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    Clinical Trial Results:
    A Phase I/III Open-label, Multicenter, Crossover Safety, Efficacy and Pharmacokinetic Study of Recombinant Coagulation Factor VIII (rFVIII ) Compared to Recombinant Human Antihaemophilic Factor VIII (rFVIII; INN: octocog alfa) in Subjects with Hemophilia A, and a Repeat PK, Safety and Efficacy Study

    Summary
    EudraCT number
    		 2011-002393-23
    Trial protocol
    		 DE   SE   AT   IT   PL   GB   ES   HU   NL   CZ  
    Global end of trial date
    12 Dec 2014

    Results information
    Results version number
    		 v2(current)
    This version publication date
    29 Jul 2016
    First version publication date
    10 Jul 2015
    Other versions
    		 v1
    Version creation reason
    • Correction of full data set
    Minor corrections made

    Trial information

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    Trial identification
    Sponsor protocol code
    CSL627_1001
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01486927
    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
    Clin.Trial Registration Coordinator, CSL Behring GmbH, clinicaltrials@cslbehring.com
    Scientific contact
    Clin.Trial Registration Coordinator, CSL Behring GmbH, clinicaltrials@cslbehring.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-001215-PIP01-11
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    23 Jan 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    12 Dec 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To characterize the pharmacokinetic (PK) profile of rVIII-SingleChain To demonstrate efficacy in the prevention and treatment of bleeding events To demonstrate the efficacy of routine prophylaxis treatment over on-demand treatment To demonstrate the efficacy of rVIII-SingleChain in surgical prophylaxis To characterize the rate of inhibitor formation
    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 or the subject’s legally acceptable representative (ie, for subjects ≥ 12 to < 18 years), 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 could cease study treatment and withdraw the subject, or the subject could withdraw himself from participation in the study at any time. The decision to withdraw consent and discontinue participation in the study could not prejudice the subject’s future medical treatment in any way.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    15 Feb 2012
    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
    Netherlands: 4
    Country: Number of subjects enrolled
    Poland: 24
    Country: Number of subjects enrolled
    Spain: 3
    Country: Number of subjects enrolled
    South Africa: 16
    Country: Number of subjects enrolled
    United Kingdom: 3
    Country: Number of subjects enrolled
    Austria: 5
    Country: Number of subjects enrolled
    Ukraine: 11
    Country: Number of subjects enrolled
    Czech Republic: 2
    Country: Number of subjects enrolled
    United States: 22
    Country: Number of subjects enrolled
    Germany: 19
    Country: Number of subjects enrolled
    Hungary: 2
    Country: Number of subjects enrolled
    Italy: 10
    Country: Number of subjects enrolled
    Australia: 8
    Country: Number of subjects enrolled
    Canada: 1
    Country: Number of subjects enrolled
    Japan: 10
    Country: Number of subjects enrolled
    Lebanon: 3
    Country: Number of subjects enrolled
    Malaysia: 9
    Country: Number of subjects enrolled
    Philippines: 10
    Country: Number of subjects enrolled
    Romania: 3
    Country: Number of subjects enrolled
    Russian Federation: 9
    Worldwide total number of subjects
    174
    EEA total number of subjects
    75
    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)
    14
    Adults (18-64 years)
    160
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 This multicenter, multinational study enrolled subjects at 54 participating study centers in the United States, Japan, Europe, Australia, Canada, Lebanon, Malaysia, Philippines, Russian Federation, South Africa, and Ukraine.

    Pre-assignment
    Screening details
    		 Screening took place 4 to 28 days prior to first dose of study product (rVIII-SingleChain). A total of 204 subjects were screened, 29 of these did not fulfill all eligibility criteria and were therefore screening failures. A total of 175 subjects were enrolled; 174 subjects were exposed to treatment with rVIII-SingleChain.

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Recombinant Factor VIII (rFVIII)
    Arm description
    		 In Part 1 of the study (a single-sequence crossover pharmacokinetic [PK] analysis), 27 subjects received a single injection of octocog alfa followed by a single injection of rVIII-SingleChain. Twenty-six of the 27 subjects from Part 1 then entered Part 2 of the study where they were assigned either to an on-demand or prophylaxis regimen with repeat injections of rVIII-SingleChain until they reached 50 exposure days (EDs). In Part 3 of the study, 148 additional subjects were enrolled and were assigned either to an on-demand or prophylaxis regimen with repeat injections of rVIII-SingleChain until they reached 50 EDs; 64 of these subjects participated in additional PK analyses. Overall, 174 subjects received rVIII-SingleChain as either on-demand or prophylaxis regimens, and 13 subjects participated in the surgical substudy.
    Arm type
    		 Experimental

    Investigational medicinal product name
    rVIII-SingleChain
    Investigational medicinal product code
    CSL627
    Other name
    Pharmaceutical forms
    Powder and solvent for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    In Part 1 of the study, subjects received a single infusion of 50 IU/kg rVIII-SingleChain preceded by a 4-day washout period. In Parts 2 and 3 of the study, subjects received repeat injections of rVIII-SingleChain either as an on-demand or prophylaxis regimen at a dose and frequency determined by their study doctor. Subjects participating in the Part 3 PK analyses received a single infusion of 50 IU/kg rVIII-SingleChain and a repeat dose of the same strength of rVIII-SingleChain, after 3 to 6 months. Subjects from Parts 2 and 3 participating in the surgical substudy received an individualized dose regimen of rVIII-SingleChain, based on the type of surgery and the clinical status of the subject.

    Investigational medicinal product name
    Octocog alfa
    Investigational medicinal product code
    Other name
    Human coagulation factor VIII (rDNA)
    Pharmaceutical forms
    Powder and solvent for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    In Part 1 of the study, subjects received a single infusion of 50 IU/kg of octocog alfa preceded by a 4-day washout period.

    Number of subjects in period 1
    		Recombinant Factor VIII (rFVIII)
    Started
    174
    Completed
    161
    Not completed
    13
         50 Exposure days not reached
    2
         Subject did not reach 6 months of treatment
    1
         Consent withdrawn by subject
    8
         Physician decision
    1
         Right knee surgery (prior to surgery substudy)
    1

    Baseline characteristics

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

    Reporting group values
    		 Overall trial Total
    Number of subjects
    		 174 174
    Age categorical
    Units: Subjects
        Adolescents (12-17 years)
    		 14 14
        Adults (18-65 years)
    		 160 160
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 31.3 ± 11.77 -
    Gender categorical
    Units: Subjects
        Female
    		 0 0
        Male
    		 174 174
    Type of FVIII product used before enrollment
    Type of FVIII product used by the subjects before enrollment into the study. This could have been a plasma-derived FVIII product or a recombinant FVIII product.
    Units: Subjects
        Plasma-derived Product
    		 83 83
        Recombinant Product
    		 91 91
    Treatment modality of FVIII therapy before enrollment
    Treatment modality of FVIII therapy before enrollment, ie, routine prophylaxis or on-demand treatment. If a subject used both modalities, only the most recent one was counted.
    Units: Subjects
        Prophylaxis
    		 82 82
        On-demand
    		 92 92

    End points

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    End points reporting groups
    Reporting group title
    Recombinant Factor VIII (rFVIII)
    Reporting group description
    		 In Part 1 of the study (a single-sequence crossover pharmacokinetic [PK] analysis), 27 subjects received a single injection of octocog alfa followed by a single injection of rVIII-SingleChain. Twenty-six of the 27 subjects from Part 1 then entered Part 2 of the study where they were assigned either to an on-demand or prophylaxis regimen with repeat injections of rVIII-SingleChain until they reached 50 exposure days (EDs). In Part 3 of the study, 148 additional subjects were enrolled and were assigned either to an on-demand or prophylaxis regimen with repeat injections of rVIII-SingleChain until they reached 50 EDs; 64 of these subjects participated in additional PK analyses. Overall, 174 subjects received rVIII-SingleChain as either on-demand or prophylaxis regimens, and 13 subjects participated in the surgical substudy.

    Subject analysis set title
    PK population (Part 1)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    The PK population (Part 1) consisted of subjects who had received 1 dose of 50 IU/kg of rVIII-SingleChain and for whom a sufficient number of analyzable PK samples were obtained to permit the evaluation of the PK profile. In the Part 1 PK analysis, these subjects also received 1 dose of 50 IU/kg octocog alfa. There were 27 subjects in the PK population (Part 1).

    Subject analysis set title
    rVIII-SingleChain PK population (Part 3)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    The rVIII-SingleChain PK population (Part 3) consisted of subjects who received rVIII-SingleChain during Part 3 of the study (initial and repeat dose) and for whom a sufficient number of analyzable PK samples were obtained to permit the evaluation of the PK profile. In Part 3, 64 subjects participated in the initial PK, of whom 30 also participated in the repeat PK.

    Subject analysis set title
    rVIII-SingleChain On-demand
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The rVIII-SingleChain On-demand group consisted of all subjects in the efficacy population who received at least 1 dose rVIII-SingleChain as part of on-demand treatment during Parts 2 or 3 of the study. There were 27 subjects in the rVIII-SingleChain On-demand group.

    Subject analysis set title
    rVIII-SingleChain Prophylaxis
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The rVIII-SingleChain Prophylaxis group consisted of all subjects in the efficacy population who received at least 1 dose rVIII-SingleChain as part of routine prophylaxis treatment during Parts 2 or 3 of the study. There were 146 subjects in the rVIII-SingleChain Prophylaxis group.

    Subject analysis set title
    rVIII-SingleChain Surgical
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    The rVIII-SingleChain Surgical group included all subjects enrolled in the surgical sub-study who received at least 1 dose of rVIII-SingleChain during the surgical sub-study. There were 13 subjects in the rVIII-SingleChain Surgical group.

    Subject analysis set title
    rVIII-SingleChain
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The Efficacy population consisted of all subjects who received at least one dose of rVIII-SingleChain as part of either routine prophylaxis treatment or on-demand treatment during Parts 2 or 3 of the study. There were 173 subjects in the Efficacy population.

    Primary: Treatment success

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    End point title
    		 Treatment success [1]
    End point description
    The investigator rated the efficacy of the treatment based on a 4-point rating scale "excellent, good, moderate or poor/no response". Efficacy ratings of "excellent" or "good" were considered treatment success for this end point; the percentage of bleeding events with a rating of excellent or good and the 95% confidence interval are presented. The denominator includes all treated bleeding events. The 95% confidence interval is based on a model to account for within-subject correlation.
    End point type
    Primary
    End point timeframe
    Up to 24 months
    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: Data were analyzed using descriptive statistics only.
    End point values
    		 rVIII-SingleChain On-demand rVIII-SingleChain Prophylaxis rVIII-SingleChain
    Number of subjects analysed
    27 [2]
    146 [3]
    173 [4]
    Units: % bleeding events successfully treated
        number (confidence interval 95%)
    92.4 (87.8 to 95.3)
    92.2 (86.3 to 95.8)
    92.3 (88.9 to 94.8)
    Notes
    [2] - Number of treated bleeding events = 590
    [3] - Number of treated bleeding events = 258
    [4] - Number of treated bleeding events = 848
    No statistical analyses for this end point

    Primary: Inhibitor formation to FVIII

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    End point title
    		 Inhibitor formation to FVIII [5]
    End point description
    Number of subjects who develop inhibitors to FVIII
    End point type
    Primary
    End point timeframe
    Up to 24 months
    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: Data were analyzed using descriptive statistics only.
    End point values
    		 Recombinant Factor VIII (rFVIII)
    Number of subjects analysed
    174
    Units: Subjects
    0
    No statistical analyses for this end point

    Primary: Annualized spontaneous bleeding rate

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    End point title
    		 Annualized spontaneous bleeding rate
    End point description
    The annualized spontaneous bleeding rate (AsBR) was derived for each subject as follows: 365.25*(number of spontaneous bleeding episodes requiring treatment) / (observed treatment period of interest).
    End point type
    Primary
    End point timeframe
    Up to 24 months
    End point values
    		 rVIII-SingleChain On-demand rVIII-SingleChain Prophylaxis
    Number of subjects analysed
    27
    146
    Units: Number of spontaneous bleeds per year
        median (inter-quartile range (Q1-Q3))
    11.73 (2.8 to 36.5)
    0 (0 to 2.4)
    Statistical analysis title
    		 Prophylaxis/On-demand
    Comparison groups
    rVIII-SingleChain Prophylaxis v rVIII-SingleChain On-demand
    Number of subjects included in analysis
    173
    Analysis specification
    Pre-specified
    Analysis type
    		 other [6]
    P-value
    		 < 0.0001
    Method
    		 Poisson, regression
    Parameter type
    		 Rate ratio
    Point estimate
    0.08
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.07
         upper limit
    		 0.1
    Notes
    [6] - A test of the null hypothesis of no difference on AsBR between the 2 comparison groups was based on the Poisson Regression method. The corresponding prophylaxis/on-demand ratio with 95% CI was calculated.

    Primary: Treatment success during the peri-operative surgical sub-study

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    End point title
    		 Treatment success during the peri-operative surgical sub-study [7]
    End point description
    Subjects received rVIII-SingleChain before and during surgery based on the type of surgery and the clinical status of the subject. The investigator rated the efficacy of the treatment based on a 4-point surgical treatment rating scale of "excellent, good, moderate or poor/no response". Efficacy ratings of "excellent" or "good" were considered treatment success for this endpoint. The rate of success, defined as the percentage of surgeries with a rating of excellent or good for hemostatic efficacy on the surgical treatment scale is presented for the Surgical Population, based on the total number of surgeries (N=16) as denominator.
    End point type
    Primary
    End point timeframe
    From the start of surgery through the post-operative recovery (generally up to 14 days after surgery)
    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: Data were analyzed using descriptive statistics only.
    End point values
    		 rVIII-SingleChain Surgical
    Number of subjects analysed
    13
    Units: % of surgeries with successful treatment
        number (not applicable)
    100
    No statistical analyses for this end point

    Secondary: AUC0-∞ (Part 1)

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    End point title
    		 AUC0-∞ (Part 1)
    End point description
    AUC0-∞ (AUC from 0 extrapolated to infinity) of a single infusion of octocog alfa and rVIII-SingleChain without correction for subject's predose plasma FVIII activity. FVIII activity values for octocog alfa are dose-adjusted for chromogenic potency.
    End point type
    Secondary
    End point timeframe
    Before infusion and at up to 10 time points within 72 hours of infusion
    End point values
    		 PK population (Part 1)
    Number of subjects analysed
    27
    Units: IU*h/dL
    arithmetic mean (standard deviation)
        Octocog alfa
    1550 ± 552
        rVIII-SingleChain
    2090 ± 650
    No statistical analyses for this end point

    Secondary: Cmax (Part 1)

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    End point title
    		 Cmax (Part 1)
    End point description
    Cmax of a single infusion of octocog alfa and rVIII-SingleChain with correction for subject's predose plasma FVIII activity. FVIII activity values for octocog alfa are dose-adjusted for chromogenic potency.
    End point type
    Secondary
    End point timeframe
    Before infusion and at up to 10 time points within 72 hours of infusion
    End point values
    		 PK population (Part 1)
    Number of subjects analysed
    27
    Units: IU/dL
    arithmetic mean (standard deviation)
        Octocog alfa
    116 ± 18.1
        rVIII-SingleChain
    113 ± 17.4
    No statistical analyses for this end point

    Secondary: Tmax (Part 1)

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    End point title
    		 Tmax (Part 1)
    End point description
    Tmax = time of Cmax (with correction for subject's predose plasma FVIII activity) after a single infusion of octocog alfa and rVIII-SingleChain.
    End point type
    Secondary
    End point timeframe
    Before infusion and at up to 10 time points within 72 hours of infusion
    End point values
    		 PK population (Part 1)
    Number of subjects analysed
    27
    Units: hours
    median (full range (min-max))
        Octocog alfa
    0.583 (0.45 to 0.8)
        rVIII-SingleChain
    0.683 (0.467 to 1.25)
    No statistical analyses for this end point

    Secondary: Half-life (t1/2) (Part 1)

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    End point title
    		 Half-life (t1/2) (Part 1)
    End point description
    Half-life (t1/2) of a single infusion of octocog alfa and rVIII-SingleChain without correction for subject's predose plasma FVIII activity.
    End point type
    Secondary
    End point timeframe
    Before infusion and at up to 10 time points within 72 hours of infusion.
    End point values
    		 PK population (Part 1)
    Number of subjects analysed
    27
    Units: hours
    arithmetic mean (standard deviation)
        Octocog alfa
    13.3 ± 4.36
        rVIII-SingleChain
    14.5 ± 3.77
    No statistical analyses for this end point

    Secondary: Mean residence time (MRT) (Part 1)

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    End point title
    		 Mean residence time (MRT) (Part 1)
    End point description
    Mean residence time (MRT) of a single infusion of octocog alfa and rVIII-SingleChain without correction for subject's predose plasma FVIII activity.
    End point type
    Secondary
    End point timeframe
    Before infusion and at up to 10 time points within 72 hours of infusion
    End point values
    		 PK population (Part 1)
    Number of subjects analysed
    27
    Units: hours
    arithmetic mean (standard deviation)
        Octocog alfa
    17.1 ± 5.57
        rVIII-SingleChain
    20.4 ± 5.49
    No statistical analyses for this end point

    Secondary: Clearance (Cl) (Part 1)

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    End point title
    		 Clearance (Cl) (Part 1)
    End point description
    Clearance (Cl) of a single infusion of octocog alfa and rVIII-SingleChain without correction for subject's predose plasma FVIII activity. FVIII activity values for octocog alfa are dose-adjusted for chromogenic potency.
    End point type
    Secondary
    End point timeframe
    Before infusion and at up to 10 time points within 72 hours of infusion
    End point values
    		 PK population (Part 1)
    Number of subjects analysed
    27
    Units: mL/h/kg
    arithmetic mean (standard deviation)
        Octocog alfa
    3.68 ± 1.41
        rVIII-SingleChain
    2.64 ± 0.846
    No statistical analyses for this end point

    Secondary: Volume of distribution at steady-state (Vss) (Part 1)

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    End point title
    		 Volume of distribution at steady-state (Vss) (Part 1)
    End point description
    Volume of distribution at steady-state (Vss) of a single infusion of octocog alfa and rVIII-SingleChain without correction for subject's predose plasma FVIII activity. FVIII activity values for octocog alfa are dose-adjusted for chromogenic potency.
    End point type
    Secondary
    End point timeframe
    Before infusion and at up to 10 time points within 72 hours of infusion
    End point values
    		 PK population (Part 1)
    Number of subjects analysed
    27
    Units: mL/kg
    arithmetic mean (standard deviation)
        Octocog alfa
    57.1 ± 11.3
        rVIII-SingleChain
    50 ± 7.51
    No statistical analyses for this end point

    Secondary: Incremental recovery (Part 1)

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    End point title
    		 Incremental recovery (Part 1)
    End point description
    Incremental recovery of a single infusion of octocog alfa and rVIII-SingleChain with correction for subject's predose plasma FVIII activity. FVIII activity values for octocog alfa are dose-adjusted for chromogenic potency.
    End point type
    Secondary
    End point timeframe
    At 30 minutes after infusion
    End point values
    		 PK population (Part 1)
    Number of subjects analysed
    27
    Units: [IU/dL]/[IU/kg]
    arithmetic mean (standard deviation)
        Octocog alfa
    2.32 ± 0.381
        rVIII-SingleChain
    2.24 ± 0.357
    No statistical analyses for this end point

    Secondary: Annualized bleeding rate for total bleeds and traumatic bleeds

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    End point title
    		 Annualized bleeding rate for total bleeds and traumatic bleeds
    End point description
    The annualized bleeding rate was derived for each subject as follows: 365.25*(number of bleeding episodes requiring treatment) / (observed treatment period of interest).
    End point type
    Secondary
    End point timeframe
    Up to 24 months
    End point values
    		 rVIII-SingleChain On-demand rVIII-SingleChain Prophylaxis
    Number of subjects analysed
    27
    146
    Units: Number of bleeds per year
    median (inter-quartile range (Q1-Q3))
        Total Bleeds
    19.64 (6.2 to 46.5)
    1.14 (0 to 4.2)
        Traumatic Bleeds
    3.12 (0 to 8.4)
    0 (0 to 0.9)
    No statistical analyses for this end point

    Secondary: Proportion of bleeding episodes requiring 1, 2, 3 or > 3 infusions of rVIII-SingleChain to achieve hemostasis

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    End point title
    		 Proportion of bleeding episodes requiring 1, 2, 3 or > 3 infusions of rVIII-SingleChain to achieve hemostasis
    End point description
    Percentage of bleeding episodes requiring 1, 2, 3 or > 3 infusions of rVIII-SingleChain (rVIII-SC) to achieve hemostasis. The denominator includes all treated bleeding episodes.
    End point type
    Secondary
    End point timeframe
    During the study (up to 24 months; assessed at Months 1, 2, 3, 4, 5, 6, 9, 12, 15, 18, 21 and 24)
    End point values
    		 rVIII-SingleChain On-demand rVIII-SingleChain Prophylaxis rVIII-SingleChain
    Number of subjects analysed
    27 [8]
    146 [9]
    173 [10]
    Units: Percentage of bleeding episodes
    number (not applicable)
        Requiring 1 rVIII-SC infusion for hemostasis
    82.7
    76.7
    80.9
        Requiring 2 rVIII-SC infusions for hemostasis
    12
    14
    12.6
        Requiring 3 rVIII-SC infusions for hemostasis
    3.22
    3.88
    3.42
        Requiring >3 rVIII-SC infusions for hemostasis
    2.03
    5.43
    3.07
    Notes
    [8] - Number of treated bleeding episodes = 590
    [9] - Number of treated bleeding episodes = 258
    [10] - Number of treated bleeding episodes = 848
    No statistical analyses for this end point

    Other pre-specified: AUC0-∞ (Part 3)

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    End point title
    		 AUC0-∞ (Part 3)
    End point description
    AUC0-∞ (AUC from 0 extrapolated to infinity) of an initial and repeat infusion of rVIII-SingleChain without correction for subject's predose plasma FVIII activity.
    End point type
    Other pre-specified
    End point timeframe
    Before infusion and at up to 12 time points within 96 hours of infusion
    End point values
    		 rVIII-SingleChain PK population (Part 3)
    Number of subjects analysed
    64
    Units: IU*h/dL
    arithmetic mean (standard deviation)
        Initial, n = 64
    1830 ± 640
        Repeat, n = 30
    1880 ± 649
    No statistical analyses for this end point

    Other pre-specified: Cmax (Part 3)

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    End point title
    		 Cmax (Part 3)
    End point description
    Cmax of an initial and repeat infusion of rVIII-SingleChain with correction for subject's predose plasma FVIII activity.
    End point type
    Other pre-specified
    End point timeframe
    Before infusion and at up to 12 time points within 96 hours of infusion
    End point values
    		 rVIII-SingleChain PK population (Part 3)
    Number of subjects analysed
    63
    Units: IU/dL
    arithmetic mean (standard deviation)
        Initial, n = 63
    99.9 ± 19.9
        Repeat, n = 29
    108 ± 18.5
    No statistical analyses for this end point

    Other pre-specified: Tmax (Part 3)

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    End point title
    		 Tmax (Part 3)
    End point description
    Tmax = time of Cmax (with correction for subject's predose plasma FVIII activity) after an initial and repeat infusion of rVIII-SingleChain.
    End point type
    Other pre-specified
    End point timeframe
    Before infusion and at up to 12 time points within 96 hours of infusion.
    End point values
    		 rVIII-SingleChain PK population (Part 3)
    Number of subjects analysed
    63
    Units: hours
    median (full range (min-max))
        Initial, n = 63
    0.333 (0.117 to 1.22)
        Repeat, n = 29
    0.317 (0.117 to 0.667)
    No statistical analyses for this end point

    Other pre-specified: Half-life (t1/2) (Part 3)

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    End point title
    		 Half-life (t1/2) (Part 3)
    End point description
    Half-life (t1/2) of an initial and repeat infusion of rVIII-SingleChain without correction for subject's predose plasma FVIII activity.
    End point type
    Other pre-specified
    End point timeframe
    Before infusion and at up to 12 time points within 96 hours of infusion.
    End point values
    		 rVIII-SingleChain PK population (Part 3)
    Number of subjects analysed
    64
    Units: hours
    arithmetic mean (standard deviation)
        Initial, n = 64
    14.1 ± 3.82
        Repeat, n = 30
    12.9 ± 3.7
    No statistical analyses for this end point

    Other pre-specified: Mean residence time (MRT) (Part 3)

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    End point title
    		 Mean residence time (MRT) (Part 3)
    End point description
    Mean residence time (MRT) of an initial and repeat infusion of rVIII-SingleChain without correction for subject's predose plasma FVIII activity.
    End point type
    Other pre-specified
    End point timeframe
    Before infusion and at up to 12 time points within 96 hours of infusion.
    End point values
    		 rVIII-SingleChain PK population (Part 3)
    Number of subjects analysed
    64
    Units: hours
    arithmetic mean (standard deviation)
        Initial, n = 64
    20.3 ± 5.36
        Repeat, n = 30
    18.9 ± 5.39
    No statistical analyses for this end point

    Other pre-specified: Clearance (Cl) (Part 3)

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    End point title
    		 Clearance (Cl) (Part 3)
    End point description
    Clearance (Cl) of an initial and repeat infusion of rVIII-SingleChain without correction for subject's predose plasma FVIII activity.
    End point type
    Other pre-specified
    End point timeframe
    Before infusion and at up to 12 time points within 96 hours of infusion.
    End point values
    		 rVIII-SingleChain PK population (Part 3)
    Number of subjects analysed
    64
    Units: mL/h/kg
    arithmetic mean (standard deviation)
        Initial, n = 64
    3.15 ± 1.21
        Repeat, n = 30
    3.05 ± 1.1
    No statistical analyses for this end point

    Other pre-specified: Volume of distribution at steady-state (Vss) (Part 3)

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    End point title
    		 Volume of distribution at steady-state (Vss) (Part 3)
    End point description
    Volume of distribution at steady-state (Vss) of an initial and repeat infusion of rVIII-SingleChain without correction for subject's predose plasma FVIII activity.
    End point type
    Other pre-specified
    End point timeframe
    Before infusion and at up to 12 time points within 96 hours of infusion.
    End point values
    		 rVIII-SingleChain PK population (Part 3)
    Number of subjects analysed
    64
    Units: mL/kg
    arithmetic mean (standard deviation)
        Initial, n = 64
    59.5 ± 14.2
        Repeat, n = 30
    53.1 ± 8.74
    No statistical analyses for this end point

    Other pre-specified: Incremental recovery (Part 3)

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    End point title
    		 Incremental recovery (Part 3)
    End point description
    Incremental recovery of an initial and repeat infusion of rVIII-SingleChain with correction for subject's predose plasma FVIII activity.
    End point type
    Other pre-specified
    End point timeframe
    At 30 minutes after infusion
    End point values
    		 rVIII-SingleChain PK population (Part 3)
    Number of subjects analysed
    63
    Units: [IU/dL]/[IU/kg]
    arithmetic mean (standard deviation)
        Initial, n = 63
    1.85 ± 0.404
        Repeat, n = 29
    1.99 ± 0.352
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    For the duration of the study, approximately 2 years, 10 months.
    Adverse event reporting additional description
    The Safety Population comprised all subjects treated with rVIII-SingleChain. A total of 14592 rVIII-SingleChain infusions were administered to 174 subjects during the study.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    14.1
    Reporting groups
    Reporting group title
    Safety Population
    Reporting group description
    		 The Safety Population comprised all subjects treated with rVIII-SingleChain.

    Serious adverse events
    		 Safety Population
    Total subjects affected by serious adverse events
         subjects affected / exposed
    8 / 174 (4.60%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Investigations
    Blood uric acid increased
         subjects affected / exposed
    1 / 174 (0.57%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Injury, poisoning and procedural complications
    Ankle fracture
         subjects affected / exposed
    1 / 174 (0.57%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 174 (0.57%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    1 / 174 (0.57%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    1 / 174 (0.57%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Varices oesophageal
         subjects affected / exposed
    1 / 174 (0.57%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Tonsillar haemorrhage
         subjects affected / exposed
    1 / 174 (0.57%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Psychiatric disorders
    Suicidal ideation
         subjects affected / exposed
    1 / 174 (0.57%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Postoperative wound infection
         subjects affected / exposed
    1 / 174 (0.57%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Viral infection
         subjects affected / exposed
    1 / 174 (0.57%)
         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
    45 / 174 (25.86%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    13 / 174 (7.47%)
         occurrences all number
    14
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    20 / 174 (11.49%)
         occurrences all number
    22
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    18 / 174 (10.34%)
         occurrences all number
    22

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    29 Feb 2012
    Protocol Amendment 1 included the following main change: PK sample collection time in Part 1 changed from 28 to 32 h post dose throughout protocol.
    06 Jul 2012
    Protocol Amendment 2 included the following main changes: • PK sample collection time points changed in Part 3 • Statement of inclusion of Japanese centers in Part 3 • Schedule of Assessment tables revised for clarity • IMP reconstitution table updated for multiple presentations and concentrations • Number of evaluable subjects required clarified • Exclusion of subjects not capable of home treatment added • Additional safety criteria added • Prior FVIII half-life and recovery collection specified for Part 3 • Clarification of pharmacokinetic population
    24 May 2013
    Protocol Amendment 3 included the following main changes: • The duration of the subject study participation was clarified to allow subjects to be treated with rVIII-SingleChain for 50 EDs and continue on treatment until the end of study visit or extension study. • Cohort screening size was increased to ensure sufficient evaluable subjects. • Laboratory assessments and confirmation of results were clarified for central and local laboratories. • The roles and responsibilities of the IDMC were updated to provide increased subject safety. • Recording of actual dosing over nominal dosing was clarified to accurately reflect dosing. • Definitions of overdose, treatment compliance, and retention of samples were added to guide sites in proper study conduct. • Additional subject information (gene defect and blood group, if available) was collected. • Assessment for antibodies against CHO cells was added for subject safety. • Assessment for antibodies against FVIII at screening / Day 1 for subject safety. • AE reporting processes were updated. • Statistical analyses and methods were clarified.
    10 Mar 2014
    Protocol Amendment 4 included the following main changes: • Addition of a co-primary objective of efficacy of routine prophylaxis treatment over on-demand treatment. • Addition of AsBR as a primary endpoint. • Addition of annualized bleeding rate as a secondary endpoint. • The statistical methodology was updated.

    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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