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    Clinical Trial Results:
    A Multicenter, Open-Label, Phase III Study to Evaluate the Efficacy, Safety, Pharmacokinetics, and Pharmacodynamics of Emicizumab Given Every 4 Weeks (Q4W) in Patients with Hemophilia A

    Summary
    EudraCT number
    2016-001094-33
    Trial protocol
    ES   PL   BE  
    Global end of trial date

    Results information
    Results version number
    v1(current)
    This version publication date
    20 Dec 2018
    First version publication date
    20 Dec 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    BO39182
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT03020160
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    F. Hoffmann-La Roche AG
    Sponsor organisation address
    Grenzacherstrasse 124, Basel, Switzerland, CH-4070
    Public contact
    F. Hoffmann-La Roche AG, F. Hoffmann-La Roche AG, +41 616878333, global.trial_information@roche.com
    Scientific contact
    F. Hoffmann-La Roche AG, F. Hoffmann-La Roche AG, +41 616878333, global.trial_information@roche.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
    Interim
    Date of interim/final analysis
    15 Dec 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    15 Dec 2017
    Global end of trial reached?
    No
    General information about the trial
    Main objective of the trial
    The main objectives of the Pharmacokinetics (PK) Run-In and the Expansion Parts of this study are the following: PK Run-In Part Objectives: - To investigate the pharmacokinetics (PK) of emicizumab after single and multiple (every 4 weeks [Q4W]) subcutaneous (SC) administration of 6 milligrams per kilogram (mg/kg) - To assess the safety and tolerability of emicizumab after 6 mg/kg Q4W SC administration Expansion Part Objectives: - To evaluate the clinical effect of prophylactic emicizumab on the number of treated bleeds over time, all bleeds over time, joint bleeds over time, target joint bleeds over time, and spontaneous bleeds over time - To evaluate the health-related quality of life, health status, and patient preference for treatment regimen - To evaluate the overall safety of emicizumab given Q4W in patients with hemophilia A - To characterize the pharmacokinetics of multiple Q4W doses of 6mg/kg emicizumab
    Protection of trial subjects
    This study will be conducted in full conformance with the ICH E6 guideline for Good Clinical Practice and the principles of the Declaration of Helsinki, or the laws and regulations of the country in which the research is conducted, whichever affords the greater protection to the individual. Each study subject or their legally authorized representative was required to read and sign an Informed Consent Form or an Informed Assent Form (ages 12-17), as applicable.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    30 Jan 2017
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Australia: 5
    Country: Number of subjects enrolled
    Belgium: 4
    Country: Number of subjects enrolled
    Japan: 8
    Country: Number of subjects enrolled
    Poland: 6
    Country: Number of subjects enrolled
    Spain: 14
    Country: Number of subjects enrolled
    United States: 11
    Worldwide total number of subjects
    48
    EEA total number of subjects
    24
    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)
    4
    Adults (18-64 years)
    41
    From 65 to 84 years
    3
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    A total of 7 patients were screened and enrolled in the PK run-in cohort of the study. For the expansion cohort, a total of 44 patients were screened, of whom 41 were enrolled.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Emicizumab: PK Run-In Part
    Arm description
    Subjects will received SC emicizumab at a dose of 6 mg/kg every 4 weeks for a minimum of 24 weeks.
    Arm type
    Experimental

    Investigational medicinal product name
    Emicizumab
    Investigational medicinal product code
    B02BX06
    Other name
    Hemlibra, RO5534262
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects will received SC emicizumab at a dose of 6 mg/kg every 4 weeks for a minimum of 24 weeks.

    Arm title
    Emicizumab: Expansion Part
    Arm description
    Subjects will receive SC emicizumab at a loading dose of 3 mg/kg every week for initial 4 weeks followed by a maintenance dose of 6 mg/kg every 4 weeks for a minimum of 24 weeks.
    Arm type
    Experimental

    Investigational medicinal product name
    Emicizumab
    Investigational medicinal product code
    B02BX06
    Other name
    Hemlibra, RO5534262
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects will receive SC emicizumab at a loading dose of 3 mg/kg every week for initial 4 weeks followed by a maintenance dose of 6 mg/kg every 4 weeks for a minimum of 24 weeks.

    Number of subjects in period 1
    Emicizumab: PK Run-In Part Emicizumab: Expansion Part
    Started
    7
    41
    Completed 24 weeks in the study
    7
    41
    Completed
    0
    0
    Not completed
    7
    41
         Continuing to receive emicizumab
    7
    41

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Emicizumab: PK Run-In Part
    Reporting group description
    Subjects will received SC emicizumab at a dose of 6 mg/kg every 4 weeks for a minimum of 24 weeks.

    Reporting group title
    Emicizumab: Expansion Part
    Reporting group description
    Subjects will receive SC emicizumab at a loading dose of 3 mg/kg every week for initial 4 weeks followed by a maintenance dose of 6 mg/kg every 4 weeks for a minimum of 24 weeks.

    Reporting group values
    Emicizumab: PK Run-In Part Emicizumab: Expansion Part Total
    Number of subjects
    7 41 48
    Age Categorical
    Units: Subjects
        Adolescents (12-17 years)
    1 3 4
        Adults (18-64 years)
    6 35 41
        Elderly (From 65-84 years)
    0 3 3
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    37.3 ± 13.3 38.7 ± 15.7 -
    Sex: Female, Male
    Units: Subjects
        Female
    0 0 0
        Male
    7 41 48
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    0 0 0
        Asian
    2 8 10
        Native Hawaiian or Other Pacific Islander
    0 0 0
        Black or African American
    0 1 1
        White
    5 31 36
        More than one race
    0 0 0
        Unknown or Not Reported
    0 1 1
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    1 2 3
        Not Hispanic or Latino
    6 38 44
        Unknown or Not Reported
    0 1 1
    Number of Subjects with 0, 1, or >1 Target Joints in the Last 24 Weeks Prior to Study Entry
    A target joint was defined as a a joint location where at least 3 bleeds have occurred over the last 24 weeks prior to study entry.
    Units: Subjects
        0 Target Joints
    1 16 17
        1 Target Joint
    2 8 10
        >1 Target Joints
    4 17 21

    End points

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    End points reporting groups
    Reporting group title
    Emicizumab: PK Run-In Part
    Reporting group description
    Subjects will received SC emicizumab at a dose of 6 mg/kg every 4 weeks for a minimum of 24 weeks.

    Reporting group title
    Emicizumab: Expansion Part
    Reporting group description
    Subjects will receive SC emicizumab at a loading dose of 3 mg/kg every week for initial 4 weeks followed by a maintenance dose of 6 mg/kg every 4 weeks for a minimum of 24 weeks.

    Primary: Expansion Part: Annualized Bleeding Rate (ABR) for Treated Bleeds

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    End point title
    Expansion Part: Annualized Bleeding Rate (ABR) for Treated Bleeds [1] [2]
    End point description
    The number of treated bleeds over the efficacy period is presented as an annualized bleeding rate (ABR) that was analyzed using a negative binomial regression model with efficacy period as an offset to account for the difference in follow-up times. A bleed is considered a “treated bleed” if it is directly followed (i.e., no intervening bleed) by a hemophilia medication reported to be a “treatment for bleed”, irrespective of time between treatment and the preceding bleed. A bleed and the first treatment thereafter and before a new bleed starts, are considered to be pairs, with the following exception: if multiple bleeds occur on the same calendar day, the subsequent treatment is considered to apply for each of these multiple bleeds. The 72-hour rule was implemented: two bleeds of the same type and at the same anatomical location are counted as one bleed if the second bleed occurs within 72 hours from the last treatment for the first bleed. Bleeds due to surgery/procedure are excluded.
    End point type
    Primary
    End point timeframe
    From Baseline to at least 24 weeks
    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 formal hypothesis testing was planned for this study. All analyses are descriptive.
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The efficacy end points of this study were planned to be primarily evaluated based on subjects in the expansion cohort of the study. The overall sample size of 40 subjects in the expansion cohort was based on clinical considerations taking into account the limited number of patients with hemophilia A. It is expected that a sample size of 40 subjects would, nonetheless, provide statistically robust point estimates with meaningfully narrow confidence intervals.
    End point values
    Emicizumab: Expansion Part
    Number of subjects analysed
    41
    Units: treated bleed rate per year
        number (confidence interval 95%)
    2.4 (1.38 to 4.28)
    No statistical analyses for this end point

    Primary: Expansion Part: Annualized Bleeding Rate (ABR) for All Bleeds

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    End point title
    Expansion Part: Annualized Bleeding Rate (ABR) for All Bleeds [3] [4]
    End point description
    The number of all bleeds over the efficacy period is presented as an annualized bleeding rate (ABR) that was analyzed using a negative binomial regression model with efficacy period as an offset to account for the difference in follow-up times (i.e., the time that each participant stays in the study). In this outcome measure, all bleeds are included, irrespective of treatment with coagulation factors, with the following exception: bleeds due to surgery/procedure are excluded. As “all bleeds” comprises both treated and non-treated bleeds, the 72-hour rule was implemented separately for treated and non-treated bleeds. For treated bleeds, the 72-hour rule was implemented exactly as defined for the “treated bleeds” outcome measure. For non-treated bleeds, the 72-hour rule was implemented by calculating a treatment-free period of 72 hours from the bleed itself.
    End point type
    Primary
    End point timeframe
    From Baseline to at least 24 weeks
    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 formal hypothesis testing was planned for this study. All analyses are descriptive.
    [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The efficacy end points of this study were planned to be primarily evaluated based on subjects in the expansion cohort of the study. The overall sample size of 40 subjects in the expansion cohort was based on clinical considerations taking into account the limited number of patients with hemophilia A. It is expected that a sample size of 40 subjects would, nonetheless, provide statistically robust point estimates with meaningfully narrow confidence intervals.
    End point values
    Emicizumab: Expansion Part
    Number of subjects analysed
    41
    Units: all bleed rate per year
        number (confidence interval 95%)
    4.5 (3.10 to 6.60)
    No statistical analyses for this end point

    Primary: Expansion Part: Annualized Bleeding Rate (ABR) for Treated Spontaneous Bleeds

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    End point title
    Expansion Part: Annualized Bleeding Rate (ABR) for Treated Spontaneous Bleeds [5] [6]
    End point description
    The number of treated spontaneous bleeds over the efficacy period is presented as an annualized bleeding rate (ABR) that was analyzed using a negative binomial regression model with efficacy period as an offset to account for the difference in follow-up times (i.e., the time that each participant stays in the study). A bleed is classified as "spontaneous" if there is no other known contributing factor such as trauma or procedure/surgery. A “treated spontaneous bleed” is a spontaneous bleed that also fulfills the conditions of a treated bleed (see ABR for Treated Bleeds for the definition). Treated bleeds that fulfilled the 72-hour rule were included in the analysis of spontaneous bleeds. Bleeds due to surgery/procedure are excluded.
    End point type
    Primary
    End point timeframe
    From Baseline to at least 24 weeks
    Notes
    [5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No formal hypothesis testing was planned for this study. All analyses are descriptive.
    [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The efficacy end points of this study were planned to be primarily evaluated based on subjects in the expansion cohort of the study. The overall sample size of 40 subjects in the expansion cohort was based on clinical considerations taking into account the limited number of patients with hemophilia A. It is expected that a sample size of 40 subjects would, nonetheless, provide statistically robust point estimates with meaningfully narrow confidence intervals.
    End point values
    Emicizumab: Expansion Part
    Number of subjects analysed
    41
    Units: treated spontaneous bleed rate per year
        number (confidence interval 95%)
    0.6 (0.27 to 1.53)
    No statistical analyses for this end point

    Primary: Expansion Part: Annualized Bleeding Rate (ABR) for Treated Joint Bleeds

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    End point title
    Expansion Part: Annualized Bleeding Rate (ABR) for Treated Joint Bleeds [7] [8]
    End point description
    The number of treated joint bleeds over the efficacy period is presented as an annualized bleeding rate (ABR) that was analyzed using a negative binomial regression model with efficacy period as an offset to account for the difference in follow-up times (i.e., the time that each participant stays in the study). A "joint bleed" is defined as a bleed with type reported as “joint” and with at least one of the following symptoms: increasing swelling or warmth of the skin over the joint and/or increasing pain, decreased range of motion, or difficulty using the joint compared with baseline. A “treated joint bleed” is a joint bleed that also fulfills the conditions of a treated bleed (see ABR for Treated Bleeds for the definition). Treated bleeds that fulfilled the 72-hour rule were included in the analysis of joint bleeds, excluding bleeds due to surgery/procedure.
    End point type
    Primary
    End point timeframe
    From Baseline to at least 24 weeks
    Notes
    [7] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No formal hypothesis testing was planned for this study. All analyses are descriptive.
    [8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The efficacy end points of this study were planned to be primarily evaluated based on subjects in the expansion cohort of the study. The overall sample size of 40 subjects in the expansion cohort was based on clinical considerations taking into account the limited number of patients with hemophilia A. It is expected that a sample size of 40 subjects would, nonetheless, provide statistically robust point estimates with meaningfully narrow confidence intervals.
    End point values
    Emicizumab: Expansion Part
    Number of subjects analysed
    41
    Units: treated joint bleed rate per year
        number (confidence interval 95%)
    1.7 (0.82 to 3.68)
    No statistical analyses for this end point

    Primary: Expansion Part: Annualized Bleeding Rate (ABR) for Treated Target Joint Bleeds

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    End point title
    Expansion Part: Annualized Bleeding Rate (ABR) for Treated Target Joint Bleeds [9] [10]
    End point description
    The number of treated target joint bleeds over the efficacy period is presented as an annualized bleeding rate (ABR) that was analyzed using a negative binomial regression model with efficacy period as an offset to account for the difference in follow-up times (i.e., the time that each participant stays in the study). A "target joint bleed" is defined as a joint bleed in a target joint, which is a joint location where at least 3 bleeds have occurred over the last 24 weeks prior to study entry. A “treated target joint bleed” is a target joint bleed that also fulfills the conditions of a treated bleed (see ABR for Treated Bleeds for the definition). Bleeds due to surgery/procedure are excluded.
    End point type
    Primary
    End point timeframe
    From Baseline to at least 24 weeks
    Notes
    [9] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No formal hypothesis testing was planned for this study. All analyses are descriptive.
    [10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The efficacy end points of this study were planned to be primarily evaluated based on subjects in the expansion cohort of the study. The overall sample size of 40 subjects in the expansion cohort was based on clinical considerations taking into account the limited number of patients with hemophilia A. It is expected that a sample size of 40 subjects would, nonetheless, provide statistically robust point estimates with meaningfully narrow confidence intervals.
    End point values
    Emicizumab: Expansion Part
    Number of subjects analysed
    41
    Units: treated target joint bleed rate per year
        number (confidence interval 95%)
    1.0 (0.31 to 3.26)
    No statistical analyses for this end point

    Secondary: Expansion Part: Change from Baseline to Week 25 in the Hemophilia A Quality of Life (Haem-A-QoL) Questionnaire Total Score for Adult Subjects (≥18 Years of Age)

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    End point title
    Expansion Part: Change from Baseline to Week 25 in the Hemophilia A Quality of Life (Haem-A-QoL) Questionnaire Total Score for Adult Subjects (≥18 Years of Age) [11]
    End point description
    The Haem-A-QoL is a patient-reported questionnaire that was designed for adult participants with hemophilia. It consists of 46 items comprising 10 dimensions (physical health, sports and leisure, school and work, dealing with hemophilia, family planning, feelings, relationships, treatment, view of yourself, and outlook for the future) and a scale representing Total Score. Items are rated along five response options: never, rarely, sometimes, often, or all the time; although for some items there is also a “not applicable” option. Scale scores range from 0 to 100 with lower scores reflective of better quality of life. A decrease of 7 points or more on the Total Score was defined as the threshold for a clinically meaningful improvement. The analysis included all adult subjects enrolled in the expansion part of the study. The number of subjects analyzed indicates those who completed the questionnaire at Baseline and Week 25.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 25
    Notes
    [11] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The efficacy end points of this study were planned to be primarily evaluated based on subjects in the expansion cohort of the study. The overall sample size of 40 subjects in the expansion cohort was based on clinical considerations taking into account the limited number of patients with hemophilia A. It is expected that a sample size of 40 subjects would, nonetheless, provide statistically robust point estimates with meaningfully narrow confidence intervals.
    End point values
    Emicizumab: Expansion Part
    Number of subjects analysed
    37
    Units: units on a scale
        arithmetic mean (confidence interval 95%)
    -13.62 (-18.36 to -8.88)
    No statistical analyses for this end point

    Secondary: Expansion Part: Percentage of Adult Subjects (≥18 Years of Age) with a Clinically Meaningful Improvement from Baseline to Week 25 in the Haem-A-QoL Questionnaire Total Score

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    End point title
    Expansion Part: Percentage of Adult Subjects (≥18 Years of Age) with a Clinically Meaningful Improvement from Baseline to Week 25 in the Haem-A-QoL Questionnaire Total Score [12]
    End point description
    The Haem-A-QoL is a patient-reported questionnaire that was designed for adult participants with hemophilia. It consists of 46 items comprising 10 dimensions (physical health, sports and leisure, school and work, dealing with hemophilia, family planning, feelings, relationships, treatment, view of yourself, and outlook for the future) and a scale representing Total Score. Items are rated along five response options: never, rarely, sometimes, often, or all the time; although for some items there is also a “not applicable” option. Scale scores range from 0 to 100 with lower scores reflective of better quality of life. A decrease of 7 points or more on the Total Score was defined as the threshold for a clinically meaningful improvement. The analysis included all adult subjects enrolled in the expansion part of the study. The number of subjects analyzed indicates those who completed the questionnaire at Baseline and Week 25.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 25
    Notes
    [12] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The efficacy end points of this study were planned to be primarily evaluated based on subjects in the expansion cohort of the study. The overall sample size of 40 subjects in the expansion cohort was based on clinical considerations taking into account the limited number of patients with hemophilia A. It is expected that a sample size of 40 subjects would, nonetheless, provide statistically robust point estimates with meaningfully narrow confidence intervals.
    End point values
    Emicizumab: Expansion Part
    Number of subjects analysed
    37
    Units: percentage of subjects
        number (not applicable)
    67.6
    No statistical analyses for this end point

    Secondary: Expansion Part: Change from Baseline to Week 25 in the Haem-A-QoL Questionnaire Physical Health Score for Adult Subjects (≥18 Years of Age)

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    End point title
    Expansion Part: Change from Baseline to Week 25 in the Haem-A-QoL Questionnaire Physical Health Score for Adult Subjects (≥18 Years of Age) [13]
    End point description
    The Haem-A-QoL is a patient-reported questionnaire that was designed for adult participants with hemophilia. It consists of 46 items comprising 10 dimensions (physical health, sports and leisure, school and work, dealing with hemophilia, family planning, feelings, relationships, treatment, view of yourself, and outlook for the future) and a scale representing Total Score. Items are rated along five response options: never, rarely, sometimes, often, or all the time; although for some items there is also a “not applicable” option. Scale scores range from 0 to 100 with lower scores reflective of better quality of life. A decrease of 10 points or more on the Physical Health Score was defined as the threshold for a clinically meaningful improvement. The analysis included all adult subjects enrolled in the expansion part of the study. The number of subjects analyzed indicates those who completed the questionnaire at Baseline and Week 25.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 25
    Notes
    [13] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The efficacy end points of this study were planned to be primarily evaluated based on subjects in the expansion cohort of the study. The overall sample size of 40 subjects in the expansion cohort was based on clinical considerations taking into account the limited number of patients with hemophilia A. It is expected that a sample size of 40 subjects would, nonetheless, provide statistically robust point estimates with meaningfully narrow confidence intervals.
    End point values
    Emicizumab: Expansion Part
    Number of subjects analysed
    37
    Units: units on a scale
        arithmetic mean (confidence interval 95%)
    -15.14 (-22.44 to -7.83)
    No statistical analyses for this end point

    Secondary: Expansion Part: Percentage of Adult Subjects (≥18 Years of Age) with a Clinically Meaningful Improvement from Baseline to Week 25 in the Haem-A-QoL Questionnaire Physical Health Score

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    End point title
    Expansion Part: Percentage of Adult Subjects (≥18 Years of Age) with a Clinically Meaningful Improvement from Baseline to Week 25 in the Haem-A-QoL Questionnaire Physical Health Score [14]
    End point description
    The Haem-A-QoL is a patient-reported questionnaire that was designed for adult participants with hemophilia. It consists of 46 items comprising 10 dimensions (physical health, sports and leisure, school and work, dealing with hemophilia, family planning, feelings, relationships, treatment, view of yourself, and outlook for the future) and a scale representing Total Score. Items are rated along five response options: never, rarely, sometimes, often, or all the time; although for some items there is also a “not applicable” option. Scale scores range from 0 to 100 with lower scores reflective of better quality of life. A decrease of 10 points or more on the Physical Health Score was defined as the threshold for a clinically meaningful improvement. The analysis included all adult subjects enrolled in the expansion part of the study. The number of subjects analyzed indicates those who completed the questionnaire at Baseline and Week 25.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 25
    Notes
    [14] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The efficacy end points of this study were planned to be primarily evaluated based on subjects in the expansion cohort of the study. The overall sample size of 40 subjects in the expansion cohort was based on clinical considerations taking into account the limited number of patients with hemophilia A. It is expected that a sample size of 40 subjects would, nonetheless, provide statistically robust point estimates with meaningfully narrow confidence intervals.
    End point values
    Emicizumab: Expansion Part
    Number of subjects analysed
    37
    Units: percentage of subjects
        number (not applicable)
    67.6
    No statistical analyses for this end point

    Secondary: Expansion Part: Change from Baseline to Week 25 in the Hemophilia-Quality of Life-Short Form (Haemo-QoL-SF) Questionnaire Total Score for Adolescent Subjects (12-17 Years of Age)

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    End point title
    Expansion Part: Change from Baseline to Week 25 in the Hemophilia-Quality of Life-Short Form (Haemo-QoL-SF) Questionnaire Total Score for Adolescent Subjects (12-17 Years of Age) [15]
    End point description
    The Haemo-QoL-SF was developed in a series of age-related questionnaires to measure health-related quality of life (HRQoL) in children and adolescents with hemophilia. The short version for older children containing 35 items was selected for adolescents in this study. Items are rated along five response options: never, rarely, sometimes, often, or all the time. This version covers nine dimensions considered relevant for the children’s HRQoL (physical health, feelings, view of yourself, family, friends, other people, sports and school, dealing with hemophilia, and treatment). Scale scores range from 0 to 100, with lower scores indicating better HRQoL. The analysis included all adolescent subjects enrolled in the expansion part of the study. The number of subjects analyzed indicates those who completed the questionnaire at Baseline and Week 25. Given the small number of adolescent subjects, the results of the Haemo-QoL-SF questionnaire should be interpreted with caution.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 25
    Notes
    [15] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The efficacy end points of this study were planned to be primarily evaluated based on subjects in the expansion cohort of the study. The overall sample size of 40 subjects in the expansion cohort was based on clinical considerations taking into account the limited number of patients with hemophilia A. It is expected that a sample size of 40 subjects would, nonetheless, provide statistically robust point estimates with meaningfully narrow confidence intervals.
    End point values
    Emicizumab: Expansion Part
    Number of subjects analysed
    3
    Units: units on a scale
        arithmetic mean (standard deviation)
    -8.10 ± 6.48
    No statistical analyses for this end point

    Secondary: Expansion Part: Change from Baseline to Week 25 in the European Quality of Life-5 Dimensions-5 Levels (EQ-5D-5L) Questionnaire Visual Analogue Scale (VAS) Score

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    End point title
    Expansion Part: Change from Baseline to Week 25 in the European Quality of Life-5 Dimensions-5 Levels (EQ-5D-5L) Questionnaire Visual Analogue Scale (VAS) Score [16]
    End point description
    The EQ-5D-5L is a self-reported health status questionnaire that consists of six questions used to calculate a health utility score for use in health economic analysis. There are two components to the EQ-5D-5L: a five-item health state profile that assesses mobility, self-care, usual activities, pain/discomfort, and anxiety/depression used to obtain an Index Utility Score, as well as a visual analogue scale (VAS) that measures health state. The VAS is designed to rate the subject's current health state on a scale from 0 to 100, where 0 represents the worst imaginable health state and 100 represents the best imaginable health state. An increase in the VAS score of 7 points or greater was defined as the threshold for a meaningful improvement. The analysis included all subjects enrolled in the expansion part of the study. The number of subjects analyzed indicates those who completed the questionnaire at Baseline and Week 25.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 25
    Notes
    [16] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The efficacy end points of this study were planned to be primarily evaluated based on subjects in the expansion cohort of the study. The overall sample size of 40 subjects in the expansion cohort was based on clinical considerations taking into account the limited number of patients with hemophilia A. It is expected that a sample size of 40 subjects would, nonetheless, provide statistically robust point estimates with meaningfully narrow confidence intervals.
    End point values
    Emicizumab: Expansion Part
    Number of subjects analysed
    40
    Units: units on a scale
        arithmetic mean (confidence interval 95%)
    5.53 (1.15 to 9.90)
    No statistical analyses for this end point

    Secondary: Expansion Part: Percentage of Subjects with a Meaningful Improvement from Baseline to Week 25 in the EQ-5D-5L Questionnaire VAS Score

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    End point title
    Expansion Part: Percentage of Subjects with a Meaningful Improvement from Baseline to Week 25 in the EQ-5D-5L Questionnaire VAS Score [17]
    End point description
    The EQ-5D-5L is a self-reported health status questionnaire that consists of six questions used to calculate a health utility score for use in health economic analysis. There are two components to the EQ-5D-5L: a five-item health state profile that assesses mobility, self-care, usual activities, pain/discomfort, and anxiety/depression used to obtain an Index Utility Score, as well as a visual analogue scale (VAS) that measures health state. The VAS is designed to rate the subject's current health state on a scale from 0 to 100, where 0 represents the worst imaginable health state and 100 represents the best imaginable health state. An increase in the VAS score of 7 points or greater was defined as the threshold for a meaningful improvement. The analysis included all subjects enrolled in the expansion part of the study. The number of subjects analyzed indicates those who completed the questionnaire at Baseline and Week 25.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 25
    Notes
    [17] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The efficacy end points of this study were planned to be primarily evaluated based on subjects in the expansion cohort of the study. The overall sample size of 40 subjects in the expansion cohort was based on clinical considerations taking into account the limited number of patients with hemophilia A. It is expected that a sample size of 40 subjects would, nonetheless, provide statistically robust point estimates with meaningfully narrow confidence intervals.
    End point values
    Emicizumab: Expansion Part
    Number of subjects analysed
    40
    Units: percentage of subjects
        number (not applicable)
    35.0
    No statistical analyses for this end point

    Secondary: Expansion Part: Change from Baseline to Week 25 in the EQ-5D-5L Questionnaire Index Utility Score

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    End point title
    Expansion Part: Change from Baseline to Week 25 in the EQ-5D-5L Questionnaire Index Utility Score [18]
    End point description
    The EQ-5D-5L is a self-reported health status questionnaire that consists of six questions used to calculate a health utility score for use in health economic analysis. There are two components to the EQ-5D-5L: a five-item health state profile that assesses mobility, self-care, usual activities, pain/discomfort, and anxiety/depression used to obtain an Index Utility Score, as well as a visual analogue scale (VAS) that measures health state. Published weighting systems allow for creation of a single summary score for the Index Utility Score where overall scores range from 0 to 1, with lower scores representing a higher level of dysfunction. An increase in the Index Utility Score of 0.07 points or greater was defined as the threshold for a meaningful improvement. The analysis included all subjects enrolled in the expansion part of the study. The number of subjects analyzed indicates those who completed the questionnaire at Baseline and Week 25.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 25
    Notes
    [18] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The efficacy end points of this study were planned to be primarily evaluated based on subjects in the expansion cohort of the study. The overall sample size of 40 subjects in the expansion cohort was based on clinical considerations taking into account the limited number of patients with hemophilia A. It is expected that a sample size of 40 subjects would, nonetheless, provide statistically robust point estimates with meaningfully narrow confidence intervals.
    End point values
    Emicizumab: Expansion Part
    Number of subjects analysed
    40
    Units: units on a scale
        arithmetic mean (confidence interval 95%)
    0.06 (0.03 to 0.10)
    No statistical analyses for this end point

    Secondary: Expansion Part: Percentage of Subjects with a Meaningful Improvement from Baseline to Week 25 in the EQ-5D-5L Questionnaire Index Utility Score

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    End point title
    Expansion Part: Percentage of Subjects with a Meaningful Improvement from Baseline to Week 25 in the EQ-5D-5L Questionnaire Index Utility Score [19]
    End point description
    The EQ-5D-5L is a self-reported health status questionnaire that consists of six questions used to calculate a health utility score for use in health economic analysis. There are two components to the EQ-5D-5L: a five-item health state profile that assesses mobility, self-care, usual activities, pain/discomfort, and anxiety/depression used to obtain an Index Utility Score, as well as a visual analogue scale (VAS) that measures health state. Published weighting systems allow for creation of a single summary score for the Index Utility Score where overall scores range from 0 to 1, with lower scores representing a higher level of dysfunction. An increase in the Index Utility Score of 0.07 points or greater was defined as the threshold for a meaningful improvement. The analysis included all subjects enrolled in the expansion part of the study. The number of subjects analyzed indicates those who completed the questionnaire at Baseline and Week 25.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 25
    Notes
    [19] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The efficacy end points of this study were planned to be primarily evaluated based on subjects in the expansion cohort of the study. The overall sample size of 40 subjects in the expansion cohort was based on clinical considerations taking into account the limited number of patients with hemophilia A. It is expected that a sample size of 40 subjects would, nonetheless, provide statistically robust point estimates with meaningfully narrow confidence intervals.
    End point values
    Emicizumab: Expansion Part
    Number of subjects analysed
    40
    Units: percentage of subjects
        number (not applicable)
    47.5
    No statistical analyses for this end point

    Secondary: Expansion Part: Proportion of Days Away from Work to Expected Days at Work in the Previous Four Weeks

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    End point title
    Expansion Part: Proportion of Days Away from Work to Expected Days at Work in the Previous Four Weeks [20]
    End point description
    Subjects enrolled in the expansion part of the study reported at each time point the number of days away from work (i.e., days of work missed) and the expected number of days at work in the previous four weeks, which is reported here as the proportion of the number of days away from work to the expected number of days at work. The number of subjects who were working and completed the questionnaire at Baseline, Week 13, and Week 25 is reported in brackets.
    End point type
    Secondary
    End point timeframe
    Predose at Baseline, Weeks 13 and 25, and every 12 weeks thereafter up to study completion/early termination (up to approximately 4 years)
    Notes
    [20] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The efficacy end points of this study were planned to be primarily evaluated based on subjects in the expansion cohort of the study. The overall sample size of 40 subjects in the expansion cohort was based on clinical considerations taking into account the limited number of patients with hemophilia A. It is expected that a sample size of 40 subjects would, nonetheless, provide statistically robust point estimates with meaningfully narrow confidence intervals.
    End point values
    Emicizumab: Expansion Part
    Number of subjects analysed
    41
    Units: away/expected work days
    arithmetic mean (confidence interval 95%)
        Baseline (n = 28)
    0.05 (0.01 to 0.10)
        Week 13 (n = 28)
    0.00 (0.00 to 0.00)
        Week 25 (n = 27)
    0.01 (0.00 to 0.02)
    No statistical analyses for this end point

    Secondary: Expansion Part: Proportion of Days Away from School to Expected Days at School in the Previous Four Weeks

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    End point title
    Expansion Part: Proportion of Days Away from School to Expected Days at School in the Previous Four Weeks [21]
    End point description
    Subjects enrolled in the expansion part of the study reported at each time point the number of days away from school (i.e., days of school missed) and the expected number of days at school in the previous four weeks, which is reported here as the proportion of the number of days away from school to the expected number of days at school. The number of subjects who were enrolled in school and completed the questionnaire at Baseline, Week 13, and Week 25 is reported in brackets.
    End point type
    Secondary
    End point timeframe
    Predose at Baseline, Weeks 13 and 25, and every 12 weeks thereafter up to study completion/early termination (up to approximately 4 years)
    Notes
    [21] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The efficacy end points of this study were planned to be primarily evaluated based on subjects in the expansion cohort of the study. The overall sample size of 40 subjects in the expansion cohort was based on clinical considerations taking into account the limited number of patients with hemophilia A. It is expected that a sample size of 40 subjects would, nonetheless, provide statistically robust point estimates with meaningfully narrow confidence intervals.
    End point values
    Emicizumab: Expansion Part
    Number of subjects analysed
    41
    Units: away/expected school days
    arithmetic mean (confidence interval 95%)
        Baseline (n = 10)
    0.12 (0.01 to 0.24)
        Week 13 (n = 8)
    0.00 (0.00 to 0.00)
        Week 25 (n = 10)
    0.03 (0.00 to 0.10)
    No statistical analyses for this end point

    Secondary: Expansion Part: Number of Days Hospitalized

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    End point title
    Expansion Part: Number of Days Hospitalized [22]
    End point description
    At the clinical cut-off date for primary analysis (15 Dec 2017), the median observation time was 43.71 weeks (range: 41.7-45.7 weeks); all subjects had completed at least 24 weeks of treatment.
    End point type
    Secondary
    End point timeframe
    From Baseline until at least 24 weeks of treatment through to study completion (up to approximately 4 years)
    Notes
    [22] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The efficacy end points of this study were planned to be primarily evaluated based on subjects in the expansion cohort of the study. The overall sample size of 40 subjects in the expansion cohort was based on clinical considerations taking into account the limited number of patients with hemophilia A. It is expected that a sample size of 40 subjects would, nonetheless, provide statistically robust point estimates with meaningfully narrow confidence intervals.
    End point values
    Emicizumab: Expansion Part
    Number of subjects analysed
    41
    Units: days
        arithmetic mean (standard deviation)
    0 ± 0
    No statistical analyses for this end point

    Secondary: Expansion Part: Percentage of Subjects Who Preferred Either the New Emicizumab Subcutaneous (SC) Treatment or Their Previous Hemophilia Intravenous (IV) Treatment, or Had No Preference, as Assessed Using the Emicizumab Preference Survey

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    End point title
    Expansion Part: Percentage of Subjects Who Preferred Either the New Emicizumab Subcutaneous (SC) Treatment or Their Previous Hemophilia Intravenous (IV) Treatment, or Had No Preference, as Assessed Using the Emicizumab Preference Survey [23]
    End point description
    The Emicizumab Preference Survey is a fit-for-purpose questionnaire developed by the sponsor to record the subject’s preference for treatment with intravenous (IV) factor VIIII (FVIII) or subcutaneous (SC) emicizumab, or no preference.
    End point type
    Secondary
    End point timeframe
    Predose at Week 17
    Notes
    [23] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The efficacy end points of this study were planned to be primarily evaluated based on subjects in the expansion cohort of the study. The overall sample size of 40 subjects in the expansion cohort was based on clinical considerations taking into account the limited number of patients with hemophilia A. It is expected that a sample size of 40 subjects would, nonetheless, provide statistically robust point estimates with meaningfully narrow confidence intervals.
    End point values
    Emicizumab: Expansion Part
    Number of subjects analysed
    41
    Units: percentage of participants
    number (confidence interval 95%)
        Prefer the New Emicizumab SC Treatment
    100 (91.40 to 100.00)
        Prefer My Old Hemophilia Treatment (IV)
    0.0 (0.00 to 8.60)
        Have No Preference
    0.0 (0.00 to 8.60)
    No statistical analyses for this end point

    Secondary: PK Run-In Part: Time to Reach Maximum Observed Plasma Concentration (Tmax) of Emicizumab

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    End point title
    PK Run-In Part: Time to Reach Maximum Observed Plasma Concentration (Tmax) of Emicizumab [24]
    End point description
    End point type
    Secondary
    End point timeframe
    Predose (0 hr) and 8 hrs postdose on Day 1; Days 3,5,8,11,15,18,22,25,29,36,43,50,57,85,113,141,148,155,162,169, once between 2 emicizumab administrations between Weeks 9 and 21, and once every 12 weeks from Week 25 to study completion (up to 4 years)
    Notes
    [24] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The study plan was to evaluate Tmax only in the PK run-in cohort of the study.
    End point values
    Emicizumab: PK Run-In Part
    Number of subjects analysed
    7
    Units: day
    median (full range (min-max))
        After First Dose (Weeks 1-5)
    6.95 (3.99 to 7.18)
        After Sixth Dose (Weeks 21-25)
    6.98 (6.90 to 14.03)
    No statistical analyses for this end point

    Secondary: PK Run-In Part: Maximum Observed Plasma Concentration (Cmax) of Emicizumab

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    End point title
    PK Run-In Part: Maximum Observed Plasma Concentration (Cmax) of Emicizumab [25]
    End point description
    End point type
    Secondary
    End point timeframe
    Predose (0 hr) and 8 hrs postdose on Day 1; Days 3,5,8,11,15,18,22,25,29,36,43,50,57,85,113,141,148,155,162,169, once between 2 emicizumab administrations between Weeks 9 and 21, and once every 12 weeks from Week 25 to study completion (up to 4 years)
    Notes
    [25] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The study plan was to evaluate Cmax only in the PK run-in cohort of the study.
    End point values
    Emicizumab: PK Run-In Part
    Number of subjects analysed
    7
    Units: μg/mL
    geometric mean (geometric coefficient of variation)
        After First Dose (Weeks 1-5)
    31.8 ± 19.3
        After Sixth Dose (Weeks 21-25)
    62.7 ± 17.3
    No statistical analyses for this end point

    Secondary: PK Run-In Part: Area Under the Plasma Concentration-Time Curve from Time Zero to End of Dosing Interval (AUC[0-tau]) of Emicizumab

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    End point title
    PK Run-In Part: Area Under the Plasma Concentration-Time Curve from Time Zero to End of Dosing Interval (AUC[0-tau]) of Emicizumab [26]
    End point description
    End point type
    Secondary
    End point timeframe
    Predose (0 hr) and 8 hrs postdose on Day 1; Days 3,5,8,11,15,18,22,25,29,36,43,50,57,85,113,141,148,155,162,169, once between 2 emicizumab administrations between Weeks 9 and 21, and once every 12 weeks from Week 25 to study completion (up to 4 years)
    Notes
    [26] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The study plan was to evaluate AUC[0-tau] only in the PK run-in cohort of the study.
    End point values
    Emicizumab: PK Run-In Part
    Number of subjects analysed
    7
    Units: day*μg/mL
    geometric mean (geometric coefficient of variation)
        After First Dose (Weeks 1-5)
    663 ± 19.6
        After Sixth Dose (Weeks 21-25)
    1420 ± 20.7
    No statistical analyses for this end point

    Secondary: PK Run-In Part: Area Under the Plasma Concentration-Time Curve from Time Zero to Extrapolated Infinite Time (AUC[0-inf]) of Emicizumab

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    End point title
    PK Run-In Part: Area Under the Plasma Concentration-Time Curve from Time Zero to Extrapolated Infinite Time (AUC[0-inf]) of Emicizumab [27]
    End point description
    t1/2 was not properly estimated after the first dose due to sampling time and dosing schedule; hence, dependent PK parameters, such as AUC[0-inf], could not be estimated after the sixth dose of emicizumab (as indicated by the entered value '99999').
    End point type
    Secondary
    End point timeframe
    Predose (0 hr) and 8 hrs postdose on Day 1; Days 3,5,8,11,15,18,22,25,29,36,43,50,57,85,113,141,148,155,162,169, once between 2 emicizumab administrations between Weeks 9 and 21, and once every 12 weeks from Week 25 to study completion (up to 4 years)
    Notes
    [27] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The study plan was to evaluate AUC[0-inf] only in the PK run-in cohort of the study.
    End point values
    Emicizumab: PK Run-In Part
    Number of subjects analysed
    7
    Units: day*μg/mL
    geometric mean (geometric coefficient of variation)
        After First Dose (Weeks 1-5)
    1490 ± 27.2
        After Sixth Dose (Weeks 21-25)
    99999 ± 99999
    No statistical analyses for this end point

    Secondary: PK Run-In Part: Apparent Plasma Terminal Half-Life (t1/2) of Emicizumab

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    End point title
    PK Run-In Part: Apparent Plasma Terminal Half-Life (t1/2) of Emicizumab [28]
    End point description
    t1/2 was not properly estimated after the first dose due to sampling time and dosing schedule; hence, t1/2 could not be determined after the sixth dose of emicizumab, as indicated by the entered value '99999'.
    End point type
    Secondary
    End point timeframe
    Predose (0 hr) and 8 hrs postdose on Day 1; Days 3,5,8,11,15,18,22,25,29,36,43,50,57,85,113,141,148,155,162,169, once between 2 emicizumab administrations between Weeks 9 and 21, and once every 12 weeks from Week 25 to study completion (up to 4 years)
    Notes
    [28] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The study plan was to evaluate t1/2 only in the PK run-in cohort of the study.
    End point values
    Emicizumab: PK Run-In Part
    Number of subjects analysed
    7
    Units: day
    geometric mean (geometric coefficient of variation)
        After First Dose (Weeks 1-5)
    29.5 ± 38.5
        After Sixth Dose (Weeks 21-25)
    99999 ± 99999
    No statistical analyses for this end point

    Secondary: PK Run-In Part: Apparent Clearance (CL/F) of Emicizumab

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    End point title
    PK Run-In Part: Apparent Clearance (CL/F) of Emicizumab [29]
    End point description
    Only CL/F is reported after the first dose; the apparent clearance at steady state (CLss/F) is reported after the sixth dose instead. This is because t1/2 was not properly estimated after the first dose due to sampling time and dosing schedule, and dependent PK parameters, such as CL/F, could not be estimated.
    End point type
    Secondary
    End point timeframe
    Predose (0 hr) and 8 hrs postdose on Day 1; Days 3,5,8,11,15,18,22,25,29,36,43,50,57,85,113,141,148,155,162,169, once between 2 emicizumab administrations between Weeks 9 and 21, and once every 12 weeks from Week 25 to study completion (up to 4 years)
    Notes
    [29] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The study plan was to evaluate CL/F only in the PK run-in cohort of the study.
    End point values
    Emicizumab: PK Run-In Part
    Number of subjects analysed
    7
    Units: mL/h
    geometric mean (geometric coefficient of variation)
        After First Dose (Weeks 1-5)
    10.7 ± 23.9
        After Sixth Dose (Weeks 21-25)
    11.1 ± 20.8
    No statistical analyses for this end point

    Secondary: Expansion Part: Minimum Observed Plasma Concentration (Cmin) of Emicizumab

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    End point title
    Expansion Part: Minimum Observed Plasma Concentration (Cmin) of Emicizumab [30]
    End point description
    The analysis included all subjects enrolled in the expansion part of the study. The value 'n =' represents the number of subjects with an evaluable sample at a given time point. '9999' indicates that Cmin could not be estimated because the value was lower than the quantifiable limit.
    End point type
    Secondary
    End point timeframe
    Predose at Weeks 1, 2, 3, 4, 5, 9, 13, 17, 21, 25, once every 12 weeks from Week 25 to study completion (up to approximately 4 years)
    Notes
    [30] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The study plan was to evaluate Cmin only in the expansion cohort of the study.
    End point values
    Emicizumab: Expansion Part
    Number of subjects analysed
    41
    Units: μg/mL
    geometric mean (geometric coefficient of variation)
        Week 1 (n = 41)
    9999 ± 9999
        Week 2 (n = 41)
    16.0 ± 36.8
        Week 3 (n = 41)
    29.8 ± 30.5
        Week 4 (n = 40)
    41.3 ± 32.4
        Week 5 (n = 41)
    48.8 ± 32.2
        Week 9 (n = 41)
    40.4 ± 45.7
        Week 13 (n = 40)
    38.8 ± 48.8
        Week 17 (n = 41)
    36.1 ± 53.8
        Week 21 (n = 41)
    37.4 ± 48.5
        Week 25 (n = 41)
    37.7 ± 52.8
    No statistical analyses for this end point

    Secondary: Number of Subjects with At Least One Adverse Event

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    End point title
    Number of Subjects with At Least One Adverse Event
    End point description
    The number of subjects experiencing at least one adverse event, including all non-serious and serious adverse events, is reported here. The analysis included all subjects who received at least one dose of emicizumab. At the clinical cut-off date for primary analysis (15 Dec 2017), the median observation time was 43.71 weeks (range: 41.7-45.7 weeks).
    End point type
    Secondary
    End point timeframe
    From Baseline to study completion (up to approximately 4 years)
    End point values
    Emicizumab: PK Run-In Part Emicizumab: Expansion Part
    Number of subjects analysed
    7
    41
    Units: subjects
    7
    30
    No statistical analyses for this end point

    Secondary: Number of Subjects with Grade ≥3 Adverse Events

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    End point title
    Number of Subjects with Grade ≥3 Adverse Events
    End point description
    The World Health Organization (WHO) toxicity grading scale will be used for assessing adverse event severity. For adverse events that are not specifically listed in the WHO toxicity grading scale, a grade 3 adverse event is defined as: severe, marked limitation in activity, some assistance usually required, medical intervention or therapy required, hospitalization possible; and a grade 4 adverse event is defined as: life-threatening, extreme limitation in activity, significant assistance required, significant medical intervention or therapy required, hospitalization or hospice care probable. The analysis included all subjects who received at least one dose of emicizumab. At the clinical cut-off date for primary analysis (15 Dec 2017), the median observation time was 43.71 weeks (range: 41.7-45.7 weeks).
    End point type
    Secondary
    End point timeframe
    From Baseline to study completion (up to approximately 4 years)
    End point values
    Emicizumab: PK Run-In Part Emicizumab: Expansion Part
    Number of subjects analysed
    7
    41
    Units: subjects
    1
    1
    No statistical analyses for this end point

    Secondary: Number of Subjects with Adverse Events Leading to Withdrawal from Treatment

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    End point title
    Number of Subjects with Adverse Events Leading to Withdrawal from Treatment
    End point description
    The analysis included all subjects who received at least one dose of emicizumab. At the clinical cut-off date for primary analysis (15 Dec 2017), the median observation time was 43.71 weeks (range: 41.7-45.7 weeks).
    End point type
    Secondary
    End point timeframe
    From Baseline to study completion (up to approximately 4 years)
    End point values
    Emicizumab: PK Run-In Part Emicizumab: Expansion Part
    Number of subjects analysed
    7
    41
    Units: subjects
    0
    0
    No statistical analyses for this end point

    Secondary: Number of Subjects with Adverse Events of Changes from Baseline in Vital Signs

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    End point title
    Number of Subjects with Adverse Events of Changes from Baseline in Vital Signs
    End point description
    The number of subjects with adverse events of changes from baseline in vital signs is reported here. Vital signs measurements consisted of heart and respiratory rate, temperature, and systolic and diastolic blood pressures, with an abnormal vital sign value being outside of the normal range. An abnormal vital sign result is reported as an adverse event if it meets any of the following criteria: is accompanied by clinical symptoms; results in a change in study treatment (e.g., dosage modification, treatment interruption or discontinuation); results in a medical intervention or a change in concomitant therapy; or is clinically significant in the investigator's judgment. The analysis included all subjects who received at least one dose of emicizumab. At the clinical cut-off date for primary analysis (15 Dec 2017), the median observation time was 43.71 weeks (range: 41.7-45.7 weeks).
    End point type
    Secondary
    End point timeframe
    From Baseline to study completion (up to approximately 4 years)
    End point values
    Emicizumab: PK Run-In Part Emicizumab: Expansion Part
    Number of subjects analysed
    7
    41
    Units: subjects
    0
    0
    No statistical analyses for this end point

    Secondary: Number of Subjects with Adverse Events of Changes from Baseline in Physical Examination Findings

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    End point title
    Number of Subjects with Adverse Events of Changes from Baseline in Physical Examination Findings
    End point description
    Post-baseline physical examination abnormalities that were not present at baseline or worsened were reported as adverse events. The analysis included all subjects who received at least one dose of emicizumab. At the clinical cut-off date for primary analysis (15 Dec 2017), the median observation time was 43.71 weeks (range: 41.7-45.7 weeks).
    End point type
    Secondary
    End point timeframe
    From Baseline to study completion (up to approximately 4 years)
    End point values
    Emicizumab: PK Run-In Part Emicizumab: Expansion Part
    Number of subjects analysed
    7
    41
    Units: subjects
    0
    0
    No statistical analyses for this end point

    Secondary: Number of Subjects with Adverse Events of Abnormal Laboratory Values

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    End point title
    Number of Subjects with Adverse Events of Abnormal Laboratory Values
    End point description
    The number of subjects with adverse events of abnormal laboratory values is reported here. An abnormal laboratory value is defined as a laboratory test result outside of the normal range for hematology or serum chemistries. It is reported as an adverse event if it meets any of the following criteria: is accompanied by clinical symptoms; results in a change in study treatment (e.g., dosage modification, treatment interruption or discontinuation); results in a medical intervention or a change in concomitant therapy; or is clinically significant in the investigator's judgment. The analysis included all subjects who received at least one dose of emicizumab. At the clinical cut-off date for primary analysis (15 Dec 2017), the median observation time was 43.71 weeks (range: 41.7-45.7 weeks).
    End point type
    Secondary
    End point timeframe
    From Baseline to study completion (up to approximately 4 years)
    End point values
    Emicizumab: PK Run-In Part Emicizumab: Expansion Part
    Number of subjects analysed
    7
    41
    Units: subjects
    0
    0
    No statistical analyses for this end point

    Secondary: Number of Subjects with Local Injection-Site Reactions

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    End point title
    Number of Subjects with Local Injection-Site Reactions
    End point description
    Local adverse events that occurred within 24 hours after study drug administration and, in the investigator’s opinion, were judged to be related to study drug injection, were captured as an “injection-site reaction” on the Adverse Event electronic Case Report Form (eCRF). An injection-related reaction that was localized was marked as a “local injection-site reaction.” The analysis included all subjects who received at least one dose of emicizumab. At the clinical cut-off date for primary analysis (15 Dec 2017), the median observation time was 43.71 weeks (range: 41.7-45.7 weeks).
    End point type
    Secondary
    End point timeframe
    From Baseline to study completion (up to approximately 4 years)
    End point values
    Emicizumab: PK Run-In Part Emicizumab: Expansion Part
    Number of subjects analysed
    7
    41
    Units: subjects
    1
    9
    No statistical analyses for this end point

    Secondary: Number of Subjects with Thromboembolic Events

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    End point title
    Number of Subjects with Thromboembolic Events
    End point description
    The analysis included all subjects who received at least one dose of emicizumab. At the clinical cut-off date for primary analysis (15 Dec 2017), the median observation time was 43.71 weeks (range: 41.7-45.7 weeks).
    End point type
    Secondary
    End point timeframe
    From Baseline to study completion (up to approximately 4 years)
    End point values
    Emicizumab: PK Run-In Part Emicizumab: Expansion Part
    Number of subjects analysed
    7
    41
    Units: subjects
    0
    0
    No statistical analyses for this end point

    Secondary: Number of Subjects with Thrombotic Microangiopathy

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    End point title
    Number of Subjects with Thrombotic Microangiopathy
    End point description
    The analysis included all subjects who received at least one dose of emicizumab. At the clinical cut-off date for primary analysis (15 Dec 2017), the median observation time was 43.71 weeks (range: 41.7-45.7 weeks).
    End point type
    Secondary
    End point timeframe
    From Baseline to study completion (up to approximately 4 years)
    End point values
    Emicizumab: PK Run-In Part Emicizumab: Expansion Part
    Number of subjects analysed
    7
    41
    Units: subjects
    0
    0
    No statistical analyses for this end point

    Secondary: Number of Subjects with Systemic Hypersensitivity, Anaphylaxis, or Anaphylactoid Reactions

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    End point title
    Number of Subjects with Systemic Hypersensitivity, Anaphylaxis, or Anaphylactoid Reactions
    End point description
    The analysis included all subjects who received at least one dose of emicizumab. At the clinical cut-off date for primary analysis (15 Dec 2017), the median observation time was 43.71 weeks (range: 41.7-45.7 weeks).
    End point type
    Secondary
    End point timeframe
    From Baseline to study completion (up to approximately 4 years)
    End point values
    Emicizumab: PK Run-In Part Emicizumab: Expansion Part
    Number of subjects analysed
    7
    41
    Units: subjects
    0
    0
    No statistical analyses for this end point

    Secondary: Number of Subjects with Anti-Drug Antibodies to Emicizumab

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    End point title
    Number of Subjects with Anti-Drug Antibodies to Emicizumab
    End point description
    A validated enzyme-linked immunosorbent assay (ELISA) method was used to analyze the levels of anti-drug antibodies to emicizumab in blood plasma samples. A sample was considered positive for anti-drug antibodies if the test result reached or exceeded a pre-determined threshold. The analysis included all subjects who received at least one dose of emicizumab. The number of subjects analyzed indicates those with both baseline and post-baseline assessments. At the clinical cut-off date for primary analysis (15 Dec 2017), the median observation time was 43.71 weeks (range: 41.7-45.7 weeks).
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 5, 9, 13, 17, 21, and 25, and every 12 weeks thereafter until study completion (up to approximately 4 years)
    End point values
    Emicizumab: PK Run-In Part Emicizumab: Expansion Part
    Number of subjects analysed
    7
    40
    Units: subjects
    0
    0
    No statistical analyses for this end point

    Secondary: Number of Subjects With De Novo Development of Anti-Factor VIII (FVIII) Antibodies

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    End point title
    Number of Subjects With De Novo Development of Anti-Factor VIII (FVIII) Antibodies
    End point description
    The levels of anti-FVIII antibodies (inhibitors) were analyzed using a validated FVIII activity assay. A subject was considered to have developed de novo FVIII inhibitors if the inhibitor levels detected in a post-baseline sample reached or exceeded a pre-determined threshold. The analysis included all subjects who received at least one dose of emicizumab. At the clinical cut-off date for primary analysis (15 Dec 2017), the median observation time was 43.71 weeks (range: 41.7-45.7 weeks).
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 9 and 17 (for non-inhibitor subjects only), Week 25, and every 12 weeks thereafter until study completion (up to approximately 4 years)
    End point values
    Emicizumab: PK Run-In Part Emicizumab: Expansion Part
    Number of subjects analysed
    7
    41
    Units: subjects
    0
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From Baseline until the clinical cut-off date (15-Dec-2017) for the primary analysis (median observation time was 43.71 weeks [range: 41.7-45.7 weeks])
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    20.1
    Reporting groups
    Reporting group title
    Emicizumab: PK Run-In Part
    Reporting group description
    Participants will received SC emicizumab at a dose of 6 mg/kg every 4 weeks for a minimum of 24 weeks.

    Reporting group title
    Emicizumab: Expansion Part
    Reporting group description
    Participants will received SC emicizumab at a loading dose of 3 mg/kg every week for initial 4 weeks followed by a maintenance dose of 6 mg/kg every 4 weeks for a minimum of 24 weeks.

    Serious adverse events
    Emicizumab: PK Run-In Part Emicizumab: Expansion Part
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 41 (2.44%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    Vascular disorders
    Hypertension
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Rhabdomyolysis
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    Emicizumab: PK Run-In Part Emicizumab: Expansion Part
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    7 / 7 (100.00%)
    30 / 41 (73.17%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 41 (0.00%)
         occurrences all number
    1
    0
    Aneurysm
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 41 (2.44%)
         occurrences all number
    0
    1
    General disorders and administration site conditions
    Injection site reaction
         subjects affected / exposed
    1 / 7 (14.29%)
    9 / 41 (21.95%)
         occurrences all number
    1
    26
    Asthenia
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 41 (2.44%)
         occurrences all number
    0
    1
    Chills
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 41 (2.44%)
         occurrences all number
    0
    1
    Injection site pain
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 41 (2.44%)
         occurrences all number
    0
    1
    Fatigue
         subjects affected / exposed
    0 / 7 (0.00%)
    2 / 41 (4.88%)
         occurrences all number
    0
    2
    Malaise
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 41 (2.44%)
         occurrences all number
    0
    3
    Pain
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 41 (2.44%)
         occurrences all number
    0
    2
    Pyrexia
         subjects affected / exposed
    0 / 7 (0.00%)
    2 / 41 (4.88%)
         occurrences all number
    0
    3
    Psychiatric disorders
    Sleep disorder
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 41 (2.44%)
         occurrences all number
    0
    1
    Insomnia
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 41 (2.44%)
         occurrences all number
    0
    1
    Reproductive system and breast disorders
    Benign prostatic hyperplasia
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 41 (2.44%)
         occurrences all number
    0
    1
    Genital tract inflammation
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 41 (2.44%)
         occurrences all number
    0
    1
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 41 (0.00%)
         occurrences all number
    2
    0
    Post procedural inflammation
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 41 (0.00%)
         occurrences all number
    1
    0
    Tongue injury
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 41 (0.00%)
         occurrences all number
    1
    0
    Fall
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 41 (2.44%)
         occurrences all number
    0
    1
    Joint injury
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 41 (2.44%)
         occurrences all number
    0
    1
    Laceration
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 41 (2.44%)
         occurrences all number
    0
    2
    Ligament sprain
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 41 (2.44%)
         occurrences all number
    0
    1
    Muscle strain
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 41 (2.44%)
         occurrences all number
    0
    1
    Road traffic accident
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 41 (2.44%)
         occurrences all number
    0
    1
    Venomous sting
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 41 (2.44%)
         occurrences all number
    0
    1
    Wound
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 41 (2.44%)
         occurrences all number
    0
    3
    Investigations
    Glycosylated haemoglobin increased
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 41 (2.44%)
         occurrences all number
    0
    1
    Cardiac disorders
    Atrioventricular block first degree
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 41 (2.44%)
         occurrences all number
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Bronchospasm
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 41 (2.44%)
         occurrences all number
    0
    1
    Cough
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 41 (2.44%)
         occurrences all number
    0
    1
    Rhinorrhea
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 41 (2.44%)
         occurrences all number
    0
    1
    Oropharyngeal pain
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 41 (2.44%)
         occurrences all number
    0
    2
    Blood and lymphatic system disorders
    Splenomegaly
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 41 (2.44%)
         occurrences all number
    0
    1
    Thrombocytopenia
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 41 (2.44%)
         occurrences all number
    0
    1
    Nervous system disorders
    Headache
         subjects affected / exposed
    2 / 7 (28.57%)
    5 / 41 (12.20%)
         occurrences all number
    3
    7
    Dizziness
         subjects affected / exposed
    0 / 7 (0.00%)
    2 / 41 (4.88%)
         occurrences all number
    0
    3
    Hypoaesthesia
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 41 (2.44%)
         occurrences all number
    0
    3
    Presyncope
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 41 (2.44%)
         occurrences all number
    0
    1
    Eye disorders
    Eczema eyelids
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 41 (0.00%)
         occurrences all number
    1
    0
    Cataract
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 41 (2.44%)
         occurrences all number
    0
    1
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 41 (0.00%)
         occurrences all number
    1
    0
    Dyspepsia
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 41 (0.00%)
         occurrences all number
    3
    0
    Aphthous ulcer
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 41 (2.44%)
         occurrences all number
    0
    1
    Diarrhoea
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 41 (2.44%)
         occurrences all number
    0
    1
    Dental caries
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 41 (2.44%)
         occurrences all number
    0
    1
    Faeces discoloured
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 41 (2.44%)
         occurrences all number
    0
    1
    Renal and urinary disorders
    Dysuria
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 41 (2.44%)
         occurrences all number
    0
    1
    Hydronephrosis
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 41 (2.44%)
         occurrences all number
    0
    1
    Nephrolithiasis
         subjects affected / exposed
    0 / 7 (0.00%)
    2 / 41 (4.88%)
         occurrences all number
    0
    2
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 41 (0.00%)
         occurrences all number
    1
    0
    Liver disorder
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 41 (2.44%)
         occurrences all number
    0
    1
    Skin and subcutaneous tissue disorders
    Dermatitis
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 41 (2.44%)
         occurrences all number
    0
    1
    Erythema
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 41 (2.44%)
         occurrences all number
    0
    1
    Erythema nodosum
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 41 (2.44%)
         occurrences all number
    0
    1
    Psoriasis
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 41 (2.44%)
         occurrences all number
    0
    1
    Rash
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 41 (2.44%)
         occurrences all number
    0
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    2 / 7 (28.57%)
    8 / 41 (19.51%)
         occurrences all number
    8
    15
    Back pain
         subjects affected / exposed
    2 / 7 (28.57%)
    1 / 41 (2.44%)
         occurrences all number
    7
    1
    Myalgia
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 41 (2.44%)
         occurrences all number
    1
    1
    Joint lock
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 41 (0.00%)
         occurrences all number
    1
    0
    Osteitis
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 41 (0.00%)
         occurrences all number
    1
    0
    Musculoskeletal chest pain
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 41 (0.00%)
         occurrences all number
    1
    0
    Osteoarthritis
         subjects affected / exposed
    2 / 7 (28.57%)
    0 / 41 (0.00%)
         occurrences all number
    2
    0
    Synovitis
         subjects affected / exposed
    1 / 7 (14.29%)
    2 / 41 (4.88%)
         occurrences all number
    1
    4
    Temporomandibular joint syndrome
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 41 (0.00%)
         occurrences all number
    1
    0
    Tendon disorder
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 41 (0.00%)
         occurrences all number
    1
    0
    Muscle contracture
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 41 (2.44%)
         occurrences all number
    0
    1
    Neck pain
         subjects affected / exposed
    0 / 7 (0.00%)
    2 / 41 (4.88%)
         occurrences all number
    0
    2
    Pain in jaw
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 41 (2.44%)
         occurrences all number
    0
    1
    Pain in extremity
         subjects affected / exposed
    0 / 7 (0.00%)
    4 / 41 (9.76%)
         occurrences all number
    0
    4
    Endocrine disorders
    Goitre
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 41 (2.44%)
         occurrences all number
    0
    1
    Metabolism and nutrition disorders
    Hyperglycaemia
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 41 (2.44%)
         occurrences all number
    0
    1
    Iron deficiency
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 41 (2.44%)
         occurrences all number
    0
    1
    Vitamin B12 deficiency
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 41 (2.44%)
         occurrences all number
    0
    1
    Infections and infestations
    Device related infection
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 41 (0.00%)
         occurrences all number
    1
    0
    Ear infection
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 41 (0.00%)
         occurrences all number
    1
    0
    Pharyngitis
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 41 (0.00%)
         occurrences all number
    1
    0
    Upper respiratory tract infection
         subjects affected / exposed
    2 / 7 (28.57%)
    3 / 41 (7.32%)
         occurrences all number
    3
    3
    Chronic sinusitis
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 41 (2.44%)
         occurrences all number
    0
    1
    Gastroenteritis
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 41 (2.44%)
         occurrences all number
    0
    1
    Gastroenteritis viral
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 41 (2.44%)
         occurrences all number
    0
    1
    Nasopharyngitis
         subjects affected / exposed
    0 / 7 (0.00%)
    11 / 41 (26.83%)
         occurrences all number
    0
    12
    Oral herpes
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 41 (2.44%)
         occurrences all number
    0
    1
    Otitis media
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 41 (2.44%)
         occurrences all number
    0
    1
    Urinary tract infection
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 41 (2.44%)
         occurrences all number
    0
    1

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    19 Nov 2016
    Protocol amendment 1 (version 2) included safety information on thromboembolic and thrombotic microangiopathy events observed in Study BH29884, as well as refinement of the study efficacy objectives. All subject enrollment commenced under this version of the protocol.
    25 Jul 2017
    Protocol amendment 2 (version 3) included updated information on safety findings of thrombotic microangiopathy in Study BH29884 and ways to mitigate risks. Key changes to the protocol that modified the study design or analyses in this amendment, along with a rationale for each change, are summarized: -Updated safety findings of thrombotic microangiopathy observed in Study BH29884; -Clarification on activated prothrombin complex concentrate (aPCC) use was added: aPCC in combination with emicizumab were to be avoided completely in patients who had the option of using other bypassing agents to treat bleeds; -Clarification about anti-fibrinolytics use was added: Anti-fibrinolytics in combination with recombinant activated factor VII were to be used with caution and avoided in combination with aPCC or Byclot; -Clarification regarding laboratory monitoring of coagulation status after any bypassing agent use was added; -Definition of "joint bleeds" was modified from the ISTH definition because of lack of clarity. The previous definition of "joint bleed" required the reporting of a combination of an “unusual sensation (aura) in the joint” and another joint bleed symptom (e.g., decreased range of motion) as per the bleed/medication questionnaire. The definition of "joint bleed" was redefined as bleeds with bleed type “joint bleed” reported with at least one of the symptoms of joint bleed as per the questionnaire except for the symptom “unusual sensation (aura) in the joint” reported alone; -New safety risk associated with emicizumab was added for life-threatening bleeding due to unreliable standard coagulation tests and inhibitors assays in the setting of emicizumab; -The sample size section was aligned with the approved statistical analysis plan.

    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.
    Given the small number of adolescent participants, the results of the Haemo-QoL-SF questionnaire should be interpreted with caution.
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