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    Clinical Trial Results:
    Pharmacokinetic Comparison of Advate (rAHF-PFM) With Recombinate (rAHF) in Patients With Severe Hemophilia A: A Phase 4, Prospective, Randomized, Controlled, Cross-over, Single Center Study

    Due to the EudraCT – Results system being out of service between 31 July 2015 and 12 January 2016, these results have been published in compliance with revised timelines.
    Summary
    EudraCT number
    		 2007-004834-18
    Trial protocol
    		 DE  
    Global end of trial date
    18 Feb 2009

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

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    060601
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00666406
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Baxalta US Inc.
    Sponsor organisation address
    One Baxter Way, Westlake Village, United States, CA 91362
    Public contact
    Clinical Trial Registries and Results Disclosure, Baxalta US Inc., ClinicalTrialsDisclosure@baxalta.com
    Scientific contact
    Clinical Trial Registries and Results Disclosure, Baxalta US Inc., ClinicalTrialsDisclosure@baxalta.com
    Sponsor organisation name
    Baxalta Innovations GmbH
    Sponsor organisation address
    Industriestrasse 67, Vienna, Austria, 1221
    Public contact
    Clinical Trial Registries and Results Disclosure, Baxalta Innovations GmbH, ClinicalTrialsDisclosure@baxalta.com
    Scientific contact
    Clinical Trial Registries and Results Disclosure, Baxalta Innovations GmbH, ClinicalTrialsDisclosure@baxalta.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    23 Mar 2010
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    18 Feb 2009
    Global end of trial reached?
    Yes
    Global end of trial date
    18 Feb 2009
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objective of this study was to further evaluate observations of decreased efficacy in subjects who had been switched to Advate (rAHF-PFM) from Recombinate (rAHF) by comparing the pharmacokinetic (PK) parameters of the two products in PTPs with severe hemophilia A (factor VIII level < 1%) in whom decreased efficacy with Advate (rAHF-PFM) compared to Recombinate (rAHF) had been observed clinically. Speicifically, the following PK parameters were compared: Area under the plasma concentration vs. time curve from 0 to 48 hours (AUC 0-48h), total area under the plasma concentration vs. time curve (AUC 0-inf), plasma half-life, maximum concentration (Cmax), minimal time to reach maximum concentration (Tmax), incremental recovery (IR), clearance (Cl), mean residence time (MRT), volume of distribution at steady state (Vss).
    Protection of trial subjects
    This study was conducted in accordance with the clinical protocol, the International Conference on Harmonisation Guideline for Good Clinical Practice E6 (ICH GCP, April 1996), Title 21 of the US Code of Federal Regulations (US CFR), the European Clinical Trial Directive (2001/20/EC and 2005/28/EC), and applicable national and local regulatory requirements.
    Background therapy
    		 -
    Evidence for comparator
    		 The purpose of this study was to compare the pharmacokinetic parameters of Advate (rAHF-PFM) versus Recombinate (rAHF) in previously treated patients (PTPs) with severe hemophilia A (factor VIII level < 1%) in whom decreased efficacy with Advate (rAHF-PFM) compared to Recombinate (rAHF) was observed clinically after they had been switched to Advate (rAHF-PFM) from Recombinate (rAHF).
    Actual start date of recruitment
    31 Mar 2008
    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
    Germany: 9
    Worldwide total number of subjects
    9
    EEA total number of subjects
    9
    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)
    8
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 9 unique participants were enrolled and treated at a single study site in Germany.

    Pre-assignment
    Screening details
    		 Participants required a factor VIII (FVIII) washout period ≥48 hours before receiving any pharmacokinetic (PK) infusions and could not be actively bleeding at the time of the infusion.

    Pre-assignment period milestones
    Number of subjects started
    		 9
    Number of subjects completed
    		 9

    Period 1
    Period 1 title
    PK Infusions (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 PK Infusion with Advate rAHF-PFM and then Recombinate rAHF
    Arm description
    		 All 9 treated subjects received a PK infusion with ADVATE and a PK infusion with Recombinate. The order of the PK infusions was determined by randomization. Infusion 2 was to be administered 7-28 days after first PK infusion.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Advate
    Investigational medicinal product code
    Other name
    rAHF-PFM (Antihemophilic Factor (Recombinant) – Plasma/Albumin Free Method)
    Pharmaceutical forms
    Powder and solvent for solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Dose of 50 +/-5 IU/kg for PK infusion

    Investigational medicinal product name
    Recombinate
    Investigational medicinal product code
    Other name
    rAHF (Antihemophilic Factor (Recombinant))
    Pharmaceutical forms
    Powder and solution for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Dose of 50 +/-5 IU/kg for PK infusion

    Arm title
    		 PK Infusion with Recombinate rAHF and then Advate rAHF-PFM
    Arm description
    		 All 9 treated subjects received a PK infusion with ADVATE and a PK infusion with Recombinate. The order of the PK infusions was determined by randomization. Infusion 2 was to be administered 7-28 days after first PK infusion.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Advate
    Investigational medicinal product code
    Other name
    rAHF-PFM (Antihemophilic Factor (Recombinant) – Plasma/Albumin Free Method)
    Pharmaceutical forms
    Powder and solvent for solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Dose of 50 +/-5 IU/kg for PK infusion

    Investigational medicinal product name
    Recombinate
    Investigational medicinal product code
    Other name
    rAHF (Antihemophilic Factor (Recombinant))
    Pharmaceutical forms
    Powder and solution for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Dose of 50 +/-5 IU/kg for PK infusion

    Number of subjects in period 1
    		PK Infusion with Advate rAHF-PFM and then Recombinate rAHF PK Infusion with Recombinate rAHF and then Advate rAHF-PFM
    Started
    6
    3
    Completed
    6
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    PK Infusion with Advate rAHF-PFM and then Recombinate rAHF
    Reporting group description
    		 All 9 treated subjects received a PK infusion with ADVATE and a PK infusion with Recombinate. The order of the PK infusions was determined by randomization. Infusion 2 was to be administered 7-28 days after first PK infusion.

    Reporting group title
    PK Infusion with Recombinate rAHF and then Advate rAHF-PFM
    Reporting group description
    		 All 9 treated subjects received a PK infusion with ADVATE and a PK infusion with Recombinate. The order of the PK infusions was determined by randomization. Infusion 2 was to be administered 7-28 days after first PK infusion.

    Reporting group values
    		 PK Infusion with Advate rAHF-PFM and then Recombinate rAHF PK Infusion with Recombinate rAHF and then Advate rAHF-PFM Total
    Number of subjects
    		 6 3 9
    Age categorical
    Units: Subjects
        85 years and over
    		 0 0 0
        From 65-84 years
    		 0 0 0
        Adults (18-64 years)
    		 5 3 8
        Adolescents (12-17 years)
    		 1 0 1
        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
    Age continuous description
    Units: years
        arithmetic mean (standard deviation)
    		 0 ( 0 ) 0 ( 0 ) -
    Gender categorical
    Gender categorical description
    Units: Subjects
        Female
    		 0 0 0
        Male
    		 6 3 9
    Region of Enrollment
    Units: Subjects
        Germany
    		 6 3 9
    Subject analysis sets

    Subject analysis set title
    Advate rAHF-PFM
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    PK infusion with ADVATE.

    Subject analysis set title
    Recombinate rAHF
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    PK infusion with Recombinate.

    Subject analysis sets values
    		 Advate rAHF-PFM Recombinate rAHF
    Number of subjects
    9
    9
    Age categorical
    Units: Subjects
        85 years and over
    0
    0
        From 65-84 years
    0
    0
        Adults (18-64 years)
    8
    8
        Adolescents (12-17 years)
    1
    1
        Children (2-11 years)
    0
    0
        Infants and toddlers (28 days-23 months)
    0
    0
        Newborns (0-27 days)
    0
    0
        Preterm newborn infants (gestational age < 37 wks)
    0
    0
        In utero
    0
    0
    Age continuous
    Age continuous description
    Units: years
        arithmetic mean (standard deviation)
    37.3 ( 14.9 )
    37.3 ( 14.9 )
    Gender categorical
    Gender categorical description
    Units: Subjects
        Female
    0
    0
        Male
    9
    9
    Region of Enrollment
    Units: Subjects
        Germany
    9
    9

    End points

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    End points reporting groups
    Reporting group title
    PK Infusion with Advate rAHF-PFM and then Recombinate rAHF
    Reporting group description
    		 All 9 treated subjects received a PK infusion with ADVATE and a PK infusion with Recombinate. The order of the PK infusions was determined by randomization. Infusion 2 was to be administered 7-28 days after first PK infusion.

    Reporting group title
    PK Infusion with Recombinate rAHF and then Advate rAHF-PFM
    Reporting group description
    		 All 9 treated subjects received a PK infusion with ADVATE and a PK infusion with Recombinate. The order of the PK infusions was determined by randomization. Infusion 2 was to be administered 7-28 days after first PK infusion.

    Subject analysis set title
    Advate rAHF-PFM
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    PK infusion with ADVATE.

    Subject analysis set title
    Recombinate rAHF
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    PK infusion with Recombinate.

    Primary: Area under the plasma concentration versus time curve (AUC) from 0 to 48 hours. One-Stage Activated Partial Thromboplastin Time (aPTT) -Based Assay Performed at Central Laboratory (Medical University Vienna)

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    End point title
    		 Area under the plasma concentration versus time curve (AUC) from 0 to 48 hours. One-Stage Activated Partial Thromboplastin Time (aPTT) -Based Assay Performed at Central Laboratory (Medical University Vienna)
    End point description
    AUC estimated by linear trapezoidal method. The linear trapezoidal method is a numerical method used to approximate the area under a curve.
    End point type
    Primary
    End point timeframe
    0-30 minutes before infusion up to 48 hours post-infusion
    End point values
    		 Advate rAHF-PFM Recombinate rAHF
    Number of subjects analysed
    9
    9
    Units: IU*h/dL
        geometric mean (confidence interval 90%)
    1104 (950 to 1328)
    1294 (1149 to 1536)
    Statistical analysis title
    		 Statistical analysis 1
    Comparison groups
    Advate rAHF-PFM v Recombinate rAHF
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Ratio of the geometric means
    Point estimate
    1.173
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 1.089
         upper limit
    		 1.262

    Primary: Area under the plasma concentration versus time curve (AUC) from 0 to 48 hours. Chromogenic Assay Performed at Local Laboratory (i.e., University of Bonn, the study site)

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    End point title
    		 Area under the plasma concentration versus time curve (AUC) from 0 to 48 hours. Chromogenic Assay Performed at Local Laboratory (i.e., University of Bonn, the study site)
    End point description
    AUC estimated by linear trapezoidal method. The linear trapezoidal method is a numerical method used to approximate the area under a curve.
    End point type
    Primary
    End point timeframe
    0-30 minutes before infusion up to 48 hours post-infusion
    End point values
    		 Advate rAHF-PFM Recombinate rAHF
    Number of subjects analysed
    9
    9
    Units: IU*h/dL
        geometric mean (confidence interval 90%)
    1180 (999 to 1497)
    1358 (1146 to 1547)
    Statistical analysis title
    		 Statistical analysis 1
    Comparison groups
    Advate rAHF-PFM v Recombinate rAHF
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Ratio of the geometric means
    Point estimate
    1.139
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 1.043
         upper limit
    		 1.243

    Primary: Area under the plasma concentration versus time curve (AUC) from 0 to 48 hours. FVIII One-Stage Clotting Assay (Bonn Method) Performed at Local Laboratory (i.e., University of Bonn, the study site)

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    End point title
    		 Area under the plasma concentration versus time curve (AUC) from 0 to 48 hours. FVIII One-Stage Clotting Assay (Bonn Method) Performed at Local Laboratory (i.e., University of Bonn, the study site)
    End point description
    AUC estimated by linear trapezoidal method. The linear trapezoidal method is a numerical method used to approximate the area under a curve.
    End point type
    Primary
    End point timeframe
    0-30 minutes before infusion up to 48 hours post-infusion
    End point values
    		 Advate rAHF-PFM Recombinate rAHF
    Number of subjects analysed
    9
    9
    Units: IU*h/dL
        geometric mean (confidence interval 90%)
    833 (697 to 970)
    901 (629 to 1070)
    Statistical analysis title
    		 Statistical analysis 1
    Comparison groups
    Advate rAHF-PFM v Recombinate rAHF
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Ratio of the geometric means
    Point estimate
    1.06
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.866
         upper limit
    		 1.297

    Primary: Area under the plasma concentration versus time curve (AUC) from 0 to 48 hours. FVIII Clotting Assay. Performed at Local Laboratory (i.e., University of Bonn, the study site)

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    End point title
    		 Area under the plasma concentration versus time curve (AUC) from 0 to 48 hours. FVIII Clotting Assay. Performed at Local Laboratory (i.e., University of Bonn, the study site)
    End point description
    AUC estimated by linear trapezoidal method. The linear trapezoidal method is a numerical method used to approximate the area under a curve.
    End point type
    Primary
    End point timeframe
    0-30 minutes before infusion up to 48 hours post-infusion
    End point values
    		 Advate rAHF-PFM Recombinate rAHF
    Number of subjects analysed
    9
    9
    Units: IU*h/dL
        geometric mean (confidence interval 90%)
    1505 (1215 to 1741)
    1664 (1340 to 1911)
    Statistical analysis title
    		 Statistical analysis 1
    Comparison groups
    Advate rAHF-PFM v Recombinate rAHF
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Ratio of the geometric means
    Point estimate
    1.071
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.972
         upper limit
    		 1.179

    Secondary: Area under the plasma concentration versus time curve (AUC) from 0 to Infinity. One-Stage aPTT-Based Assay Performed at Central Laboratory (Medical University Vienna)

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    End point title
    		 Area under the plasma concentration versus time curve (AUC) from 0 to Infinity. One-Stage aPTT-Based Assay Performed at Central Laboratory (Medical University Vienna)
    End point description
    AUC estimated by linear trapezoidal method. The linear trapezoidal method is a numerical method used to approximate the area under a curve. FVIII activity measurement
    End point type
    Secondary
    End point timeframe
    0-30 minutes before infusion up to 48 hours post-infusion
    End point values
    		 Advate rAHF-PFM Recombinate rAHF
    Number of subjects analysed
    9
    9
    Units: IU*h/dL
        geometric mean (confidence interval 90%)
    1190 (1031 to 1360)
    1393 (1232 to 1574)
    Statistical analysis title
    		 Statistical analysis 1
    Comparison groups
    Advate rAHF-PFM v Recombinate rAHF
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Ratio of the geometric means
    Point estimate
    1.171
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 1.099
         upper limit
    		 1.247

    Secondary: Area under the plasma concentration versus time curve (AUC) from 0 to infinity. Chromogenic Assay performed at Local Laboratory (i.e., University of Bonn, the study site)

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    End point title
    		 Area under the plasma concentration versus time curve (AUC) from 0 to infinity. Chromogenic Assay performed at Local Laboratory (i.e., University of Bonn, the study site)
    End point description
    AUC estimated by linear trapezoidal method. The linear trapezoidal method is a numerical method used to approximate the area under a curve.
    End point type
    Secondary
    End point timeframe
    0-30 minutes before infusion up to 48 hours post-infusion
    End point values
    		 Advate rAHF-PFM Recombinate rAHF
    Number of subjects analysed
    9
    9
    Units: IU*h/dL
        geometric mean (confidence interval 90%)
    1282 (1037 to 1626)
    1452 (1137 to 1696)
    Statistical analysis title
    		 Statistical analysis 1
    Comparison groups
    Advate rAHF-PFM v Recombinate rAHF
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Ratio of the geometric means
    Point estimate
    1.135
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 1.092
         upper limit
    		 1.18

    Secondary: Area under the plasma concentration versus time curve (AUC) from 0 to infinity. FVIII One-Stage Clotting Assay (Bonn Method) Performed at Local Laboratory (i.e., University of Bonn, the study site)

    		 Close Top of page
    End point title
    		 Area under the plasma concentration versus time curve (AUC) from 0 to infinity. FVIII One-Stage Clotting Assay (Bonn Method) Performed at Local Laboratory (i.e., University of Bonn, the study site)
    End point description
    AUC estimated by linear trapezoidal method. The linear trapezoidal method is a numerical method used to approximate the area under a curve.
    End point type
    Secondary
    End point timeframe
    0-30 minutes before infusion up to 48 hours post-infusion
    End point values
    		 Advate rAHF-PFM Recombinate rAHF
    Number of subjects analysed
    9
    9
    Units: IU*h/dL
        geometric mean (confidence interval 90%)
    874 (734 to 1031)
    926 (655 to 1152)
    Statistical analysis title
    		 Statistical analysis 1
    Comparison groups
    Advate rAHF-PFM v Recombinate rAHF
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Ratio of the geometric means
    Point estimate
    1.036
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.857
         upper limit
    		 1.253

    Secondary: Area under the plasma concentration versus time curve (AUC) from 0 to infinity. FVIII Clotting Assay. Performed at Local Laboratory (i.e., University of Bonn, the study site)

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    End point title
    		 Area under the plasma concentration versus time curve (AUC) from 0 to infinity. FVIII Clotting Assay. Performed at Local Laboratory (i.e., University of Bonn, the study site)
    End point description
    AUC estimated by linear trapezoidal method. The linear trapezoidal method is a numerical method used to approximate the area under a curve.
    End point type
    Secondary
    End point timeframe
    0-30 minutes before infusion up to 48 hours post-infusion
    End point values
    		 Advate rAHF-PFM Recombinate rAHF
    Number of subjects analysed
    9
    9
    Units: IU*h/dL
        geometric mean (confidence interval 90%)
    1598 (1340 to 1923)
    1731 (1453 to 2162)
    Statistical analysis title
    		 Statistical analysis 1
    Comparison groups
    Advate rAHF-PFM v Recombinate rAHF
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Ratio of the geometric means
    Point estimate
    1.093
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 1.007
         upper limit
    		 1.186

    Secondary: Systemic clearance (Cl). One-Stage aPTT-Based Assay Performed at Central Laboratory (Medical University Vienna)

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    End point title
    		 Systemic clearance (Cl). One-Stage aPTT-Based Assay Performed at Central Laboratory (Medical University Vienna)
    End point description
    Systemic clearance in mL/kg/h will be calculated as the dose in IU/kg divided by the total area under the curve.
    End point type
    Secondary
    End point timeframe
    0-30 minutes before infusion up to 48 hours post-infusion
    End point values
    		 Advate rAHF-PFM Recombinate rAHF
    Number of subjects analysed
    9
    9
    Units: mL/h/kg
        geometric mean (confidence interval 90%)
    4.31 (3.92 to 4.85)
    3.68 (3.41 to 4.19)
    Statistical analysis title
    		 Statistical analysis 1
    Comparison groups
    Advate rAHF-PFM v Recombinate rAHF
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Ratio of the geometric means
    Point estimate
    0.854
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.798
         upper limit
    		 0.913

    Secondary: Systemic clearance (Cl). Chromogenic Assay performed at Local Laboratory (i.e., University of Bonn, the study site)

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    End point title
    		 Systemic clearance (Cl). Chromogenic Assay performed at Local Laboratory (i.e., University of Bonn, the study site)
    End point description
    Systemic clearance in mL/kg/h will be calculated as the dose in IU/kg divided by the total area under the curve.
    End point type
    Secondary
    End point timeframe
    0-30 minutes before infusion up to 48 hours post-infusion
    End point values
    		 Advate rAHF-PFM Recombinate rAHF
    Number of subjects analysed
    9
    9
    Units: mL/h/kg
        geometric mean (confidence interval 90%)
    4 (3.28 to 4.88)
    3.53 (3.03 to 4.43)
    Statistical analysis title
    		 Statistical analysis 1
    Comparison groups
    Advate rAHF-PFM v Recombinate rAHF
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Ratio of the geometric means
    Point estimate
    0.881
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.847
         upper limit
    		 0.916

    Secondary: Systemic clearance (Cl). FVIII One-Stage Clotting Assay (Bonn Method) Performed at Local Laboratory (i.e., University of Bonn, the study site)

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    End point title
    		 Systemic clearance (Cl). FVIII One-Stage Clotting Assay (Bonn Method) Performed at Local Laboratory (i.e., University of Bonn, the study site)
    End point description
    Systemic clearance in mL/kg/h will be calculated as the dose in IU/kg divided by the total area under the curve.
    End point type
    Secondary
    End point timeframe
    0-30 minutes before infusion up to 48 hours post-infusion
    End point values
    		 Advate rAHF-PFM Recombinate rAHF
    Number of subjects analysed
    9
    9
    Units: mL/h/kg
        geometric mean (confidence interval 90%)
    5.87 (4.4 to 7.35)
    5.53 (4.28 to 8.19)
    Statistical analysis title
    		 Statistical analysis 1
    Comparison groups
    Advate rAHF-PFM v Recombinate rAHF
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Ratio of the geometric means
    Point estimate
    0.964
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.799
         upper limit
    		 1.164

    Secondary: Systemic clearance (Cl). FVIII Clotting Assay. Performed at Local Laboratory (i.e., University of Bonn, the study site)

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    End point title
    		 Systemic clearance (Cl). FVIII Clotting Assay. Performed at Local Laboratory (i.e., University of Bonn, the study site)
    End point description
    Systemic clearance in mL/kg/h will be calculated as the dose in IU/kg divided by the total area under the curve.
    End point type
    Secondary
    End point timeframe
    0-30 minutes before infusion up to 48 hours post-infusion
    End point values
    		 Advate rAHF-PFM Recombinate rAHF
    Number of subjects analysed
    9
    9
    Units: mL/h/kg
        geometric mean (confidence interval 90%)
    3.21 (2.63 to 3.85)
    2.96 (2.35 to 3.79)
    Statistical analysis title
    		 Statistical analysis 1
    Comparison groups
    Advate rAHF-PFM v Recombinate rAHF
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Ratio of the geometric means
    Point estimate
    0.915
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.841
         upper limit
    		 0.995

    Secondary: Maximum plasma concentration (C-max). One-Stage aPTT-Based Assay Performed at Central Laboratory (Medical University Vienna)

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    End point title
    		 Maximum plasma concentration (C-max). One-Stage aPTT-Based Assay Performed at Central Laboratory (Medical University Vienna)
    End point description
    C-max will be calculated as the maximum concentration following infusion of either Advate or Recombinate.
    End point type
    Secondary
    End point timeframe
    0-30 minutes before infusion up to 48 hours post-infusion
    End point values
    		 Advate rAHF-PFM Recombinate rAHF
    Number of subjects analysed
    9
    9
    Units: IU/dL
        geometric mean (confidence interval 90%)
    93 (74 to 112)
    108 (91 to 130)
    Statistical analysis title
    		 Statistical analysis 1
    Comparison groups
    Advate rAHF-PFM v Recombinate rAHF
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Ratio of the geometric means
    Point estimate
    1.177
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 1.104
         upper limit
    		 1.256

    Secondary: Maximum Plasma Concentration (C-max). Chromogenic Assay performed at Local Laboratory (i.e., University of Bonn, the study site)

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    End point title
    		 Maximum Plasma Concentration (C-max). Chromogenic Assay performed at Local Laboratory (i.e., University of Bonn, the study site)
    End point description
    C-max will be calculated as the maximum concentration following infusion of either Advate or Recombinate.
    End point type
    Secondary
    End point timeframe
    0-30 minutes before infusion up to 48 hours post-infusion
    End point values
    		 Advate rAHF-PFM Recombinate rAHF
    Number of subjects analysed
    9
    9
    Units: IU/dL
        geometric mean (confidence interval 90%)
    104 (79 to 148)
    119 (104 to 144)
    Statistical analysis title
    		 Statistical analysis 1
    Comparison groups
    Advate rAHF-PFM v Recombinate rAHF
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Ratio of the geometric means
    Point estimate
    1.152
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 1.039
         upper limit
    		 1.277

    Secondary: Maximum Plasma Concentration (C-max). FVIII One-Stage Clotting Assay (Bonn Method) Performed at Local Laboratory (i.e., University of Bonn, the study site)

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    End point title
    		 Maximum Plasma Concentration (C-max). FVIII One-Stage Clotting Assay (Bonn Method) Performed at Local Laboratory (i.e., University of Bonn, the study site)
    End point description
    C-max will be calculated as the maximum concentration following infusion of either Advate or Recombinate.
    End point type
    Secondary
    End point timeframe
    0-30 minutes before infusion up to 48 hours post-infusion
    End point values
    		 Advate rAHF-PFM Recombinate rAHF
    Number of subjects analysed
    9
    9
    Units: IU/dL
        geometric mean (confidence interval 90%)
    78 (66 to 100)
    94 (72 to 149)
    Statistical analysis title
    		 Statistical analysis 1
    Comparison groups
    Advate rAHF-PFM v Recombinate rAHF
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Ratio of the geometric means
    Point estimate
    1.182
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 1.029
         upper limit
    		 1.359

    Secondary: Maximum Plasma Concentration (C-max). FVIII Clotting Assay. Performed at Local Laboratory (i.e., University of Bonn, the study site)

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    End point title
    		 Maximum Plasma Concentration (C-max). FVIII Clotting Assay. Performed at Local Laboratory (i.e., University of Bonn, the study site)
    End point description
    C-max will be calculated as the maximum concentration following infusion of either Advate or Recombinate.
    End point type
    Secondary
    End point timeframe
    0-30 minutes before infusion up to 48 hours post-infusion
    End point values
    		 Advate rAHF-PFM Recombinate rAHF
    Number of subjects analysed
    9
    9
    Units: IU/dL
        geometric mean (confidence interval 90%)
    100 (72 to 121)
    112 (92 to 137)
    Statistical analysis title
    		 Statistical analysis 1
    Comparison groups
    Advate rAHF-PFM v Recombinate rAHF
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Ratio of the geometric means
    Point estimate
    1.133
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 1.01
         upper limit
    		 1.27

    Secondary: Terminal Half-life. One-Stage aPTT-Based Assay Performed at Central Laboratory (Medical University Vienna)

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    End point title
    		 Terminal Half-life. One-Stage aPTT-Based Assay Performed at Central Laboratory (Medical University Vienna)
    End point description
    Computed from the terminal or disposition rate constant obtained from log-linear fitting using the least squares deviation to the last five quantifiable concentrations (9 to 48 hours).
    End point type
    Secondary
    End point timeframe
    0-30 minutes before infusion up to 48 hours post-infusion
    End point values
    		 Advate rAHF-PFM Recombinate rAHF
    Number of subjects analysed
    9
    9
    Units: hours
        geometric mean (confidence interval 90%)
    10.7 (8.3 to 12.8)
    10.9 (9.1 to 13.1)
    Statistical analysis title
    		 Statistical analysis 1
    Comparison groups
    Advate rAHF-PFM v Recombinate rAHF
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Ratio of the geometric means
    Point estimate
    1.008
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.969
         upper limit
    		 1.05

    Secondary: Terminal Half-life. Chromogenic Assay performed at Local Laboratory (i.e., University of Bonn, the study site)

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    End point title
    		 Terminal Half-life. Chromogenic Assay performed at Local Laboratory (i.e., University of Bonn, the study site)
    End point description
    Computed from the terminal or disposition rate constant obtained from log-linear fitting using the least squares deviation to the last five quantifiable concentrations.
    End point type
    Secondary
    End point timeframe
    0-30 minutes before infusion up to 48 hours post-infusion
    End point values
    		 Advate rAHF-PFM Recombinate rAHF
    Number of subjects analysed
    9
    9
    Units: hours
        geometric mean (confidence interval 90%)
    11.7 (8.5 to 13.5)
    10.8 (8.2 to 12.2)
    Statistical analysis title
    		 Statistical analysis 1
    Comparison groups
    Advate rAHF-PFM v Recombinate rAHF
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Ratio of the geometric means
    Point estimate
    0.964
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.843
         upper limit
    		 1.102

    Secondary: Terminal Half-life. FVIII One-Stage Clotting Assay (Bonn Method) Performed at Local Laboratory (i.e., University of Bonn, the study site)

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    End point title
    		 Terminal Half-life. FVIII One-Stage Clotting Assay (Bonn Method) Performed at Local Laboratory (i.e., University of Bonn, the study site)
    End point description
    Computed from the terminal or disposition rate constant obtained from log-linear fitting using the least squares deviation to the last five quantifiable concentrations.
    End point type
    Secondary
    End point timeframe
    0-30 minutes before infusion up to 48 hours post-infusion
    End point values
    		 Advate rAHF-PFM Recombinate rAHF
    Number of subjects analysed
    9
    9
    Units: hours
        geometric mean (confidence interval 90%)
    9.5 (7.5 to 12.8)
    9.9 (7.6 to 11.5)
    Statistical analysis title
    		 Statistical analysis 1
    Comparison groups
    Advate rAHF-PFM v Recombinate rAHF
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Ratio of the geometric means
    Point estimate
    1.038
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.926
         upper limit
    		 1.163

    Secondary: Terminal Half-life. FVIII Clotting Assay. Performed at Local Laboratory (i.e., University of Bonn, the study site)

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    End point title
    		 Terminal Half-life. FVIII Clotting Assay. Performed at Local Laboratory (i.e., University of Bonn, the study site)
    End point description
    Computed from the terminal or disposition rate constant obtained from log-linear fitting using the least squares deviation to the last five quantifiable concentrations.
    End point type
    Secondary
    End point timeframe
    0-30 minutes before infusion up to 48 hours post-infusion
    End point values
    		 Advate rAHF-PFM Recombinate rAHF
    Number of subjects analysed
    9
    9
    Units: hours
        geometric mean (confidence interval 90%)
    12.4 (9.3 to 14.2)
    12.1 (8.9 to 13.9)
    Statistical analysis title
    		 Statistical analysis 1
    Comparison groups
    Advate rAHF-PFM v Recombinate rAHF
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Ratio of the geometric means
    Point estimate
    1.015
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.901
         upper limit
    		 1.144

    Secondary: Incremental recovery. One-Stage aPTT-Based Assay Performed at Central Laboratory (Medical University Vienna)

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    End point title
    		 Incremental recovery. One-Stage aPTT-Based Assay Performed at Central Laboratory (Medical University Vienna)
    End point description
    Increase in factor VIII concentration from pre- to post-infusion.
    End point type
    Secondary
    End point timeframe
    0-30 minutes before infusion up to 48 hours post-infusion
    End point values
    		 Advate rAHF-PFM Recombinate rAHF
    Number of subjects analysed
    9
    9
    Units: (IU/dL)/(IU/kg)
        geometric mean (confidence interval 90%)
    1.81 (1.52 to 2.1)
    2.11 (1.89 to 2.42)
    Statistical analysis title
    		 Statistical analysis 1
    Comparison groups
    Advate rAHF-PFM v Recombinate rAHF
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Ratio of the geometric means
    Point estimate
    1.178
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 1.106
         upper limit
    		 1.254

    Secondary: Incremental recovery. Chromogenic Assay performed at Local Laboratory (i.e., University of Bonn, the study site)

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    End point title
    		 Incremental recovery. Chromogenic Assay performed at Local Laboratory (i.e., University of Bonn, the study site)
    End point description
    Computed from the terminal or disposition rate constant obtained from log_e -linear fitting using the least squares deviation to the last five quantifiable concentrations.
    End point type
    Secondary
    End point timeframe
    0-30 minutes before infusion up to 48 hours post-infusion
    End point values
    		 Advate rAHF-PFM Recombinate rAHF
    Number of subjects analysed
    9
    9
    Units: (IU/dL)/(IU/kg)
        geometric mean (confidence interval 90%)
    2.04 (1.53 to 2.7)
    2.33 (2.02 to 2.69)
    Statistical analysis title
    		 Statistical analysis 1
    Comparison groups
    Advate rAHF-PFM v Recombinate rAHF
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Ratio of the geometric means
    Point estimate
    1.152
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 1.038
         upper limit
    		 1.279

    Secondary: Incremental recovery. FVIII One-Stage Clotting Assay (Bonn Method) Performed at Local Laboratory (i.e., University of Bonn, the study site)

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    End point title
    		 Incremental recovery. FVIII One-Stage Clotting Assay (Bonn Method) Performed at Local Laboratory (i.e., University of Bonn, the study site)
    End point description
    Increase in factor VIII concentration from pre- to post-infusion
    End point type
    Secondary
    End point timeframe
    0-30 minutes before infusion up to 48 hours post-infusion
    End point values
    		 Advate rAHF-PFM Recombinate rAHF
    Number of subjects analysed
    9
    9
    Units: (IU/dL)/(IU/kg)
        geometric mean (confidence interval 90%)
    1.53 (1.24 to 1.82)
    1.84 (1.49 to 2.82)
    Statistical analysis title
    		 Statistical analysis 1
    Comparison groups
    Advate rAHF-PFM v Recombinate rAHF
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Ratio of the geometric means
    Point estimate
    1.183
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 1.027
         upper limit
    		 1.362

    Secondary: Incremental recovery. FVIII Clotting Assay. Performed at Local Laboratory (i.e., University of Bonn, the study site)

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    End point title
    		 Incremental recovery. FVIII Clotting Assay. Performed at Local Laboratory (i.e., University of Bonn, the study site)
    End point description
    Increase in factor VIII concentration from pre- to post-infusion
    End point type
    Secondary
    End point timeframe
    0-30 minutes before infusion up to 48 hours post-infusion
    End point values
    		 Advate rAHF-PFM Recombinate rAHF
    Number of subjects analysed
    9
    9
    Units: (IU/dL)/(IU/kg)
        geometric mean (confidence interval 90%)
    1.94 (1.44 to 2.27)
    2.19 (1.74 to 2.64)
    Statistical analysis title
    		 Statistical analysis 1
    Comparison groups
    Advate rAHF-PFM v Recombinate rAHF
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Ratio of the geometric means
    Point estimate
    1.133
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 1.012
         upper limit
    		 1.27

    Secondary: Mean Residence Time (MRT). One-Stage aPTT-Based Assay Performed at Central Laboratory (Medical University Vienna)

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    End point title
    		 Mean Residence Time (MRT). One-Stage aPTT-Based Assay Performed at Central Laboratory (Medical University Vienna)
    End point description
    The MRT in hours will be calculated as total area under the moment curve divided by the total area under the curve.
    End point type
    Secondary
    End point timeframe
    0-30 minutes before infusion up to 48 hours post-infusion
    End point values
    		 Advate rAHF-PFM Recombinate rAHF
    Number of subjects analysed
    9
    9
    Units: Hours
        geometric mean (confidence interval 90%)
    14.1 (11 to 17.5)
    14.4 (12.1 to 17.6)
    Statistical analysis title
    		 Statistical analysis 1
    Comparison groups
    Advate rAHF-PFM v Recombinate rAHF
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Ratio of the geometric means
    Point estimate
    1.009
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.964
         upper limit
    		 1.056

    Secondary: Mean Residence Time (MRT). Chromogenic Assay performed at Local Laboratory (i.e., University of Bonn, the study site)

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    End point title
    		 Mean Residence Time (MRT). Chromogenic Assay performed at Local Laboratory (i.e., University of Bonn, the study site)
    End point description
    The MRT in hours will be calculated as total area under the moment curve divided by the total area under the curve.
    End point type
    Secondary
    End point timeframe
    0-30 minutes before infusion up to 48 hours post-infusion
    End point values
    		 Advate rAHF-PFM Recombinate rAHF
    Number of subjects analysed
    9
    9
    Units: Hours
        geometric mean (confidence interval 90%)
    15.1 (10.9 to 18.6)
    14.2 (10.3 to 16.2)
    Statistical analysis title
    		 Statistical analysis 1
    Comparison groups
    Advate rAHF-PFM v Recombinate rAHF
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Ratio of the geometric means
    Point estimate
    0.971
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.849
         upper limit
    		 1.112

    Secondary: Mean Residence Time (MRT). FVIII One-Stage Clotting Assay (Bonn Method) Performed at Local Laboratory (i.e., University of Bonn, the study site)

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    End point title
    		 Mean Residence Time (MRT). FVIII One-Stage Clotting Assay (Bonn Method) Performed at Local Laboratory (i.e., University of Bonn, the study site)
    End point description
    The MRT in hours will be calculated as total area under the moment curve divided by the total area under the curve.
    End point type
    Secondary
    End point timeframe
    0-30 minutes before infusion up to 48 hours post-infusion
    End point values
    		 Advate rAHF-PFM Recombinate rAHF
    Number of subjects analysed
    9
    9
    Units: Hours
        geometric mean (confidence interval 90%)
    12.5 (9.1 to 16.7)
    12.8 (10.1 to 16.4)
    Statistical analysis title
    		 Statistical analysis 1
    Comparison groups
    Advate rAHF-PFM v Recombinate rAHF
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Ratio of the geometric means
    Point estimate
    1.02
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.938
         upper limit
    		 1.109

    Secondary: Mean Residence Time (MRT). FVIII Clotting Assay. Performed at Local Laboratory (i.e., University of Bonn, the study site)

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    End point title
    		 Mean Residence Time (MRT). FVIII Clotting Assay. Performed at Local Laboratory (i.e., University of Bonn, the study site)
    End point description
    The MRT in hours will be calculated as total area under the moment curve divided by the total area under the curve.
    End point type
    Secondary
    End point timeframe
    0-30 minutes before infusion up to 48 hours post-infusion
    End point values
    		 Advate rAHF-PFM Recombinate rAHF
    Number of subjects analysed
    9
    9
    Units: Hours
        geometric mean (confidence interval 90%)
    17.3 (12.4 to 19.6)
    16.9 (13.2 to 19.6)
    Statistical analysis title
    		 Statistical analysis 1
    Comparison groups
    Advate rAHF-PFM v Recombinate rAHF
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Ratio of the geometric means
    Point estimate
    0.996
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.894
         upper limit
    		 1.111

    Secondary: Time to reach the maximum plasma concentration (Tmax). One-Stage aPTT-Based Assay Performed at Central Laboratory (Medical University Vienna)

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    End point title
    		 Time to reach the maximum plasma concentration (Tmax). One-Stage aPTT-Based Assay Performed at Central Laboratory (Medical University Vienna)
    End point description
    Tmax in hours was defined as the minimum time to reach Maximum plasma concentration (Cmax).
    End point type
    Secondary
    End point timeframe
    0-30 minutes before infusion up to 48 hours post-infusion
    End point values
    		 Advate rAHF-PFM Recombinate rAHF
    Number of subjects analysed
    9
    9
    Units: Hours
        geometric mean (confidence interval 90%)
    0.25 (0.25 to 0.25)
    0.25 (0.25 to 0.25)
    Statistical analysis title
    		 Statistical analysis 1
    Comparison groups
    Advate rAHF-PFM v Recombinate rAHF
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Ratio of the geometric means
    Point estimate
    1
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 1
         upper limit
    		 1

    Secondary: Time to reach the maximum plasma concentration (Tmax). Chromogenic Assay performed at Local Laboratory (i.e., University of Bonn, the study site)

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    End point title
    		 Time to reach the maximum plasma concentration (Tmax). Chromogenic Assay performed at Local Laboratory (i.e., University of Bonn, the study site)
    End point description
    Tmax in hours was defined as the minimum time to reach Maximum plasma concentration (Cmax).
    End point type
    Secondary
    End point timeframe
    0-30 minutes before infusion up to 48 hours post-infusion
    End point values
    		 Advate rAHF-PFM Recombinate rAHF
    Number of subjects analysed
    9
    9
    Units: Hours
        geometric mean (confidence interval 90%)
    0.31 (0.25 to 0.5)
    0.42 (0.25 to 1)
    Statistical analysis title
    		 Statistical analysis 1
    Comparison groups
    Advate rAHF-PFM v Recombinate rAHF
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Ratio of the geometric means
    Point estimate
    1.303
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.841
         upper limit
    		 2.02

    Secondary: Time to reach the maximum plasma concentration (Tmax). FVIII One-Stage Clotting Assay (Bonn Method) Performed at Local Laboratory (i.e., University of Bonn, the study site)

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    End point title
    		 Time to reach the maximum plasma concentration (Tmax). FVIII One-Stage Clotting Assay (Bonn Method) Performed at Local Laboratory (i.e., University of Bonn, the study site)
    End point description
    Tmax in hours was defined as the minimum time to reach Maximum plasma concentration (Cmax).
    End point type
    Secondary
    End point timeframe
    0-30 minutes before infusion up to 48 hours post-infusion
    End point values
    		 Advate rAHF-PFM Recombinate rAHF
    Number of subjects analysed
    9
    9
    Units: Hours
        geometric mean (confidence interval 90%)
    0.45 (0.25 to 1)
    0.31 (0.25 to 0.5)
    Statistical analysis title
    		 Statistical analysis 1
    Comparison groups
    Advate rAHF-PFM v Recombinate rAHF
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Ratio of the geometric means
    Point estimate
    0.724
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.304
         upper limit
    		 1.728

    Secondary: Time to reach the maximum plasma concentration (Tmax). FVIII Clotting Assay. Performed at Local Laboratory (i.e., University of Bonn, the study site)

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    End point title
    		 Time to reach the maximum plasma concentration (Tmax). FVIII Clotting Assay. Performed at Local Laboratory (i.e., University of Bonn, the study site)
    End point description
    Tmax in hours was defined as the minimum time to reach Maximum plasma concentration (Cmax).
    End point type
    Secondary
    End point timeframe
    0-30 minutes before infusion up to 48 hours post-infusion
    End point values
    		 Advate rAHF-PFM Recombinate rAHF
    Number of subjects analysed
    9
    9
    Units: Hours
        geometric mean (confidence interval 90%)
    0.38 (0.25 to 1)
    0.51 (0.25 to 3)
    Statistical analysis title
    		 Statistical analysis 1
    Comparison groups
    Advate rAHF-PFM v Recombinate rAHF
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Ratio of the geometric means
    Point estimate
    1.059
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.442
         upper limit
    		 2.539

    Secondary: Volume of Distribution at Steady State (Vss). One-Stage aPTT-Based Assay Performed at Central Laboratory (Medical University Vienna)

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    End point title
    		 Volume of Distribution at Steady State (Vss). One-Stage aPTT-Based Assay Performed at Central Laboratory (Medical University Vienna)
    End point description
    Computed as weight-adjusted Clearance * Mean Residence Time
    End point type
    Secondary
    End point timeframe
    0-30 minutes before infusion up to 48 hours post-infusion
    End point values
    		 Advate rAHF-PFM Recombinate rAHF
    Number of subjects analysed
    9
    9
    Units: mL/kg
        geometric mean (confidence interval 90%)
    60.8 (48.2 to 75.7)
    52.9 (43.9 to 62)
    Statistical analysis title
    		 Statistical analysis 1
    Comparison groups
    Advate rAHF-PFM v Recombinate rAHF
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Ratio of the geometric means
    Point estimate
    0.862
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.807
         upper limit
    		 0.92

    Secondary: Volume of Distribution at Steady State (Vss). Chromogenic Assay performed at Local Laboratory (i.e., University of Bonn, the study site)

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    End point title
    		 Volume of Distribution at Steady State (Vss). Chromogenic Assay performed at Local Laboratory (i.e., University of Bonn, the study site)
    End point description
    Computed as weight-adjusted Clearance (CL) * Mean Residence Time
    End point type
    Secondary
    End point timeframe
    0-30 minutes before infusion up to 48 hours post-infusion
    End point values
    		 Advate rAHF-PFM Recombinate rAHF
    Number of subjects analysed
    9
    9
    Units: mL/kg
        geometric mean (confidence interval 90%)
    60.4 (45.5 to 76.6)
    50.2 (45.4 to 58.2)
    Statistical analysis title
    		 Statistical analysis 1
    Comparison groups
    Advate rAHF-PFM v Recombinate rAHF
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Ratio of the geometric means
    Point estimate
    0.855
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.73
         upper limit
    		 1.002

    Secondary: Volume of Distribution at Steady State (Vss). FVIII One-Stage Clotting Assay (Bonn Method) Performed at Local Laboratory (i.e., University of Bonn, the study site)

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    End point title
    		 Volume of Distribution at Steady State (Vss). FVIII One-Stage Clotting Assay (Bonn Method) Performed at Local Laboratory (i.e., University of Bonn, the study site)
    End point description
    Computed as weight-adjusted CL * Mean Residence Time
    End point type
    Secondary
    End point timeframe
    0-30 minutes before infusion up to 48 hours post-infusion
    End point values
    		 Advate rAHF-PFM Recombinate rAHF
    Number of subjects analysed
    9
    9
    Units: mL/kg
        geometric mean (confidence interval 90%)
    73.2 (54.6 to 87.5)
    70.9 (67.5 to 89.5)
    Statistical analysis title
    		 Statistical analysis 1
    Comparison groups
    Advate rAHF-PFM v Recombinate rAHF
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Ratio of the geometric means
    Point estimate
    0.984
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.788
         upper limit
    		 1.228

    Secondary: Volume of Distribution at Steady State (Vss). FVIII Clotting Assay. Performed at Local Laboratory (i.e., University of Bonn, the study site)

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    End point title
    		 Volume of Distribution at Steady State (Vss). FVIII Clotting Assay. Performed at Local Laboratory (i.e., University of Bonn, the study site)
    End point description
    Computed as weight-adjusted CL * Mean Residence Time
    End point type
    Secondary
    End point timeframe
    0-30 minutes before infusion up to 48 hours post-infusion
    End point values
    		 Advate rAHF-PFM Recombinate rAHF
    Number of subjects analysed
    9
    9
    Units: mL/kg
        geometric mean (confidence interval 90%)
    55.6 (40.4 to 69.1)
    50 (39.8 to 63.8)
    Statistical analysis title
    		 Statistical analysis 1
    Comparison groups
    Advate rAHF-PFM v Recombinate rAHF
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Ratio of the geometric means
    Point estimate
    0.911
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.8
         upper limit
    		 1.039

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    Slightly less than 1 year (31Mar2008 - 18Feb2009)
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    N/A
    Reporting groups
    Reporting group title
    All Study Participants
    Reporting group description
    		 Includes all 9 treated subjects (ie, all subjects who received a PK infusion with Advate rAHF-PFM and a PK infusion with Recombinate rAHF).

    Serious adverse events
    		 All Study Participants
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 9 (0.00%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 All Study Participants
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    0 / 9 (0.00%)
    Notes
    [1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported.
    Justification: No AEs were reported for any of the 9 subjects enrolled and treated in this study.

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    04 Jul 2008
    - Original target enrollment of 15-20 previously treated patients (PTPs) reduced to 15 PTPs - Exclusion criterion of detectable factor VIII inhibitor titer ≥ 0.4 BU not limited to central laboratory measurements any more but also applicable when measured at the local laboratory - More flexibility allowed in the choice of butterfly gauge catheter to be used for infusion of the study product or for blood draws: change from previously allowed 23-gauge butterfly catheter to 21- or 23-gauge butterfly catheter

    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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