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    Clinical Trial Results:
    Efficacy and Safety of B-Domain Deleted Recombinant Porcine Factor VIII (OBI-1) in the Treatment of Acquired Hemophilia A Due to Autoimmune Anti-Factor VIII Inhibitory Antibodies

    Summary
    EudraCT number
    		 2011-000181-34
    Trial protocol
    		 GB   SE   DE   HU   IT  
    Global end of trial date
    09 Oct 2013

    Results information
    Results version number
    		 v1(current)
    This version publication date
    18 Feb 2016
    First version publication date
    06 Aug 2015
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    OBI-1-301
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01178294
    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, 91362
    Public contact
    Clinical Trial Registries and Results Disclosure, Baxalta US Inc., ClinicalTrialsDisclosure@baxalta.com
    Scientific contact
    Clinical Trial Registries and Results Disclosure, Baxalta US Inc., ClinicalTrialsDisclosure@baxalta.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    27 May 2014
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    15 Jul 2013
    Global end of trial reached?
    Yes
    Global end of trial date
    09 Oct 2013
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of Studies OBI-1-301 and extended protocol OBI-1-301a were to evaluate the efficacy of OBI-1 for the treatment of serious bleeding events in subjects with acquired hemophilia with autoimmune inhibitory antibodies to human factor VIII. The primary efficacy outcome was the proportion of serious bleeding events responsive to OBI-1 therapy at 24 hours after the initiation of treatment determined using a well-defined, ordinal scale (effective - partially effective - poorly effective - not effective).
    Protection of trial subjects
    This study was conducted in accordance with the clinical protocol, the International Conference on Harmonization Guideline for Good Clinical Practice E6 (ICH GCP, April 1996), Title 21 of the US Code of Federal Regulations (US CFR), the European Clinical Trial Directive (2001/20/EC and 2005/28/EC), and applicable national and local regulatory requirements.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    10 Nov 2010
    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
    Canada: 5
    Country: Number of subjects enrolled
    United States: 16
    Country: Number of subjects enrolled
    United Kingdom: 4
    Country: Number of subjects enrolled
    India: 4
    Worldwide total number of subjects
    29
    EEA total number of subjects
    4
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    10
    From 65 to 84 years
    16
    85 years and over
    3

    Subject disposition

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    Recruitment
    Recruitment details
    		 Enrollment was conducted at 12 clinical sites in 4 countries (USA, Canada, UK, India). Eight sites enrolled subjects under Protocol OBI-1-301 only. Two US sites enrolled subjects under the expanded access protocol OBI-1-301a and subsequently under protocol OBI-1-301. Another 2 US sites enrolled subjects under OBI-1-301a only.

    Pre-assignment
    Screening details
    		 -

    Pre-assignment period milestones
    Number of subjects started
    		 29
    Number of subjects completed
    		 29

    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
    		 Treatment of serious bleeding episodes
    Arm description
    		 Initial treatment with OBI-1 at dose of 200 U/kg, additional doses at the discretion of the investigator based on FVIII activity level and clinical assessment of response to treatment (upper limit: 400 U/kg every 2 hours)
    Arm type
    		 Experimental

    Investigational medicinal product name
    OBI-1
    Investigational medicinal product code
    Other name
    Obizur
    Pharmaceutical forms
    Powder and solution for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Initial dose: 200 U/kg - additional doses at the discretion of the investigator based on FVIII activity level and clinical assessment of response to treatment (upper limit: 400 U/kg every 2 hours)

    Number of subjects in period 1
    		Treatment of serious bleeding episodes
    Started
    29
    Completed
    18
    Not completed
    11
         Adverse event, serious fatal
    1
         Adverse event, non-fatal
    3
         Lost to follow-up
    3
         Death, OBI-1 inhibitors, subject terminal
    3
         Lack of efficacy
    1

    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
    		 29 29
    Age categorical
    Units: Subjects
        85 years and over
    		 3 3
        From 65-84 years
    		 16 16
        Adults (18-64 years)
    		 10 10
        Adolescents (12-17 years)
    		 0 0
        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)
    		 69.8 ( 13.28 ) -
    Gender categorical
    Units:
        Female
    		 10 10
        Male
    		 19 19
    Subject analysis sets

    Subject analysis set title
    Intent to Treat Population
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Comprises subjects with initial serious bleeding episodes who were dosed and fro whom any post-screening data are available.

    Subject analysis set title
    Pharmacokinetic Population
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    Consists of all subjects in the ITT population with available PK data

    Subject analysis set title
    Safety Population
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Comprises all subjects who received one or more doses of investigational product.

    Subject analysis sets values
    		 Intent to Treat Population Pharmacokinetic Population Safety Population
    Number of subjects
    29
    5
    29
    Age categorical
    Units: Subjects
        85 years and over
    3
    1
    3
        From 65-84 years
    16
    1
    16
        Adults (18-64 years)
    10
    3
    10
        Adolescents (12-17 years)
    0
    0
    0
        Children (2-11 years)
    0
    0
    0
        Infants and toddlers (28 days-23 months)
    0
    0
    0
        Newborns (0-27 days)
    0
    0
    0
        Preterm newborn infants (gestational age < 37 wks)
    0
    0
    0
        In utero
    0
    0
    0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    69.8 ( 13.28 )
    68.8 ( )
    69.8 ( 13.28 )
    Gender categorical
    Units:
        Female
    10
    1
    10
        Male
    19
    4
    19

    End points

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    End points reporting groups
    Reporting group title
    Treatment of serious bleeding episodes
    Reporting group description
    		 Initial treatment with OBI-1 at dose of 200 U/kg, additional doses at the discretion of the investigator based on FVIII activity level and clinical assessment of response to treatment (upper limit: 400 U/kg every 2 hours)

    Subject analysis set title
    Intent to Treat Population
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Comprises subjects with initial serious bleeding episodes who were dosed and fro whom any post-screening data are available.

    Subject analysis set title
    Pharmacokinetic Population
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    Consists of all subjects in the ITT population with available PK data

    Subject analysis set title
    Safety Population
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Comprises all subjects who received one or more doses of investigational product.

    Primary: Percentage of Serious Bleeding Episodes Responsive to OBI-1

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    End point title
    		 Percentage of Serious Bleeding Episodes Responsive to OBI-1
    End point description
    The initial serious ("qualifying") bleeding episode for each subject was analyzed for the primary efficacy outcome measure. A 'positive response' is defined as 'effective' (bleeding stopped with clinical control and FVIII levels of 50% or higher ) or 'partially effective' (bleeding reduced with clinical stabilization and FVIII levels of 20% or higher) control of bleeding, as determined by the investigator using a 4-point rating scale (effective - partially effective - poorly effective - not effective). 'Poorly effective' is defined as 'bleeding slightly reduced or unchanged and FVIII levels of less than 50%'. 'Not effective' is defined as 'bleeding worsening and FVIII levels of less than 50%'.
    End point type
    Primary
    End point timeframe
    24 hours after initiation of treatment
    End point values
    		 Treatment of serious bleeding episodes Intent to Treat Population
    Number of subjects analysed
    29
    29
    Units: Percentage of serious bleeding episodes
        arithmetic mean (confidence interval 100%)
    100 (88.1 to 100)
    100 (88.1 to 100)
    Statistical analysis title
    		 Statistical significance
    Statistical analysis description
    Summary statistics for the percentage of participants with serious bleeding episodes responsive at 24 hours after the initiation of treatment are presented, along with the 95% confidence interval (two-sided 95% Clopper-Pearson confidence interval).
    Comparison groups
    Treatment of serious bleeding episodes v Intent to Treat Population
    Number of subjects included in analysis
    58
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.001 [1]
    Method
    		 one-sided binomial exact test
    Confidence interval
    Notes
    [1] - The p-value was determined from an exact approach because of the relatively small sample size.

    Secondary: Overall Percentage of Serious Bleeding Episodes Successfully Controlled With OBI-1 Therapy, as Assessed by the Investigator

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    End point title
    		 Overall Percentage of Serious Bleeding Episodes Successfully Controlled With OBI-1 Therapy, as Assessed by the Investigator
    End point description
    Treatment success was defined as control of qualifying bleeding episode at the time of final treatment dosing. A serious bleeding episode was considered 'successfully controlled' if the investigator had checked 'completed OBI-1 therapy as treatment success' on the eCRF.
    End point type
    Secondary
    End point timeframe
    At the time of final treatment dosing (varied from participant to participant depending on bleeding episodes)
    End point values
    		 Treatment of serious bleeding episodes Intent to Treat Population
    Number of subjects analysed
    29
    29
    Units: Percentage of serious bleeding episodes
        number (confidence interval 86.2%)
    86.2 (68.3 to 96.1)
    86.2 (68.3 to 96.1)
    No statistical analyses for this end point

    Secondary: Percentage of Serious Bleeding Episodes Responsive to OBI-1 Therapy at 8 Hours After the Initiation of Therapy, as Assessed by the Investigator

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    End point title
    		 Percentage of Serious Bleeding Episodes Responsive to OBI-1 Therapy at 8 Hours After the Initiation of Therapy, as Assessed by the Investigator
    End point description
    A 'positive response' is defined as 'effective' (bleeding stopped with clinical control and FVIII levels of 50% or higher ) or 'partially effective' (bleeding reduced with clinical stabilization and FVIII levels of 20% or higher) control of bleeding, as determined by the investigator using a 4-point rating scale (effective - partially effective - poorly effective - not effective). 'Poorly effective' is defined as 'bleeding slightly reduced or unchanged and FVIII levels of less than 50%'. 'Not effective' is defined as 'bleeding worsening and FVIII levels of less than 50%'. Please note that 21 subjects of the ITT population (n=29) had responses available at 8 hours after initial infusion of OBI-1.
    End point type
    Secondary
    End point timeframe
    8 hours after initiation of therapy
    End point values
    		 Treatment of serious bleeding episodes Intent to Treat Population
    Number of subjects analysed
    21
    21
    Units: Percentage
        number (confidence interval 95.2%)
    95.2 (76.2 to 99.9)
    95.2 (76.2 to 99.9)
    No statistical analyses for this end point

    Secondary: Percentage of Serious Bleeding Episodes Responsive to OBI-1 Therapy at 16 Hours After the Initiation of Therapy, as Assessed by the Investigator

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    End point title
    		 Percentage of Serious Bleeding Episodes Responsive to OBI-1 Therapy at 16 Hours After the Initiation of Therapy, as Assessed by the Investigator
    End point description
    A 'positive response' is defined as 'effective' (bleeding stopped with clinical control and FVIII levels of 50% or higher ) or 'partially effective' (bleeding reduced with clinical stabilization and FVIII levels of 20% or higher) control of bleeding, as determined by the investigator using a 4-point rating scale (effective - partially effective - poorly effective - not effective). 'Poorly effective' is defined as 'bleeding slightly reduced or unchanged and FVIII levels of less than 50%'. 'Not effective' is defined as 'bleeding worsening and FVIII levels of less than 50%'. Please note that 19 subjects of the ITT population (n=29) had responses available at 16 hours after initial infusion of OBI-1.
    End point type
    Secondary
    End point timeframe
    16 hours after initiation of therapy
    End point values
    		 Treatment of serious bleeding episodes Intent to Treat Population
    Number of subjects analysed
    19
    19
    Units: Percentage of serious bleeding episodes
        number (confidence interval 100%)
    100 (82.4 to 100)
    100 (82.4 to 100)
    No statistical analyses for this end point

    Secondary: Frequency of Infusions of OBI-1 Required to Successfully Control Qualifying Bleeding Episodes

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    End point title
    		 Frequency of Infusions of OBI-1 Required to Successfully Control Qualifying Bleeding Episodes
    End point description
    'Frequency of infusions' was calculated as the 'average number of infusions per day'. 'Qualifying bleeding episode' was defined as the 'initial, serious bleeding episode'. The analysis was performed in 25 of 29 participants in the ITT population whose 'qualifying' bleeding episode was controlled successfully.
    End point type
    Secondary
    End point timeframe
    Time of successful control of qualifying bleeding episode (varied from subject to subject)
    End point values
    		 Treatment of serious bleeding episodes Intent to Treat Population
    Number of subjects analysed
    25
    25
    Units: Infusions per day
        arithmetic mean (standard deviation)
    2.1 ( 1.109 )
    2.1 ( 1.109 )
    No statistical analyses for this end point

    Secondary: Total Dose of OBI-1 Required to Successfully Control 'Qualifying' Bleeding Episodes

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    End point title
    		 Total Dose of OBI-1 Required to Successfully Control 'Qualifying' Bleeding Episodes
    End point description
    'Qualifying bleeding episode' was defined as the 'initial, serious bleeding episode'.
    End point type
    Secondary
    End point timeframe
    Time of successful control of qualifying bleeding episode (varied from subject to subject)
    End point values
    		 Treatment of serious bleeding episodes Intent to Treat Population
    Number of subjects analysed
    25
    25
    Units: U/kg
        arithmetic mean (standard deviation)
    2683.2 ( 2928.61 )
    2683.2 ( 2928.61 )
    No statistical analyses for this end point

    Secondary: Total Number of Infusions of OBI-1 Required to Successfully Control 'Qualifying' Bleeding Episodes

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    End point title
    		 Total Number of Infusions of OBI-1 Required to Successfully Control 'Qualifying' Bleeding Episodes
    End point description
    'Qualifying bleeding episode' was defined as the 'initial, serious bleeding episode'. A serious bleeding episode was considered 'successfully controlled' if the investigator had checked 'completed OBI-1 therapy as treatment success' on the eCRF.
    End point type
    Secondary
    End point timeframe
    Time of successful control of qualifying bleeding episode (varied from subject to subject)
    End point values
    		 Treatment of serious bleeding episodes Intent to Treat Population
    Number of subjects analysed
    25
    25
    Units: Infusions per subject
        arithmetic mean (standard deviation)
    15.4 ( 12.64 )
    15.4 ( 12.64 )
    No statistical analyses for this end point

    Secondary: Correlation Between Response to OBI-1 Therapy at 8 Hours and Eventual Control of Serious Bleeding Episodes

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    End point title
    		 Correlation Between Response to OBI-1 Therapy at 8 Hours and Eventual Control of Serious Bleeding Episodes
    End point description
    It was assessed how many of the subjects who had a positive response at 8 hours after initial infusion of OBI-1 had their qualifying bleeding event eventually controlled. Of 21 subjects in the ITT population (n=29) with responses available at 8 hours after initial infusion of OBI-1, 20 had a positive response.
    End point type
    Secondary
    End point timeframe
    Time of successful control of qualifying bleeding episode (varied from subject to subject)
    End point values
    		 Treatment of serious bleeding episodes Intent to Treat Population
    Number of subjects analysed
    21
    21
    Units: subjects with eventual bleed control
        Response at 8 hours (n=21)
    17
    17
        Positive response at 8 hours (n=20)
    17
    17
    No statistical analyses for this end point

    Secondary: Correlation Between Response to OBI-1 Therapy at 16 Hours and Eventual Control of Serious Bleeding Episodes

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    End point title
    		 Correlation Between Response to OBI-1 Therapy at 16 Hours and Eventual Control of Serious Bleeding Episodes
    End point description
    It was assessed how many of the subjects who had a positive response at 16 hours after initial infusion of OBI-1 had their qualifying bleeding event eventually controlled. All 19 subjects in the ITT population (n=29) with responses available at 16 hours after initial infusion of OBI-1 had a positive response.
    End point type
    Secondary
    End point timeframe
    Time of successful control of qualifying bleeding episode (varied from subject to subject)
    End point values
    		 Treatment of serious bleeding episodes Intent to Treat Population
    Number of subjects analysed
    19
    19
    Units: subjects with eventual bleed control
        Response at 16 hours (n=19)
    17
    17
        Positive response at 16 hours (n=19)
    17
    17
    No statistical analyses for this end point

    Secondary: Correlation Between Response to OBI-1 Therapy at 24 Hours and Eventual Control of Serious Bleeding Episodes

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    End point title
    		 Correlation Between Response to OBI-1 Therapy at 24 Hours and Eventual Control of Serious Bleeding Episodes
    End point description
    It was assessed how many of the subjects who had a positive response at 24 hours after initial infusion of OBI-1 had their qualifying bleeding event eventually controlled. Of 29 subjects in the ITT population (n=29) with responses available at 24 hours after initial infusion of OBI-1, 25 had a positive response.
    End point type
    Secondary
    End point timeframe
    Time of successful control of qualifying bleeding episode (varied from subject to subject)
    End point values
    		 Treatment of serious bleeding episodes Intent to Treat Population
    Number of subjects analysed
    29
    29
    Units: subjects
        Response at 24 hours (n=29)
    25
    25
        Positive response at 24 hours (n=25)
    25
    25
    No statistical analyses for this end point

    Secondary: Pharmacokinetic (PK) Analysis: Plasma clearance

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    End point title
    		 Pharmacokinetic (PK) Analysis: Plasma clearance
    End point description
    Participation in the PK sampling was optional. PK parameters obtained from the non-bleeding state were summarized with descriptive statistics.
    End point type
    Secondary
    End point timeframe
    Pre-infusion: 15-20 minutes, Post-infusion: 1, 3, 6, 12, 18, 24 hours
    End point values
    		 Pharmacokinetic Population
    Number of subjects analysed
    5
    Units: U/(percent activity*hours)
    arithmetic mean (standard deviation)
        Chromogenic FVIII activity assay
    11.8 ( 13.44 )
        One-stage FVIII activity assay
    18.07 ( 21.78 )
    No statistical analyses for this end point

    Secondary: PK Analysis: Volume of distribution at steady state

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    End point title
    		 PK Analysis: Volume of distribution at steady state
    End point description
    Participation in the PK sampling was optional. PK parameters obtained from the non-bleeding state were summarized with descriptive statistics.
    End point type
    Secondary
    End point timeframe
    Pre-infusion: 15-20 minutes, Post-infusion: 1, 3, 6, 12, 18, 24 hours
    End point values
    		 Pharmacokinetic Population
    Number of subjects analysed
    5
    Units: U/percent activity
    arithmetic mean (standard deviation)
        Chromogenic FVIII activity assay
    53.8 ( 52.9 )
        One-stage FVIII activity assay
    65.1 ( 45.1 )
    No statistical analyses for this end point

    Secondary: PK Analysis: Area Under the concentration-time curve (AUC) from time 0 to the last measurable concentration

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    End point title
    		 PK Analysis: Area Under the concentration-time curve (AUC) from time 0 to the last measurable concentration
    End point description
    Participation in the PK sampling was optional. PK parameters obtained from the non-bleeding state were summarized with descriptive statistics. AUC was calculated as area under the percent activity-time curve.
    End point type
    Secondary
    End point timeframe
    Pre-infusion: 15-20 minutes, Post-infusion: 1, 3, 6, 12, 18, 24 hours
    End point values
    		 Pharmacokinetic Population
    Number of subjects analysed
    5
    Units: percent activity*hours
    arithmetic mean (standard deviation)
        Chromogenic FVIII activity assay
    599 ( 459 )
        One-stage FVIII activity assay
    423 ( 340 )
    No statistical analyses for this end point

    Secondary: PK Analysis: Terminal half-life

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    End point title
    		 PK Analysis: Terminal half-life
    End point description
    Participation in the PK sampling was optional. PK parameters obtained from the non-bleeding state were summarized with descriptive statistics. Half-life was calculated as the time it took to reduce percent activity by half.
    End point type
    Secondary
    End point timeframe
    Pre-infusion: 15-20 minutes, Post-infusion: 1, 3, 6, 12, 18, 24 hours
    End point values
    		 Pharmacokinetic Population
    Number of subjects analysed
    5
    Units: hours
    arithmetic mean (standard deviation)
        Chromogenic FVIII activity assay
    3.3 ( 0.4 )
        One-stage FVIII activity assay
    3.5 ( 1 )
    No statistical analyses for this end point

    Secondary: Number of subjects who developed de novo anti-OBI-1 antibody titers

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    End point title
    		 Number of subjects who developed de novo anti-OBI-1 antibody titers
    End point description
    Of 28 eligible subjects with acquired hemophilia A and autoimmune inhibitors to hFVIII in the ITT population (n=29), 18 had no detectable anti-porcine FVIII inhibitor titers at baseline (<0.6 BU) and 10 had detectable anti-porcine FVIII antibody titers at baseline (>=0.6 BU).
    End point type
    Secondary
    End point timeframe
    Through 90 days ± 7 days following final OBI-1 dose
    End point values
    		 Treatment of serious bleeding episodes Intent to Treat Population
    Number of subjects analysed
    28
    28
    Units: subjects
    5
    5
    No statistical analyses for this end point

    Secondary: Number of subjects who developed an anti-host cell protein baby hamster kidney (BHK) antibody titer

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    End point title
    		 Number of subjects who developed an anti-host cell protein baby hamster kidney (BHK) antibody titer
    End point description
    21 subjects in the ITT population (n=29) had baseline and follow-up test results available.
    End point type
    Secondary
    End point timeframe
    Through 90 days ± 7 days following final OBI-1 dose
    End point values
    		 Treatment of serious bleeding episodes Intent to Treat Population
    Number of subjects analysed
    21
    21
    Units: subjects
    0
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Through 90 days ± 7 days following final OBI-1 dose
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    13.1
    Reporting groups
    Reporting group title
    Safety Analysis Population
    Reporting group description
    		 Comprises all subjects who received one or more doses of investigational product (OBI-1).

    Serious adverse events
    		 Safety Analysis Population
    Total subjects affected by serious adverse events
         subjects affected / exposed
    13 / 29 (44.83%)
         number of deaths (all causes)
    7
         number of deaths resulting from adverse events
    0
    Injury, poisoning and procedural complications
    Tracheostomy malfunction
         subjects affected / exposed
    1 / 29 (3.45%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Fall
         subjects affected / exposed
    1 / 29 (3.45%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Vascular pseudoaneurysm
         subjects affected / exposed
    1 / 29 (3.45%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Vascular disorders
    Hematoma
         subjects affected / exposed
    1 / 29 (3.45%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    1 / 29 (3.45%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorders
    Brain edema
         subjects affected / exposed
    1 / 29 (3.45%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Dizziness
         subjects affected / exposed
    1 / 29 (3.45%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Grand mal convulsion
         subjects affected / exposed
    1 / 29 (3.45%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Transient ischemic attack
         subjects affected / exposed
    1 / 29 (3.45%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Intracranial hemorrhage
         subjects affected / exposed
    2 / 29 (6.90%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 2
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 29 (3.45%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Immune system disorders
    Anaphylactic reaction
         subjects affected / exposed
    1 / 29 (3.45%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Esophagitis
         subjects affected / exposed
    1 / 29 (3.45%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Intestinal hemorrhage
         subjects affected / exposed
    1 / 29 (3.45%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Gastrointestinal hemorrhage
         subjects affected / exposed
    1 / 29 (3.45%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hepatobiliary disorders
    Cholangitis
         subjects affected / exposed
    1 / 29 (3.45%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Respiratory, thoracic and mediastinal disorders
    Respiratory failure
         subjects affected / exposed
    1 / 29 (3.45%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Renal and urinary disorders
    Renal failure
         subjects affected / exposed
    1 / 29 (3.45%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 29 (3.45%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Hemarthrosis
         subjects affected / exposed
    1 / 29 (3.45%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Joint swelling
         subjects affected / exposed
    1 / 29 (3.45%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    3 / 29 (10.34%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Systemic mycosis
         subjects affected / exposed
    1 / 29 (3.45%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Urinary tract infection
         subjects affected / exposed
    1 / 29 (3.45%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Sepsis
         subjects affected / exposed
    2 / 29 (6.90%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 2
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Safety Analysis Population
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    27 / 29 (93.10%)
    Investigations
    Antibody test positive
    Additional description: Positive OBI-1 (anti-porcine FVIII) inhibitor test result
         subjects affected / exposed
    2 / 29 (6.90%)
         occurrences all number
    2
    Troponin I increased
         subjects affected / exposed
    2 / 29 (6.90%)
         occurrences all number
    2
    Vascular disorders
    Hypertension
         subjects affected / exposed
    3 / 29 (10.34%)
         occurrences all number
    4
    Hypotension
         subjects affected / exposed
    2 / 29 (6.90%)
         occurrences all number
    2
    Cardiac disorders
    Cardiac failure congestive
         subjects affected / exposed
    2 / 29 (6.90%)
         occurrences all number
    2
    Blood and lymphatic system disorders
    Anemia
         subjects affected / exposed
    6 / 29 (20.69%)
         occurrences all number
    6
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    2 / 29 (6.90%)
         occurrences all number
    2
    Fatigue
         subjects affected / exposed
    2 / 29 (6.90%)
         occurrences all number
    2
    Peripheral edema
         subjects affected / exposed
    6 / 29 (20.69%)
         occurrences all number
    7
    Pyrexia
         subjects affected / exposed
    3 / 29 (10.34%)
         occurrences all number
    5
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    2 / 29 (6.90%)
         occurrences all number
    3
    Abdominal pain upper
         subjects affected / exposed
    2 / 29 (6.90%)
         occurrences all number
    3
    Constipation
         subjects affected / exposed
    12 / 29 (41.38%)
         occurrences all number
    12
    Diarrhea
         subjects affected / exposed
    7 / 29 (24.14%)
         occurrences all number
    7
    Mouth ulceration
         subjects affected / exposed
    2 / 29 (6.90%)
         occurrences all number
    2
    Nausea
         subjects affected / exposed
    4 / 29 (13.79%)
         occurrences all number
    5
    Vomiting
         subjects affected / exposed
    2 / 29 (6.90%)
         occurrences all number
    2
    Respiratory, thoracic and mediastinal disorders
    Wheezing
         subjects affected / exposed
    2 / 29 (6.90%)
         occurrences all number
    3
    Skin and subcutaneous tissue disorders
    Ecchymosis
         subjects affected / exposed
    3 / 29 (10.34%)
         occurrences all number
    3
    Pruritus
         subjects affected / exposed
    2 / 29 (6.90%)
         occurrences all number
    2
    Psychiatric disorders
    Depression
         subjects affected / exposed
    2 / 29 (6.90%)
         occurrences all number
    2
    Insomnia
         subjects affected / exposed
    4 / 29 (13.79%)
         occurrences all number
    6
    Musculoskeletal and connective tissue disorders
    Muscle hemorrhage
         subjects affected / exposed
    2 / 29 (6.90%)
         occurrences all number
    3
    Pain in extremity
         subjects affected / exposed
    2 / 29 (6.90%)
         occurrences all number
    2
    Infections and infestations
    Bacteriuria
         subjects affected / exposed
    2 / 29 (6.90%)
         occurrences all number
    2
    Bacteremia
         subjects affected / exposed
    2 / 29 (6.90%)
         occurrences all number
    2
    Candidiasis
         subjects affected / exposed
    3 / 29 (10.34%)
         occurrences all number
    3
    Oral candidiasis
         subjects affected / exposed
    3 / 29 (10.34%)
         occurrences all number
    3
    Sepsis
         subjects affected / exposed
    3 / 29 (10.34%)
         occurrences all number
    3
    Urinary tract infection
         subjects affected / exposed
    2 / 29 (6.90%)
         occurrences all number
    2
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    3 / 29 (10.34%)
         occurrences all number
    3
    Hypoglycemia
         subjects affected / exposed
    2 / 29 (6.90%)
         occurrences all number
    2
    Hypokalemia
         subjects affected / exposed
    7 / 29 (24.14%)
         occurrences all number
    11
    Hypomagnesemia
         subjects affected / exposed
    2 / 29 (6.90%)
         occurrences all number
    2
    Hypophosphatemia
         subjects affected / exposed
    2 / 29 (6.90%)
         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
    14 Jul 2010
    - PK analyses modified to indicate that PK would be performed in both the non-bleeding and bleeding states (However, PK in bleeding state eventually not performed due to lack of acceptable data) - Clarification made why serious subsequent bleeds would not be considered new qualifying bleeds - Subjects who have received bypassing agents (eg, rFVIIa) or blood products would not be automatically excluded - New maximum target blood level of FVIII for OBI-1 provided - Inclusion and exclusion criteria were modified to clarify the required life expectancy before the qualifying bleeding event, the limit for prothrombin time (PT), and the required wash-out period for previous bypass therapy
    25 Jan 2011
    - Schedule of assessments was modified beyond the 24-hour primary efficacy assessment to be less demanding for subjects who do not require frequent dosing, without changing the primary endpoint - In response to an IRB request, language was added to specify that investigators are not required to collect information from pregnant subjects after study end but are required to provide counseling regarding risks to all pregnant subjects
    12 Feb 2012
    The following changes were made based on comments received from health authorities in the United Kingdom, India and from the Voluntary Harmonized Procedure countries (France, Germany, Italy, Hungary and Sweden) during their assessment of the clinical trial application: - Changes were made to indicate that no subject could be included in the primary endpoint analysis for more than one bleeding event and that all subsequent bleeding events after the initial qualifying bleed would only be included in the safety analysis. - Inclusion criteria were added to indicate that subjects of reproductive age must use acceptable methods of contraception and if female, undergo pregnancy testing as part of the screening process. - The scale used for the primary endpoint was changed from a three-point to a four-point ordinal scale with the inclusion of the assessment of “poorly controlled” bleeding. - The minimum number of subjects to be included in the study was changed from 20 to 28. The following additional change was made in response to a request from the DSMB: - Assessment of complete blood count (CBC) with platelets was added to the schedule of assessments.
    13 May 2012
    The wording of one inclusion criterion and two exclusion criteria was changed slightly in response to comments received from the French central ethics committee.
    03 Jul 2012
    Wording of one inclusion criterion changed to allow for inclusion of a subject if consent is given by the subject, a trusted person or a person who is legally authorized to sign on behalf of the subject
    17 Apr 2013
    The sponsor was changed from Inspiration Biopharmaceuticals, Inc. to Baxter.

    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.
    Due to the low number of subjects available for evaluation, statistical tests could only be performed for the primary outcome measure. The results of all other outcome measures are descriptive.
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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