8
    123.7 ± 262.8
    222 ± 323.7
    12.5 ± 24.5
    No statistical analyses for this end point

    Secondary: Postoperative hemostatic efficacy at drain removal

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    End point title
    Postoperative hemostatic efficacy at drain removal
    End point description
    Only 14 subjects who underwent major surgery had a drain placed. The postoperative hemostatic efficacy was to be assessed by the operating surgeon according to the following criteria (4-point ordinal scale): - Excellent: Volume in drain was less than or equal than that expected for the type of procedure performed in a hemostatically normal subject (≤ 100% ) - Good: Volume in drain was up to 50% more than expected for the type of procedure performed in a hemostatically normal subject (101% - 150%) - Fair: Volume in drain was more than 50% of that expected for the type of procedure performed in a hemostatically normal subject (> 150%) - None: Uncontrolled bleeding that was the result of inadequate therapeutic response despite proper dosing, necessitating a change of FIX concentrate
    End point type
    Secondary
    End point timeframe
    At drain removal (if a drain was placed)
    End point values
    Full Analysis Set Per-Protocol Analysis Set Subjects undergoing major surgery
    Number of subjects analysed
    14
    13
    14
    Units: subjects
        Excellent
    10
    10
    10
        Good
    4
    3
    4
        Fair
    0
    0
    0
        None
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Postoperative hemostatic efficacy at postoperative day 3

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    End point title
    Postoperative hemostatic efficacy at postoperative day 3
    End point description
    If no drain was placed, the postoperative hemostatic efficacy was to be assessed for major surgeries by the operating surgeon on postoperative day 3 according to the following criteria (4-point ordinal scale): - Excellent: Postoperative hemostasis achieved with BAX 326 was as good or better than that expected for the type of surgical procedure performed in a hemostatically normal subject - Good: Postoperative hemostasis achieved with BAX 326 was probably as good as that expected for the type of surgical procedure performed in a hemostatically normal subject - Fair: Postoperative hemostasis with BAX 326 was clearly less than optimal for the type of procedure performed but was maintained without the need to change the FIX concentrate - None: Subject experienced uncontrolled bleeding that was the result of inadequate therapeutic response despite proper dosing, necessitating a change of FIX concentrate
    End point type
    Secondary
    End point timeframe
    At postoperative day 3 (approximately 72 hours postoperatively)
    End point values
    Full Analysis Set Per-Protocol Analysis Set Subjects undergoing major surgery Subjects undergoing minor surgery
    Number of subjects analysed
    8
    8
    7
    1
    Units: subjects
        Excellent
    7
    7
    6
    1
        Good
    1
    1
    1
    0
        Fair
    0
    0
    0
    0
        None
    0
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Postoperative hemostatic efficacy on day of discharge

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    End point title
    Postoperative hemostatic efficacy on day of discharge
    End point description
    On the day of discharge from hospital, the hemostatic efficacy was to be assessed by the investigator, ie, hemophilia physician. The rating criteria for "excellent", "good", "fair" and "none" were the same as for postoperative day 3.
    End point type
    Secondary
    End point timeframe
    At discharge from hospital
    End point values
    Full Analysis Set Per-Protocol Analysis Set Subjects undergoing major surgery Subjects undergoing minor surgery
    Number of subjects analysed
    38
    37
    21
    17
    Units: subjects
        Excellent
    29
    29
    12
    17
        Good
    7
    6
    7
    0
        Fair
    2
    2
    2
    0
        None
    0
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Actual postoperative blood loss

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    End point title
    Actual postoperative blood loss
    End point description
    Postoperative blood loss was based on the drainage fluid and was only assessed for subjects who had a drain placed (n=14).
    End point type
    Secondary
    End point timeframe
    At drain removal
    End point values
    Full Analysis Set Per-Protocol Analysis Set Subjects undergoing major surgery
    Number of subjects analysed
    14
    13
    14
    Units: mL
        arithmetic mean (standard deviation)
    603.6 ± 388.7
    552.4 ± 351.9
    603.6 ± 388.7
    No statistical analyses for this end point

    Secondary: Actual postoperative blood loss compared to average and maximum blood loss predicted preoperatively by the operating surgeon

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    End point title
    Actual postoperative blood loss compared to average and maximum blood loss predicted preoperatively by the operating surgeon
    End point description
    Predicted average/maximum blood loss minus actual blood loss; was only assessed for subjects with major surgery who had a drain placed (n=14).
    End point type
    Secondary
    End point timeframe
    At drain removal
    End point values
    Full Analysis Set Per-Protocol Analysis Set Subjects undergoing major surgery
    Number of subjects analysed
    14
    13
    14
    Units: mL
    arithmetic mean (standard deviation)
        Difference from predicted average blood loss
    -221.4 ± 331.7
    -171.5 ± 285.4
    -221.4 ± 331.7
        Difference from predicted maximum blood loss
    147.1 ± 330.1
    179.2 ± 320
    147.1 ± 330.1
    No statistical analyses for this end point

    Secondary: Daily weight-adjusted dose of BAX326 per subject

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    End point title
    Daily weight-adjusted dose of BAX326 per subject
    End point description
    Daily weight-adjusted doses of BAX326 per subject were recorded from the day of surgery until postoperative day 11+. The number of subjects in the FAS and the reporting groups who were exposed to daily doses of BAX326 after surgery decreases towards day 11.
    End point type
    Secondary
    End point timeframe
    From initiation of surgery until the time of discharge (minor surgery: 1-3 days, major surgery: approximately 2 weeks)
    End point values
    Full Analysis Set Per-Protocol Analysis Set Subjects undergoing major surgery Subjects undergoing minor surgery
    Number of subjects analysed
    38 [4]
    37 [5]
    21 [6]
    17 [7]
    Units: IU/kg
    arithmetic mean (standard deviation)
        Day of surgery
    144.8 ± 70.3
    142.6 ± 69.9
    191.5 ± 50.6
    87.2 ± 42.9
        Postoperative Day 1
    103.9 ± 44.6
    102.7 ± 44.5
    136.7 ± 30.1
    63.5 ± 18
        Postoperative Day 2
    115 ± 40.2
    113.7 ± 40.3
    134.2 ± 27.6
    64.6 ± 16.2
        Postoperative Day 3
    111.6 ± 43.9
    110 ± 44.1
    123.5 ± 39.4
    61.6 ± 20.8
        Postoperative Day 4
    115.2 ± 63
    113.6 ± 64
    123.5 ± 62.4
    56.9 ± 29.3
        Postoperative Day 5
    104.4 ± 47.4
    102.3 ± 47.4
    108.6 ± 46.6
    60.4 ± 41.9
        Postoperative Day 6
    105.6 ± 44
    103.3 ± 43.9
    106.6 ± 44.9
    86 ± 0
        Postoperative Day 7
    94.6 ± 46.7
    91.8 ± 46.1
    96.1 ± 47.4
    65.5 ± 0
        Postoperative Day 8
    93 ± 45.8
    94 ± 46.9
    93 ± 45.8
    0 ± 0
        Postoperative Day 9
    93 ± 46.9
    94 ± 48.1
    93 ± 46.9
    0 ± 0
        Postoperative Day 10
    89.9 ± 49.7
    90.8 ± 51.1
    89.9 ± 49.7
    0 ± 0
        Postoperative Day 11+
    75.3 ± 44.8
    75.3 ± 44.8
    75.3 ± 44.8
    0 ± 0
    Notes
    [4] - Day2:n=29,Day3:n=26,Day4:n=24,Day5:n=23,Day6:n=21,Day7:n=21,Day8:n=19,Day9:n=19,D10:n=18,D11+:n=15
    [5] - Day2:n=28,Day3:n=25,Day4:n=23,Day5:n=22,Day6:n=20,Day7:n=20,Day8:n=18,Day9:n=18,D10:n=17,D11+:n=15
    [6] - Day 6: n=20, Day 7: n=20, Day 8: n=19, Day 9: n=19, Day 10: n=18, Day 11+: n=15
    [7] - Day 2: n=8, Day 3: n=5, Day 4: n=3, Day 5: n=2, Day 6: n=1, Day 7: n=1, Days 8-11: n=0
    No statistical analyses for this end point

    Secondary: Total weight-adjusted dose of BAX326 per subject

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    End point title
    Total weight-adjusted dose of BAX326 per subject
    End point description
    Assessed for the intra- and postoperative periods
    End point type
    Secondary
    End point timeframe
    From initiation of surgery until the time of discharge (minor surgery: 1-3 days, major surgery: approximately 2 weeks)
    End point values
    Full Analysis Set Per-Protocol Analysis Set Subjects undergoing major surgery Subjects undergoing minor surgery
    Number of subjects analysed
    38
    37
    21
    17
    Units: IU/kg
    arithmetic mean (standard deviation)
        Intraoperative period
    145 ± 70
    143 ± 70
    191 ± 51
    87 ± 43
        Postoperative period
    808 ± 766
    795 ± 773
    1350 ± 617
    138 ± 136
    No statistical analyses for this end point

    Secondary: Number of units of blood product transfused

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    End point title
    Number of units of blood product transfused
    End point description
    Blood product transfusions consisted of packed red blood cells (PRBC) or fresh frozen plasma (FFP) or both. Six subjects who underwent major orthopedic surgery received blood product transfusions in the intraoperative period; 2 of these subjects also received blood product infusions in the postoperative period.
    End point type
    Secondary
    End point timeframe
    From initiation of surgery until the time of discharge (minor surgery: 1-3 days, major surgery: approximately 2 weeks)
    End point values
    Full Analysis Set Per-Protocol Analysis Set Subjects undergoing major surgery
    Number of subjects analysed
    6 [8]
    5 [9]
    6 [10]
    Units: units
    arithmetic mean (standard deviation)
        Intraoperative period
    2.8 ± 1.2
    2.8 ± 1.3
    2.8 ± 1.2
        Postoperative period
    1.5 ± 0.7
    1 ± 0
    1.5 ± 0.7
    Notes
    [8] - Only 2 subjects received blood product transfusions in the postoperative period.
    [9] - Only 1 subject received blood product transfusions in the postoperative period.
    [10] - Only 2 subjects received blood product transfusions in the postoperative period.
    No statistical analyses for this end point

    Secondary: Amount of blood product transfused (in mL)

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    End point title
    Amount of blood product transfused (in mL)
    End point description
    Blood product transfusions consisted of packed red blood cells (PRBC) or fresh frozen plasma (FFP) or both. Six subjects who underwent major orthopedic surgery received blood product transfusions in the intraoperative period; 2 of these subjects also received blood product infusions in the postoperative period.
    End point type
    Secondary
    End point timeframe
    From initiation of surgery until the time of discharge (minor surgery: 1-3 days, major surgery: approximately 2 weeks)
    End point values
    Full Analysis Set Per-Protocol Analysis Set Subjects undergoing major surgery
    Number of subjects analysed
    6 [11]
    5 [12]
    6 [13]
    Units: mL
    arithmetic mean (standard deviation)
        Intraoperative period
    834.3 ± 358.7
    756.2 ± 339.1
    834.3 ± 358.7
        Postoperative period
    414 ± 227.7
    253 ± 0
    414 ± 227.7
    Notes
    [11] - Only 2 subjects received blood product transfusions in the postoperative period.
    [12] - Only 1 subject received blood product transfusions in the postoperative period.
    [13] - Only 2 subjects received blood product transfusions in the postoperative period.
    No statistical analyses for this end point

    Secondary: Safety: Development of inhibitory antibodies to FIX

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    End point title
    Safety: Development of inhibitory antibodies to FIX
    End point description
    End point type
    Secondary
    End point timeframe
    Entire study duration: approx. 2.5 years; study participation per subject: mean of 43.3 days (standard deviation: 30.1 days (range: 4-110 days)
    End point values
    Safety Analysis Set
    Number of subjects analysed
    40
    Units: subjects
    0
    No statistical analyses for this end point

    Secondary: Safety: Development of total binding antibodies to FIX

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    End point title
    Safety: Development of total binding antibodies to FIX
    End point description
    If more than 2-dilution increase as compared to pre-study level at screening
    End point type
    Secondary
    End point timeframe
    Entire study duration: approx. 2.5 years; study participation per subject: mean of 43.3 days (standard deviation: 30.1 days (range: 4-110 days)
    End point values
    Safety Analysis Set
    Number of subjects analysed
    40
    Units: subjects
    0
    No statistical analyses for this end point

    Secondary: Safety: Adverse events (AEs) related to BAX326

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    End point title
    Safety: Adverse events (AEs) related to BAX326
    End point description
    End point type
    Secondary
    End point timeframe
    Entire study duration: approx. 2.5 years; study participation per subject: mean of 43.3 days (standard deviation: 30.1 days (range: 4-110 days)
    End point values
    Safety Analysis Set
    Number of subjects analysed
    40
    Units: Related AEs
    1
    No statistical analyses for this end point

    Secondary: Safety: Occurrence of thrombotic events

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    End point title
    Safety: Occurrence of thrombotic events
    End point description
    End point type
    Secondary
    End point timeframe
    Entire study duration: approx. 2.5 years; study participation per subject: mean of 43.3 days (standard deviation: 30.1 days (range: 4-110 days)
    End point values
    Safety Analysis Set
    Number of subjects analysed
    40
    Units: subjects
    0
    No statistical analyses for this end point

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

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    End point title
    Presurgical Pharmacokinetics (PK): Area under the plasma concentration versus time curve from 0 to 72 hours post-infusion per dose (AUC 0-72h/dose)
    End point description
    AUC0-72h [IU·hr/dL] (area under the plasma concentration/time curve from time 0 to 72 hours) was computed using the linear trapezoidal method. The concentration at 72 hours was interpolated from the two nearest sampling time points or extrapolated using the last quantifiable concentration and the terminal rate constant λz. λz was estimated from the slope of natural log-linear fitting to latter quantifiable concentrations, with largest adjusted R2.
    End point type
    Secondary
    End point timeframe
    0.5 hour (h) before start of PK infusion to 72±2 h after the infusion
    End point values
    PK Analysis Set
    Number of subjects analysed
    12
    Units: [IU•hour (hr)/dL] : IU/kg
        arithmetic mean (standard deviation)
    18.48 ± 6.43
    No statistical analyses for this end point

    Secondary: Presurgical PK: Total area under the plasma concentration versus time curve per dose (total AUC/dose)

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    End point title
    Presurgical PK: Total area under the plasma concentration versus time curve per dose (total AUC/dose)
    End point description
    AUC0-inf [IU·hr/dL] (area under the plasma concentration/time curve from time 0 to infinity) was defined as AUC0-t + Ct / λz, where t is the time of last quantifiable concentration, and Ct is the last quantifiable concentration.
    End point type
    Secondary
    End point timeframe
    0.5 hour (h) before start of PK infusion to 72±2 h after the infusion
    End point values
    PK Analysis Set
    Number of subjects analysed
    12
    Units: [IU•hour (hr)/dL] : IU/kg
        arithmetic mean (standard deviation)
    20.6 ± 7.32
    No statistical analyses for this end point

    Secondary: Presurgical PK: Mean residence time (MRT)

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    End point title
    Presurgical PK: Mean residence time (MRT)
    End point description
    MRT [hr] was computed as AUMC0-inf / AUC0-∞, where AUMC0-inf was determined in a similar manner as AUC0-inf.
    End point type
    Secondary
    End point timeframe
    0.5 hour (h) before start of PK infusion to 72±2 h after the infusion
    End point values
    PK Analysis Set
    Number of subjects analysed
    12
    Units: hours (hr)
        arithmetic mean (standard deviation)
    27.17 ± 4.03
    No statistical analyses for this end point

    Secondary: Presurgical PK: Factor IX clearance (CL)

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    End point title
    Presurgical PK: Factor IX clearance (CL)
    End point description
    CL [dL/(kg·hr)] (clearance) was computed as Dose / AUC0-inf.
    End point type
    Secondary
    End point timeframe
    0.5 hour (h) before start of PK infusion to 72±2 h after the infusion
    End point values
    PK Analysis Set
    Number of subjects analysed
    12
    Units: dL/(kg•hr)
        arithmetic mean (standard deviation)
    0.0523 ± 0.0126
    No statistical analyses for this end point

    Secondary: Presurgical PK: Incremental recovery (IR) at 30 min

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    End point title
    Presurgical PK: Incremental recovery (IR) at 30 min
    End point description
    IR [IU/dL:IU/kg] was defined as (C post-infusion - C pre-infusion) / Dose, where C post-infusion is the measured concentration achieved at 30±5 minutes for pre-surgical PK and at 15±5 minutes for loading dose.
    End point type
    Secondary
    End point timeframe
    0.5 hour (h) before start of PK infusion and at 0.5 h ± 5 min after the infusion
    End point values
    PK Analysis Set
    Number of subjects analysed
    12
    Units: IU/dL : IU/kg
        arithmetic mean (standard deviation)
    1 ± 0.29
    No statistical analyses for this end point

    Secondary: Presurgical PK: Elimination phase half-life (T 1/2)

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    End point title
    Presurgical PK: Elimination phase half-life (T 1/2)
    End point description
    T1/2 [hr] (elimination phase half-life) was determined as ln2 / λz.
    End point type
    Secondary
    End point timeframe
    0.5 hour (h) before start of PK infusion to 72±2 h after the infusion
    End point values
    PK Analysis Set
    Number of subjects analysed
    12
    Units: hr
        arithmetic mean (standard deviation)
    23.6 ± 3.6
    No statistical analyses for this end point

    Secondary: Presurgical PK: Volume of distribution at steady state (Vss)

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    End point title
    Presurgical PK: Volume of distribution at steady state (Vss)
    End point description
    Vss [dL/kg] (volume of distribution at steady state) was computed as CL·MRT.
    End point type
    Secondary
    End point timeframe
    0.5 hour (h) before start of PK infusion to 72±2 h after the infusion
    End point values
    PK Analysis Set
    Number of subjects analysed
    12
    Units: dL/kg
        arithmetic mean (standard deviation)
    1.41 ± 0.38
    No statistical analyses for this end point

    Secondary: Presurgical PK: Incremental recovery (IR) at 15±5 minutes following loading dose prior to surgery

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    End point title
    Presurgical PK: Incremental recovery (IR) at 15±5 minutes following loading dose prior to surgery
    End point description
    End point type
    Secondary
    End point timeframe
    Within 60 minutes prior to surgery and 15±5 minutes after loading dose/rebolus, if applicable
    End point values
    Full Analysis Set
    Number of subjects analysed
    36
    Units: [IU/dL] : [IU/kg]
        arithmetic mean (standard deviation)
    0.91 ± 0.1787
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Entire study duration: approx. 2.5 years; study participation per subject: mean of 43.3 days (standard deviation: 30.1 days (range: 4-110 days)
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    N/A
    Reporting groups
    Reporting group title
    Safety Analysis Set
    Reporting group description
    Comprises all subjects exposed to investigational product during the study (n=40)

    Serious adverse events
    Safety Analysis Set
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 40 (0.00%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Safety Analysis Set
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    15 / 40 (37.50%)
    Injury, poisoning and procedural complications
    Post procedural haematoma
         subjects affected / exposed
    2 / 40 (5.00%)
         occurrences all number
    2
    Post procedural swelling
         subjects affected / exposed
    4 / 40 (10.00%)
         occurrences all number
    4
    Procedural pain
         subjects affected / exposed
    9 / 40 (22.50%)
         occurrences all number
    15
    Blood and lymphatic system disorders
    Haemorrhagic anaemia
         subjects affected / exposed
    3 / 40 (7.50%)
         occurrences all number
    3
    Thrombocytosis
         subjects affected / exposed
    4 / 40 (10.00%)
         occurrences all number
    4
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    2 / 40 (5.00%)
         occurrences all number
    2

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    11 Oct 2011
    - Design was modified so that subjects taking part in the BAX326 pediatric study (251101) could also be recruited into the surgery study. - Occurrence of thrombotic events was added as a safety endpoint. A daily clinical evaluation of thrombosis following surgery was added to the schedule of study procedures and assessments. - Subjects could undergo 2 parallel surgeries, such as bilateral knee replacement, but prior approval had to be obtained from the sponsor.
    26 Feb 2013
    - Tailoring of dose was specified ‘to raise FIX concentration to at least 80%-100% of normal for major surgeries and to at least 30%-60% of normal for minor surgeries to ensure that the recommended pre-infusion FIX levels are maintained in the perioperative period’. - To ensure that subjects were hemostatically sufficiently covered on the day of surgery, the results of the pre-infusion FIX activity had to be available within 4 hours of infusion of BAX 326, and a second FIX activity level had to be determined within 12 hours of surgery, preferably within 6-8 h. - In case of major surgery, the subject’s individual PK parameters, in particular IR and half-life, determined as part of the PK assessment, had to be available prior to the start of surgery, to determine the adequate dose and dose frequency. - The formula for calculating the required units was revised as follows due to a revised IR based on the PK data of the BAX326 pivotal study (from 0.8 to 0.9) in subjects ≥12 years of age: ‘body weight (kg) x desired FIX rise (% or (IU/dL)) x 1.1 IU/kg’ (previously 1.3 IU/kg). - Dosing adjustments based on aPTT values were no longer allowed. The following text was added: ‘ALL subsequent infusions of BAX 326 must be preceded by measurement of residual FIX levels and the dose adjusted as needed – dosing adjustments based on aPTT values are not allowed’. Postoperative aPTT assessments were removed from the protocol. - In the event that high doses of BAX326 were required, it was recommended that these should be administered in 1-3 infusions over 24 hours, most commonly in 2 infusions, to avoid supraphysiological peaks. - For subjects transitioning to the surgery study from the BAX326 pivotal, continuation, or pediatric study, the transition stages from one study to another were clarified. - In the event that at least 3 pediatric subjects <12 years of age had been enrolled, a separate analysis of the pediatric cohort would have had to be performed.
    12 Apr 2013
    - The previous number of approximately 30 elective or emergency surgical, dental or other invasive procedures in approximately 30 subjects was increased to 40 procedures/subjects.

    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

    Online references

    http://www.ncbi.nlm.nih.gov/pubmed/24697870
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