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    Clinical Trial Results:
    A Phase 3, Multicenter, Open Label Study of Efficacy and Safety of PEGylated rFVIII (BAX 855) in Previously Treated Patients With Severe Hemophilia A Undergoing Surgical or Other Invasive Procedures

    Summary
    EudraCT number
    2013-001359-11
    Trial protocol
    GB   BE   LT   BG   ES   DE   NL  
    Global end of trial date
    23 Sep 2016

    Results information
    Results version number
    v1(current)
    This version publication date
    06 Apr 2017
    First version publication date
    06 Apr 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    261204
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01913405
    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-001296-PIP01-12
    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
    23 Sep 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    23 Sep 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    23 Sep 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the perioperative hemostatic efficacy of BAX 855 in male previously treated patients aged 2-75 years with severe hemophilia A (FVIII<1%) undergoing major or minor elective or minor emergency surgical, dental or other invasive procedures as determined by the Global Hemostatic Efficacy Assessment.
    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. The enrollment of subjects <12years of age was limited to subjects participating in the pediatric study 261202. In the Russian Federation, all subjects were required to be >18 years old at the time of enrollment.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    20 Dec 2013
    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: 8
    Country: Number of subjects enrolled
    Russian Federation: 2
    Country: Number of subjects enrolled
    United Kingdom: 1
    Country: Number of subjects enrolled
    Bulgaria: 6
    Country: Number of subjects enrolled
    Lithuania: 1
    Country: Number of subjects enrolled
    Spain: 3
    Country: Number of subjects enrolled
    Switzerland: 2
    Worldwide total number of subjects
    23
    EEA total number of subjects
    11
    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)
    22
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Twelve study sites have enrolled subjects in seven countries (US, Russia, UK, Bulgaria, Lithuania, Spain, Switzerland). There were 30 surgical enrollments in a total of 23 unique subjects. Seven unique subjects enrolled more than once, of whom five received study product for more than one surgical procedure.

    Pre-assignment
    Screening details
    A total of 23 subjects provided informed consent and were screened for study participation. There were 3 screen failures, of which 2 participated and completed the study. 22 unique subjects (29 surgical enrollments) were exposed to study product. One subject discontinued prior to surgery and one subject discontinued after surgery.

    Pre-assignment period milestones
    Number of subjects started
    23
    Number of subjects completed
    22

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    Screen failure: 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 BAX855 for pre-surgical PK infusion, surgery and postoperative treatment.
    Arm type
    Experimental

    Investigational medicinal product name
    BAX 855
    Investigational medicinal product code
    Other name
    Adynovate, Adynovi
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects undergoing major surgery initially underwent a pharmacokinetic (PK) evaluation with BAX855 (60 +/-5 IU/kg), if PK parameters were not already available from a BAX855 parent study. For subjects undergoing minor surgery an individual IR was determined. Individual dosing based on the patients PK/IR parameters was outlined in the FVIII substitution plan. For the loading dose prior surgery the FVIII target levels were to be 80-100% of normal (major surgery) and 30-60% of normal (minor surgery). Subsequent infusions were preceeded by measurement of residual FVIII levels and the dose adjusted as needed. The following FVIII trough levels were to be targeted: Postoperative day 1-3: not below 80%, day 4-7: not below 50%, day 8 to discharge: not below 30%

    Number of subjects in period 1 [1]
    Overall trial
    Started
    22
    Completed
    20
    Not completed
    2
         Adverse event, non-fatal
    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 23 subjects provided informed consent and were screened for study participation. One subject was a screen failure and did not enter the baseline period. Two other subjects were also screen failures but did enter the baseline period and were treated with study product.

    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
    22 22
    Age categorical
    Units: Subjects
        2 to <18 years
    1 1
        18 to 75 years
    21 21
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    34.8 ± 13.47 -
    Gender categorical
    Units:
        Male
    22 22
    Subject analysis sets

    Subject analysis set title
    Full Analysis Set
    Subject analysis set type
    Full analysis
    Subject analysis set description
    The FAS comprises all subjects with at least one available hemostatic assessment. N=26 surgical enrollments in 21 unique subjects.

    Subject analysis set title
    Per-Protocol Analysis Set
    Subject analysis set type
    Per protocol
    Subject analysis set description
    The PPAS comprises all subjects with available intraoperative efficacy assessment performed by the surgeon within 60 minutes post-surgery, postoperative hemostatic control assessed by the operating surgeon postoperatively at 24 hours and perioperative hemostatic control assessed by the investigator during end of study visit. Only subjects who met all study entry criteria and who had no major protocol violation that impacted hemostatic efficacy assessment were included in the PPAS. N=12 surgical enrollments in 11 unique subjects.

    Subject analysis set title
    Safety Analysis Set
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    The SAS comprises all subjects who received at least one infusion of BAX855. N= 29 surgical enrollments in 22 unique subjects.

    Subject analysis set title
    Pharmacokinetic Analysis Set
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    The PKAS comprises only subjects who underwent a PK assessment. N=25 surgical enrollments in 20 unique subjects.

    Subject analysis set title
    Major orthopedic surgery
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Comprises all subjects treated with BAX855 for major orthopedic surgery. N=14 surgical enrollments in 12 unique subjects.

    Subject analysis set title
    Major non-orthopedic surgery
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Comprises all subjects treated with BAX855 for major non-orthopedic surgery. N=7 surgical enrollments in 6 unique subjects.

    Subject analysis set title
    Minor surgery
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Comprises all subjects treated with BAX855 for minor surgery. N=5 surgical enrollments in 4 unique subjects.

    Subject analysis sets values
    Full Analysis Set Per-Protocol Analysis Set Safety Analysis Set Pharmacokinetic Analysis Set Major orthopedic surgery Major non-orthopedic surgery Minor surgery
    Number of subjects
    21
    11
    22
    20
    12
    6
    4
    Age categorical
    Units: Subjects
        2 to <18 years
    1
    1
    1
    1
    1
    0
    0
        18 to 75 years
    20
    10
    21
    19
    11
    6
    4
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    34 ± 13.3
    30.2 ± 10.15
    34.8 ± 13.47
    36.7 ± 13.48
    ±
    ±
    ±
    Gender categorical
    Units:
        Male
    21
    11
    22
    20
    12
    6
    4

    End points

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    End points reporting groups
    Reporting group title
    Overall trial
    Reporting group description
    Treatment with BAX855 for pre-surgical PK infusion, surgery and postoperative treatment.

    Subject analysis set title
    Full Analysis Set
    Subject analysis set type
    Full analysis
    Subject analysis set description
    The FAS comprises all subjects with at least one available hemostatic assessment. N=26 surgical enrollments in 21 unique subjects.

    Subject analysis set title
    Per-Protocol Analysis Set
    Subject analysis set type
    Per protocol
    Subject analysis set description
    The PPAS comprises all subjects with available intraoperative efficacy assessment performed by the surgeon within 60 minutes post-surgery, postoperative hemostatic control assessed by the operating surgeon postoperatively at 24 hours and perioperative hemostatic control assessed by the investigator during end of study visit. Only subjects who met all study entry criteria and who had no major protocol violation that impacted hemostatic efficacy assessment were included in the PPAS. N=12 surgical enrollments in 11 unique subjects.

    Subject analysis set title
    Safety Analysis Set
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    The SAS comprises all subjects who received at least one infusion of BAX855. N= 29 surgical enrollments in 22 unique subjects.

    Subject analysis set title
    Pharmacokinetic Analysis Set
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    The PKAS comprises only subjects who underwent a PK assessment. N=25 surgical enrollments in 20 unique subjects.

    Subject analysis set title
    Major orthopedic surgery
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Comprises all subjects treated with BAX855 for major orthopedic surgery. N=14 surgical enrollments in 12 unique subjects.

    Subject analysis set title
    Major non-orthopedic surgery
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Comprises all subjects treated with BAX855 for major non-orthopedic surgery. N=7 surgical enrollments in 6 unique subjects.

    Subject analysis set title
    Minor surgery
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Comprises all subjects treated with BAX855 for minor surgery. N=5 surgical enrollments in 4 unique subjects.

    Primary: Global Hemostatic Efficacy Assessment score (GHEA)

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    End point title
    Global Hemostatic Efficacy Assessment score (GHEA) [1]
    End point description
    The GHEA is composed of three individual ratings: a. Assessment of intraoperative hemostatic efficacy of BAX 855 performed by the operating surgeon; b. Assessment of postoperative hemostatic efficacy of BAX 855 at postoperative Day 1 (approx. 24 hours post surgery) performed by the operating surgeon; c. Assessment of perioperative hemostatic efficacy of BAX855 at Day 14 or discharge, whichever is first, performed by the investigator. The scores of the individual ratings are added for the GHEA. Treatment success is a GHEA score of excellent or good. Point estimates and corresponding two-sided exact (Clopper-Pearson) confidence intervals at 90% confidence level are calculated. Number of subjects analysed is based on surgical enrollments and the same as number of surgeries. Main analysis was done on the FAS with 24 surgeries with at least one available hemostatic assessment, supportive analysis was done on the PPAS with 12 surgeries with all hemostatic assessments available.
    End point type
    Primary
    End point timeframe
    Hemostatic efficacy assessments were performed intraoperatively, postoperatively on day 1 (approximately 24 hours after surgery) and perioperatively at day 14 or discharge (whichever was first).
    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
    Full Analysis Set Per-Protocol Analysis Set Major orthopedic surgery Major non-orthopedic surgery Minor surgery
    Number of subjects analysed
    24
    12
    14
    7
    3
    Units: Percentage of surgeries
    number (confidence interval 90%)
        Treatment Success (GHEA score excellent or good)
    100 (88.3 to 100)
    100 (77.9 to 100)
    100 (80.7 to 100)
    100 (65.2 to 100)
    100 (36.8 to 100)
        Excellent
    100 (88.3 to 100)
    100 (77.9 to 100)
    100 (80.7 to 100)
    100 (65.2 to 100)
    100 (36.8 to 100)
        Good
    0 (0 to 11.7)
    0 (0 to 22.1)
    0 (0 to 19.3)
    0 (0 to 34.8)
    0 (0 to 63.2)
    No statistical analyses for this end point

    Secondary: Intraoperative blood loss

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    End point title
    Intraoperative blood loss
    End point description
    Actual intraoperative blood loss was assessed at the end of surgery and was compared to the estimated volume of expected average and maximum blood loss in a hemostatically normal individual of the same sex, age and stature as the study subject. Expected intraoperative blood loss was predicted pre-operatively by the investigator/surgeon. Number of subjects is counted based on surgical enrollment.
    End point type
    Secondary
    End point timeframe
    From initiation of surgery until end of surgery.
    End point values
    Full Analysis Set Major orthopedic surgery Major non-orthopedic surgery Minor surgery
    Number of subjects analysed
    25 [2]
    14
    6 [3]
    5
    Units: Milliliter
    median (inter-quartile range (Q1-Q3))
        Actual blood loss
    10 (4 to 30)
    10 (10 to 30)
    4.5 (3 to 50)
    5 (0 to 15)
        Predicted average blood loss
    20 (5 to 150)
    150 (10 to 150)
    10 (5 to 50)
    5 (0 to 15)
        Difference from predicted average blood loss
    6 (0 to 135)
    125 (0 to 140)
    1.5 (0 to 6)
    0 (0 to 0)
        Predicted maximum blood loss
    100 (7 to 300)
    300 (100 to 300)
    20 (5 to 150)
    5 (0 to 30)
        Difference from predicted maximum blood loss
    100 (4 to 280)
    275 (95 to 290)
    25 (3 to 100)
    0 (0 to 15)
    Notes
    [2] - n=26 for predicted average and maximum blood loss
    [3] - n=7 for predicted average and maximum blood loss
    No statistical analyses for this end point

    Secondary: Postoperative blood loss

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    End point title
    Postoperative blood loss
    End point description
    Actual post-operative blood loss assessed at postoperative day 1 was compared to the estimated volume of expected average and maximum blood loss in a hemostatically normal individual of the same sex, age and stature as the study subject. Expected postoperative blood loss was predicted pre-operatively by the investigator/surgeon. Number of subjects is counted based on surgical enrollment.
    End point type
    Secondary
    End point timeframe
    From completion of surgery until 24 hours after surgery.
    End point values
    Full Analysis Set Major orthopedic surgery Major non-orthopedic surgery Minor surgery
    Number of subjects analysed
    16 [4]
    9 [5]
    4 [6]
    3 [7]
    Units: Milliliter
    median (inter-quartile range (Q1-Q3))
        Actual blood loss
    10 (0 to 825)
    750 (15 to 1100)
    1 (0 to 33.5)
    0 (0 to 4)
        Predicted average blood loss
    27.5 (0 to 300)
    213.5 (30 to 700)
    1 (0 to 25)
    0 (0 to 0)
        Difference from predicted average blood loss
    -7.5 (-125 to 4)
    -50 (-400 to -15)
    4 (-7.5 to 16.5)
    0 (0 to 196)
        Predicted maximum blood loss
    75 (0 to 600)
    450 (100 to 1200)
    2 (0 to 50)
    0 (0 to 0)
        Difference from predicted maximum blood loss
    67.5 (0 to 148)
    100 (0 to 300)
    34 (9 to 67.5)
    0 (0 to 196)
    Notes
    [4] - n=26 for predicted average and maximum blood loss
    [5] - n=14 for predicted average and maximum blood loss
    [6] - n=7 for predicted average and maximum blood loss
    [7] - n=5 for predicted average and maximum blood loss
    No statistical analyses for this end point

    Secondary: Overall perioperative blood loss

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    End point title
    Overall perioperative blood loss
    End point description
    Actual overall perioperative blood loss (assessed at the end of surgery, at postoperative day 1 and until discharge or day 14 - whichever is first) was compared to the estimated volume of expected average and maximum blood loss in a hemostatically normal individual of the same sex, age and stature as the study subject. Expected perioperative blood loss was predicted pre-operatively by the investigator/surgeon. Number of subjects is counted based on surgical enrollment.
    End point type
    Secondary
    End point timeframe
    From start of surgery until discharge or day 14, whichever occurred last.
    End point values
    Full Analysis Set Major orthopedic surgery Major non-orthopedic surgery Minor surgery
    Number of subjects analysed
    25 [8]
    14
    6 [9]
    5
    Units: Milliliter
    median (inter-quartile range (Q1-Q3))
        Actual blood loss
    50 (5 to 305)
    246 (15 to 1210)
    5.5 (3 to 50)
    9 (0 to 15)
        Predicted average blood loss
    40 (5 to 800)
    675 (30 to 1000)
    20 (5 to 50)
    0 (0 to 15)
        Difference from predicted average blood loss
    0 (-50 to 20)
    -5 (-210 to 25)
    2.5 (0 to 14)
    0 (0 to 0)
        Predicted maximum blood loss
    125 (20 to 1500)
    1500 (100 to 1500)
    20 (6 to 150)
    0 (0 to 30)
        Difference from predicted maximum blood loss
    64 (6 to 250)
    122.5 (50 to 400)
    5.5 (0 to 64)
    0 (0 to 15)
    Notes
    [8] - n=26 for predicted average and maximum blood loss
    [9] - n=7 for predicted average and maximum blood loss
    No statistical analyses for this end point

    Secondary: Blood transfusion requirements

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    End point title
    Blood transfusion requirements
    End point description
    Volume of blood, red blood cells, platelets, and other blood products transfused. Only packed red blood cells were transfused in this study. Subjects are counted based on surgical enrollment. No blood transfusions were required for minor surgeries and no blood transfusion were required intraoperatively for major surgeries.
    End point type
    Secondary
    End point timeframe
    From initiation of the surgery to 24 hours after completion of the surgery.
    End point values
    Full Analysis Set Major orthopedic surgery Major non-orthopedic surgery
    Number of subjects analysed
    4
    3
    1 [10]
    Units: Milliliter
    arithmetic mean (standard deviation)
        Volume of all blood products - postoperative
    438 ± 152.86
    384 ± 132.49
    600 ± 999.99
    Notes
    [10] - Dispersion is not applicable as there is only 1 subject in the analysis set.
    No statistical analyses for this end point

    Secondary: Occurrence of bleeding episodes and additional need for surgical intervention

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    End point title
    Occurrence of bleeding episodes and additional need for surgical intervention
    End point description
    Any clinically relevant bleeding episodes (as assessed by the investigator) and any need for additional surgical intervention were recorded. If the subject had not resumed his previous treatment after discharge, the occurrence and treatment of bleeding episodes were recorded in the subject's diary. Only surgical enrollments that have encountered bleeding episodes are listed as subjects analysed. The additional need for surgeries was assessed for all 26 surgical enrollments.
    End point type
    Secondary
    End point timeframe
    From start of surgery until the last intensified treatment after hospital discharge (or until hospital discharge if there was no intensified treatment).
    End point values
    Full Analysis Set Major orthopedic surgery Major non-orthopedic surgery Minor surgery
    Number of subjects analysed
    5
    2
    2
    1
    Units: Events
        Bleeding episodes site mucosal
    2
    0
    1
    1
        Bleeding episodes site joint
    1
    1
    0
    0
        Bleeding episodes site gastrointestinal
    1
    0
    1
    0
        Bleeding episodes site muscle
    1
    1
    0
    0
        Bleeding episodes cause spontaneous
    0
    0
    0
    0
        Bleeding episodes cause injury
    5
    2
    2
    1
        Bleeding episodes severity mild
    3
    1
    1
    1
        Bleeding episodes severity moderate
    1
    0
    1
    0
        Bleeding episodes severity severe
    1
    1
    0
    0
        Additional need for surgery
    0
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Daily and total weight-adjusted consumption of BAX855 per subject

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    End point title
    Daily and total weight-adjusted consumption of BAX855 per subject
    End point description
    Daily weight-adjusted BAX855 consumption is listed from preoperative loading dose until discharge. Total weight-adjusted BAX855 consumption is calculated from first study infusion (PK/IR) until end of study. PK infusions from previous studies are not included. Subjects are counted based on their surgical enrollment. Number of subjects=surgeries (n) varies on each postoperative day as described in the categories for non-orthopedic major surgery (NOS), orthopedic major surgery (OS) and minor surgery (MS) and the full analysis set (FAS). 99.999 is listed if result is not available due to n=0 or standard deviation is not available due to n=1.
    End point type
    Secondary
    End point timeframe
    From initial loading dose until discharge for daily weight-adjusted dose and from first infusion (PK/IR) until end of study for total weight-adjusted dose.
    End point values
    Full Analysis Set Major orthopedic surgery Major non-orthopedic surgery Minor surgery
    Number of subjects analysed
    26
    14
    7
    5
    Units: IU/kg
    arithmetic mean (standard deviation)
        Total weight adjusted BAX855 consumption
    562.076 ± 343.7305
    746.103 ± 320.4581
    507.881 ± 161.8075
    122.673 ± 20.0076
        Preoperative
    62.492 ± 15.7678
    69.442 ± 14.4532
    56.852 ± 14.8899
    50.928 ± 12.27
        Postop day 0: n=18(FAS) n=11(OS) n=6(NOS) n=1(MS)
    34.195 ± 13.6755
    37.082 ± 16.016
    31.141 ± 7.5641
    20.762 ± 99.999
        Postop day 1: n=24(FAS) n=14(OS) n=6(NOS) n=4(MS)
    56.409 ± 24.8718
    62.005 ± 25.4147
    50.698 ± 29.2373
    45.388 ± 12.0692
        Postop day 2: n=19(FAS) n=13(OS) n=6(NOS) n=0(MS)
    51.697 ± 27.7558
    52.445 ± 27.4771
    50.076 ± 30.9322
    99.999 ± 99.999
        Postop day 3: n=17(FAS) n=12(OS) n=5(NOS) n=0(MS)
    45.023 ± 24.2793
    47.139 ± 27.1069
    39.943 ± 17.0764
    99.999 ± 99.999
        Postop day 4: n=16(FAS) n=12(OS) n=4(NOS) n=0(MS)
    36.593 ± 12.2194
    38.009 ± 13.6782
    32.345 ± 5.3374
    99.999 ± 99.999
        Postop day 5: n=12(FAS) n=10(OS) n=2(NOS) n=0(MS)
    32.24 ± 15.1497
    32.333 ± 15.1071
    31.775 ± 21.6822
    99.999 ± 99.999
        Postop day 6: n=9(FAS) n=7(OS) n=2(NOS) n=0(MS)
    34.135 ± 13.3132
    35.198 ± 12.8578
    30.415 ± 19.7589
    99.999 ± 99.999
        Postop day 7: n=4(FAS) n=3(OS) n=1(NOS) n=0(MS)
    22.955 ± 6.0531
    24.866 ± 5.7495
    17.223 ± 99.999
    99.999 ± 99.999
        Postop day 8+: n=2(FAS) n=2(OS) n=0(NOS) n=0(MS)
    136.808 ± 139.3781
    136.808 ± 139.3781
    99.999 ± 99.999
    99.999 ± 99.999
    No statistical analyses for this end point

    Secondary: Presurgical PK - Area under the plasma concentration/time curve

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    End point title
    Presurgical PK - Area under the plasma concentration/time curve
    End point description
    The area under the plasma concentration/time curve from time 0 to infinity (AUC 0-inf) and the area under the first movement curve from time 0 to infinity (AUMC 0-inf) was calculated as the sum of AUC and AUMC from time 0 to the time of the 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. The area under the plasma concentration/time curve from time 0 to 96 hours postinfusion (AUC 0-96h) was computed using the linear trapezoidal rule. For the calculation of AUC 0-96h the levels at 96 hours were linearly interpolated/extrapolated from the 2 nearest sampling time points. Number of subjects is counted based on surgical enrollment. Main analysis was done on the one-stage clotting assay results, supportive analysis was done on the chromogenic assay results.
    End point type
    Secondary
    End point timeframe
    PK measurements were done within 30 minutes pre-infusion, and post infusion at 15 (± 5) minutes, 3 hours (± 30 minutes), 9 hours (± 30 minutes), 32 (± 2) hours, 56 (± 4) hours and 96 (± 4) hours.
    End point values
    Pharmacokinetic Analysis Set
    Number of subjects analysed
    25
    Units: IU*h/dL
    arithmetic mean (standard deviation)
        AUC (0-96h) one-stage clotting
    2701.3 ± 719.52
        AUC (0-96h) chromogenic
    3153.7 ± 980.27
        AUC (0-inf) one-stage clotting
    2743.3 ± 751.83
        AUC (0-inf) chromogenic
    3201.8 ± 1019.13
    No statistical analyses for this end point

    Secondary: Presurgical PK - Terminal Half-Life

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    End point title
    Presurgical PK - Terminal Half-Life
    End point description
    Terminal or disposition half-life (HL) was calculated as log e(2)/λz where the terminal or disposition rate constant (λz) was estimated as the slope of a log-linear least squares regression model. Number of subjects is counted based on surgical enrollment. Main analysis was done on the one-stage clotting assay results, supportive analysis was done on the chromogenic assay results.
    End point type
    Secondary
    End point timeframe
    PK measurements were done within 30 minutes pre-infusion, and post infusion at 15 (± 5) minutes, 3 hours (± 30 minutes), 9 hours (± 30 minutes), 32 (± 2) hours, 56 (± 4) hours and 96 (± 4) hours.
    End point values
    Pharmacokinetic Analysis Set
    Number of subjects analysed
    25
    Units: hours
    arithmetic mean (standard deviation)
        One-stage clotting
    14.63 ± 3.179
        Chromogenic
    14.53 ± 3.137
    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
    Mean residence time (MRT) was calculated as total area under the moment curve divided by the total area under the curve. Number of subjects is counted based on surgical enrollment. Main analysis was done on the one-stage clotting assay results, supportive analysis was done on the chromogenic assay results.
    End point type
    Secondary
    End point timeframe
    PK measurements were done within 30 minutes pre-infusion, and post infusion at 15 (± 5) minutes, 3 hours (± 30 minutes), 9 hours (± 30 minutes), 32 (± 2) hours, 56 (± 4) hours and 96 (± 4) hours.
    End point values
    Pharmacokinetic Analysis Set
    Number of subjects analysed
    25
    Units: hours
    arithmetic mean (standard deviation)
        One-stage clotting
    19.26 ± 4.901
        Chromogenic
    18.68 ± 4.16
    No statistical analyses for this end point

    Secondary: Presurgical PK - Clearance (CL)

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    End point title
    Presurgical PK - Clearance (CL)
    End point description
    Systemic clearance (CL) was calculated as the dose in IU/kg divided by the total AUC. Number of subjects is counted based on surgical enrollment. Main analysis was done on the one-stage clotting assay results, supportive analysis was done on the chromogenic assay results.
    End point type
    Secondary
    End point timeframe
    PK measurements were done within 30 minutes pre-infusion, and post infusion at 15 (± 5) minutes, 3 hours (± 30 minutes), 9 hours (± 30 minutes), 32 (± 2) hours, 56 (± 4) hours and 96 (± 4) hours.
    End point values
    Pharmacokinetic Analysis Set
    Number of subjects analysed
    25
    Units: dL/(kg*h)
    arithmetic mean (standard deviation)
        One-stage clotting
    0.02347 ± 0.006821
        Chromogenic
    0.02042 ± 0.006041
    No statistical analyses for this end point

    Secondary: Presurgical PK - Apparent volume of distribution at steady state (Vss)

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    End point title
    Presurgical PK - Apparent volume of distribution at steady state (Vss)
    End point description
    Apparent steady state volume of distribution (Vss) was calculated as dose multiplied with AUMC(0-inf) divided by AUC(0-inf) to square. Number of subjects is counted based on surgical enrollment. Main analysis was done on the one-stage clotting assay results, supportive analysis was done on the chromogenic assay results.
    End point type
    Secondary
    End point timeframe
    PK measurements were done within 30 minutes pre-infusion, and post infusion at 15 (± 5) minutes, 3 hours (± 30 minutes), 9 hours (± 30 minutes), 32 (± 2) hours, 56 (± 4) hours and 96 (± 4) hours.
    End point values
    Pharmacokinetic Analysis Set
    Number of subjects analysed
    25
    Units: dL/kg
    arithmetic mean (standard deviation)
        One-stage clotting
    0.4316 ± 0.09633
        Chromogenic
    0.3673 ± 0.09559
    No statistical analyses for this end point

    Secondary: Presurgical PK - Incremental recovery

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    End point title
    Presurgical PK - Incremental recovery
    End point description
    Incremental recovery (IR) was calculated as C post infusion minus C pre-infusion divided by the dose. Number of subjects is counted based on surgical enrollment. Main analysis was done on the one-stage clotting assay results, supportive analysis was done on the chromogenic assay results.
    End point type
    Secondary
    End point timeframe
    PK measurements were done within 30 minutes pre-infusion, and post infusion at 15 (± 5) minutes, 3 hours (± 30 minutes), 9 hours (± 30 minutes), 32 (± 2) hours, 56 (± 4) hours and 96 (± 4) hours.
    End point values
    Pharmacokinetic Analysis Set
    Number of subjects analysed
    25
    Units: (IU/dL)/(IU/kg)
    arithmetic mean (standard deviation)
        IR at 15 min post infusion - one-stage clotting
    2.106 ± 0.3823
        IR at 15 min post infusion - chromogenic
    2.721 ± 0.5981
        IR at Cmax - one-stage clotting
    2.123 ± 0.4041
        IR at Cmax - chromogenic
    2.677 ± 0.596
    No statistical analyses for this end point

    Secondary: Summary of safety outcome measures (development of antibodies, thrombotic events, severe allergic reactions and other IP related AEs)

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    End point title
    Summary of safety outcome measures (development of antibodies, thrombotic events, severe allergic reactions and other IP related AEs)
    End point description
    Development of treatment emerging binding antibodies to FVIII IgG, FVIII IgM, BAX855 IgG, BAX855 IgM, PEG IgG, PEG IgM and CHO proteins was assessed as well as any thrombotic events and severe allergic reactions and any other Adverse Events related to the investigational product. Unique subjects with a safety outcome measure are counted.
    End point type
    Secondary
    End point timeframe
    From screening visit to end of study visit.
    End point values
    Safety Analysis Set
    Number of subjects analysed
    22
    Units: Subjects
        Inhibitory antibodies to FVIII
    0
        Treatment emerging binding antibodies to FVIII IgG
    0
        Treatment emerging binding antibodies to FVIII IgM
    0
        Treatment emerging binding antibodies to BAX855IgG
    0
        Treatment emergingbinding antibodies to BAX855IgM
    0
        Treatment emerging binding antibodies to PEG IgG
    0
        Treatment emerging binding antibodies to PEG IgM
    0
        Treatment emerg.binding antibodies to CHO proteins
    0
        Thrombotic events
    0
        Severe allergic reactions
    0
        Other IP related Adverse Events
    2
    No statistical analyses for this end point

    Secondary: Changes in vital signs - Pulse rate

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    End point title
    Changes in vital signs - Pulse rate
    End point description
    Changes in vital signs were assessed 15 minutes after the PK/IR infusion compared to the pre-infusion values. Number of subjects is counted based on surgical enrollment. The 15 minutes post-infusion measurement includes 1 hour post infusion assessments for two subjects.
    End point type
    Secondary
    End point timeframe
    Vital signs measurement prior to the PK/IR infusion and 15 minutes post-infusion.
    End point values
    Safety Analysis Set
    Number of subjects analysed
    23 [11]
    Units: beats/minute
    median (inter-quartile range (Q1-Q3))
        Pre-infusion
    70 (68 to 74)
        15 minutes post-infusion
    70 (66 to 77)
        Change at 15 min post-infusion
    -1 (-3 to 2)
    Notes
    [11] - n=25 for pre-infusion measurement
    No statistical analyses for this end point

    Secondary: Changes in vital signs - Blood pressure

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    End point title
    Changes in vital signs - Blood pressure
    End point description
    Changes in vital signs were assessed 15 minutes after the PK/IR infusion compared to the pre-infusion values. Number of subjects is counted based on surgical enrollment. The 15 minutes post-infusion measurement includes 1 hour post infusion assessments for two subjects.
    End point type
    Secondary
    End point timeframe
    Vital signs measurement prior to the PK/IR infusion and 15 minutes post-infusion.
    End point values
    Safety Analysis Set
    Number of subjects analysed
    23 [12]
    Units: mmHg
    median (inter-quartile range (Q1-Q3))
        Systolic BP - Pre-infusion
    120 (115 to 125)
        Systolic BP - 15 minutes post-infusion
    115 (110 to 125)
        Systolic BP - Change at 15 min post-infusion
    -5 (-5 to 4)
        Diastolic BP - Pre-infusion
    75 (69 to 80)
        Diastolic BP - 15 minutes post-infusion
    75 (70 to 80)
        Diastolic BP - Change at 15 min post-infusion
    0 (-5 to 1)
    Notes
    [12] - n=25 for pre-infusion measurement
    No statistical analyses for this end point

    Secondary: Changes in vital signs - Respiratory rate

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    End point title
    Changes in vital signs - Respiratory rate
    End point description
    Changes in vital signs were assessed 15 minutes after the PK/IR infusion compared to the pre-infusion values. Number of subjects is counted based on surgical enrollment. The 15 minutes post-infusion measurement includes 1 hour post infusion assessments for two subjects.
    End point type
    Secondary
    End point timeframe
    Vital signs measurement prior to the PK/IR infusion and 15 minutes post-infusion.
    End point values
    Safety Analysis Set
    Number of subjects analysed
    23 [13]
    Units: breaths/minute
    median (inter-quartile range (Q1-Q3))
        Pre-infusion
    14 (12 to 16)
        15 minutes post-infusion
    14 (12 to 16)
        Change at 15 min post-infusion
    0 (0 to 0)
    Notes
    [13] - n=25 for pre-infusion measurement
    No statistical analyses for this end point

    Secondary: Changes in vital signs - Temperature

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    End point title
    Changes in vital signs - Temperature
    End point description
    Changes in vital signs were assessed 15 minutes after the PK/IR infusion compared to the pre-infusion values. Number of subjects is counted based on surgical enrollment. The 15 minutes post-infusion measurement includes 1 hour post infusion assessments for two subjects.
    End point type
    Secondary
    End point timeframe
    Vital signs measurement prior to the PK/IR infusion and 15 minutes post-infusion.
    End point values
    Safety Analysis Set
    Number of subjects analysed
    23 [14]
    Units: Celsius
    median (inter-quartile range (Q1-Q3))
        Pre-infusion
    36.6 (36.3 to 36.7)
        15 minutes post-infusion
    36.6 (36.2 to 36.7)
        Change at 15 min post-infusion
    0 (-0.1 to 0.2)
    Notes
    [14] - n=25 for pre-infusion measurement
    No statistical analyses for this end point

    Secondary: Clinically significant changes in routine labor parameters (hematology and chemistry)

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    End point title
    Clinically significant changes in routine labor parameters (hematology and chemistry)
    End point description
    Changes in clinical chemistry and hematology parameters from a normal or abnormal not clinically significant (ncs) result at screening to an abnormal and clinically significant (cs) result at the end of study assessment (EOS) are listed. Changes did occur in the following laboratory parameters: Alanine Aminotransferase (ALT) (U/L), Hemoglobin (g/L), Hematocrit, Erythrocytes(TI/L), Eosinophils/Leucocytes. Number of subjects is counted based on surgical enrollment.
    End point type
    Secondary
    End point timeframe
    Laboratory assessment were done throughout the study from screening to study completion/termination.
    End point values
    Safety Analysis Set
    Number of subjects analysed
    26 [15]
    Units: Subjects
        ALT: normal at Screening-abnormal cs at EOS
    1
        Hemoglobin: abnormal ncs Screening-abnormal cs EOS
    1
        Hematocrit: abnormal ncs Screening-abnormal cs EOS
    1
        Erythrocytes: normal Screening-abnormal cs EOS
    1
        Eosinop/Leucocyt: normal Screening-abnormal cs EOS
    1
    Notes
    [15] - ALT: n=27, Hematocrit: n=25
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Throughout the entire study period (2 years and 9 months). For each subject the duration of treatment and therefore for the entire study period depended on the nature of each subject’s invasive procedure (ranged from 43 days to 162 days).
    Adverse event reporting additional description
    Adverse Events (AEs) were recorded throughout the entire study period from screening to completion/termination. AEs that occurred during or after treatment are summarized here, AEs that occurred prior to study treatment were listed separately and are not included.
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    19.1
    Reporting groups
    Reporting group title
    Safety Analysis Set
    Reporting group description
    The Safety Analysis Set comprises all subjects who received at least one infusion of BAX855.

    Serious adverse events
    Safety Analysis Set
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 22 (9.09%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Gastrointestinal disorders
    Diabetic gastroparesis
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Oesophageal ulcer
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Device related infection
         subjects affected / exposed
    1 / 22 (4.55%)
         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
    Safety Analysis Set
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    8 / 22 (36.36%)
    Injury, poisoning and procedural complications
    Tooth fracture
         subjects affected / exposed
    2 / 22 (9.09%)
         occurrences all number
    2
    Procedural pain
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Procedural hypotension
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Wound
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Investigations
    Hepatic enzyme increased
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Oropharyngeal pain
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Nervous system disorders
    Headache
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    General disorders and administration site conditions
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Ear and labyrinth disorders
    Hyperacusis
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Infections and infestations
    Peritonsillitis
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Rhinitis
         subjects affected / exposed
    1 / 22 (4.55%)
         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
    19 Jul 2013
    The overall study duration was extended from 24 to 41 months. The recruitment period was extended from 18 to 34 months. Pediatric PTPs transitioning from the pediatric study with BAX855 were excluded from participation in this study. Information was added to justify the inclusion of adolescents in this study with two ICH guidelines referenced. The level of detectable FVIII inhibitory antibodies which would exclude a subject from participation was changed from ≥ 0.6 BU using the Nijmegen modification of the Bethesda assay to ≥0.4 BU (due to validation of the central laboratory for this value). The wash-out period for the PK assessment was changed from 96 to 72 hours. Criteria were listed that would require a repetition of the PK assessment (e.g. bleeding episode prior to 72-hour timepoint, 2 or more PK blood sample results not evaluable). A requirement for a 72-hour wash-out period before the immunogenicity tests was added. The requirement that major surgery may only be started when the required target FVIII level (range 80-150%) has been attained was removed (as test results may not have been available within 60 minutes in most standard laboratories). In the assessment scales for ntraoperative and postoperative efficacy, the description of products for rescue therapy was deleted from the rating criterion 'none'. Viral serology tests (HBV, HCV, HIV) were added to the laboratory tests to be performed at the end-of-study/termination visit (in alignment with the pivotal study). A planned safety review was added which was to be performed upon completion of BAX855 pivotal study 261201 and was to include all major and minor surgeries performed until that time.
    30 Jan 2014
    Overall study duration decreased from 41 to 36 months.Recruitment period changed from 34 to 33 months.Targeted accrual changed to approx. 50 surgical/invasive procedures in approx. 40 subjects, to include at least 10 major procedures in at least 5 subjects. Age range changed from previously 12-65 years to 2-75 years. Enrollment of subjects < 12 years of age limited to subjects participating in the BAX855 pediatric study. For newly recruited subjects the age range 12-75 years applies. Inclusion crit. were split according to whether subjects were transitioning form another BAX 855 study or were newly recruited. Emergency procedures now allowed in this study, provided these were minor emergency surgeries. Only subjects transitioning from another BAX855 study were allowed to undergo minor emergency surgery, newly recruited subjects had to undergo major procedures. If IR<1.5 in the parent study or after screening, no participation in this study. FVIII activity analysis at the central lab to be performed by 1-stage clotting and chromogenic assay. PK not required for minor surgeries and major surgeries if done in previous study, IR sufficient for subsequent dosing. Rating from EOS done at day 14, wording of definitions changed slightly. Changes in virology status removed from sec.outcome measures and not assessed at EOS. Antibodies to murine IgG not assessed. Wash-out for immunogenicity was 72h (FVIII) and 96h (BAX855). Addition of single dose vials with nominal potency of 3000 IU rFVIII. Instructions for use of vials, potencies and lots given. Dosing schedule changed (instead of PK guided dosing target levels provided). Surgery to start after normalization of aPTT and dose adjustments based on FVIII activity. Short half life removed from criteria for withdrawal. Detailed info for thrombosis prophy and topical hemostatics. Subject diary added. ECG and thrombotic markers removed. Vital signs timepoints changed and removed at EOS. Blood pressure measured in supine position.

    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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