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    Clinical Trial Results:
    A Phase II, Multicentre, Double-blinded, Randomised, Cross-over study to Evaluate Efficacy, Safety and Pharmacokinetics of Biostate® in Subjects With Haemophilia A

    Summary
    EudraCT number
    		 2008-001104-23
    Trial protocol
    		 BG  
    Global end of trial date
    15 Oct 2010

    Results information
    Results version number
    		 v1(current)
    This version publication date
    13 Jul 2016
    First version publication date
    16 Aug 2015
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CSLCT-BIO-07-47
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    CSL Behring GmbH
    Sponsor organisation address
    Emil-von-Behring-Str. 76, Marburg, Germany, 35041
    Public contact
    Clinical Trial Disclosure Manager, CSL Behring, clinicaltrials@cslbehring.com
    Scientific contact
    Clinical Trial Disclosure Manager, CSL Behring, clinicaltrials@cslbehring.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-000312-PIP01-08
    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
    10 Dec 2010
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    15 Oct 2010
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    1. To assess the efficacy of Biostate® study product (SP) in subjects with haemophilia A 2. To assess the comparability of the pharmacokinetics of Biostate® reference product (RP)* and Biostate® SP in subjects with haemophilia A *Biostate reference product (RP), was the initial product, used in clinical studies until May 2003, and Biostate study product (SP) was the product with an additional filter (a filtration step to enhance prion clearance), used as the IMP since March 2009 (start of the clinical development of the IMP in Europe).
    Protection of trial subjects
    This study was carried out in accordance with the International Conference on Harmonisation (ICH) Good Clinical Practice guidelines, and standard operating procedures for clinical research and development at CSL Behring (CSLB). The study protocol and all amendments were approved by the Independent Ethics Committee(s) (IECs) / Institutional Review Board(s) (IRBs) of the participating centers. Before undergoing screening procedures for possible enrollment into the study, subjects were informed, in an understandable form, about the nature, scope, and possible consequences of the study. The investigator was responsible for obtaining a subject’s written informed consent to participate in the study. The investigator may cease study treatment and withdraw the subject, or the subject may withdraw himself from participation in the study at any time. If a subject is withdrawn from the study or further participation is declined, the subject will continue to have access to medical care and will be treated according to routine medical practice, but will no longer receive the investigational medicinal product (IMP).
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    31 Mar 2009
    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
    Poland: 20
    Country: Number of subjects enrolled
    Bulgaria: 34
    Country: Number of subjects enrolled
    Macedonia, the former Yugoslav Republic of: 4
    Country: Number of subjects enrolled
    Russian Federation: 23
    Worldwide total number of subjects
    81
    EEA total number of subjects
    54
    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)
    3
    Adults (18-64 years)
    77
    From 65 to 84 years
    1
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 This study included a Screening period of up to 14 days.

    Period 1
    Period 1 title
    Part 1: PK Component
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor
    Blinding implementation details
    Subjects participating in this component (PK subjects) were randomly assigned (1:1, stratified by study site) to either of these sequences. The 2 different Biostate treatments (Biostate SP and RP) were only administered during Part 1 of the study (first part of the PK component). Therefore, blinding was only applicable for Part 1 of the study and not for Parts 2 (efficacy component), or Part 3 (Repeat PK component).

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 Biostate SP (Day 1 or 8)
    Arm description
    		 A single intravenous (i.v.) dose of 50 IU/kg of Biostate SP on Day 1 or Day 8. 

    Arm type
    		 Experimental

    Investigational medicinal product name
    Human coagulation Factor VIII / von Willebrand Factor
    Investigational medicinal product code
    Other name
    Biostate®, Voncento®
    Pharmaceutical forms
    Powder and solvent for solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Biostate SP was administrated as a bolus i.v. dose at a maximum of 6 mL/min as tolerated by the subject.

    Arm title
    		 Biostate RP (Day 1 or 8)
    Arm description
    		 A single i.v. dose of 50 IU/kg of Biostate RP on Day 1 or Day 8. 

    Arm type
    		 Experimental

    Investigational medicinal product name
    Human coagulation Factor VIII / von Willebrand Factor
    Investigational medicinal product code
    Other name
    Biostate®, Voncento®
    Pharmaceutical forms
    Powder and solvent for solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Biostate RP was administrated as a bolus i.v. dose at a maximum of 6 mL/min as tolerated by the subject.

    Number of subjects in period 1
    		Biostate SP (Day 1 or 8) Biostate RP (Day 1 or 8)
    Started
    17
    17
    Completed
    17
    17
    Period 2
    Period 2 title
    Part 2: Efficacy Component
    Is this the baseline period?
    		 Yes [1]
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Biostate SP
    Arm description
    		 The frequency and dose (loading and maintenance) of Biostate SP during the efficacy component was determined by the Investigator based on the subject’s clinical condition, previous FVIII concentrate requirements, response to therapy, body weight, and reason for usage during the 6-month efficacy period (for a minimum of 50 exposure days).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Human coagulation Factor VIII / von Willebrand Factor
    Investigational medicinal product code
    Other name
    Biostate®, Voncento®
    Pharmaceutical forms
    Powder and solvent for solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Biostate SP was administrated as a bolus i.v. dose at a maximum of 6 mL/min as tolerated by the subject.

    Notes
    [1] - Period 1 is not the baseline period. It is expected that period 1 will be the baseline period.
    Justification: The first period was a PK period and did not include all enrolled subjects.
    Number of subjects in period 2
    		Biostate SP
    Started
    17
    Completed
    77
    Not completed
    4
         Consent withdrawn by subject
    3
         Development of FVIII Inhibitors
    1
    Joined
    64
         Enrolled for Part 2 Efficacy Component Only
    64
    Period 3
    Period 3 title
    Part 3: Repeat PK Component
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Biostate SP (Day 180)
    Arm description
    		 A single i.v. dose of 50 IU/kg of Biostate SP on Day 180.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Human coagulation Factor VIII / von Willebrand Factor
    Investigational medicinal product code
    Other name
    Biostate®, Voncento®
    Pharmaceutical forms
    Powder and solvent for solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Biostate SP was administrated as a bolus i.v. dose at a maximum of 6 mL/min as tolerated by the subject.

    Number of subjects in period 3 [2]
    		Biostate SP (Day 180)
    Started
    15
    Completed
    15
    Notes
    [2] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: The third period was a repeat PK period, and was only open to a subgroup of the first PK period (Period 1).

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Part 2: Efficacy Component
    Reporting group description
    		 Each subject in the efficacy component (Part 2) of the study received a dose of Biostate SP as determined by the Investigator based on the subject’s clinical condition, previous FVIII concentrate requirements, response to therapy, body weight, and reason for usage during the 6-month efficacy period (for a minimum of 50 exposure days). The frequency and dose (loading and maintenance) of Biostate SP during the efficacy component was determined by the Investigator.

    Reporting group values
    		 Part 2: Efficacy Component Total
    Number of subjects
    		 81 81
    Age categorical
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 0 0
        Adolescents (12-17 years)
    		 3 3
        Adults (18-64 years)
    		 77 77
        From 65-84 years
    		 1 1
        85 years and over
    		 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 33.1 ( 12.8 ) -
    Gender categorical
    Units: Subjects
        Female
    		 0 0
        Male
    		 81 81

    End points

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    End points reporting groups
    Reporting group title
    Biostate SP (Day 1 or 8)
    Reporting group description
    		 A single intravenous (i.v.) dose of 50 IU/kg of Biostate SP on Day 1 or Day 8. 


    Reporting group title
    Biostate RP (Day 1 or 8)
    Reporting group description
    		 A single i.v. dose of 50 IU/kg of Biostate RP on Day 1 or Day 8. 

    Reporting group title
    Biostate SP
    Reporting group description
    		 The frequency and dose (loading and maintenance) of Biostate SP during the efficacy component was determined by the Investigator based on the subject’s clinical condition, previous FVIII concentrate requirements, response to therapy, body weight, and reason for usage during the 6-month efficacy period (for a minimum of 50 exposure days).
    Reporting group title
    Biostate SP (Day 180)
    Reporting group description
    		 A single i.v. dose of 50 IU/kg of Biostate SP on Day 180.

    Primary: Investigator's Monthly Assessment of Haemostatic Efficacy

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    End point title
    		 Investigator's Monthly Assessment of Haemostatic Efficacy [1]
    End point description
    Assessment of haemostatic efficacy by the Investigator was evaluated per subject on a retrospective monthly basis. The efficacy grading scale was as follows: excellent=haemostasis achieved/cessation of bleeding; good=slight oozing/partial but adequate control of bleeding, does not require additional product for unplanned treatment; moderate=moderate bleeding/moderate control of bleeding, required additional product for unplanned treatment; none=severe uncontrolled bleeding.
    End point type
    Primary
    End point timeframe
    Up to Month 10
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Planned descriptive data for this endpoint are presented in data table.
    End point values
    		 Biostate SP
    Number of subjects analysed
    81 [2]
    Units: subjects
        Month 1: Excellent; n=81
    58
        Month 1: Good; n=81
    21
        Month 1: Moderate; n=81
    2
        Month 1: None; n=81
    0
        Month 2: Excellent; n=81
    64
        Month 2: Good; n=81
    17
        Month 2: Moderate; n=81
    0
        Month 2: None; n=81
    0
        Month 3: Excellent; n=80
    63
        Month 3: Good; n=80
    16
        Month 3: Moderate; n=80
    1
        Month 3: None; n=80
    0
        Month 4: Excellent; n=80
    64
        Month 4: Good; n=80
    16
        Month 4: Moderate; n=80
    0
        Month 4: None; n=80
    0
        Month 5: Excellent; n=79
    68
        Month 5: Good; n=79
    11
        Month 5: Moderate; n=79
    0
        Month 5: None; n=79
    0
        Month 6: Excellent; n=78
    66
        Month 6: Good; n=78
    12
        Month 6: Moderate; n=78
    0
        Month 6: None; n=78
    0
        Month 7: Excellent; n=20
    16
        Month 7: Good; n=20
    4
        Month 7: Moderate; n=20
    0
        Month 7: None; n=20
    0
        Month 8: Excellent; n=15
    13
        Month 8: Good; n=15
    2
        Month 8: Moderate; n=15
    0
        Month 8: None; n=15
    0
        Month 9: Excellent; n=9
    8
        Month 9: Good; n=9
    1
        Month 9: Moderate; n=9
    0
        Month 9: None; n=9
    0
        Month 10: Excellent; n=7
    5
        Month 10: Good; n=7
    2
        Month 10: Moderate; n=7
    0
        Month 10: None; n=7
    0
    Notes
    [2] - All subjects who received study drug; n=subjects with an assessment at given time point.
    No statistical analyses for this end point

    Primary: Blood Product Transfusions: Total Amount Received

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    End point title
    		 Blood Product Transfusions: Total Amount Received [3]
    End point description
    The total amount of blood product(s) required by a subject during the study period was recorded. Blood products included any infusions of whole blood, packed red blood cells, and platelets either from the subject’s own blood (auto red blood cells, auto plasma) or from donor blood.
    End point type
    Primary
    End point timeframe
    Screening through the Final Visit (Day 187 or within 7 days after last infusion)
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Planned descriptive data for this endpoint are presented in data table.
    End point values
    		 Biostate SP
    Number of subjects analysed
    5 [4]
    Units: mL
    median (full range (min-max))
        Any Blood Product; n=5
    910 (250 to 1530)
        Auto Red Blood Cells; n=5
    460 (250 to 540)
        Autoplasma; n =4
    600 (300 to 600)
        Packed cells; n=1
    470 (470 to 470)
    Notes
    [4] - Subjects who required transfusion; n=subjects receiving the respective blood product at least once.
    No statistical analyses for this end point

    Primary: Usage of Biostate SP: Number of Infusions Overall and By Month

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    End point title
    		 Usage of Biostate SP: Number of Infusions Overall and By Month [5]
    End point description
    End point type
    Primary
    End point timeframe
    Month 1 through Month 12
    Notes
    [5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Planned descriptive data for this endpoint are presented in data table.
    End point values
    		 Biostate SP
    Number of subjects analysed
    81 [6]
    Units: infusions
    median (full range (min-max))
        Overall Efficacy Period; n=81
    59 (2 to 2)
        Month 1; n=81
    9 (31 to 118)
        Month 2; n=81
    9 (2 to 41)
        Month 3; n=81
    9 (2 to 35)
        Month 4; n=80
    10 (3 to 20)
        Month 5; n=80
    9 (3 to 31)
        Month 6; n=79
    9 (3 to 29)
        Month 7; n=58
    4 (1 to 30)
        Month 8; n=23
    5 (1 to 12)
        Month 9; n=15
    4 (2 to 23)
        Month 10; n=9
    4 (1 to 7)
        Month 11; n=6
    3 (2 to 10)
        Month 12; n=1
    2 (1 to 4)
    Notes
    [6] - All subjects who received study drug; n=subjects with evaluable data at given time point.
    No statistical analyses for this end point

    Primary: Usage of Biostate SP: Average Dose Overall and By Month

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    End point title
    		 Usage of Biostate SP: Average Dose Overall and By Month [7]
    End point description
    End point type
    Primary
    End point timeframe
    Months 1 through 12 of efficacy period
    Notes
    [7] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Planned descriptive data for this endpoint are presented in data table.
    End point values
    		 Biostate SP
    Number of subjects analysed
    81 [8]
    Units: IU/kg
    median (full range (min-max))
        Overall Efficacy Period; n=81
    26.6 (14 to 40)
        Month 1; n=81
    25 (12 to 55)
        Month 2; n=81
    25.3 (13 to 41)
        Month 3; n=81
    25 (15 to 40)
        Month 4; n=80
    27.5 (15 to 40)
        Month 5; n=80
    26.2 (12 to 47)
        Month 6; n=79
    27 (11 to 42)
        Month 7; n=58
    26.9 (15 to 44)
        Month 8; n=23
    26 (12 to 43)
        Month 9; n=15
    25.8 (19 to 35)
        Month 10; n=9
    25.7 (18 to 33)
        Month 11; n=6
    27.1 (20 to 50)
        Month 12; n=1
    35 (35 to 35)
    Notes
    [8] - All subjects who received study drug; n=subjects with evaluable data at given time point.
    No statistical analyses for this end point

    Primary: Investigator's Assessment of Blood Loss Per Surgical Event

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    End point title
    		 Investigator's Assessment of Blood Loss Per Surgical Event [9]
    End point description
    In the case of any surgical procedures, the surgical team provided an assessment at the time of the procedure of the extent of blood loss for each specific surgical procedure performed on a subject. The blood loss was compared to the expected blood loss from a subject without a bleeding disorder undergoing the same procedure. The following grading scale was used: less than expected loss, equivalent to expected loss, more than expected loss. Major surgery included surgery involving a risk to the life of the subject; minor surgery included surgery involving little risk to the life of the subject.
    End point type
    Primary
    End point timeframe
    Efficacy Period (up to Month 12)
    Notes
    [9] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Planned descriptive data for this endpoint are presented in data table.
    End point values
    		 Biostate SP
    Number of subjects analysed
    81 [10]
    Units: Surgical Events
        All Surgeries: Less Than Expected; n=37
    15
        All Surgeries: Equivalent to Expected; n=37
    21
        All Surgeries: More Than Expected; n=37
    1
        Major Surgeries: Less Than Expected; n=12
    6
        Major Surgeries: Equivalent to Expected; n=12
    5
        Major Surgeries: More Than Expected; n=12
    1
        Minor Surgeries: Less Than Expected; n=25
    9
        Minor Surgeries: Equivalent to Expected; n=25
    16
        Minor Surgeries: More Than Expected; n=25
    0
    Notes
    [10] - Efficacy population; n=number of surgeries of given type.
    No statistical analyses for this end point

    Primary: PK Parameter, Part 1: Incremental Recovery (IR)

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    End point title
    		 PK Parameter, Part 1: Incremental Recovery (IR) [11]
    End point description
    End point type
    Primary
    End point timeframe
    Days 1 and 8: preinfusion; 30 (±5) min, 2 h (±5 min), 4 h (±15 min), 8 h (±30 min), 12 h (±30 min); Days 2 and 9: 24 h (±2 h), 28 h (±2 h); Days 3 and 10: 48 h (±2 h) after the end of infusion.
    Notes
    [11] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Planned analyses for this endpoint are presented in data table.
    End point values
    		 Biostate SP (Day 1 or 8) Biostate RP (Day 1 or 8)
    Number of subjects analysed
    16
    16
    Units: kg/mL
        arithmetic mean (standard deviation)
    0.021 ( 0.006 )
    0.023 ( 0.005 )
    No statistical analyses for this end point

    Primary: PK Parameter, Part 1: Half-life (t1/2)

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    End point title
    		 PK Parameter, Part 1: Half-life (t1/2) [12]
    End point description
    End point type
    Primary
    End point timeframe
    Days 1 and 8: preinfusion; 30 (±5) min, 2 h (±5 min), 4 h (±15 min), 8 h (±30 min), 12 h (±30 min); Days 2 and 9: 24 h (±2 h), 28 h (±2 h); Days 3 and 10: 48 h (±2 h) after the end of infusion.
    Notes
    [12] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Planned analyses for this endpoint are presented in data table.
    End point values
    		 Biostate SP (Day 1 or 8) Biostate RP (Day 1 or 8)
    Number of subjects analysed
    16
    16
    Units: hours
        arithmetic mean (standard deviation)
    13.4 ( 2.53 )
    13.07 ( 1.82 )
    No statistical analyses for this end point

    Primary: PK Parameter, Part 1: Area Under the Plasma Concentration-Time Curve From Time 0 to 48 Hours (AUC[0-48])

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    End point title
    		 PK Parameter, Part 1: Area Under the Plasma Concentration-Time Curve From Time 0 to 48 Hours (AUC[0-48])
    End point description
    End point type
    Primary
    End point timeframe
    Days 1 and 8: preinfusion; 30 (±5) min, 2 h (±5 min), 4 h (±15 min), 8 h (±30 min), 12 h (±30 min); Days 2 and 9: 24 h (±2 h), 28 h (±2 h); Days 3 and 10: 48 h (±2 h) after the end of infusion.
    End point values
    		 Biostate SP (Day 1 or 8) Biostate RP (Day 1 or 8)
    Number of subjects analysed
    16
    16
    Units: h*IU/mL
        arithmetic mean (standard deviation)
    13.79 ( 3.79 )
    14.34 ( 3.63 )
    Statistical analysis title
    		 Bioequivalence of Biostate SP versus Biostate RP
    Statistical analysis description
    From a mixed effects analysis of variance with treatment (Biostate SP, Biostate RP), period (Infusion 1, Infusion 2), and sequence (Sequence 1, Sequence 2) as fixed effects, and subject nested in sequence as random effect.
    Comparison groups
    Biostate RP (Day 1 or 8) v Biostate SP (Day 1 or 8)
    Number of subjects included in analysis
    32
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [13]
    P-value
    		 = 0.374
    Method
    		 ANOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.05
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -0.14
         upper limit
    		 0.05
    Notes
    [13] - For establishing bioequivalence, the 90% CI should lie within the acceptance interval of 0.80 - 1.25 [Chow SC and Liu JP, 1992]. It is however noted that the conclusion that products are bioequivalent is based on the overall scientific assessment of the PK studies, not only on meeting the acceptance range.

    Primary: PK Parameter, Part 1: Mean Residence Time (MRT)

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    End point title
    		 PK Parameter, Part 1: Mean Residence Time (MRT) [14]
    End point description
    End point type
    Primary
    End point timeframe
    Days 1 and 8: preinfusion; 30 (±5) min, 2 h (±5 min), 4 h (±15 min), 8 h (±30 min), 12 h (±30 min); Days 2 and 9: 24 h (±2 h), 28 h (±2 h); Days 3 and 10: 48 h (±2 h) after the end of infusion.
    Notes
    [14] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Planned analyses for this endpoint are presented in data table.
    End point values
    		 Biostate SP (Day 1 or 8) Biostate RP (Day 1 or 8)
    Number of subjects analysed
    16
    16
    Units: hours
        arithmetic mean (standard deviation)
    16.96 ( 3.68 )
    16.96 ( 2.55 )
    No statistical analyses for this end point

    Primary: PK Parameter, Part 1: Maximum Plasma Concentration (Cmax)

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    End point title
    		 PK Parameter, Part 1: Maximum Plasma Concentration (Cmax)
    End point description
    End point type
    Primary
    End point timeframe
    Days 1 and 8: preinfusion; 30 (±5) min, 2 h (±5 min), 4 h (±15 min), 8 h (±30 min), 12 h (±30 min); Days 2 and 9: 24 h (±2 h), 28 h (±2 h); Days 3 and 10: 48 h (±2 h) after the end of infusion.
    End point values
    		 Biostate SP (Day 1 or 8) Biostate RP (Day 1 or 8)
    Number of subjects analysed
    16
    16
    Units: IU/mL
        arithmetic mean (standard deviation)
    1.07 ( 0.28 )
    1.13 ( 0.27 )
    Statistical analysis title
    		 Bioequivalence of Biostate SP versus Biostate RP
    Statistical analysis description
    From a mixed effects analysis of variance with treatment (Biostate SP, Biostate RP), period (Infusion 1, Infusion 2), and sequence (Sequence 1, Sequence 2) as fixed effects, and subject nested in sequence as random effect.
    Comparison groups
    Biostate SP (Day 1 or 8) v Biostate RP (Day 1 or 8)
    Number of subjects included in analysis
    32
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [15]
    P-value
    		 = 0.384
    Method
    		 ANOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.07
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -0.22
         upper limit
    		 0.07
    Notes
    [15] - For establishing bioequivalence, the 90% CI should lie within the acceptance interval of 0.80 - 1.25 [Chow SC and Liu JP, 1992]. It is however noted that the conclusion that products are bioequivalent is based on the overall scientific assessment of the PK studies, not only on meeting the acceptance range.

    Primary: PK Parameter, Part 1: Time of Maximum Concentration (tmax)

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    End point title
    		 PK Parameter, Part 1: Time of Maximum Concentration (tmax) [16]
    End point description
    End point type
    Primary
    End point timeframe
    Days 1 and 8: preinfusion; 30 (±5) min, 2 h (±5 min), 4 h (±15 min), 8 h (±30 min), 12 h (±30 min); Days 2 and 9: 24 h (±2 h), 28 h (±2 h); Days 3 and 10: 48 h (±2 h) after the end of infusion.
    Notes
    [16] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Planned analyses for this endpoint are presented in data table.
    End point values
    		 Biostate SP (Day 1 or 8) Biostate RP (Day 1 or 8)
    Number of subjects analysed
    16
    16
    Units: hours
        median (full range (min-max))
    0.5 (0.42 to 4.03)
    0.5 (0.48 to 0.5)
    No statistical analyses for this end point

    Primary: PK Parameter, Part 1: Minimum Plasma Concentration (Cmin)

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    End point title
    		 PK Parameter, Part 1: Minimum Plasma Concentration (Cmin) [17]
    End point description
    End point type
    Primary
    End point timeframe
    Days 1 and 8: preinfusion; 30 (±5) min, 2 h (±5 min), 4 h (±15 min), 8 h (±30 min), 12 h (±30 min); Days 2 and 9: 24 h (±2 h), 28 h (±2 h); Days 3 and 10: 48 h (±2 h) after the end of infusion.
    Notes
    [17] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Planned analyses for this endpoint are presented in data table.
    End point values
    		 Biostate SP (Day 1 or 8) Biostate RP (Day 1 or 8)
    Number of subjects analysed
    16
    16
    Units: IU/mL
        arithmetic mean (standard deviation)
    0.06 ( 0.028 )
    0.061 ( 0.024 )
    No statistical analyses for this end point

    Primary: PK Parameter, Part 1: Total Clearance (CL)

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    End point title
    		 PK Parameter, Part 1: Total Clearance (CL) [18]
    End point description
    End point type
    Primary
    End point timeframe
    Days 1 and 8: preinfusion; 30 (±5) min, 2 h (±5 min), 4 h (±15 min), 8 h (±30 min), 12 h (±30 min); Days 2 and 9: 24 h (±2 h), 28 h (±2 h); Days 3 and 10: 48 h (±2 h) after the end of infusion.
    Notes
    [18] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Planned analyses for this endpoint are presented in data table.
    End point values
    		 Biostate SP (Day 1 or 8) Biostate RP (Day 1 or 8)
    Number of subjects analysed
    16
    16
    Units: mL/(h*kg)
        arithmetic mean (standard deviation)
    3.92 ( 1.22 )
    3.78 ( 1.33 )
    No statistical analyses for this end point

    Primary: PK Parameter, Part 1: Volume at Steady State (Vss)

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    End point title
    		 PK Parameter, Part 1: Volume at Steady State (Vss) [19]
    End point description
    End point type
    Primary
    End point timeframe
    Days 1 and 8: preinfusion; 30 (±5) min, 2 h (±5 min), 4 h (±15 min), 8 h (±30 min), 12 h (±30 min); Days 2 and 9: 24 h (±2 h), 28 h (±2 h); Days 3 and 10: 48 h (±2 h) after the end of infusion.
    Notes
    [19] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Planned analyses for this endpoint are presented in data table.
    End point values
    		 Biostate SP (Day 1 or 8) Biostate RP (Day 1 or 8)
    Number of subjects analysed
    16
    16
    Units: mL/kg
        arithmetic mean (standard deviation)
    65.33 ( 20.65 )
    62.57 ( 23.12 )
    No statistical analyses for this end point

    Primary: PK Parameter, Part 1 Versus Part 3: Incremental Recovery (IR)

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    End point title
    		 PK Parameter, Part 1 Versus Part 3: Incremental Recovery (IR) [20]
    End point description
    End point type
    Primary
    End point timeframe
    Days 1, 8, and Day 180: preinfusion; 30 (±5) min, 2 h (±5 min), 4 h (±15 min), 8 h (±30 min), 12 h (±30 min); Days 2, 9, and 181: 24 h (±2 h), 28 h (±2 h); Days 3, 10, and 182: 48 h (±2 h) after the end of infusion.
    Notes
    [20] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Planned analyses for this endpoint are presented in data table.
    End point values
    		 Biostate SP (Day 1 or 8) Biostate SP (Day 180)
    Number of subjects analysed
    15
    15
    Units: kg/mL
        arithmetic mean (standard deviation)
    0.021 ( 0.005 )
    0.022 ( 0.004 )
    No statistical analyses for this end point

    Primary: PK Parameter, Part 1 Versus Part 3: Half-life (t1/2)

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    End point title
    		 PK Parameter, Part 1 Versus Part 3: Half-life (t1/2) [21]
    End point description
    End point type
    Primary
    End point timeframe
    Days 1, 8, and Day 180: preinfusion; 30 (±5) min, 2 h (±5 min), 4 h (±15 min), 8 h (±30 min), 12 h (±30 min); Days 2, 9, and 181: 24 h (±2 h), 28 h (±2 h); Days 3, 10, and 182: 48 h (±2 h) after the end of infusion.
    Notes
    [21] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Planned analyses for this endpoint are presented in data table.
    End point values
    		 Biostate SP (Day 1 or 8) Biostate SP (Day 180)
    Number of subjects analysed
    15
    15
    Units: hours
        arithmetic mean (standard deviation)
    13.49 ( 2.59 )
    13.16 ( 2.01 )
    No statistical analyses for this end point

    Primary: PK Parameter, Part 1 Versus Part 3: Area Under the Plasma Concentration-Time Curve From Time 0 to 48 Hours (AUC[0-48])

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    End point title
    		 PK Parameter, Part 1 Versus Part 3: Area Under the Plasma Concentration-Time Curve From Time 0 to 48 Hours (AUC[0-48])
    End point description
    End point type
    Primary
    End point timeframe
    Days 1, 8, and Day 180: preinfusion; 30 (±5) min, 2 h (±5 min), 4 h (±15 min), 8 h (±30 min), 12 h (±30 min); Days 2, 9, and 181: 24 h (±2 h), 28 h (±2 h); Days 3, 10, and 182: 48 h (±2 h) after the end of infusion.
    End point values
    		 Biostate SP (Day 1 or 8) Biostate SP (Day 180)
    Number of subjects analysed
    15
    15
    Units: h*IU/mL
        arithmetic mean (standard deviation)
    13.26 ( 3.24 )
    14.46 ( 3.66 )
    Statistical analysis title
    		 Part 1 versus Part 3 AUC0-48
    Statistical analysis description
    From a mixed effects analysis of variance with period (Part 1, Part 3) as fixed effect and subject as random effect.
    Comparison groups
    Biostate SP (Day 1 or 8) v Biostate SP (Day 180)
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.099
    Method
    		 ANOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.09
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0
         upper limit
    		 0.18

    Primary: PK Parameter, Part 1 Versus Part 3: Mean Residence Time (MRT)

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    End point title
    		 PK Parameter, Part 1 Versus Part 3: Mean Residence Time (MRT) [22]
    End point description
    End point type
    Primary
    End point timeframe
    Days 1, 8, and Day 180: preinfusion; 30 (±5) min, 2 h (±5 min), 4 h (±15 min), 8 h (±30 min), 12 h (±30 min); Days 2, 9, and 181: 24 h (±2 h), 28 h (±2 h); Days 3, 10, and 182: 48 h (±2 h) after the end of infusion.
    Notes
    [22] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Planned analyses for this endpoint are presented in data table.
    End point values
    		 Biostate SP (Day 1 or 8) Biostate SP (Day 180)
    Number of subjects analysed
    15
    15
    Units: hours
        arithmetic mean (standard deviation)
    17.07 ( 3.78 )
    16.68 ( 3.11 )
    No statistical analyses for this end point

    Primary: PK Parameter, Part 1 Versus Part 3: Maximum Plasma Concentration (Cmax)

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    End point title
    		 PK Parameter, Part 1 Versus Part 3: Maximum Plasma Concentration (Cmax)
    End point description
    End point type
    Primary
    End point timeframe
    Days 1, 8, and Day 180: preinfusion; 30 (±5) min, 2 h (±5 min), 4 h (±15 min), 8 h (±30 min), 12 h (±30 min); Days 2, 9, and 181: 24 h (±2 h), 28 h (±2 h); Days 3, 10, and 182: 48 h (±2 h) after the end of infusion.
    End point values
    		 Biostate SP (Day 1 or 8) Biostate SP (Day 180)
    Number of subjects analysed
    15
    15
    Units: IU/mL
        arithmetic mean (standard deviation)
    1.03 ( 0.26 )
    1.08 ( 0.21 )
    Statistical analysis title
    		 Part 1 versus Part 3 AUC0-48Cmax
    Comparison groups
    Biostate SP (Day 1 or 8) v Biostate SP (Day 180)
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.471
    Method
    		 ANOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.06
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -0.09
         upper limit
    		 0.21

    Primary: PK Parameter, Part 1 Versus Part 3: Time of Maximum Concentration (tmax)

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    End point title
    		 PK Parameter, Part 1 Versus Part 3: Time of Maximum Concentration (tmax) [23]
    End point description
    End point type
    Primary
    End point timeframe
    Days 1, 8, and Day 180: preinfusion; 30 (±5) min, 2 h (±5 min), 4 h (±15 min), 8 h (±30 min), 12 h (±30 min); Days 2, 9, and 181: 24 h (±2 h), 28 h (±2 h); Days 3, 10, and 182: 48 h (±2 h) after the end of infusion.
    Notes
    [23] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Planned analyses for this endpoint are presented in data table.
    End point values
    		 Biostate SP (Day 1 or 8) Biostate SP (Day 180)
    Number of subjects analysed
    15
    15
    Units: hours
        median (full range (min-max))
    0.5 (0.42 to 4.03)
    0.5 (0.42 to 2)
    No statistical analyses for this end point

    Primary: PK Parameter, Part 1 Versus Part 3: Minimum Plasma Concentration (Cmin)

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    End point title
    		 PK Parameter, Part 1 Versus Part 3: Minimum Plasma Concentration (Cmin) [24]
    End point description
    End point type
    Primary
    End point timeframe
    Blood samples were collected prior to dosing, at 30 min, 2, 4, 8, 12, 24, 28, and 48 hours after the end of infusion on Days 1 and 8 (Part 1) or Day 180 (Part 3)
    Notes
    [24] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Planned analyses for this endpoint are presented in data table.
    End point values
    		 Biostate SP (Day 1 or 8) Biostate SP (Day 180)
    Number of subjects analysed
    15
    15
    Units: IU/mL
        arithmetic mean (standard deviation)
    0.059 ( 0.029 )
    0.06 ( 0.026 )
    No statistical analyses for this end point

    Primary: PK Parameter, Part 1 Versus Part 3: Total Clearance (CL)

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    End point title
    		 PK Parameter, Part 1 Versus Part 3: Total Clearance (CL) [25]
    End point description
    End point type
    Primary
    End point timeframe
    Days 1, 8, and Day 180: preinfusion; 30 (±5) min, 2 h (±5 min), 4 h (±15 min), 8 h (±30 min), 12 h (±30 min); Days 2, 9, and 181: 24 h (±2 h), 28 h (±2 h); Days 3, 10, and 182: 48 h (±2 h) after the end of infusion.
    Notes
    [25] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Planned analyses for this endpoint are presented in data table.
    End point values
    		 Biostate SP (Day 1 or 8) Biostate SP (Day 180)
    Number of subjects analysed
    15
    15
    Units: mL/(h*kg)
        arithmetic mean (standard deviation)
    4.03 ( 1.18 )
    3.64 ( 0.81 )
    No statistical analyses for this end point

    Primary: PK Parameter, Part 1 Versus Part 3: Volume at Steady State (Vss)

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    End point title
    		 PK Parameter, Part 1 Versus Part 3: Volume at Steady State (Vss) [26]
    End point description
    End point type
    Primary
    End point timeframe
    Days 1, 8, and Day 180: preinfusion; 30 (±5) min, 2 h (±5 min), 4 h (±15 min), 8 h (±30 min), 12 h (±30 min); Days 2, 9, and 181: 24 h (±2 h), 28 h (±2 h); Days 3, 10, and 182: 48 h (±2 h) after the end of infusion.
    Notes
    [26] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Planned analyses for this endpoint are presented in data table.
    End point values
    		 Biostate SP (Day 1 or 8) Biostate SP (Day 180)
    Number of subjects analysed
    15
    15
    Units: mL/kg
        arithmetic mean (standard deviation)
    67.35 ( 19.68 )
    60.07 ( 16.15 )
    No statistical analyses for this end point

    Secondary: Overview of Adverse Events During the Entire Study

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    End point title
    		 Overview of Adverse Events During the Entire Study
    End point description
    An adverse event (AE) was defined as any untoward medical occurrence in a subject administered a pharmaceutical product and that does not necessarily have a causal relationship to the study product. A serious AE was defined as any untoward medical occurrence that at any dose: results in death; is life-threatening; requires inpatient hospitalisation or prolongation of existing hospitalisation; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect; is another medically important condition. The intensity/severity of AEs was categorized as mild, moderate, or severe.
    End point type
    Secondary
    End point timeframe
    Day 1 through the Final Study Visit (Day 187 or within 7 days after last infusion)
    End point values
    		 Biostate SP
    Number of subjects analysed
    81 [27]
    Units: subjects
        At Least 1 Adverse Event (AE)
    39
        At Least 1 Severe AE
    3
        At Least 1 Serious AE
    4
        At Least 1 AE Leading to Discontinuation
    1
        At Least 1 AE Leading to Death
    0
    Notes
    [27] - Safety population: all subjects who received at least 1 dose of of Biostate SP or Biostate RP.
    No statistical analyses for this end point

    Secondary: Development of FVIII Inhibitors

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    End point title
    		 Development of FVIII Inhibitors
    End point description
    Testing at Screening and Day 1 was prior to treatment. No subject developed inhibitors during the study; 1 subject had a positive test result, which was also reported as SAE that led to study discontinuation, however, after the event, delayed analysis of the subject’s blood sample from Day 1 revealed that an increased inhibitor titre was already present at baseline prior to the first dose of Biostate.
    End point type
    Secondary
    End point timeframe
    Screening, Day 1, Month 1, Month 3, and Final Visit (Day 187 or within 7 days after last infusion)
    End point values
    		 Biostate SP
    Number of subjects analysed
    81 [28]
    Units: subjects
        Screening: FVIII Inhibitor Test Negative; n=81
    81
        Screening: FVIII Inhibitor Test Positive; n=81
    0
        Day 1: FVIII Inhibitor Test Negative; n=18
    17
        Day 1: FVIII Inhibitor Test Positive; n=18
    1
        Month 1: FVIII Inhibitor Test Negative; n=81
    81
        Month 1: FVIII Inhibitor Test Positive; n=81
    0
        Month 3: FVIII Inhibitor Test Negative; n=80
    80
        Month 3: FVIII Inhibitor Test Positive; n=80
    0
        Final Visit: FVIII Inhibitor Test Negative; n=79
    78
        Final Visit: FVIII Inhibitor Test Positive; n=79
    1
    Notes
    [28] - In 1 subject an inhibitor was found at final visit that was already present before the 1st dose (D1)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Day 1 through Final Visit (Day 187 or within 7 days after last infusion)
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    11.1
    Reporting groups
    Reporting group title
    Safety Population
    Reporting group description
    		 All subjects who received at least 1 dose of Biostate SP or Biostate RP were monitored throughout their participation in the study and included in the safety population analysis.

    Serious adverse events
    		 Safety Population
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 81 (4.94%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    1 / 81 (1.23%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Blood and lymphatic system disorders
    Factor VIII inhibition
         subjects affected / exposed
    1 / 81 (1.23%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Condition aggravated
         subjects affected / exposed
    1 / 81 (1.23%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Epstein-Barr virus infection
         subjects affected / exposed
    1 / 81 (1.23%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hepatic echinococciasis
         subjects affected / exposed
    1 / 81 (1.23%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pneumonia mycoplasmal
         subjects affected / exposed
    1 / 81 (1.23%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Safety Population
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    16 / 81 (19.75%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    5 / 81 (6.17%)
         occurrences all number
    5
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    7 / 81 (8.64%)
         occurrences all number
    34
    Infections and infestations
    Viral infection
         subjects affected / exposed
    8 / 81 (9.88%)
         occurrences all number
    8

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    21 Jan 2009
    - The duration of the screening period was increased from up to 7 days to up to 14 days to allow sufficient processing time for the screening assessment. - Reduced blood volumes for children were inserted. - Introduction of the Independent Data Monitoring Committee (IDMC). - Definition of major bleeding events was revised. - FVIII level, haematology, and biochemistry determinations prior to major bleeding events or surgical procedures, respectively, were deleted.
    29 Apr 2009
    - Change of the exclusion criteria to allow the admission of subjects with a positive hepatitis C viral load but to exclude subjects with an active hepatitis C. - Bicarbonate testing was deleted from biochemistry determinations as the testing procedure is contraindicated for bleeding disorders. - Inconsistencies with regard to the start of the reporting period of AEs were resolved.
    04 Nov 2009
    - Change of laboratory parameters at screening to perform HIV viral load testing only if subjects were HIV antibody positive. - Increase of the number of enrolled subjects from approximately 62 to approximately 80. This change in sample size was made in order to collect more efficacy data; the PK component and thus the sample size estimation as given in Section 9.7.2 was not affected by this change. - Increase of the number of evaluable subjects from at least 50 subjects to at least 65 subjects. - Specification of “prevention of bleedings” within the on-demand treatment regimen. As described in Section 9.4.5, it was found that in some centres subjects did not take Biostate in a prophylaxis regimen with regular administrations at intervals of 2-3 days (see Table 1) but as “prophlylactic treatment” only when they expected to have an increased bleeding risk, eg, prior to physical exercise. This mainly occurred with subjects who undertook muscle or joint exercises as part of their rehabilitation after a surgical event or after a bleeding event in joints. A dose of 25-30 IU/kg FVIII was administered prior to such exercises. An algorithm to differentiate between prophylaxis and prevention treatment, and to assign subjects to corresponding subgroups was defined in the SAP prior to final database lock.

    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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