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    Clinical Trial Results:
    A Multicenter, Open-Label, Multiple Ascending Dose Study to Evaluate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Efficacy of Subcutaneous or Intravenous PF-06741086 in Subjects With Severe Hemophilia

    Summary
    EudraCT number
    		 2016-001885-27
    Trial protocol
    		 PL   ES   FR   BG   HR  
    Global end of trial date
    03 Dec 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    02 Dec 2019
    First version publication date
    02 Dec 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    B7841002
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02974855
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Pfizer,Inc.
    Sponsor organisation address
    235 E 42nd Street, New York, United States, NY 10017
    Public contact
    Pfizer ClinicalTrials.gov Call Center, Pfizer,Inc., +1 18007181021, ClinicalTrials.gov_Inquiries@pfizer.com
    Scientific contact
    Pfizer ClinicalTrials.gov Call Center, Pfizer,Inc., +1 18007181021, ClinicalTrials.gov_Inquiries@pfizer.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    23 May 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    03 Dec 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    03 Dec 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective was to determine the safety and tolerability of multiple doses of PF-06741086 administered to severe hemophilia A and B subjects with and without inhibitors to Factor VIII (FVIII) or Factor IX (FIX).
    Protection of trial subjects
    This study was conducted in compliance with the ethical principles originating in or derived from the Declaration of Helsinki and in compliance with all International Council for Harmonization (ICH) Good Clinical Practice (GCP) Guidelines. In addition, all local regulatory requirements were followed, in particular, those affording greater protection to the safety of subjects.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    08 Mar 2017
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Efficacy, Safety
    Long term follow-up duration
    		 1 Months
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Chile: 10
    Country: Number of subjects enrolled
    Croatia: 2
    Country: Number of subjects enrolled
    Poland: 1
    Country: Number of subjects enrolled
    South Africa: 10
    Country: Number of subjects enrolled
    Switzerland: 1
    Country: Number of subjects enrolled
    United States: 2
    Worldwide total number of subjects
    26
    EEA total number of subjects
    3
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    26
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 A total of 27 subjects were enrolled in the study and assigned to 1 of 4 cohorts. Only 26 subjects received the study treatment and 1 subject withdrew after randomization but prior to dosing.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 PF-06741086 300 mg SC QW Non-Inhibitor
    Arm description
    		 Subjects without inhibitors to Factor VIII (FVIII) or Factor IX (FIX) in this cohort received PF-06741086 300 mg subcutaneously (SC) once weekly (QW) from Day 1 to Day 78.
    Arm type
    		 Experimental

    Investigational medicinal product name
    PF-06741086 Solution for Injection, 100 mg/mL
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    PF-06741086 300 mg was administered subcutaneously every week.

    Arm title
    		 PF-06741086 300 mg SC Loading + 150 mg SC QW Non-Inhibitor
    Arm description
    		 Subjects without inhibitors to FVIII or FIX in this cohort received PF-06741086 300 mg loading dose on Day 1 and 150 mg SC QW from Day 8 to Day 78.
    Arm type
    		 Experimental

    Investigational medicinal product name
    PF-06741086 Solution for Injection, 100 mg/mL
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    PF-06741086 300 mg loading dose, PF-06741086 150 mg was administered subcutaneously every week.

    Arm title
    		 PF-06741086 450 mg SC QW Non-Inhibitor
    Arm description
    		 Subjects without inhibitors to FVIII or FIX in this cohort received PF-06741086 450 mg SC QW from Day 1 to Day 78.
    Arm type
    		 Experimental

    Investigational medicinal product name
    PF-06741086 Solution for Injection, 100 mg/mL
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    PF-06741086 450 mg was administered subcutaneously every week.

    Arm title
    		 PF-06741086 300 mg SC QW Inhibitor
    Arm description
    		 Subjects with inhibitors to FVIII or FIX in this cohort received PF-06741086 300 mg SC QW from Day 1 to Day 78.
    Arm type
    		 Experimental

    Investigational medicinal product name
    PF-06741086 Solution for Injection, 100 mg/mL
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    PF-06741086 300 mg was administered subcutaneously every week.

    Number of subjects in period 1
    		PF-06741086 300 mg SC QW Non-Inhibitor PF-06741086 300 mg SC Loading + 150 mg SC QW Non-Inhibitor PF-06741086 450 mg SC QW Non-Inhibitor PF-06741086 300 mg SC QW Inhibitor
    Started
    7
    6
    6
    7
    Completed
    7
    5
    6
    6
    Not completed
    0
    1
    0
    1
         Adverse event, non-fatal
    -
    1
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    PF-06741086 300 mg SC QW Non-Inhibitor
    Reporting group description
    		 Subjects without inhibitors to Factor VIII (FVIII) or Factor IX (FIX) in this cohort received PF-06741086 300 mg subcutaneously (SC) once weekly (QW) from Day 1 to Day 78.

    Reporting group title
    PF-06741086 300 mg SC Loading + 150 mg SC QW Non-Inhibitor
    Reporting group description
    		 Subjects without inhibitors to FVIII or FIX in this cohort received PF-06741086 300 mg loading dose on Day 1 and 150 mg SC QW from Day 8 to Day 78.

    Reporting group title
    PF-06741086 450 mg SC QW Non-Inhibitor
    Reporting group description
    		 Subjects without inhibitors to FVIII or FIX in this cohort received PF-06741086 450 mg SC QW from Day 1 to Day 78.

    Reporting group title
    PF-06741086 300 mg SC QW Inhibitor
    Reporting group description
    		 Subjects with inhibitors to FVIII or FIX in this cohort received PF-06741086 300 mg SC QW from Day 1 to Day 78.

    Reporting group values
    		 PF-06741086 300 mg SC QW Non-Inhibitor PF-06741086 300 mg SC Loading + 150 mg SC QW Non-Inhibitor PF-06741086 450 mg SC QW Non-Inhibitor PF-06741086 300 mg SC QW Inhibitor Total
    Number of subjects
    		 7 6 6 7 26
    Age Categorical
    Units: Subjects
        <=18 years
    		 0 0 0 0 0
        Between 18 and 65 years
    		 7 6 6 7 26
        >=65 years
    		 0 0 0 0 0
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 31.9 ± 8.17 28.7 ± 8.31 41.7 ± 15.87 44.1 ± 9.44 -
    Sex: Female, Male
    Units: Subjects
        Female
    		 0 0 0 0 0
        Male
    		 7 6 6 7 26
    Race (NIH/OMB)
    Units: Subjects
        White
    		 3 2 6 3 14
        Black or African American
    		 4 4 0 4 12
        Other
    		 0 0 0 0 0
    Subject analysis sets

    Subject analysis set title
    Overall PF-06741086 300 mg SC
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The overall PF-06741086 300 mg SC group combined subjects from both the PF-06741086 300 mg SC QW non-inhibitor and inhibitor dose cohorts.

    Subject analysis set title
    Total
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The total group combined subjects from all PF-06741086 cohorts in this study.

    Subject analysis sets values
    		 Overall PF-06741086 300 mg SC Total
    Number of subjects
    14
    26
    Age Categorical
    Units: Subjects
        <=18 years
    0
    0
        Between 18 and 65 years
    14
    26
        >=65 years
    0
    0
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    38.0 ± 10.61
    36.7 ± 12.05
    Sex: Female, Male
    Units: Subjects
        Female
    0
    0
        Male
    14
    26
    Race (NIH/OMB)
    Units: Subjects
        White
    6
    14
        Black or African American
    8
    12
        Other
    0
    0

    End points

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    End points reporting groups
    Reporting group title
    PF-06741086 300 mg SC QW Non-Inhibitor
    Reporting group description
    		 Subjects without inhibitors to Factor VIII (FVIII) or Factor IX (FIX) in this cohort received PF-06741086 300 mg subcutaneously (SC) once weekly (QW) from Day 1 to Day 78.

    Reporting group title
    PF-06741086 300 mg SC Loading + 150 mg SC QW Non-Inhibitor
    Reporting group description
    		 Subjects without inhibitors to FVIII or FIX in this cohort received PF-06741086 300 mg loading dose on Day 1 and 150 mg SC QW from Day 8 to Day 78.

    Reporting group title
    PF-06741086 450 mg SC QW Non-Inhibitor
    Reporting group description
    		 Subjects without inhibitors to FVIII or FIX in this cohort received PF-06741086 450 mg SC QW from Day 1 to Day 78.

    Reporting group title
    PF-06741086 300 mg SC QW Inhibitor
    Reporting group description
    		 Subjects with inhibitors to FVIII or FIX in this cohort received PF-06741086 300 mg SC QW from Day 1 to Day 78.

    Subject analysis set title
    Overall PF-06741086 300 mg SC
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The overall PF-06741086 300 mg SC group combined subjects from both the PF-06741086 300 mg SC QW non-inhibitor and inhibitor dose cohorts.

    Subject analysis set title
    Total
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The total group combined subjects from all PF-06741086 cohorts in this study.

    Primary: Number of Subjects With Treatment Emergent Adverse Events (TEAEs)

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    End point title
    		 Number of Subjects With Treatment Emergent Adverse Events (TEAEs) [1]
    End point description
    An adverse event (AE) was any untoward medical occurrence in a clinical investigation participant administered a product; the event did not need to have a causal relationship with the treatment. A serious adverse event (SAE) was any untoward medical occurrence at any dose that resulted in death; was life threatening; required inpatient hospitalization or prolongation of existing hospitalization; resulted in persistent or significant disability/incapacity; resulted in congenital anomaly/birth defect. AEs included both SAEs and AEs. TEAEs were AEs occurred following the start of treatment or AEs increasing in severity during treatment. Severe TEAEs were TEAEs that interfered significantly with participants' usual function. Treatment-related TEAEs were determined by the investigator.
    End point type
    Primary
    End point timeframe
    Study Day 1 to Day 113 Visit
    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: No statistical analysis was planned for this endpoint
    End point values
    		 PF-06741086 300 mg SC QW Non-Inhibitor PF-06741086 300 mg SC Loading + 150 mg SC QW Non-Inhibitor PF-06741086 450 mg SC QW Non-Inhibitor PF-06741086 300 mg SC QW Inhibitor Overall PF-06741086 300 mg SC Total
    Number of subjects analysed
    7
    6
    6
    7
    14
    26
    Units: Subjects
        All-causalities TEAE
    7
    4
    6
    4
    11
    21
        Treatment-related TEAE
    4
    4
    3
    3
    7
    14
        All-causalities serious TEAE
    1
    1
    1
    1
    2
    4
        Treatment-related serious TEAE
    0
    0
    0
    0
    0
    0
        All-causalities Grade 3 or 4 TEAE
    0
    0
    2
    2
    2
    4
        Treatment-related Grade 3 or 4 TEAE
    0
    0
    2
    2
    2
    4
    No statistical analyses for this end point

    Primary: Number of Subjects Discontinued From Study due to TEAEs

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    End point title
    		 Number of Subjects Discontinued From Study due to TEAEs [2]
    End point description
    An AE was any untoward medical occurrence in a clinical investigation participant administered a product; the event did not need to have a causal relationship with the treatment. TEAEs were AEs occurred following the start of treatment or AEs increasing in severity during treatment. Treatment-related TEAEs were determined by the investigator.
    End point type
    Primary
    End point timeframe
    Study Day 1 to Day 113 Visit
    Notes
    [2] - 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: No statistical analysis was planned for this endpoint
    End point values
    		 PF-06741086 300 mg SC QW Non-Inhibitor PF-06741086 300 mg SC Loading + 150 mg SC QW Non-Inhibitor PF-06741086 450 mg SC QW Non-Inhibitor PF-06741086 300 mg SC QW Inhibitor Overall PF-06741086 300 mg SC Total
    Number of subjects analysed
    7
    6
    6
    7
    14
    26
    Units: Subjects
        All-causalities TEAE
    0
    1
    0
    1
    1
    2
        Treatment-related TEAE
    0
    1
    0
    1
    1
    2
    No statistical analyses for this end point

    Primary: Number of Subjects With Abnormal Laboratory Findings-Hematology

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    End point title
    		 Number of Subjects With Abnormal Laboratory Findings-Hematology [3]
    End point description
    Hematology evaluation included: hemoglobin, hematocrit, erythrocytes, platelets, leukocytes, lymphocytes, neutrophils, basophils, eosinophils and monocytes. Pre-defined criteria for hemoglobin and hematocrit: <0.8*lower limit of normal (LLN) or <0.8*Baseline(Baseline <1.0*LLN); for platelets: <100,000 *10^3/mm^3 or <= 0.77*Baseline (Baseline <1.0*LLN).
    End point type
    Primary
    End point timeframe
    Baseline to Study Day 113 Visit
    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: No statistical analysis was planned for this endpoint
    End point values
    		 PF-06741086 300 mg SC QW Non-Inhibitor PF-06741086 300 mg SC Loading + 150 mg SC QW Non-Inhibitor PF-06741086 450 mg SC QW Non-Inhibitor PF-06741086 300 mg SC QW Inhibitor Overall PF-06741086 300 mg SC Total
    Number of subjects analysed
    7
    6
    6
    7
    14
    26
    Units: Subjects
        Hemoglobin meeting pre-defined criteria
    0
    0
    0
    0
    0
    0
        Hematocrit meeting pre-defined criteria
    0
    0
    0
    0
    0
    0
        Erythrocytes <0.8*LLN
    0
    0
    0
    0
    0
    0
        Platelets meeting pre-defined criteria
    0
    0
    0
    0
    0
    0
        Leukocytes <0.6*LLN
    0
    0
    0
    0
    0
    0
        Leukocytes >1.5*upper limit of normal (ULN)
    0
    0
    0
    0
    0
    0
        Lymphocytes <0.8*LLN
    0
    1
    0
    0
    0
    1
        Lymphocytes >1.2*ULN
    0
    0
    0
    0
    0
    0
        Neutrophils <0.8*LLN
    1
    2
    0
    0
    1
    3
        Neutrophils >1.2*ULN
    0
    0
    0
    0
    0
    0
        Basophils >1.2*ULN
    0
    0
    0
    0
    0
    0
        Eosinophils >1.2*ULN
    0
    0
    0
    0
    0
    0
        Monocytes >1.2*ULN
    0
    0
    0
    0
    0
    0
    No statistical analyses for this end point

    Primary: Number of Subjects With Abnormal Laboratory Findings-Clinical Chemistry

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    End point title
    		 Number of Subjects With Abnormal Laboratory Findings-Clinical Chemistry [4]
    End point description
    Clinical chemistry evaluation included bilirubin, direct and indirect bilirubin, aspartate aminotransferase, alanine aminotransferase, gamma glutamyl transferase, alkaline phosphatase, protein, albumin, urea nitrogen, creatinine, urate, triglycerides, sodium, potassium, chloride, calcium, bicarbonate, glucose, creatine kinase, troponin I, cholesterol and fibrinogen.
    End point type
    Primary
    End point timeframe
    Baseline to Study Day 113
    Notes
    [4] - 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: No statistical analysis was planned for this endpoint
    End point values
    		 PF-06741086 300 mg SC QW Non-Inhibitor PF-06741086 300 mg SC Loading + 150 mg SC QW Non-Inhibitor PF-06741086 450 mg SC QW Non-Inhibitor PF-06741086 300 mg SC QW Inhibitor Overall PF-06741086 300 mg SC Total
    Number of subjects analysed
    7 [5]
    6 [6]
    6 [7]
    7 [8]
    14 [9]
    26 [10]
    Units: Subjects
        Bilirubin >1.5*ULN
    0
    0
    0
    0
    0
    0
        Direct Bilirubin >1.5*ULN
    0
    0
    0
    0
    0
    0
        Indirect Bilirubin >1.5*ULN
    0
    0
    0
    0
    0
    0
        Aspartate Aminotransferase >3.0*ULN
    0
    0
    1
    0
    0
    1
        Alanine Aminotransferase >3.0* ULN
    1
    1
    1
    0
    1
    3
        Gamma Glutamyl Transferase >3.0*ULN
    0
    1
    0
    0
    0
    1
        Alkaline Phosphatase|
    0
    0
    0
    0
    0
    0
        Protein <0.8*LLN
    0
    0
    0
    0
    0
    0
        Protein >1.2*ULN
    0
    0
    0
    0
    0
    0
        Albumin <0.8*LLN
    0
    0
    0
    0
    0
    0
        Albumin >1.2*ULN
    0
    0
    0
    0
    0
    0
        Urea Nitrogen >1.3*ULN
    0
    0
    0
    0
    0
    0
        Creatinine >1.3*ULN
    0
    0
    0
    0
    0
    0
        Urate >1.2*ULN
    0
    0
    0
    2
    2
    2
        Triglycerides >1.3*ULN
    0
    0
    0
    0
    0
    0
        Sodium <0.95*LLN
    0
    0
    0
    0
    0
    0
        Sodium >1.05*ULN
    0
    0
    0
    0
    0
    0
        Potassium <0.9*LLN
    1
    0
    0
    0
    1
    1
        Potassium >1.1*ULN
    0
    0
    0
    0
    0
    0
        Chloride <0.9*LLN
    0
    0
    0
    0
    0
    0
        Chloride >1.1*ULN
    0
    0
    0
    0
    0
    0
        Calcium <0.9*LLN
    0
    0
    0
    0
    0
    0
        Calcium >1.1*ULN
    0
    0
    0
    0
    0
    0
        Bicarbonate <0.9*LLN
    2
    1
    0
    0
    2
    3
        Bicarbonate >1.1*ULN
    0
    0
    0
    0
    0
    0
        Glucose <0.6*LLN
    0
    0
    0
    0
    0
    0
        Glucose >1.5*ULN
    0
    0
    2
    1
    1
    3
        Creatine Kinase >2.0*ULN
    0
    0
    0
    0
    0
    0
        Troponin I >1.0*ULN
    1
    1
    0
    2
    3
    4
        Cholesterol >1.3*ULN
    0
    0
    0
    0
    0
    0
        Fibrinogen <=0.5*LLN
    0
    0
    0
    1
    1
    1
    Notes
    [5] - Not all subjects had data for some specific categories.
    [6] - Not all subjects had data for some specific categories.
    [7] - Not all subjects had data for some specific categories.
    [8] - Not all subjects had data for some specific categories.
    [9] - Not all subjects had data for some specific categories.
    [10] - Not all subjects had data for some specific categories.
    No statistical analyses for this end point

    Primary: Number of Subjects With Abnormal Laboratory Findings-Urinalysis

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    End point title
    		 Number of Subjects With Abnormal Laboratory Findings-Urinalysis [11]
    End point description
    Urinalysis included: pH, urine glucose, ketones, urine protein, urine hemoglobin, urobilinogen, urine bilirubin, nitrite, leukocyte esterase, urine erythrocytes, urine leukocytes and bacteria.
    End point type
    Primary
    End point timeframe
    Baseline to Study Day 113 Visit
    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: No statistical analysis was planned for this endpoint
    End point values
    		 PF-06741086 300 mg SC QW Non-Inhibitor PF-06741086 300 mg SC Loading + 150 mg SC QW Non-Inhibitor PF-06741086 450 mg SC QW Non-Inhibitor PF-06741086 300 mg SC QW Inhibitor Overall PF-06741086 300 mg SC Total
    Number of subjects analysed
    7 [12]
    6 [13]
    6 [14]
    7 [15]
    14 [16]
    26 [17]
    Units: Subjects
        pH (Scalar) <4.5
    0
    0
    0
    0
    0
    0
        pH (Scalar) >8
    0
    0
    0
    0
    0
    0
        Urine glucose >=1
    0
    0
    1
    0
    0
    1
        Ketones (Scalar) >=1
    0
    0
    1
    1
    1
    2
        Urine protein >=1
    0
    0
    0
    1
    1
    1
        Urine hemoglobin (Scalar) >=1
    0
    0
    0
    0
    0
    0
        Urobilinogen >=1
    0
    0
    0
    0
    0
    0
        Urine bilirubin (Scalar) >=1
    0
    0
    0
    0
    0
    0
        Nitrite (Scalar) >=1
    0
    0
    0
    0
    0
    0
        Leukocyte esterase (Scalar) >=1
    1
    1
    0
    1
    2
    3
        Urine erythrocytes (/HPF) >=20
    0
    0
    0
    0
    0
    0
        Urine leukocytes (/HPF) >=20
    0
    1
    0
    1
    1
    2
        Bacteria (/HPF) >20
    0
    0
    0
    0
    0
    0
    Notes
    [12] - Not all subjects had data for some specific categories.
    [13] - Not all subjects had data for some specific categories.
    [14] - Not all subjects had data for some specific categories.
    [15] - Not all subjects had data for some specific categories.
    [16] - Not all subjects had data for some specific categories.
    [17] - Not all subjects had data for some specific categories.
    No statistical analyses for this end point

    Primary: Change From Baseline for Globulin by Dose Cohort

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    End point title
    		 Change From Baseline for Globulin by Dose Cohort [18]
    End point description
    Blood samples were obtained to determine globulin level in serum, total globulin was derived as total protein other than albumin.
    End point type
    Primary
    End point timeframe
    Baseline, Study Day 8, 15, 22, 29, 57, 85 and 113.
    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: No statistical analysis was planned for this endpoint
    End point values
    		 PF-06741086 300 mg SC QW Non-Inhibitor PF-06741086 300 mg SC Loading + 150 mg SC QW Non-Inhibitor PF-06741086 450 mg SC QW Non-Inhibitor PF-06741086 300 mg SC QW Inhibitor Overall PF-06741086 300 mg SC Total
    Number of subjects analysed
    7 [19]
    6 [20]
    6 [21]
    7 [22]
    14 [23]
    26 [24]
    Units: gram/liter
    arithmetic mean (standard deviation)
        Globulin, Change at Day 8
    -0.3 ± 3.04
    -1.7 ± 3.93
    -1.3 ± 2.73
    0.4 ± 2.51
    0.1 ± 2.70
    -0.7 ± 3.01
        Globulin, Change at Day 15
    -0.7 ± 2.06
    -0.8 ± 2.32
    -1.3 ± 2.50
    -1.3 ± 3.35
    -1.0 ± 2.69
    -1.0 ± 2.47
        Globulin, Change at Day 22
    -1.6 ± 2.82
    -0.5 ± 1.52
    -1.5 ± 3.08
    -0.6 ± 4.12
    -1.1 ± 3.43
    -1.0 ± 2.93
        Globulin, Change at Day 29
    -0.3 ± 3.27
    -0.3 ± 3.08
    0.2 ± 1.10
    -1.3 ± 2.75
    -0.8 ± 2.91
    -0.5 ± 2.62
        Globulin, Change at Day 57
    0.7 ± 3.72
    1.8 ± 2.99
    -0.3 ± 1.63
    -0.7 ± 2.94
    0.0 ± 3.28
    0.4 ± 2.90
        Globulin, Change at Day 85
    1.3 ± 3.15
    -1.4 ± 4.77
    -0.5 ± 3.02
    1.0 ± 2.61
    1.2 ± 2.79
    0.2 ± 3.35
        Globulin, Change at Day 113
    -0.3 ± 3.15
    -1.2 ± 4.67
    0.5 ± 2.65
    -0.8 ± 3.06
    -0.5 ± 2.99
    -0.5 ± 3.33
    Notes
    [19] - Not all subjects had data for some specific rows of time points.
    [20] - Not all subjects had data for some specific rows of time points.
    [21] - Not all subjects had data for some specific rows of time points.
    [22] - Not all subjects had data for some specific rows of time points.
    [23] - Not all subjects had data for some specific rows of time points.
    [24] - Not all subjects had data for some specific rows of time points.
    No statistical analyses for this end point

    Primary: Change From Baseline for Prothrombin International Normalized Ratio (PT/INR) by Dose Cohort

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    End point title
    		 Change From Baseline for Prothrombin International Normalized Ratio (PT/INR) by Dose Cohort [25]
    End point description
    Blood samples were obtained to evaluate this ratio. The prothrombin time (PT) is a test that helps evaluate your ability to appropriately form blood clots. The international normalized ratio (INR) is a calculation based on results of a PT that is used to monitor individuals who are being treated with the blood-thinning medication (anticoagulant) warfarin (Coumadin®).
    End point type
    Primary
    End point timeframe
    Baseline, Study Day 8, 15, 22, 29, 57, 85 and 113.
    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: No statistical analysis was planned for this endpoint
    End point values
    		 PF-06741086 300 mg SC QW Non-Inhibitor PF-06741086 300 mg SC Loading + 150 mg SC QW Non-Inhibitor PF-06741086 450 mg SC QW Non-Inhibitor PF-06741086 300 mg SC QW Inhibitor Overall PF-06741086 300 mg SC Total
    Number of subjects analysed
    7 [26]
    6 [27]
    6 [28]
    7 [29]
    14 [30]
    26 [31]
    Units: Ratio
    arithmetic mean (standard deviation)
        PT/INR, Change at Day 8
    -0.03 ± 0.049
    -0.02 ± 0.041
    0.05 ± 0.138
    0.03 ± 0.138
    0.00 ± 0.104
    0.01 ± 0.102
        PT/INR, Change at Day 15
    0.03 ± 0.076
    0.00 ± 0.063
    0.02 ± 0.041
    0.00 ± 0.082
    0.01 ± 0.077
    0.01 ± 0.065
        PT/INR, Change at Day 22
    0.03 ± 0.095
    0.00 ± 0.063
    -0.02 ± 0.041
    -0.01 ± 0.069
    0.01 ± 0.083
    0.00 ± 0.069
        PT/INR, Change at Day 29
    0.03 ± 0.082
    -0.02 ± 0.041
    0.00 ± 0.063
    0.00 ± 0.115
    0.02 ± 0.099
    0.00 ± 0.079
        PT/INR, Change at Day 57
    0.00 ± 0.126
    -0.03 ± 0.052
    0.00 ± 0.063
    -0.02 ± 0.075
    -0.01 ± 0.100
    -0.01 ± 0.080
        PT/INR, Change at Day 85
    -0.01 ± 0.107
    0.04 ± 0.152
    -0.02 ± 0.075
    -0.03 ± 0.082
    -0.02 ± 0.093
    -0.01 ± 0.102
        PT/INR, Change at Day 113
    0.06 ± 0.127
    -0.03 ± 0.052
    -0.05 ± 0.058
    0.07 ± 0.052
    0.06 ± 0.096
    0.02 ± 0.094
    Notes
    [26] - Not all subjects had data for some specific rows of time points.
    [27] - Not all subjects had data for some specific rows of time points.
    [28] - Not all subjects had data for some specific rows of time points.
    [29] - Not all subjects had data for some specific rows of time points.
    [30] - Not all subjects had data for some specific rows of time points.
    [31] - Not all subjects had data for some specific rows of time points.
    No statistical analyses for this end point

    Primary: Change From Baseline for Activated Partial Thromboplastin Time (aPTT) by Dose Cohort

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    End point title
    		 Change From Baseline for Activated Partial Thromboplastin Time (aPTT) by Dose Cohort [32]
    End point description
    The activated partial thromboplastin time (aPTT) is a screening test that helps evaluate a person's ability to appropriately form blood clots. It measures the number of seconds it takes for a clot to form in a sample of blood after substances (reagents) are added. Blood sample were obtained to evaluate aPTT.
    End point type
    Primary
    End point timeframe
    Baseline, Study Day 8, 15, 22, 29, 57, 85 and 113.
    Notes
    [32] - 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: No statistical analysis was planned for this endpoint
    End point values
    		 PF-06741086 300 mg SC QW Non-Inhibitor PF-06741086 300 mg SC Loading + 150 mg SC QW Non-Inhibitor PF-06741086 450 mg SC QW Non-Inhibitor PF-06741086 300 mg SC QW Inhibitor Overall PF-06741086 300 mg SC Total
    Number of subjects analysed
    7 [33]
    6 [34]
    6 [35]
    7 [36]
    14 [37]
    26 [38]
    Units: seconds
    arithmetic mean (standard deviation)
        aPTT, Change at Day 8
    8.49 ± 17.017
    10.63 ± 11.634
    11.03 ± 15.467
    -12.26 ± 7.082
    -1.89 ± 16.512
    3.98 ± 16.079
        aPTT, Change at Day 15
    9.50 ± 10.907
    12.50 ± 15.303
    1.20 ± 20.075
    -10.26 ± 6.757
    -0.38 ± 13.457
    2.96 ± 15.825
        aPTT, Change at Day 22
    14.79 ± 10.799
    12.15 ± 15.232
    4.50 ± 9.765
    -11.77 ± 11.247
    1.51 ± 17.381
    4.65 ± 15.543
        aPTT, Change at Day 29
    13.42 ± 11.102
    9.85 ± 15.999
    10.13 ± 10.250
    -12.87 ± 11.390
    -0.74 ± 17.386
    4.41 ± 16.009
        aPTT, Change at Day 57
    13.65 ± 13.378
    14.25 ± 14.061
    7.82 ± 11.580
    -9.13 ± 8.390
    2.26 ± 15.966
    6.65 ± 14.817
        aPTT, Change at Day 85
    9.00 ± 10.928
    3.84 ± 18.089
    7.68 ± 14.733
    -7.57 ± 10.124
    1.35 ± 13.278
    3.45 ± 14.257
        aPTT, Change at Day 113
    8.46 ± 23.391
    0.78 ± 16.332
    -0.97 ± 26.633
    9.37 ± 20.265
    8.88 ± 21.093
    5.05 ± 20.500
    Notes
    [33] - Not all subjects had data for some specific rows of time points.
    [34] - Not all subjects had data for some specific rows of time points.
    [35] - Not all subjects had data for some specific rows of time points.
    [36] - Not all subjects had data for some specific rows of time points.
    [37] - Not all subjects had data for some specific rows of time points.
    [38] - Not all subjects had data for some specific rows of time points.
    No statistical analyses for this end point

    Primary: Change From Baseline for Fibrinogen by Dose Cohort

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    End point title
    		 Change From Baseline for Fibrinogen by Dose Cohort [39]
    End point description
    Fibrinogen is a protein, specifically a clotting factor (factor I), that is essential for proper blood clot formation. Blood samples were obtained to evaluate the amount of fibrinogen.
    End point type
    Primary
    End point timeframe
    Baseline, Study Day 8, 15, 22, 29, 57, 85 and 113.
    Notes
    [39] - 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: No statistical analysis was planned for this endpoint
    End point values
    		 PF-06741086 300 mg SC QW Non-Inhibitor PF-06741086 300 mg SC Loading + 150 mg SC QW Non-Inhibitor PF-06741086 450 mg SC QW Non-Inhibitor PF-06741086 300 mg SC QW Inhibitor Overall PF-06741086 300 mg SC Total
    Number of subjects analysed
    7 [40]
    6 [41]
    6 [42]
    7 [43]
    14 [44]
    26 [45]
    Units: milligram/deciliter
    arithmetic mean (standard deviation)
        Fibrinogen, Change at Day 8
    -49.7 ± 28.72
    -59.7 ± 38.20
    -3.5 ± 24.16
    -54.4 ± 59.58
    -52.1 ± 45.00
    -42.6 ± 44.14
        Fibrinogen, Change at Day 15
    -59.4 ± 41.28
    -51.0 ± 31.84
    -8.3 ± 25.96
    -85.6 ± 94.86
    -72.5 ± 71.58
    -52.7 ± 60.78
        Fibrinogen, Change at Day 22
    -72.0 ± 40.76
    -36.8 ± 44.93
    -33.2 ± 32.41
    -87.9 ± 115.49
    -79.9 ± 83.61
    -59.2 ± 69.08
        Fibrinogen, Change at Day 29
    -84.7 ± 43.53
    -40.0 ± 26.57
    -40.3 ± 20.99
    -99.9 ± 106.59
    -92.8 ± 80.82
    -67.6 ± 65.01
        Fibrinogen, Change at Day 57
    -33.5 ± 85.81
    10.0 ± 79.34
    -21.3 ± 24.23
    -58.7 ± 71.81
    -46.1 ± 76.57
    -25.9 ± 69.68
        Fibrinogen, Change at Day 85
    -49.9 ± 47.93
    -39.4 ± 63.27
    -10.5 ± 44.94
    -40.8 ± 74.28
    -45.7 ± 58.91
    -35.6 ± 56.31
        Fibrinogen, Change at Day 113
    -38.6 ± 44.48
    -5.2 ± 29.34
    23.5 ± 26.80
    -61.7 ± 126.18
    -49.2 ± 88.13
    -25.1 ± 73.56
    Notes
    [40] - Not all subjects had data for some specific rows of time points.
    [41] - Not all subjects had data for some specific rows of time points.
    [42] - Not all subjects had data for some specific rows of time points.
    [43] - Not all subjects had data for some specific rows of time points.
    [44] - Not all subjects had data for some specific rows of time points.
    [45] - Not all subjects had data for some specific rows of time points.
    No statistical analyses for this end point

    Primary: Change From Baseline for Antithrombin III by Dose Cohort

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    End point title
    		 Change From Baseline for Antithrombin III by Dose Cohort [46]
    End point description
    Antithrombin (AT) is a protein produced by the liver that helps regulate blood clot formation (i.e., a naturally-occurring mild blood thinner). Blood samples were collected to measure the activity (function) and the amount (quantity) of antithrombin in an individual's blood is used to evaluate the person for excessive blood clotting.
    End point type
    Primary
    End point timeframe
    Baseline, Study Day 8, 15, 22 and 29.
    Notes
    [46] - 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: No statistical analysis was planned for this endpoint
    End point values
    		 PF-06741086 300 mg SC QW Non-Inhibitor PF-06741086 300 mg SC Loading + 150 mg SC QW Non-Inhibitor PF-06741086 450 mg SC QW Non-Inhibitor PF-06741086 300 mg SC QW Inhibitor Overall PF-06741086 300 mg SC Total
    Number of subjects analysed
    7 [47]
    6
    6
    7
    14 [48]
    26 [49]
    Units: Percentage of activity of AT in plasma
    arithmetic mean (standard deviation)
        Antithrombin III, Change at Day 8
    2.1 ± 5.18
    -1.8 ± 7.05
    3.7 ± 7.58
    -7.3 ± 9.32
    -2.6 ± 8.74
    -1.0 ± 8.24
        Antithrombin III, Change at Day 15
    2.4 ± 16.96
    0.5 ± 8.14
    -15.3 ± 16.45
    -6.9 ± 6.74
    -2.2 ± 13.30
    -4.6 ± 14.02
        Antithrombin III, Change at Day 22
    -7.6 ± 17.55
    5.2 ± 12.69
    -5.3 ± 9.97
    -4.4 ± 17.61
    -6.0 ± 16.97
    -3.3 ± 14.97
        Antithrombin III, Change at Day 29
    -0.8 ± 8.04
    -4.3 ± 11.55
    -10.3 ± 15.45
    -12.7 ± 12.96
    -7.2 ± 12.20
    -7.3 ± 12.51
    Notes
    [47] - Not all subjects had data at Day 29.
    [48] - Not all subjects had data at Day 29.
    [49] - Not all subjects had data at Day 29.
    No statistical analyses for this end point

    Primary: Change From Baseline for Troponin I by Dose Cohort

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    End point title
    		 Change From Baseline for Troponin I by Dose Cohort [50]
    End point description
    Blood samples were collected to measure the level of cardiac-specific troponin I in the blood to help detect heart injury.
    End point type
    Primary
    End point timeframe
    Baseline, Study Day 22 and 29
    Notes
    [50] - 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: No statistical analysis was planned for this endpoint
    End point values
    		 PF-06741086 300 mg SC QW Non-Inhibitor PF-06741086 300 mg SC Loading + 150 mg SC QW Non-Inhibitor PF-06741086 450 mg SC QW Non-Inhibitor PF-06741086 300 mg SC QW Inhibitor Overall PF-06741086 300 mg SC Total
    Number of subjects analysed
    7 [51]
    6 [52]
    6 [53]
    7 [54]
    14 [55]
    26 [56]
    Units: nanogram/milliliter
    arithmetic mean (standard deviation)
        Troponin I, Change at Day 22
    0.0042 ± 0.01021
    0 ± 0
    0 ± 0
    0.0142 ± 0.03470
    0.0092 ± 0.02494
    0.0052 ± 0.01907
        Troponin I, Change at Day 29
    0 ± 0
    0.0113 ± 0.02250
    0 ± 0
    0.0121 ± 0.03213
    0.0065 ± 0.02357
    0.0059 ± 0.02010
    Notes
    [51] - Not all subjects had data for each row of time point.
    [52] - Not all subjects had data for each row of time point.
    [53] - Not all subjects had data for each row of time point.
    [54] - Not all subjects had data for each row of time point.
    [55] - Not all subjects had data for each row of time point.
    [56] - Not all subjects had data for each row of time point.
    No statistical analyses for this end point

    Primary: Number of Subjects With Vital Signs Data Meeting Pre-specified Criteria

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    End point title
    		 Number of Subjects With Vital Signs Data Meeting Pre-specified Criteria [57]
    End point description
    Criteria for potentially clinically important findings in vital signs data were defined as: 1) supine systolic blood pressure (BP): value <90 mm Hg or change >=30 mm Hg increase; 2) Supine diastolic BP: value <50 mm Hg or change >=20 mm Hg increase; 3) Supine pulse rate: value <40 beats/min or >120 beats/min.
    End point type
    Primary
    End point timeframe
    Baseline to Study Day 113 Visit
    Notes
    [57] - 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: No statistical analysis was planned for this endpoint
    End point values
    		 PF-06741086 300 mg SC QW Non-Inhibitor PF-06741086 300 mg SC Loading + 150 mg SC QW Non-Inhibitor PF-06741086 450 mg SC QW Non-Inhibitor PF-06741086 300 mg SC QW Inhibitor Overall PF-06741086 300 mg SC Total
    Number of subjects analysed
    7
    6
    6
    7
    14
    26
    Units: Subjects
        Supine systolic BP value <90 mm Hg
    0
    0
    0
    0
    0
    0
        Supine systolic BP change >=30 mm Hg increase
    0
    1
    1
    0
    0
    2
        Supine diastolic BP value <50 mm Hg
    0
    0
    0
    0
    0
    0
        Supine diastolic BP change >=20 mm Hg increase
    0
    1
    0
    0
    0
    1
        Supine pulse rate value <40 beats/min
    0
    0
    0
    0
    0
    0
        Supine pulse rate value >120 beats/min
    0
    0
    0
    0
    0
    0
    No statistical analyses for this end point

    Primary: Number of Subjects With Electrocardiogram (ECG) Change Meeting Pre-specified Criteria

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    End point title
    		 Number of Subjects With Electrocardiogram (ECG) Change Meeting Pre-specified Criteria [58]
    End point description
    Criteria for potentially clinically important changes in ECG were defined as: PR interval baseline >200 msec and increase of >=25%; PR interval baseline <=200 msec and increase of >=50%; QRS interval increase of >=50%. Only the number of subjects meeting pre-defined criteria was reported below.
    End point type
    Primary
    End point timeframe
    Baseline to Study Day 29 Visit.
    Notes
    [58] - 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: No statistical analysis was planned for this endpoint
    End point values
    		 PF-06741086 300 mg SC QW Non-Inhibitor PF-06741086 300 mg SC Loading + 150 mg SC QW Non-Inhibitor PF-06741086 450 mg SC QW Non-Inhibitor PF-06741086 300 mg SC QW Inhibitor Overall PF-06741086 300 mg SC Total
    Number of subjects analysed
    7
    6
    6
    7
    14
    26
    Units: Subjects
    0
    0
    0
    0
    0
    0
    No statistical analyses for this end point

    Primary: Number of Subjects With Clinically Significant Changes in Physical Examination Findings

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    End point title
    		 Number of Subjects With Clinically Significant Changes in Physical Examination Findings [59]
    End point description
    Physical examination included head, ears, eyes, nose, mouth, skin, heart and lung examinations, lymph nodes, gastrointestinal, musculoskeletal, and neurological systems. Clinical significance was judged by the investigator.
    End point type
    Primary
    End point timeframe
    Baseline to Study Day 113 Visit
    Notes
    [59] - 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: No statistical analysis was planned for this endpoint
    End point values
    		 PF-06741086 300 mg SC QW Non-Inhibitor PF-06741086 300 mg SC Loading + 150 mg SC QW Non-Inhibitor PF-06741086 450 mg SC QW Non-Inhibitor PF-06741086 300 mg SC QW Inhibitor Overall PF-06741086 300 mg SC Total
    Number of subjects analysed
    7
    6
    6
    7
    14
    26
    Units: Subjects
    0
    0
    0
    0
    0
    0
    No statistical analyses for this end point

    Primary: Number of Subjects With Infusion and Injection Site Reactions

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    End point title
    		 Number of Subjects With Infusion and Injection Site Reactions [60]
    End point description
    Infusion and injection site reactions included: injection site bruising, injection site erythema, injection site haemorrhage, injection site induration, injection site pain, injection site pruritus, injection site swelling and injection site warmth. Grade of severity was defined as follows: Mild: Transient or mild discomfort (< 48 hours); no medical intervention/therapy required. Moderate: Mild to moderate limitation in activity - some assistance may be needed; no or minimal medical intervention/therapy required. Severe: Marked limitation in activity, some assistance usually required; medical intervention/therapy required, hospitalizations possible.
    End point type
    Primary
    End point timeframe
    Baseline to Study Day 113 Visit
    Notes
    [60] - 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: No statistical analysis was planned for this endpoint
    End point values
    		 PF-06741086 300 mg SC QW Non-Inhibitor PF-06741086 300 mg SC Loading + 150 mg SC QW Non-Inhibitor PF-06741086 450 mg SC QW Non-Inhibitor PF-06741086 300 mg SC QW Inhibitor Overall PF-06741086 300 mg SC Total
    Number of subjects analysed
    7
    6
    6
    7
    14
    26
    Units: Subjects
        All-causality Mild
    3
    1
    0
    1
    4
    5
        Treatment-related Mild
    3
    1
    0
    1
    4
    5
        All-causality Moderate
    0
    0
    0
    1
    1
    1
        Treatment-related Moderate
    0
    0
    0
    1
    1
    1
        All-causality Severe
    0
    0
    2
    0
    0
    2
        Treatment-related Severe
    0
    0
    2
    0
    0
    2
    No statistical analyses for this end point

    Secondary: Annualized Bleeding Rate (ABR)

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    End point title
    		 Annualized Bleeding Rate (ABR)
    End point description
    Pre-treatment ABR = number of bleeding episodes within 6 months prior to study enrollment (total number of bleeding episodes in hemophilia history CRF) × 2; On-study ABR = number of bleeding episodes occurred within 9 days after the last dose / ([last dose date + 9 - first dose date + 1] / 365.25)
    End point type
    Secondary
    End point timeframe
    Pre-treatment: within 6 months prior to study enrollment; On-study: Day 1 to 9 days after the last dose (Day 78)
    End point values
    		 PF-06741086 300 mg SC QW Non-Inhibitor PF-06741086 300 mg SC Loading + 150 mg SC QW Non-Inhibitor PF-06741086 450 mg SC QW Non-Inhibitor PF-06741086 300 mg SC QW Inhibitor Overall PF-06741086 300 mg SC Total
    Number of subjects analysed
    6
    6
    6
    6
    12
    24
    Units: Bleeding episodes per year
    arithmetic mean (standard deviation)
        Pre-Treatment
    23.00 ± 7.457
    14.67 ± 1.633
    20.33 ± 10.838
    17.33 ± 3.011
    20.17 ± 6.177
    18.83 ± 7.100
        On-Study
    4.22 ± 3.799
    1.62 ± 2.533
    4.17 ± 6.467
    0.65 ± 1.603
    2.43 ± 3.345
    2.67 ± 4.092
    No statistical analyses for this end point

    Secondary: Plasma PF-06741086 concentrations

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    End point title
    		 Plasma PF-06741086 concentrations
    End point description
    Plasma PF-06741086 concentrations were analyzed using a validated, sensitive and specific electrochemiluminescence (ECL) method. Not all subjects had data at each visit.
    End point type
    Secondary
    End point timeframe
    pre-dose on Study Day 1, 24hours (h), 72h post Study Day 1 dosing, pre-dose on Study Day 8, 15 and 22, pre-dose on Study Day 29, 24h, 96h post Study Day 29 dosing, pre-dose on Study Day 57, 168h, 840h post Study Day 57 dosing
    End point values
    		 PF-06741086 300 mg SC QW Non-Inhibitor PF-06741086 300 mg SC Loading + 150 mg SC QW Non-Inhibitor PF-06741086 450 mg SC QW Non-Inhibitor PF-06741086 300 mg SC QW Inhibitor Overall PF-06741086 300 mg SC
    Number of subjects analysed
    7 [61]
    6 [62]
    6 [63]
    7 [64]
    14 [65]
    Units: nanogram/milliliter
    arithmetic mean (standard deviation)
        Pre-dose on Day 1
    99999 ± 99999
    99999 ± 99999
    99999 ± 99999
    99999 ± 99999
    99999 ± 99999
        24h post Day 1 dosing
    12180 ± 8500.2
    15620 ± 8055.3
    11640 ± 4670.6
    18130 ± 9111.3
    15150 ± 9011.0
        72h post Day 1 dosing
    17560 ± 10637
    20850 ± 8433.7
    24270 ± 8018.9
    20640 ± 8978.4
    19100 ± 9591.3
        Pre-dose on Day 8
    11290 ± 10019
    14060 ± 6201.2
    16700 ± 5689.1
    11940 ± 4981.7
    11610 ± 7609.2
        Pre-dose on Day 15
    22850 ± 15142
    16680 ± 7668.8
    28180 ± 10163
    24870 ± 5726.8
    23860 ± 11048
        Pre-dose on Day 22
    33010 ± 19724
    17900 ± 10509
    41200 ± 17504
    36450 ± 10432
    34600 ± 15590
        Pre-dose on Day 29
    46180 ± 21357
    16780 ± 7939.7
    59950 ± 30625
    41500 ± 13884
    43840 ± 17161
        24h post Day 29 dosing
    66500 ± 27135
    23530 ± 8548.4
    73780 ± 22425
    69920 ± 27902
    68210 ± 26010
        96h post Day 29 dosing
    69130 ± 30459
    20680 ± 11580
    74950 ± 27538
    58150 ± 18753
    62860 ± 22794
        Pre-dose on Day 57
    54580 ± 29022
    18260 ± 15062
    66480 ± 45529
    59140 ± 24377
    56860 ± 25382
        168h post Day 57 dosing
    53890 ± 43483
    24800 ± 2994.4
    87500 ± 37163
    66700 ± 28971
    60300 ± 35481
        840h post Day 57 dosing
    586.6 ± 1318.4
    99999 ± 99999
    99999 ± 99999
    90.00 ± 180.00
    406.0 ± 1056.1
    Notes
    [61] - Not all subjects had data for some specific rows of time points.
    [62] - Not all subjects had data for some specific rows of time points.
    [63] - Not all subjects had data for some specific rows of time points.
    [64] - Not all subjects had data for some specific rows of time points.
    [65] - Not all subjects had data for some specific rows of time points.
    No statistical analyses for this end point

    Secondary: Area Under the Concentration-time Profile From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) of PF-06741086

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    End point title
    		 Area Under the Concentration-time Profile From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) of PF-06741086
    End point description
    AUClast was calculated by linear/Log trapezoidal method.
    End point type
    Secondary
    End point timeframe
    Pre-dose on Day 1, 24 and 96 hours post Day 1 dosing
    End point values
    		 PF-06741086 300 mg SC QW Non-Inhibitor PF-06741086 300 mg SC Loading + 150 mg SC QW Non-Inhibitor PF-06741086 450 mg SC QW Non-Inhibitor PF-06741086 300 mg SC QW Inhibitor Overall PF-06741086 300 mg SC
    Number of subjects analysed
    7
    6
    6
    7
    14
    Units: nanogram*hour/milliliter
        geometric mean (geometric coefficient of variation)
    1818000 ± 79
    2675000 ± 41
    2806000 ± 37
    2495000 ± 40
    2130000 ± 61
    No statistical analyses for this end point

    Secondary: Maximum Plasma Concentration (Cmax) of PF-06741086

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    End point title
    		 Maximum Plasma Concentration (Cmax) of PF-06741086
    End point description
    Cmax was observed directly from data. Not all subjects had data at Day 29.
    End point type
    Secondary
    End point timeframe
    Pre-dose on Day 1, 24 and 96 hours post Day 1 dosing, pre-dose on Day 29, 24 and 96 hours post Day 29 dosing
    End point values
    		 PF-06741086 300 mg SC QW Non-Inhibitor PF-06741086 300 mg SC Loading + 150 mg SC QW Non-Inhibitor PF-06741086 450 mg SC QW Non-Inhibitor PF-06741086 300 mg SC QW Inhibitor Overall PF-06741086 300 mg SC
    Number of subjects analysed
    7 [66]
    6
    6 [67]
    7 [68]
    14 [69]
    Units: nanogram/milliliter
    geometric mean (geometric coefficient of variation)
        Cmax, Day 1
    14880 ± 70
    19480 ± 42
    23070 ± 37
    19680 ± 51
    17110 ± 61
        Cmax, Day 29
    61850 ± 47
    24150 ± 44
    73490 ± 38
    66070 ± 44
    63930 ± 43
    Notes
    [66] - Not all subjects had data for some specific time points.
    [67] - Not all subjects had data for some specific time points.
    [68] - Not all subjects had data for some specific time points.
    [69] - Not all subjects had data for some specific time points.
    No statistical analyses for this end point

    Secondary: Lowest Concentration Observed During the Dosing Interval (Cmin) of PF-06741086

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    End point title
    		 Lowest Concentration Observed During the Dosing Interval (Cmin) of PF-06741086
    End point description
    Cmin was observed directly from data. Not all subjects had data at Day 29.
    End point type
    Secondary
    End point timeframe
    Post-dose on Day 2 (-6 hours/+1 day), Day 4 (-6 hours/+1 day), Day 30 (-6 hours/+1 day) and Day 33 (-6 hours/+1 day).
    End point values
    		 PF-06741086 300 mg SC QW Non-Inhibitor PF-06741086 300 mg SC Loading + 150 mg SC QW Non-Inhibitor PF-06741086 450 mg SC QW Non-Inhibitor PF-06741086 300 mg SC QW Inhibitor Overall PF-06741086 300 mg SC
    Number of subjects analysed
    7 [70]
    6
    6 [71]
    7 [72]
    14 [73]
    Units: nanogram/milliliter
    geometric mean (geometric coefficient of variation)
        Cmin, Day 1
    7980 ± 112
    13040 ± 43
    15660 ± 44
    11140 ± 41
    9429 ± 78
        Cmin, Day 29
    42120 ± 52
    15000 ± 59
    53630 ± 61
    39490 ± 37
    40790 ± 42
    Notes
    [70] - Not all subjects had data for some specific time points.
    [71] - Not all subjects had data for some specific time points.
    [72] - Not all subjects had data for some specific time points.
    [73] - Not all subjects had data for some specific time points.
    No statistical analyses for this end point

    Secondary: Time to Reach Maximum Plasma Concentration (Tmax) of PF-06741086

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    End point title
    		 Time to Reach Maximum Plasma Concentration (Tmax) of PF-06741086
    End point description
    Tmax was observed directly from data as time of first occurrence. Not all subjects had data at Day 29.
    End point type
    Secondary
    End point timeframe
    Pre-dose on Day 1, 24 and 96 hours post Day 1 dosing, pre-dose on Day 29, 24 and 96 hours post Day 29 dosing
    End point values
    		 PF-06741086 300 mg SC QW Non-Inhibitor PF-06741086 300 mg SC Loading + 150 mg SC QW Non-Inhibitor PF-06741086 450 mg SC QW Non-Inhibitor PF-06741086 300 mg SC QW Inhibitor Overall PF-06741086 300 mg SC
    Number of subjects analysed
    7 [74]
    6
    6 [75]
    7 [76]
    14 [77]
    Units: hours
    median (full range (min-max))
        Tmax, Day 1
    70.0 (69.1 to 72.8)
    69.7 (68.2 to 71.1)
    71.6 (67.6 to 72.3)
    70.7 (22.8 to 167)
    70.1 (22.8 to 167)
        Tmax, Day 29
    23.7 (23.1 to 94.2)
    23.7 (22.0 to 71.7)
    58.5 (23.3 to 97.0)
    22.8 (22.1 to 94.7)
    23.3 (22.1 to 94.7)
    Notes
    [74] - Not all subjects had data for some specific time points.
    [75] - Not all subjects had data for some specific time points.
    [76] - Not all subjects had data for some specific time points.
    [77] - Not all subjects had data for some specific time points.
    No statistical analyses for this end point

    Secondary: Area Under the Serum Concentration-time Curve Over the Dosing Interval tau (AUCtau) of PF-06741086

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    End point title
    		 Area Under the Serum Concentration-time Curve Over the Dosing Interval tau (AUCtau) of PF-06741086
    End point description
    The dosing interval tau was 1 week. AUCtau was obtained by linear/log trapezoidal method.
    End point type
    Secondary
    End point timeframe
    Pre-dose on Day 29, 24 and 96 hours post Day 29 dosing
    End point values
    		 PF-06741086 300 mg SC QW Non-Inhibitor PF-06741086 300 mg SC Loading + 150 mg SC QW Non-Inhibitor PF-06741086 450 mg SC QW Non-Inhibitor PF-06741086 300 mg SC QW Inhibitor Overall PF-06741086 300 mg SC
    Number of subjects analysed
    5
    6
    4
    5
    10
    Units: nanogram*hour/milliliter
        geometric mean (geometric coefficient of variation)
    9045000 ± 49
    3309000 ± 50
    11090000 ± 43
    9248000 ± 38
    9146000 ± 41
    No statistical analyses for this end point

    Secondary: Apparent Clearance After Oral Dose (CL/F) of PF-06741086

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    End point title
    		 Apparent Clearance After Oral Dose (CL/F) of PF-06741086
    End point description
    CL/F was calculated by dose/AUCtau.
    End point type
    Secondary
    End point timeframe
    Pre-dose on Day 29, 24 and 96 hours post Day 29 dosing
    End point values
    		 PF-06741086 300 mg SC QW Non-Inhibitor PF-06741086 300 mg SC Loading + 150 mg SC QW Non-Inhibitor PF-06741086 450 mg SC QW Non-Inhibitor PF-06741086 300 mg SC QW Inhibitor Overall PF-06741086 300 mg SC
    Number of subjects analysed
    5
    6
    4
    5
    10
    Units: milliliter/hour
        geometric mean (geometric coefficient of variation)
    33.16 ± 49
    45.34 ± 50
    40.60 ± 43
    32.43 ± 38
    32.79 ± 41
    No statistical analyses for this end point

    Secondary: Change From Baseline in Total Tissue Factor Pathway Inhibitor (TFPI)

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    End point title
    		 Change From Baseline in Total Tissue Factor Pathway Inhibitor (TFPI)
    End point description
    Total amount of tissue factor pathway inhibitor (TFPI) (bound and unbound) in plasma. TFPI is a protease inhibitor which acts as an antagonist of the extrinsic coagulation pathway via inhibition of tissue factor activated coagulation factor VII (FVIIa) and activated factor X (FXa). Human plasma samples were analyzed for total TFPI concentrations using a validated, sensitive and specific high-performance liquid chromatography tandem mass spectrometric method (LC-MS/MS). Mixed model repeated measures (MMRM) was used to analyze the change from baseline on TFPI.
    End point type
    Secondary
    End point timeframe
    Baseline, Study Day 2, 4, 8, 15, 22, 29, 30, 33, 57, 85 and 113
    End point values
    		 PF-06741086 300 mg SC QW Non-Inhibitor PF-06741086 300 mg SC Loading + 150 mg SC QW Non-Inhibitor PF-06741086 450 mg SC QW Non-Inhibitor PF-06741086 300 mg SC QW Inhibitor Overall PF-06741086 300 mg SC
    Number of subjects analysed
    7 [78]
    6 [79]
    6 [80]
    7 [81]
    14 [82]
    Units: nanogram/milliliter
    arithmetic mean (standard deviation)
        TFPI, Change at Day 2
    3.9 ± 31.43
    -13.4 ± 17.17
    8.2 ± 19.83
    0.4 ± 46.81
    2.1 ± 38.35
        TFPI, Change at Day 4
    39.4 ± 46.10
    43.2 ± 25.76
    74.0 ± 22.03
    86.0 ± 29.71
    62.7 ± 44.41
        TFPI, Change at Day 8
    42.7 ± 82.52
    72.4 ± 10.81
    120.5 ± 34.41
    55.9 ± 69.84
    49.3 ± 73.76
        TFPI, Change at Day 15
    143.9 ± 107.56
    78.8 ± 43.36
    186.5 ± 52.80
    156.1 ± 83.87
    150.0 ± 92.88
        TFPI, Change at Day 22
    256.1 ± 137.09
    110.0 ± 80.96
    301.5 ± 84.39
    223.3 ± 128.08
    239.7 ± 128.59
        TFPI, Change at Day 29
    324.2 ± 127.46
    106.6 ± 77.56
    334.7 ± 120.67
    222.1 ± 135.29
    269.2 ± 136.83
        TFPI, Change at Day 30
    363.8 ± 156.87
    115.6 ± 86.41
    347.8 ± 170.70
    286.7 ± 103.72
    325.3 ± 133.04
        TFPI, Change at Day 33
    337.7 ± 129.05
    165.8 ± 35.20
    351.0 ± 161.54
    296.3 ± 112.30
    317.0 ± 117.34
        TFPI, Change at Day 57
    383.3 ± 137.17
    140.0 ± 126.96
    460.5 ± 247.37
    371.0 ± 178.73
    377.2 ± 152.03
        TFPI, Change at Day 85
    396.7 ± 216.54
    246.7 ± 51.81
    492.2 ± 308.46
    425.0 ± 266.57
    409.8 ± 230.80
        TFPI, Change at Day 113
    30.0 ± 72.30
    41.5 ± 28.99
    39.0 ± 16.15
    -14.0 ± 33.17
    9.7 ± 59.94
    Notes
    [78] - Number of subjects analyzed was 6 at Day 29.
    [79] - Not all subjects were analyzed for some specific rows of time points.
    [80] - Not all subjects were analyzed for some specific rows of time points.
    [81] - Not all subjects were analyzed for some specific rows of time points.
    [82] - Not all subjects were analyzed for some specific rows of time points
    No statistical analyses for this end point

    Secondary: Change From Baseline in Thrombin Generation (TGA) Lag Time

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    End point title
    		 Change From Baseline in Thrombin Generation (TGA) Lag Time
    End point description
    An ex vivo pharmacodynamic measure of thrombin generation (initiation of thrombin generation), the lag time is the time needed to form the first traces of thrombin.
    End point type
    Secondary
    End point timeframe
    Baseline, Study Day 2, 4, 8, 15, 22, 29, 30, 33, 57, 85 and 113
    End point values
    		 PF-06741086 300 mg SC QW Non-Inhibitor PF-06741086 300 mg SC Loading + 150 mg SC QW Non-Inhibitor PF-06741086 450 mg SC QW Non-Inhibitor PF-06741086 300 mg SC QW Inhibitor Overall PF-06741086 300 mg SC
    Number of subjects analysed
    7 [83]
    6 [84]
    6 [85]
    7 [86]
    14 [87]
    Units: minutes
    arithmetic mean (standard deviation)
        TGA lag time, Change at Day 2
    -7.16 ± 5.865
    -2.77 ± 1.517
    -3.93 ± 1.919
    -4.13 ± 1.238
    -5.64 ± 4.365
        TGA lag time, Change at Day 4
    -6.80 ± 6.079
    -2.80 ± 1.399
    -3.48 ± 1.957
    -4.17 ± 1.501
    -5.49 ± 4.467
        TGA lag time, Change at Day 8
    -6.94 ± 5.882
    -2.88 ± 1.292
    -3.57 ± 2.018
    -4.43 ± 1.506
    -5.69 ± 4.327
        TGA lag time, Change at Day 15
    -6.90 ± 5.897
    -3.07 ± 1.221
    -3.27 ± 1.870
    -4.29 ± 1.342
    -5.59 ± 4.327
        TGA lag time, Change at Day 22
    -6.94 ± 5.978
    -2.80 ± 1.585
    -3.12 ± 2.097
    -4.34 ± 1.638
    -5.64 ± 4.422
        TGA lag time, Change at Day 29
    -5.33 ± 4.871
    -2.77 ± 1.392
    -3.43 ± 2.016
    -4.32 ± 1.781
    -4.83 ± 3.537
        TGA lag time, Change at Day 30
    -5.22 ± 4.893
    -2.77 ± 1.372
    -3.50 ± 2.082
    -4.48 ± 1.681
    -4.88 ± 3.640
        TGA lag time, Change at Day 33
    -5.08 ± 4.414
    -2.40 ± 1.568
    -3.35 ± 2.261
    -4.52 ± 1.771
    -4.83 ± 3.329
        TGA lag time, Change at Day 57
    -4.73 ± 4.711
    -2.28 ± 2.020
    -3.42 ± 1.962
    -3.78 ± 1.376
    -4.26 ± 3.346
        TGA lag time, Change at Day 85
    -6.34 ± 5.745
    -3.10 ± 1.344
    -3.27 ± 2.014
    -3.33 ± 1.755
    -4.95 ± 4.497
        TGA lag time, Change at Day 113
    -0.79 ± 7.428
    0.80 ± 0.283
    1.53 ± 5.306
    0.78 ± 5.251
    -0.06 ± 6.304
    Notes
    [83] - Not all subjects were analyzed for some specific rows of time points.
    [84] - Not all subjects were analyzed for some specific rows of time points.
    [85] - Not all subjects were analyzed for some specific rows of time points.
    [86] - Not all subjects were analyzed for some specific rows of time points.
    [87] - Not all subjects were analyzed for some specific rows of time points.
    No statistical analyses for this end point

    Secondary: Change From Baseline in Thrombin Generation (TGA) Peak

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    End point title
    		 Change From Baseline in Thrombin Generation (TGA) Peak
    End point description
    An ex vivo pharmacodynamic measure of thrombin generation (initiation of thrombin generation). The peak represents the highest thrombin concentration that can be generated. There may be patients who reach the peak faster or slower than others and this may represent hyper- or hypocoagulability, respectively.
    End point type
    Secondary
    End point timeframe
    Baseline, Study Day 2, 4, 8, 15, 22, 29, 30, 33, 57, 85 and 113
    End point values
    		 PF-06741086 300 mg SC QW Non-Inhibitor PF-06741086 300 mg SC Loading + 150 mg SC QW Non-Inhibitor PF-06741086 450 mg SC QW Non-Inhibitor PF-06741086 300 mg SC QW Inhibitor Overall PF-06741086 300 mg SC
    Number of subjects analysed
    7 [88]
    6 [89]
    6 [90]
    7 [91]
    14 [92]
    Units: nanomole
    arithmetic mean (standard deviation)
        TGA peak, Change at Day 2
    72.93 ± 35.734
    70.92 ± 23.721
    68.18 ± 15.693
    63.41 ± 9.743
    68.17 ± 25.642
        TGA peak, Change at Day 4
    60.00 ± 30.196
    59.28 ± 30.156
    50.87 ± 20.687
    51.79 ± 14.929
    55.89 ± 23.278
        TGA peak, Change at Day 8
    49.36 ± 32.033
    56.00 ± 33.636
    50.30 ± 14.019
    54.36 ± 15.007
    51.86 ± 24.171
        TGA peak, Change at Day 15
    49.01 ± 23.471
    52.57 ± 28.440
    46.40 ± 22.985
    40.90 ± 7.886
    44.96 ± 17.340
        TGA peak, Change at Day 22
    44.50 ± 27.260
    52.07 ± 33.558
    38.15 ± 16.313
    44.41 ± 22.567
    44.46 ± 24.042
        TGA peak, Change at Day 29
    42.95 ± 24.026
    49.72 ± 29.316
    38.23 ± 21.808
    42.48 ± 23.057
    42.72 ± 22.452
        TGA peak, Change at Day 30
    35.93 ± 26.177
    51.75 ± 29.276
    37.72 ± 24.136
    48.62 ± 21.427
    41.70 ± 23.878
        TGA peak, Change at Day 33
    76.68 ± 69.887
    46.83 ± 37.084
    36.25 ± 21.955
    54.10 ± 28.276
    66.42 ± 53.861
        TGA peak, Change at Day 57
    37.13 ± 21.866
    32.57 ± 20.368
    34.67 ± 20.584
    33.93 ± 7.688
    35.53 ± 15.716
        TGA peak, Change at Day 85
    37.60 ± 21.142
    69.92 ± 40.250
    30.15 ± 18.614
    30.15 ± 22.743
    34.16 ± 21.306
        TGA peak, Change at Day 113
    24.37 ± 33.703
    16.05 ± 36.557
    43.33 ± 68.794
    6.93 ± 15.334
    16.32 ± 27.345
    Notes
    [88] - Not all subjects were analyzed for some specific rows of time points.
    [89] - Not all subjects were analyzed for some specific rows of time points.
    [90] - Not all subjects were analyzed for some specific rows of time points.
    [91] - Not all subjects were analyzed for some specific rows of time points.
    [92] - Not all subjects were analyzed for some specific rows of time points.
    No statistical analyses for this end point

    Secondary: Change From Baseline in Endogenous Thrombin Generation (TGA) Potential

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    End point title
    		 Change From Baseline in Endogenous Thrombin Generation (TGA) Potential
    End point description
    An ex vivo pharmacodynamic measure of thrombin generation.The endogenous TGA potential represents the total amount of active thrombin formed during thrombin generation and the peak height the maximal amount of thrombin formed.
    End point type
    Secondary
    End point timeframe
    Baseline, Study Day 2, 4, 8, 15, 22, 29, 30, 33, 57, 85 and 113
    End point values
    		 PF-06741086 300 mg SC QW Non-Inhibitor PF-06741086 300 mg SC Loading + 150 mg SC QW Non-Inhibitor PF-06741086 450 mg SC QW Non-Inhibitor PF-06741086 300 mg SC QW Inhibitor Overall PF-06741086 300 mg SC
    Number of subjects analysed
    7 [93]
    6 [94]
    6 [95]
    7 [96]
    14 [97]
    Units: nanomole*minute
    arithmetic mean (standard deviation)
        Endogenous TGA Potential, Change at Day 2
    864.0 ± 250.60
    816.8 ± 211.13
    999.8 ± 249.59
    1065.3 ± 161.71
    964.6 ± 227.95
        Endogenous TGA Potential, Change at Day 4
    766.7 ± 236.94
    714.8 ± 275.75
    808.7 ± 288.78
    825.1 ± 294.44
    795.9 ± 258.54
        Endogenous TGA Potential, Change at Day 8
    691.9 ± 301.43
    659.8 ± 295.11
    796.5 ± 151.00
    918.6 ± 276.26
    805.2 ± 301.66
        Endogenous TGA Potential, Change at Day 15
    674.9 ± 244.61
    608.5 ± 242.81
    800.8 ± 334.99
    639.3 ± 145.74
    657.1 ± 194.32
        Endogenous TGA Potential, Change at Day 22
    646.9 ± 295.05
    589.0 ± 274.33
    647.0 ± 236.38
    731.4 ± 302.89
    689.1 ± 290.60
        Endogenous TGA Potential, Change at Day 29
    588.2 ± 239.00
    623.0 ± 188.84
    618.3 ± 276.51
    660.5 ± 340.36
    624.3 ± 282.93
        Endogenous TGA Potential, Change at Day 30
    494.8 ± 247.86
    672.0 ± 226.25
    603.3 ± 332.44
    710.2 ± 272.54
    592.7 ± 270.33
        Endogenous TGA Potential, Change at Day 33
    716.5 ± 391.60
    606.0 ± 280.39
    583.7 ± 291.25
    848.8 ± 387.17
    776.6 ± 376.05
        Endogenous TGA Potential, Change at Day 57
    586.8 ± 200.04
    445.2 ± 220.86
    564.5 ± 287.43
    579.7 ± 147.04
    583.3 ± 167.42
        Endogenous TGA Potential, Change at Day 85
    566.6 ± 202.22
    812.2 ± 198.80
    526.7 ± 297.03
    493.7 ± 368.68
    532.9 ± 280.20
        Endogenous TGA Potential, Change at Day 113
    256.4 ± 347.91
    50.5 ± 290.62
    306.5 ± 440.04
    142.3 ± 361.25
    203.8 ± 344.10
    Notes
    [93] - Not all subjects were analyzed for some specific rows of time points.
    [94] - Not all subjects were analyzed for some specific rows of time points.
    [95] - Not all subjects were analyzed for some specific rows of time points.
    [96] - Not all subjects were analyzed for some specific rows of time points.
    [97] - Not all subjects were analyzed for some specific rows of time points.
    No statistical analyses for this end point

    Secondary: Change From Baseline in Prothrombin Fragments 1 + 2

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    End point title
    		 Change From Baseline in Prothrombin Fragments 1 + 2
    End point description
    An in vivo pharmacodynamic measure of thrombin generation (prothrombin cleavage). Prothrombin fragment 1+2 (F 1+2) is the amino terminus fragment of the prothrombin molecule. It is a polypeptide with a half-life of approximately 90 minutes. F 1+2 is released from prothrombin when prothrombin is converted to thrombin by the prothrombinase complex.
    End point type
    Secondary
    End point timeframe
    Baseline, Study Day 2, 4, 8, 15, 22, 29, 30, 33, 57, 85 and 113
    End point values
    		 PF-06741086 300 mg SC QW Non-Inhibitor PF-06741086 300 mg SC Loading + 150 mg SC QW Non-Inhibitor PF-06741086 450 mg SC QW Non-Inhibitor PF-06741086 300 mg SC QW Inhibitor Overall PF-06741086 300 mg SC
    Number of subjects analysed
    7 [98]
    6 [99]
    6 [100]
    7 [101]
    14 [102]
    Units: picomole/liter
    arithmetic mean (standard deviation)
        Prothrombin fragments 1 + 2, Change at Day 2
    430.0 ± 383.03
    498.3 ± 484.40
    275.7 ± 206.71
    438.9 ± 507.68
    434.4 ± 432.08
        Prothrombin fragments 1 + 2, Change at Day 4
    548.1 ± 455.67
    1096.7 ± 1403.57
    574.5 ± 363.37
    730.3 ± 537.21
    639.2 ± 487.82
        Prothrombin fragments 1 + 2, Change at Day 8
    450.3 ± 396.09
    562.2 ± 605.07
    413.0 ± 171.50
    580.7 ± 259.63
    515.5 ± 328.78
        Prothrombin fragments 1 + 2, Change at Day 15
    481.7 ± 330.26
    349.7 ± 212.59
    389.2 ± 228.56
    571.1 ± 474.23
    526.4 ± 395.34
        Prothrombin fragments 1 + 2, Change at Day 22
    608.1 ± 336.97
    322.3 ± 161.76
    420.2 ± 166.66
    524.1 ± 577.08
    566.1 ± 456.08
        Prothrombin fragments 1 + 2, Change at Day 29
    650.3 ± 415.58
    288.0 ± 259.19
    577.7 ± 302.76
    429.3 ± 257.91
    531.3 ± 344.06
        Prothrombin fragments 1 + 2, Change at Day 30
    655.7 ± 496.35
    486.0 ± 608.26
    521.0 ± 165.25
    580.8 ± 507.83
    618.3 ± 480.35
        Prothrombin fragments 1 + 2, Change at Day 33
    761.3 ± 509.02
    642.5 ± 759.02
    1527.7 ± 2499.96
    609.2 ± 380.74
    685.3 ± 435.87
        Prothrombin fragments 1 + 2, Change at Day 57
    586.5 ± 473.53
    216.5 ± 173.44
    465.3 ± 300.84
    463.5 ± 397.57
    525.0 ± 421.78
        Prothrombin fragments 1 + 2, Change at Day 85
    588.3 ± 483.80
    378.2 ± 207.16
    470.2 ± 244.21
    362.2 ± 378.54
    483.9 ± 436.47
        Prothrombin fragments 1 + 2, Change at Day 113
    -6.6 ± 151.87
    16.5 ± 19.09
    -75.5 ± 76.86
    -58.2 ± 121.15
    -30.4 ± 135.52
    Notes
    [98] - Not all subjects were analyzed for some specific rows of time points.
    [99] - Not all subjects were analyzed for some specific rows of time points.
    [100] - Not all subjects were analyzed for some specific rows of time points.
    [101] - Not all subjects were analyzed for some specific rows of time points.
    [102] - Not all subjects were analyzed for some specific rows of time points.
    No statistical analyses for this end point

    Secondary: Change From Baseline in D-Dimer

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    End point title
    		 Change From Baseline in D-Dimer
    End point description
    An in vivo pharmacodynamic measure of thrombin generation (fibrin degradation). D-dimer is a fibrin degradation product, a small protein fragment present in the blood after a blood clot is degraded by fibrinolysis. D-dimer is one of the protein fragments produced when a blood clot gets dissolved in the body. It is normally undetectable or detectable at a very low level unless the body is forming and breaking down blood clots. Then, its level in the blood can significantly rise.
    End point type
    Secondary
    End point timeframe
    Baseline, Study Day 2, 4, 8, 15, 22, 29, 30, 33, 57, 85 and 113
    End point values
    		 PF-06741086 300 mg SC QW Non-Inhibitor PF-06741086 300 mg SC Loading + 150 mg SC QW Non-Inhibitor PF-06741086 450 mg SC QW Non-Inhibitor PF-06741086 300 mg SC QW Inhibitor Overall PF-06741086 300 mg SC
    Number of subjects analysed
    7 [103]
    6 [104]
    6 [105]
    7 [106]
    14 [107]
    Units: microgram/milliliter
    arithmetic mean (standard deviation)
        D-dimer, Change at Day 2
    0.0393 ± 0.16303
    0.0792 ± 0.22238
    0.1900 ± 0.09301
    0.1086 ± 0.30536
    0.0739 ± 0.23790
        D-dimer, Change at Day 4
    0.2050 ± 0.24491
    0.2842 ± 0.36896
    0.3217 ± 0.23248
    0.6729 ± 0.62524
    0.4389 ± 0.51676
        D-dimer, Change at Day 8
    0.0743 ± 0.26111
    0.2017 ± 0.29753
    0.3292 ± 0.40635
    0.5614 ± 0.54901
    0.3179 ± 0.48422
        D-dimer, Change at Day 15
    0.0979 ± 0.25666
    0.1942 ± 0.28748
    0.2500 ± 0.23424
    0.1900 ± 0.82310
    0.1439 ± 0.58769
        D-dimer, Change at Day 22
    0.1364 ± 0.27802
    0.2167 ± 0.33877
    0.2000 ± 0.26109
    0.1829 ± 1.27802
    0.1596 ± 0.88887
        D-dimer, Change at Day 29
    0.0633 ± 0.20029
    0.2308 ± 0.32355
    0.1517 ± 0.42347
    -0.0129 ± 1.17491
    0.0223 ± 0.84172
        D-dimer, Change at Day 30
    0.1350 ± 0.32388
    0.1492 ± 0.26345
    0.2133 ± 0.33914
    -0.0833 ± 1.31549
    0.0258 ± 0.92048
        D-dimer, Change at Day 33
    0.0800 ± 0.28796
    0.1283 ± 0.37519
    0.1233 ± 0.49855
    -0.1700 ± 1.68635
    -0.0450 ± 1.16076
        D-dimer, Change at Day 57
    0.1942 ± 0.30049
    0.2175 ± 0.22554
    0.1233 ± 0.36122
    0.4033 ± 0.37120
    0.2988 ± 0.34001
        D-dimer, Change at Day 85
    0.1664 ± 0.30521
    0.5860 ± 1.00003
    0.1833 ± 0.43840
    0.2300 ± 0.60395
    0.1958 ± 0.44682
        D-dimer, Change at Day 113
    -0.1000 ± 0.22127
    0.1875 ± 0.26517
    0.0175 ± 0.41838
    -0.7833 ± 1.60090
    -0.4154 ± 1.10366
    Notes
    [103] - Not all subjects were analyzed for some specific rows of time points.
    [104] - Not all subjects were analyzed for some specific rows of time points.
    [105] - Not all subjects were analyzed for some specific rows of time points.
    [106] - Not all subjects were analyzed for some specific rows of time points.
    [107] - Not all subjects were analyzed for some specific rows of time points.
    No statistical analyses for this end point

    Secondary: Change From Baseline in Dilute Prothrombin Time

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    End point title
    		 Change From Baseline in Dilute Prothrombin Time
    End point description
    An ex vivo pharmacodynamic measure of thrombin generation (via extrinsic pathway). Clotting time is measured using a dilute prothrombin time reagent consisting of a unique formulation of relipidated recombinant tissue factor and calcium.
    End point type
    Secondary
    End point timeframe
    Baseline, Study Day 2, 4, 8, 15, 22, 29, 30, 33, 57, 85 and 113
    End point values
    		 PF-06741086 300 mg SC QW Non-Inhibitor PF-06741086 300 mg SC Loading + 150 mg SC QW Non-Inhibitor PF-06741086 450 mg SC QW Non-Inhibitor PF-06741086 300 mg SC QW Inhibitor Overall PF-06741086 300 mg SC
    Number of subjects analysed
    7 [108]
    6 [109]
    6 [110]
    7 [111]
    14 [112]
    Units: seconds
    arithmetic mean (standard deviation)
        Dilute prothrombin Time, Change at Day 2
    -27.84 ± 21.023
    -13.32 ± 25.780
    -31.25 ± 13.606
    -17.14 ± 26.167
    -22.49 ± 23.470
        Dilute prothrombin Time, Change at Day 4
    -30.03 ± 24.312
    -17.87 ± 20.042
    -34.50 ± 18.306
    -14.70 ± 30.971
    -22.36 ± 27.907
        Dilute prothrombin Time, Change at Day 8
    -23.63 ± 19.991
    -15.10 ± 22.129
    -31.23 ± 19.645
    -20.97 ± 33.969
    -22.30 ± 26.813
        Dilute prothrombin Time, Change at Day 15
    -20.73 ± 23.070
    -19.33 ± 20.853
    -33.53 ± 14.880
    1.11 ± 27.208
    -9.81 ± 26.753
        Dilute prothrombin Time, Change at Day 22
    -21.40 ± 22.351
    -10.55 ± 16.057
    -26.78 ± 32.501
    -21.61 ± 30.842
    -21.51 ± 25.877
        Dilute prothrombin Time, Change at Day 29
    -15.32 ± 13.867
    -7.10 ± 20.643
    -40.40 ± 22.458
    -18.03 ± 24.600
    -16.78 ± 19.613
        Dilute prothrombin Time, Change at Day 30
    -13.27 ± 13.399
    -23.45 ± 19.413
    -45.18 ± 21.372
    -17.47 ± 25.729
    -15.37 ± 19.680
        Dilute prothrombin Time, Change at Day 33
    -23.35 ± 17.690
    -21.23 ± 20.010
    -29.10 ± 20.783
    -19.97 ± 19.297
    -21.66 ± 17.737
        Dilute prothrombin Time, Change at Day 57
    -14.75 ± 14.393
    -12.03 ± 30.806
    -26.80 ± 12.911
    -11.72 ± 42.872
    -13.23 ± 30.531
        Dilute prothrombin Time, Change at Day 85
    -20.99 ± 25.424
    -25.80 ± 24.334
    -23.43 ± 26.166
    -12.42 ± 34.871
    -17.03 ± 29.148
        Dilute prothrombin Time, Change at Day 113
    -16.44 ± 13.578
    14.30 ± 61.235
    -39.63 ± 20.182
    -12.78 ± 28.226
    -14.75 ± 20.682
    Notes
    [108] - Not all subjects were analyzed for some specific rows of time points.
    [109] - Not all subjects were analyzed for some specific rows of time points.
    [110] - Not all subjects were analyzed for some specific rows of time points.
    [111] - Not all subjects were analyzed for some specific rows of time points.
    [112] - Not all subjects were analyzed for some specific rows of time points.
    No statistical analyses for this end point

    Secondary: Number of Subjects Who Tested Positive for Anti-PF-06741086 Antibody (ADA)

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    End point title
    		 Number of Subjects Who Tested Positive for Anti-PF-06741086 Antibody (ADA)
    End point description
    Human plasma ADA samples were analyzed for the detection of anti PF-06741086 antibodies by using semi-quantitative electrochemiluminescence (ECL) method. The criterion for positive result of ADA samples was ADA titer >=1.53. Treatment induced are negative prior to dosing and become positive during/after dosing. Treatment boosted are positive prior to dosing but titer increases during/after dosing.
    End point type
    Secondary
    End point timeframe
    Baseline up to Study Day 113
    End point values
    		 PF-06741086 300 mg SC QW Non-Inhibitor PF-06741086 300 mg SC Loading + 150 mg SC QW Non-Inhibitor PF-06741086 450 mg SC QW Non-Inhibitor PF-06741086 300 mg SC QW Inhibitor Overall PF-06741086 300 mg SC Total
    Number of subjects analysed
    7
    6
    6
    7
    14
    26
    Units: Subjects
        ADA incidence
    0
    1
    2
    0
    0
    3
        Subjects with treatment induced ADA incidence
    0
    1
    2
    0
    0
    3
        Subjects with treatment boosted ADA incidence
    0
    0
    0
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Number of Subjects Who Tested Positive for Neutralizing Antibody (NAb)

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    End point title
    		 Number of Subjects Who Tested Positive for Neutralizing Antibody (NAb)
    End point description
    Human plasma NAb samples were analyzed for the presence or absence of NAb to PF 06741086 using semi-quantitative electrochemiluminescence (ECL) method. Treatment induced are negative prior to dosing and become positive during/after dosing. Treatment boosted are positive prior to dosing but titer increases during/after dosing.
    End point type
    Secondary
    End point timeframe
    Baseline up to Study Day 113
    End point values
    		 PF-06741086 300 mg SC QW Non-Inhibitor PF-06741086 300 mg SC Loading + 150 mg SC QW Non-Inhibitor PF-06741086 450 mg SC QW Non-Inhibitor PF-06741086 300 mg SC QW Inhibitor Overall PF-06741086 300 mg SC Total
    Number of subjects analysed
    0 [113]
    1
    2
    0 [114]
    0 [115]
    3
    Units: Subjects
        NAb incidence|
    0
    0
    0
        Subjects with treatment induced NAb incidence
    0
    0
    0
        Subjects with treatment boosted NAb incidence
    0
    0
    0
    Notes
    [113] - Only subjects who had positive ADA sample were tested in the NAb assay.
    [114] - Only subjects who had positive ADA sample were tested in the NAb assay.
    [115] - Only subjects who had positive ADA sample were tested in the NAb assay.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    113 days
    Adverse event reporting additional description
    The same event may appear as both an AE and an SAE. An event may be categorized as serious in one subject and as non-serious in another subject, or one subject may have experienced both a serious and non-serious event during the study. Total number at risk below refers to the number of subjects evaluable for SAEs or AEs.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21.1
    Reporting groups
    Reporting group title
    PF-06741086 300 mg SC QW Non-Inhibitor
    Reporting group description
    		 Subjects without inhibitors to FVIII or FIX in this cohort received PF-06741086 300 mg subcutaneously (SC) once weekly (QW) from Day 1 to Day 78.

    Reporting group title
    PF-06741086 300 mg SC Loading + 150 mg SC QW Non-Inhibitor
    Reporting group description
    		 Subjects without inhibitors to FVIII or FIX in this cohort received PF-06741086 300 mg loading dose on Day 1 and 150 mg SC QW from Day 8 to Day 78.

    Reporting group title
    PF-06741086 450 mg SC QW Non-Inhibitor
    Reporting group description
    		 Subjects without inhibitors to FVIII or FIX in this cohort received PF-06741086 450 mg SC QW from Day 1 to Day 78.

    Reporting group title
    PF-06741086 300 mg SC QW Inhibitor
    Reporting group description
    		 Subjects with inhibitors to FVIII or FIX in this cohort received PF-06741086 300 mg SC QW from Day 1 to Day 78.

    Reporting group title
    Overall PF-06741086 300 mg SC
    Reporting group description
    		 The overall PF-06741086 300 mg SC group combined subjects from both the PF-06741086 300 mg SC QW non-inhibitor and inhibitor dose cohorts.

    Reporting group title
    Total
    Reporting group description
    		 The total group combined subjects from all PF-06741086 cohorts in this study.

    Serious adverse events
    		 PF-06741086 300 mg SC QW Non-Inhibitor PF-06741086 300 mg SC Loading + 150 mg SC QW Non-Inhibitor PF-06741086 450 mg SC QW Non-Inhibitor PF-06741086 300 mg SC QW Inhibitor Overall PF-06741086 300 mg SC Total
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    1 / 7 (14.29%)
    2 / 14 (14.29%)
    4 / 26 (15.38%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    Social circumstances
    Physical assault
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 14 (0.00%)
    1 / 26 (3.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Tooth socket haemorrhage
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    1 / 14 (7.14%)
    1 / 26 (3.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 14 (0.00%)
    1 / 26 (3.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 14 (7.14%)
    1 / 26 (3.85%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 PF-06741086 300 mg SC QW Non-Inhibitor PF-06741086 300 mg SC Loading + 150 mg SC QW Non-Inhibitor PF-06741086 450 mg SC QW Non-Inhibitor PF-06741086 300 mg SC QW Inhibitor Overall PF-06741086 300 mg SC Total
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    6 / 7 (85.71%)
    4 / 6 (66.67%)
    6 / 6 (100.00%)
    4 / 7 (57.14%)
    10 / 14 (71.43%)
    20 / 26 (76.92%)
    Investigations
    Blood fibrinogen decreased
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    1 / 14 (7.14%)
    1 / 26 (3.85%)
         occurrences all number
    0
    0
    0
    1
    1
    1
    Fibrin D dimer increased
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 14 (7.14%)
    1 / 26 (3.85%)
         occurrences all number
    1
    0
    0
    0
    1
    1
    Prothrombin time prolonged
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 7 (14.29%)
    1 / 14 (7.14%)
    2 / 26 (7.69%)
         occurrences all number
    0
    0
    1
    1
    1
    2
    Troponin I increased
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    2 / 14 (14.29%)
    2 / 26 (7.69%)
         occurrences all number
    1
    0
    0
    1
    2
    2
    Troponin increased
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 14 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    1
    0
    0
    0
    1
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    1 / 14 (7.14%)
    2 / 26 (7.69%)
         occurrences all number
    1
    0
    1
    0
    1
    2
    Occupational exposure to product
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 14 (7.14%)
    1 / 26 (3.85%)
         occurrences all number
    1
    0
    0
    0
    1
    1
    Road traffic accident
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 14 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    0
    1
    0
    0
    1
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 7 (0.00%)
    2 / 6 (33.33%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 14 (0.00%)
    3 / 26 (11.54%)
         occurrences all number
    0
    2
    1
    0
    0
    3
    Nervous system disorders
    Cerebrospinal fluid leakage
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 14 (7.14%)
    1 / 26 (3.85%)
         occurrences all number
    1
    0
    0
    0
    1
    1
    Dizziness
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 14 (7.14%)
    1 / 26 (3.85%)
         occurrences all number
    1
    0
    0
    0
    1
    1
    Headache
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    2 / 6 (33.33%)
    0 / 7 (0.00%)
    0 / 14 (0.00%)
    2 / 26 (7.69%)
         occurrences all number
    0
    0
    2
    0
    0
    2
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    1 / 14 (7.14%)
    2 / 26 (7.69%)
         occurrences all number
    1
    0
    1
    0
    1
    2
    Injection site bruising
         subjects affected / exposed
    2 / 7 (28.57%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    2 / 14 (14.29%)
    2 / 26 (7.69%)
         occurrences all number
    2
    0
    0
    0
    2
    2
    Injection site erythema
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    1 / 14 (7.14%)
    1 / 26 (3.85%)
         occurrences all number
    0
    0
    0
    1
    1
    1
    Injection site haemorrhage
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    1 / 14 (7.14%)
    1 / 26 (3.85%)
         occurrences all number
    0
    0
    0
    1
    1
    1
    Injection site induration
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    1 / 14 (7.14%)
    2 / 26 (7.69%)
         occurrences all number
    1
    0
    1
    0
    1
    2
    Injection site pain
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    1 / 14 (7.14%)
    3 / 26 (11.54%)
         occurrences all number
    2
    1
    6
    0
    2
    9
    Injection site pruritus
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    1 / 14 (7.14%)
    1 / 26 (3.85%)
         occurrences all number
    0
    0
    0
    1
    1
    1
    Injection site swelling
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    2 / 6 (33.33%)
    1 / 7 (14.29%)
    1 / 14 (7.14%)
    3 / 26 (11.54%)
         occurrences all number
    0
    0
    3
    1
    1
    4
    Injection site warmth
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 14 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    0
    1
    0
    0
    1
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 14 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    0
    2
    0
    0
    2
    Dyspepsia
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 14 (7.14%)
    1 / 26 (3.85%)
         occurrences all number
    1
    0
    0
    0
    1
    1
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 14 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    1
    0
    0
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Rhinitis allergic
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 14 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    1
    0
    0
    0
    1
    Skin and subcutaneous tissue disorders
    Pruritus generalised
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    1 / 14 (7.14%)
    1 / 26 (3.85%)
         occurrences all number
    0
    0
    0
    1
    1
    1
    Rash erythematous
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    1 / 14 (7.14%)
    1 / 26 (3.85%)
         occurrences all number
    0
    0
    0
    1
    1
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    2 / 14 (14.29%)
    2 / 26 (7.69%)
         occurrences all number
    2
    0
    0
    1
    3
    3
    Back pain
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 14 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    0
    1
    0
    0
    1
    Bursitis
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 14 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    1
    0
    0
    0
    1
    Haemarthrosis
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 14 (7.14%)
    1 / 26 (3.85%)
         occurrences all number
    1
    0
    0
    0
    1
    1
    Haemophilic arthropathy
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 14 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    1
    0
    0
    0
    1
    Infections and infestations
    Influenza
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    1 / 14 (7.14%)
    2 / 26 (7.69%)
         occurrences all number
    0
    1
    0
    1
    1
    2
    Periodontitis
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    1 / 14 (7.14%)
    2 / 26 (7.69%)
         occurrences all number
    0
    1
    0
    1
    1
    2
    Respiratory tract infection
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 14 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    1
    0
    0
    0
    1
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 14 (7.14%)
    1 / 26 (3.85%)
         occurrences all number
    1
    0
    0
    0
    1
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    09 Sep 2016
    1. Added EudraCT # on protocol title page 2.Revised inclusion criterion #2 to restrict subjects from>=12 and <18 years of age to cohorts at a dose level and route of administration previously studied which has not met the protocol safety criteria for termination of dose escalation.
    02 Nov 2016
    1. Added US IND # to protocol 2. Revised nominal doses planned for Cohorts 2 through 4 added to new section (1.3.3.2 Dose Progression). 3.Removed option for self administration for SC cohorts and specified visits for SC cohorts. 4.Inclusion Criterion #5: criterion was revised to state that only patients currently treated with episodic (on demand) factor replacement therapy are eligible for this study.
    12 Dec 2016
    1.Added new criteria and references for dose escalation and stopping rules. 2.Revised Inclusion Criterion #2 to state that only adult subjects (18 to 65 years of age) are eligible for the study, added Exclusion Criterion #4 to state that subjects with pro thrombotic conditions are excluded from the study.
    02 Oct 2017
    1.Removed “AND” from “AND/OR” to conform to previous amendment that removed a combination subcutaneous and intravenous dose. 2. Added language anywhere applicable allowing for the inclusion of subjects with inhibitors against FVIII or FIX and specified analyses for inhibitor subjects.

    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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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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