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    Clinical Trial Results:
    A Randomized, Multicenter, Open-Label, Phase III Clinical Trial to Evaluate the Efficacy, Safety, and Pharmacokinetics of Prophylactic Emicizumab Versus no Prophylaxis in Hemophilia A Patients With Inhibitors

    Summary
    EudraCT number
    		 2015-002866-21
    Trial protocol
    		 DE   ES   GB   PL   FR   IT  
    Global end of trial date

    Results information
    Results version number
    		 v1
    This version publication date
    04 Nov 2017
    First version publication date
    04 Nov 2017
    Other versions
    		 v2

    Trial information

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    Trial identification
    Sponsor protocol code
    BH29884
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02622321
    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
    Roche Trial Information Hotline, F. Hoffmann-La Roche AG, +41 61 6878333, global.trial_information@roche.com
    Scientific contact
    Roche Trial Information Hotline, F. Hoffmann-La Roche AG, +41 61 6878333, 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
    25 Oct 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    25 Oct 2016
    Global end of trial reached?
    No
    General information about the trial
    Main objective of the trial
    The main objective of this study was to evaluate the safety, efficacy and pharmacokinetics of prophylactic emicizumab treatment in participants previously treated with episodic or prophylactic bypassing agents.
    Protection of trial subjects
    The study was conducted in accordance with the principles of the “Declaration of Helsinki” and Good Clinical Practice (GCP) according to the regulations and procedures described in the protocol.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    18 Nov 2015
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Australia: 4
    Country: Number of subjects enrolled
    Costa Rica: 5
    Country: Number of subjects enrolled
    France: 7
    Country: Number of subjects enrolled
    Germany: 6
    Country: Number of subjects enrolled
    United Kingdom: 5
    Country: Number of subjects enrolled
    Italy: 6
    Country: Number of subjects enrolled
    Japan: 12
    Country: Number of subjects enrolled
    New Zealand: 2
    Country: Number of subjects enrolled
    Poland: 9
    Country: Number of subjects enrolled
    South Africa: 6
    Country: Number of subjects enrolled
    Korea, Republic of: 1
    Country: Number of subjects enrolled
    Spain: 6
    Country: Number of subjects enrolled
    Taiwan: 4
    Country: Number of subjects enrolled
    United States: 36
    Worldwide total number of subjects
    109
    EEA total number of subjects
    39
    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)
    32
    Adults (18-64 years)
    73
    From 65 to 84 years
    4
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 A total of 114 participants were screened, of which 5 were screen failure and 109 were enrolled in this study. Participants in Arm A and Arm B were randomized in a 2:1 ratio; participants in Arm C and Arm D were enrolled without randomization.

    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
    		 Arm A (Episodic Treatment): Emicizumab
    Arm description
    		 Participants, who received episodic treatment with bypassing agents prior to study entry, received prophylactic emicizumab. Emicizumab was administered at a loading dose of 3 milligrams per kilogram per week (mg/kg/week) subcutaneously (SC) for the first 4 weeks followed by a maintenance dose of 1.5 mg/kg/week SC up to the end of study. Participants continued to receive episodic bypassing agent therapy to treat breakthrough bleeds, with recombinant activated factor VII (rFVIIa) and/or activated prothrombin complex concentrate (aPCC).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Emicizumab
    Investigational medicinal product code
    RO5534262
    Other name
    ACE910
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Emicizumab was administered at a loading dose of 3 milligrams per kilogram per week (mg/kg/week) for the first 4 weeks followed by a maintenance dose of 1.5 mg/kg/week up to the end of study.

    Arm title
    		 Arm B (Episodic Treatment): No Emicizumab
    Arm description
    		 Participants, who received episodic treatment with bypassing agents prior to study entry, did not receive emicizumab prophylaxis. Participants in this arm could switch to emicizumab prophylaxis after completing at least 24 weeks on-study. Participants continued to receive bypassing agent therapy to treat breakthrough bleeds, with rFVIIa and/or aPCC.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Emicizumab
    Investigational medicinal product code
    RO5534262
    Other name
    ACE910
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Emicizumab was administered at a loading dose of 3 mg/kg/week for the first 4 weeks followed by a maintenance dose of 1.5 mg/kg/week up to the end of study.

    Arm title
    		 Arm C (Prophylactic Treatment): Emicizumab
    Arm description
    		 Participants, who received prophylactic bypassing agents prior to study entry, received prophylactic emicizumab. Emicizumab was administered at a loading dose of 3 mg/kg/week SC for the first 4 weeks followed by a maintenance dose of 1.5 mg/kg/week SC up to the end of study. Participants continued to receive bypassing agent therapy to treat breakthrough bleeds, with rFVIIa and/or aPCC.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Emicizumab
    Investigational medicinal product code
    RO5534262
    Other name
    ACE910
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Emicizumab was administered at a loading dose of 3 mg/kg/week for the first 4 weeks followed by a maintenance dose of 1.5 mg/kg/week up to the end of study.

    Arm title
    		 Arm D (Episodic or Prophylactic Treatment): Emicizumab
    Arm description
    		 Participants, who received episodic bypassing agents prior to study entry, who participated in Study BH29768 but were unable to enroll in Arms A or B, were enrolled in this arm to receive prophylactic emicizumab. Emicizumab was administered at a loading dose of 3 mg/kg/week SC for the first 4 weeks followed by a maintenance dose of 1.5 mg/kg/week SC up to the end of study. Participants continued to receive bypassing agent therapy to treat breakthrough bleeds, with rFVIIa and/or aPCC.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Emicizumab
    Investigational medicinal product code
    RO5534262
    Other name
    ACE910
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Emicizumab was administered at a loading dose of 3 mg/kg/week for the first 4 weeks followed by a maintenance dose of 1.5 mg/kg/week up to the end of study.

    Number of subjects in period 1
    		Arm A (Episodic Treatment): Emicizumab Arm B (Episodic Treatment): No Emicizumab Arm C (Prophylactic Treatment): Emicizumab Arm D (Episodic or Prophylactic Treatment): Emicizumab
    Started
    35
    18
    49
    7
    Treated
    34
    18
    49
    7
    Completed
    0
    0
    0
    0
    Not completed
    35
    18
    49
    7
         Ongoing treatment with no emicizumab
    -
    5
    -
    -
         Consent withdrawn by subject
    1
    -
    -
    -
         Ongoing in safety follow-up
    3
    -
    -
    -
         Ongoing treatment with emicizumab
    31
    13
    49
    7

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Arm A (Episodic Treatment): Emicizumab
    Reporting group description
    		 Participants, who received episodic treatment with bypassing agents prior to study entry, received prophylactic emicizumab. Emicizumab was administered at a loading dose of 3 milligrams per kilogram per week (mg/kg/week) subcutaneously (SC) for the first 4 weeks followed by a maintenance dose of 1.5 mg/kg/week SC up to the end of study. Participants continued to receive episodic bypassing agent therapy to treat breakthrough bleeds, with recombinant activated factor VII (rFVIIa) and/or activated prothrombin complex concentrate (aPCC).

    Reporting group title
    Arm B (Episodic Treatment): No Emicizumab
    Reporting group description
    		 Participants, who received episodic treatment with bypassing agents prior to study entry, did not receive emicizumab prophylaxis. Participants in this arm could switch to emicizumab prophylaxis after completing at least 24 weeks on-study. Participants continued to receive bypassing agent therapy to treat breakthrough bleeds, with rFVIIa and/or aPCC.

    Reporting group title
    Arm C (Prophylactic Treatment): Emicizumab
    Reporting group description
    		 Participants, who received prophylactic bypassing agents prior to study entry, received prophylactic emicizumab. Emicizumab was administered at a loading dose of 3 mg/kg/week SC for the first 4 weeks followed by a maintenance dose of 1.5 mg/kg/week SC up to the end of study. Participants continued to receive bypassing agent therapy to treat breakthrough bleeds, with rFVIIa and/or aPCC.

    Reporting group title
    Arm D (Episodic or Prophylactic Treatment): Emicizumab
    Reporting group description
    		 Participants, who received episodic bypassing agents prior to study entry, who participated in Study BH29768 but were unable to enroll in Arms A or B, were enrolled in this arm to receive prophylactic emicizumab. Emicizumab was administered at a loading dose of 3 mg/kg/week SC for the first 4 weeks followed by a maintenance dose of 1.5 mg/kg/week SC up to the end of study. Participants continued to receive bypassing agent therapy to treat breakthrough bleeds, with rFVIIa and/or aPCC.

    Reporting group values
    		 Arm A (Episodic Treatment): Emicizumab Arm B (Episodic Treatment): No Emicizumab Arm C (Prophylactic Treatment): Emicizumab Arm D (Episodic or Prophylactic Treatment): Emicizumab Total
    Number of subjects
    		 35 18 49 7 109
    Age Categorical
    Units: Subjects
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 35.8 ± 13.9 37.2 ± 13.7 25.6 ± 16.8 30.3 ± 10.8 -
    Gender Categorical
    Units: Subjects
        Female
    		 0 0 0 0 0
        Male
    		 35 18 49 7 109

    End points

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    End points reporting groups
    Reporting group title
    Arm A (Episodic Treatment): Emicizumab
    Reporting group description
    		 Participants, who received episodic treatment with bypassing agents prior to study entry, received prophylactic emicizumab. Emicizumab was administered at a loading dose of 3 milligrams per kilogram per week (mg/kg/week) subcutaneously (SC) for the first 4 weeks followed by a maintenance dose of 1.5 mg/kg/week SC up to the end of study. Participants continued to receive episodic bypassing agent therapy to treat breakthrough bleeds, with recombinant activated factor VII (rFVIIa) and/or activated prothrombin complex concentrate (aPCC).

    Reporting group title
    Arm B (Episodic Treatment): No Emicizumab
    Reporting group description
    		 Participants, who received episodic treatment with bypassing agents prior to study entry, did not receive emicizumab prophylaxis. Participants in this arm could switch to emicizumab prophylaxis after completing at least 24 weeks on-study. Participants continued to receive bypassing agent therapy to treat breakthrough bleeds, with rFVIIa and/or aPCC.

    Reporting group title
    Arm C (Prophylactic Treatment): Emicizumab
    Reporting group description
    		 Participants, who received prophylactic bypassing agents prior to study entry, received prophylactic emicizumab. Emicizumab was administered at a loading dose of 3 mg/kg/week SC for the first 4 weeks followed by a maintenance dose of 1.5 mg/kg/week SC up to the end of study. Participants continued to receive bypassing agent therapy to treat breakthrough bleeds, with rFVIIa and/or aPCC.

    Reporting group title
    Arm D (Episodic or Prophylactic Treatment): Emicizumab
    Reporting group description
    		 Participants, who received episodic bypassing agents prior to study entry, who participated in Study BH29768 but were unable to enroll in Arms A or B, were enrolled in this arm to receive prophylactic emicizumab. Emicizumab was administered at a loading dose of 3 mg/kg/week SC for the first 4 weeks followed by a maintenance dose of 1.5 mg/kg/week SC up to the end of study. Participants continued to receive bypassing agent therapy to treat breakthrough bleeds, with rFVIIa and/or aPCC.

    Subject analysis set title
    Arm Anis: Episodic Bypassing Agents in NIS BH29768
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    This arm includes data up to 52 weeks before study entry (assessed retrospectively at baseline) from Arm A participants who participated in NIS BH29768 before study entry and received episodic bypassing agents (rFVIIa or/and aPCC) during NIS BH29768.

    Subject analysis set title
    Arm Cnis: Prophylactic Bypassing Agents in NIS BH29768
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    This arm includes data up to 52 weeks before study entry (assessed retrospectively at baseline) from Arm C participants who participated in NIS BH29768 before study entry and received prophylactic bypassing agents (rFVIIa or/and aPCC) during NIS BH29768.

    Subject analysis set title
    Arm Bemi: Emicizumab after Week 24
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    This arm includes Arm B participants who switched to emicizumab prophylaxis after completing at least 24-week no prophylaxis. Emicizumab was administered at a loading dose of 3 mg/kg/week SC for the first 4 weeks (after at least Week 24) followed by a maintenance dose of 1.5 mg/kg/week SC up to the end of study.

    Primary: Arms A and B: Annualized Bleed Rate (ABR) for Treated Bleeds

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    End point title
    		 Arms A and B: Annualized Bleed Rate (ABR) for Treated Bleeds [1]
    End point description
    Number of treated bleeds over the efficacy period was assessed through ABR using a negative binomial (NB) regression model. Treated bleeds were defined as a bleed for which coagulation factors were administered. Bleeds due to surgery/procedure were excluded. Intent-to-treat (ITT) population defined as all participants who were randomized to Arm A or Arm B.
    End point type
    Primary
    End point timeframe
    From Baseline up to clinical cut-off date (25 Oct 2016) (up to approximately 1 year)
    Notes
    [1] - 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 endpoint is applicable only for the reported arms; hence, other arms are not included.
    End point values
    		 Arm A (Episodic Treatment): Emicizumab Arm B (Episodic Treatment): No Emicizumab
    Number of subjects analysed
    35
    18
    Units: treated bleeds per year
        number (confidence interval 95%)
    2.9 (1.69 to 5.02)
    23.3 (12.33 to 43.89)
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Analysis was performed using an NB regression model, which accounted for different follow-up times, with the participant’s number of bleeds as a function of randomization and the time that each participant stays in the study included as an offset in the model. The model also included the number of bleeds (less than [<] 9 or greater than or equal to [>/=] 9) in the last 24 weeks prior to study entry as a stratification factor in the randomization.
    Comparison groups
    Arm B (Episodic Treatment): No Emicizumab v Arm A (Episodic Treatment): Emicizumab
    Number of subjects included in analysis
    53
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [2]
    Method
    		 Stratified Wald Test
    Parameter type
    		 ABR Ratio
    Point estimate
    0.13
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.057
         upper limit
    		 0.277
    Notes
    [2] - Statistical significance was controlled at a two-sided alpha level of 0.05 based on a Wald testing procedure.

    Secondary: Arms A and B: ABR for All Bleeds

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    End point title
    		 Arms A and B: ABR for All Bleeds [3]
    End point description
    Number of all bleeds over the efficacy period was assessed through ABR using an NB regression model. All bleeds included both treated (with coagulation factors) and not treated bleeds. Bleeds due to surgery/procedure were excluded. ITT population.
    End point type
    Secondary
    End point timeframe
    From Baseline up to clinical cut-off date (25 Oct 2016) (up to approximately 1 year)
    Notes
    [3] - 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 endpoint is applicable only for the reported arms; hence, other arms are not included.
    End point values
    		 Arm A (Episodic Treatment): Emicizumab Arm B (Episodic Treatment): No Emicizumab
    Number of subjects analysed
    35
    18
    Units: all bleeds per year
        number (confidence interval 95%)
    5.5 (3.58 to 8.60)
    28.3 (16.79 to 47.76)
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Analysis was performed using an NB regression model, which accounted for different follow-up times, with the participant’s number of bleeds as a function of randomization and the time that each participant stays in the study included as an offset in the model. The model also included the number of bleeds (<9 or >/=9) in the last 24 weeks prior to study entry as a stratification factor in the randomization.
    Comparison groups
    Arm A (Episodic Treatment): Emicizumab v Arm B (Episodic Treatment): No Emicizumab
    Number of subjects included in analysis
    53
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [4]
    Method
    		 Stratified Wald Test
    Parameter type
    		 ABR Ratio
    Point estimate
    0.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.102
         upper limit
    		 0.375
    Notes
    [4] - Statistical significance was controlled at a two-sided alpha level of 0.05 based on a Wald testing procedure.

    Secondary: Arms A and Anis: ABR for All Bleeds

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    End point title
    		 Arms A and Anis: ABR for All Bleeds [5]
    End point description
    Number of all bleeds over the efficacy period was assessed through ABR using an NB regression model. All bleeds included both treated (with coagulation factors) and not treated bleeds. Bleeds due to surgery/procedure were excluded. Intra-participant comparison of ABR of all bleeds prior to study entry, while receiving episodic bypassing agents during non-interventional study (NIS) BH29768 (NCT02476942) (Arm Anis), with ABR of all bleeds on emicizumab prophylaxis (in this study) (Arm A) was reported. Arm A NIS population included all Arm A participants who participated in NIS BH29768 before study entry and received episodic bypassing agents during NIS BH29768.
    End point type
    Secondary
    End point timeframe
    For Arm Anis: up to 52 weeks before study entry (assessed retrospectively at baseline); for Arm A: From Baseline up to clinical cut-off date (25 Oct 2016) (up to approximately 1 year)
    Notes
    [5] - 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 endpoint is applicable only for the reported arms; hence, other arms are not included.
    End point values
    		 Arm A (Episodic Treatment): Emicizumab Arm Anis: Episodic Bypassing Agents in NIS BH29768
    Number of subjects analysed
    24
    24
    Units: all bleeds per year
        number (confidence interval 95%)
    4.1 (2.10 to 8.02)
    37.7 (28.40 to 50.04)
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    This intra-participant comparison of ABR for all bleeds was performed using an NB regression model. There was a total of 24 participants (not 48) analyzed over two different periods: before study entry (Arm Anis) and on study (Arm A).
    Comparison groups
    Arm A (Episodic Treatment): Emicizumab v Arm Anis: Episodic Bypassing Agents in NIS BH29768
    Number of subjects included in analysis
    48
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [6]
    Method
    		 Non-Stratified Wald Test
    Parameter type
    		 ABR Ratio
    Point estimate
    0.11
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.055
         upper limit
    		 0.218
    Notes
    [6] - Statistical significance was controlled at a two-sided alpha level of 0.05 based on a Wald testing procedure.

    Secondary: Arms A and Anis: ABR for Treated Bleeds

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    End point title
    		 Arms A and Anis: ABR for Treated Bleeds [7]
    End point description
    Number of treated bleeds over the efficacy period was assessed through ABR using an NB regression model. Treated bleeds were defined as a bleed for which coagulation factors were administered. Bleeds due to surgery/procedure were excluded. Intra-participant comparison of ABR of treated bleeds prior to study entry, while receiving episodic bypassing agents during NIS BH29768 (Arm Anis), with ABR of treated bleeds on emicizumab prophylaxis (in this study) (Arm A) was reported. Arm A NIS population included all Arm A participants who participated in NIS BH29768 before study entry and received episodic bypassing agents during NIS BH29768.
    End point type
    Secondary
    End point timeframe
    For Arm Anis: up to 52 weeks before study entry (assessed retrospectively at baseline); for Arm A: From Baseline up to clinical cut-off date (25 Oct 2016) (up to approximately 1 year)
    Notes
    [7] - 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 endpoint is applicable only for the reported arms; hence, other arms are not included.
    End point values
    		 Arm A (Episodic Treatment): Emicizumab Arm Anis: Episodic Bypassing Agents in NIS BH29768
    Number of subjects analysed
    24
    24
    Units: treated bleeds per year
        number (confidence interval 95%)
    1.7 (0.71 to 4.06)
    21.6 (15.40 to 30.22)
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    This intra-participant comparison of ABR for treated bleeds was performed using an NB regression model. There was a total of 24 participants (not 48) analyzed over two different periods: before study entry (Arm Anis) and on study (Arm A).
    Comparison groups
    Arm A (Episodic Treatment): Emicizumab v Arm Anis: Episodic Bypassing Agents in NIS BH29768
    Number of subjects included in analysis
    48
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [8]
    Method
    		 Non-Stratified Wald Test
    Parameter type
    		 ABR Ratio
    Point estimate
    0.08
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.031
         upper limit
    		 0.198
    Notes
    [8] - Statistical significance was controlled at a two-sided alpha level of 0.05 based on a Wald testing procedure.

    Secondary: Arms A and B: ABR for Treated Joint Bleeds

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    End point title
    		 Arms A and B: ABR for Treated Joint Bleeds [9]
    End point description
    Number of treated joint bleeds over the efficacy period was assessed through ABR using an NB regression model. Treated joint bleeds were defined as treated bleeds in a joint associated with unusual sensation (aura) in a joint, in combination with another symptom: unusual sensation, swelling/warmth, pain/decreased range of motion (RoM), difficulty moving the joint. Bleeds due to surgery/procedure were excluded. ITT population.
    End point type
    Secondary
    End point timeframe
    From Baseline up to clinical cut-off date (25 Oct 2016) (up to approximately 1 year)
    Notes
    [9] - 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 endpoint is applicable only for the reported arms; hence, other arms are not included.
    End point values
    		 Arm A (Episodic Treatment): Emicizumab Arm B (Episodic Treatment): No Emicizumab
    Number of subjects analysed
    35
    18
    Units: treated joint bleeds per year
        number (confidence interval 95%)
    0.8 (0.26 to 2.20)
    6.7 (1.99 to 22.42)
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Analysis was performed using an NB regression model, which accounted for different follow-up times, with the participant’s number of bleeds as a function of randomization and the time that each participant stays in the study included as an offset in the model. The model also included the number of bleeds (<9 or >/=9) in the last 24 weeks prior to study entry as a stratification factor in the randomization.
    Comparison groups
    Arm A (Episodic Treatment): Emicizumab v Arm B (Episodic Treatment): No Emicizumab
    Number of subjects included in analysis
    53
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.005 [10]
    Method
    		 Stratified Wald Test
    Parameter type
    		 ABR Ratio
    Point estimate
    0.11
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.025
         upper limit
    		 0.52
    Notes
    [10] - Statistical significance was controlled at a two-sided alpha level of 0.05 based on a Wald testing procedure.

    Secondary: Arms C and Cnis: ABR for All Bleeds

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    End point title
    		 Arms C and Cnis: ABR for All Bleeds [11]
    End point description
    Number of all bleeds over the efficacy period was assessed through ABR using an NB regression model. All bleeds included both treated (with coagulation factors) and not treated bleeds. Bleeds due to surgery/procedure were excluded. Intra-participant comparison of ABR of all bleeds prior to study entry, while receiving prophylactic bypassing agents during NIS BH29768 (Arm Cnis), with ABR of all bleeds on emicizumab prophylaxis (in this study) (Arm C) was reported. Arm C NIS population included all Arm C participants who participated in NIS BH29768 before study entry and received prophylactic bypassing agents during NIS BH29768.
    End point type
    Secondary
    End point timeframe
    For Arm Cnis: up to 52 weeks before study entry (assessed retrospectively at baseline); for Arm C: From Baseline up to clinical cut-off date (25 Oct 2016) (up to approximately 1 year)
    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 endpoint is applicable only for the reported arms; hence, other arms are not included.
    End point values
    		 Arm C (Prophylactic Treatment): Emicizumab Arm Cnis: Prophylactic Bypassing Agents in NIS BH29768
    Number of subjects analysed
    24
    24
    Units: all bleeds per year
        number (confidence interval 95%)
    5.5 (2.98 to 10.26)
    24.3 (18.11 to 32.67)
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    This intra-participant comparison of ABR for all bleeds was performed using an NB regression model. There was a total of 24 participants (not 48) analyzed over two different periods: before study entry (Arm Cnis) and on study (Arm C).
    Comparison groups
    Arm C (Prophylactic Treatment): Emicizumab v Arm Cnis: Prophylactic Bypassing Agents in NIS BH29768
    Number of subjects included in analysis
    48
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [12]
    Method
    		 Non-Stratified Wald Test
    Parameter type
    		 ABR Ratio
    Point estimate
    0.23
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.119
         upper limit
    		 0.435
    Notes
    [12] - Statistical significance was controlled at a two-sided alpha level of 0.05 based on a Wald testing procedure.

    Secondary: Arms C and Cnis: ABR for Treated Bleeds

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    End point title
    		 Arms C and Cnis: ABR for Treated Bleeds [13]
    End point description
    Number of treated bleeds over the efficacy period was assessed through ABR using an NB regression model. Treated bleeds were defined as a bleed for which coagulation factors were administered. Bleeds due to surgery/procedure were excluded. Intra-participant comparison of ABR of treated bleeds prior to study entry, while receiving prophylactic bypassing agents during NIS BH29768 (Arm Cnis), with ABR of treated bleeds on emicizumab prophylaxis (in this study) (Arm C) was reported. Arm C NIS population included all Arm C participants who participated in NIS BH29768 before study entry and received prophylactic bypassing agents during NIS BH29768.
    End point type
    Secondary
    End point timeframe
    For Arm Cnis: up to 52 weeks before study entry (assessed retrospectively at baseline); for Arm C: From Baseline up to clinical cut-off date (25 Oct 2016) (up to approximately 1 year)
    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 endpoint is applicable only for the reported arms; hence, other arms are not included.
    End point values
    		 Arm C (Prophylactic Treatment): Emicizumab Arm Cnis: Prophylactic Bypassing Agents in NIS BH29768
    Number of subjects analysed
    24
    24
    Units: treated bleeds per year
        number (confidence interval 95%)
    3.3 (1.33 to 8.08)
    15.7 (11.08 to 22.29)
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    This intra-participant comparison of ABR for treated bleeds between arms was performed using an NB regression model. There was a total of 24 participants (not 48) analyzed over two different periods: before study entry (Arm Cnis) and on study (Arm C).
    Comparison groups
    Arm C (Prophylactic Treatment): Emicizumab v Arm Cnis: Prophylactic Bypassing Agents in NIS BH29768
    Number of subjects included in analysis
    48
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0003 [14]
    Method
    		 Non-Stratified Wald Test
    Parameter type
    		 ABR Ratio
    Point estimate
    0.21
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.089
         upper limit
    		 0.486
    Notes
    [14] - Statistical significance was controlled at a two-sided alpha level of 0.05 based on a Wald testing procedure.

    Secondary: Arms A and B: ABR for Treated Spontaneous Bleeds

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    End point title
    		 Arms A and B: ABR for Treated Spontaneous Bleeds [15]
    End point description
    Number of treated spontaneous bleeds over the efficacy period was assessed through ABR using an NB regression model. Treated spontaneous bleeds were defined as treated (with coagulation factors) bleeds with no known contributing factor (e.g., trauma, surgery). ITT population.
    End point type
    Secondary
    End point timeframe
    From Baseline up to clinical cut-off date (25 Oct 2016) (up to approximately 1 year)
    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 endpoint is applicable only for the reported arms; hence, other arms are not included.
    End point values
    		 Arm A (Episodic Treatment): Emicizumab Arm B (Episodic Treatment): No Emicizumab
    Number of subjects analysed
    35
    18
    Units: treated spontaneous bleeds per year
        number (confidence interval 95%)
    1.3 (0.73 to 2.19)
    16.8 (9.94 to 28.30)
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Analysis was performed using an NB regression model, which accounted for different follow-up times, with the participant’s number of bleeds as a function of randomization and the time that each participant stays in the study included as an offset in the model. The model also included the number of bleeds (<9 or >/=9) in the last 24 weeks prior to study entry as a stratification factor in the randomization
    Comparison groups
    Arm A (Episodic Treatment): Emicizumab v Arm B (Episodic Treatment): No Emicizumab
    Number of subjects included in analysis
    53
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [16]
    Method
    		 Stratified Wald Test
    Parameter type
    		 ABR Ratio
    Point estimate
    0.08
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.037
         upper limit
    		 0.154
    Notes
    [16] - Statistical significance was controlled at a two-sided alpha level of 0.05 based on a Wald testing procedure.

    Secondary: Arms A and B: ABR for Treated Target Joint Bleeds

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    End point title
    		 Arms A and B: ABR for Treated Target Joint Bleeds [17]
    End point description
    Number of treated target joint bleeds over the efficacy period was assessed through ABR using an NB regression model. Treated target joint bleeds included treated (with coagulation factors) joint bleeds in a target joint, defined as a joint in which greater than or equal to (>/=) 3 treated joint bleeds occurred during the last 24 weeks prior to study entry. Bleeds due to surgery/procedure are excluded. ITT population.
    End point type
    Secondary
    End point timeframe
    From Baseline up to clinical cut-off date (25 Oct 2016) (up to approximately 1 year)
    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 endpoint is applicable only for the reported arms; hence, other arms are not included.
    End point values
    		 Arm A (Episodic Treatment): Emicizumab Arm B (Episodic Treatment): No Emicizumab
    Number of subjects analysed
    35
    18
    Units: treated target joint bleeds per year
        number (confidence interval 95%)
    0.1 (0.03 to 0.58)
    3.0 (0.96 to 9.13)
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Analysis was performed using an NB regression model, which accounted for different follow-up times, with the participant’s number of bleeds as a function of randomization and the time that each participant stays in the study included as an offset in the model. The model also included the number of bleeds (<9 or >/=9) in the last 24 weeks prior to study entry as a stratification factor in the randomization.
    Comparison groups
    Arm A (Episodic Treatment): Emicizumab v Arm B (Episodic Treatment): No Emicizumab
    Number of subjects included in analysis
    53
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0002 [18]
    Method
    		 Stratified Wald Test
    Parameter type
    		 ABR Ratio
    Point estimate
    0.05
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.009
         upper limit
    		 0.227
    Notes
    [18] - Statistical significance was controlled at a two-sided alpha level of 0.05 based on a Wald testing procedure.

    Secondary: Arm A and B: Hemophilia-Specific Quality of Life (Haem-A-QoL) Questionnaire Physical Health Score in Adult Participants (>/=18 Years Old)

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    End point title
    		 Arm A and B: Hemophilia-Specific Quality of Life (Haem-A-QoL) Questionnaire Physical Health Score in Adult Participants (>/=18 Years Old) [19]
    End point description
    Haem-A-QoL questionnaire has been developed and used in hemophilia A participants. As a hemophilia-specific questionnaire, this measure assesses very specific aspects of dealing with hemophilia. This questionnaire consists of items pertaining to 10 domains specific to living with hemophilia. The 10 domains are: physical health, sports and leisure, school and work, dealing with hemophilia, family planning, feeling, relationships, treatment, view of yourself, and outlook for the future. The total score for each domain range from 0 to 100 with lower scores reflective of better quality of life. Physical Health domain score is reported. Physical Health domain score is reported (range 0 to 100, with lower scores reflective of better physical health). ITT population. Number of subjects analyzed=participants with available data for this endpoint.
    End point type
    Secondary
    End point timeframe
    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 endpoint is applicable only for the reported arms; hence, other arms are not included.
    End point values
    		 Arm A (Episodic Treatment): Emicizumab Arm B (Episodic Treatment): No Emicizumab
    Number of subjects analysed
    26
    14
    Units: units on a scale
        arithmetic mean (standard deviation)
    30.19 ± 26.59
    57.14 ± 23.35
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Actual number of participants included for inferential statistics in Arm A is 25. Means adjusted for covariates: baseline score, treatment group and treatment by baseline interaction term. Analysis was performed using Analysis of Covariance (ANCOVA).
    Comparison groups
    Arm A (Episodic Treatment): Emicizumab v Arm B (Episodic Treatment): No Emicizumab
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0029 [20]
    Method
    		 ANCOVA
    Parameter type
    		 Adjusted Mean Difference
    Point estimate
    21.55
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 7.89
         upper limit
    		 35.22
    Notes
    [20] - Statistical significance was controlled at a two-sided alpha level of 0.05.

    Secondary: Arm A and B: Haem-A-QoL Questionnaire Total Score in Adult Participants (>/=18 Years Old)

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    End point title
    		 Arm A and B: Haem-A-QoL Questionnaire Total Score in Adult Participants (>/=18 Years Old) [21]
    End point description
    Haem-A-QoL questionnaire has been developed and used in hemophilia A participants. As a hemophilia-specific questionnaire, this measure assesses very specific aspects of dealing with hemophilia. This questionnaire consists of items pertaining to 10 domains specific to living with hemophilia. The 10 domains are: physical health, sports and leisure, school and work, dealing with hemophilia, family planning, feeling, relationships, treatment, view of yourself, and outlook for the future. The total score for each domain range from 0 to 100 with lower scores reflective of better quality of life. Haem-A-QoL Questionnaire Total Score is the average of the all domain scores and range from 0 to 100, with lower scores reflective of better quality of life. ITT population. Number of subjects analyzed=participants with available data for this endpoint.
    End point type
    Secondary
    End point timeframe
    Week 25
    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 endpoint is applicable only for the reported arms; hence, other arms are not included.
    End point values
    		 Arm A (Episodic Treatment): Emicizumab Arm B (Episodic Treatment): No Emicizumab
    Number of subjects analysed
    26
    14
    Units: units on a scale
        arithmetic mean (standard deviation)
    26.465 ± 18.666
    47.504 ± 17.435
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Actual number of participants included for inferential statistics in Arm A is 25. Means adjusted for covariates: baseline score, treatment group and treatment by baseline interaction term.
    Comparison groups
    Arm A (Episodic Treatment): Emicizumab v Arm B (Episodic Treatment): No Emicizumab
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0019 [22]
    Method
    		 ANCOVA
    Parameter type
    		 Adjusted Mean Difference
    Point estimate
    14.01
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 5.56
         upper limit
    		 22.45
    Notes
    [22] - Statistical significance was controlled at a two-sided alpha level of 0.05.

    Secondary: Arm A and B: European Quality of Life-5 Dimensions-5 Levels (EQ-5D-5L) Visual Analog Scale Score

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    End point title
    		 Arm A and B: European Quality of Life-5 Dimensions-5 Levels (EQ-5D-5L) Visual Analog Scale Score [23]
    End point description
    EQ-5D-5L is a standardized, participant-rated questionnaire to assess health-related quality of life. The EQ-5D-5L includes 2 components: the EQ-5D-5L health state profile (descriptive system) and the EQ-5D-5L Visual Analog Scale. The Visual Analogue Scale is designed to rate the participant'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. ITT population. Number of subjects analyzed=participants with available data for this endpoint.
    End point type
    Secondary
    End point timeframe
    Week 25
    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 endpoint is applicable only for the reported arms; hence, other arms are not included.
    End point values
    		 Arm A (Episodic Treatment): Emicizumab Arm B (Episodic Treatment): No Emicizumab
    Number of subjects analysed
    30
    16
    Units: units on a scale
        arithmetic mean (standard deviation)
    83.8 ± 12.9
    76.4 ± 15.7
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Actual number of participants included for inferential statistics in Arm A is 29. Means adjusted for covariates: baseline score, treatment group and treatment by baseline interaction term.
    Comparison groups
    Arm A (Episodic Treatment): Emicizumab v Arm B (Episodic Treatment): No Emicizumab
    Number of subjects included in analysis
    46
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0171 [24]
    Method
    		 ANCOVA
    Parameter type
    		 Adjusted Mean Difference
    Point estimate
    -9.72
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -17.62
         upper limit
    		 -1.82
    Notes
    [24] - Statistical significance was controlled at a two-sided alpha level of 0.05.

    Secondary: Arm A and B: EQ-5D-5L Index Utility Score

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    End point title
    		 Arm A and B: EQ-5D-5L Index Utility Score [25]
    End point description
    EQ-5D-5L is a standardized, participant-rated questionnaire to assess health-related quality of life. The EQ-5D-5L includes 2 components: the EQ-5D-5L health state profile (descriptive system) and the EQ-5D-5L Visual Analog Scale. The EQ-5D-5L health state profile is designed to record the participant's current health state in 5 domains: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Responses from the five domains are used to calculate a single utility index value ranging from 1 to 5, where 1 indicates better health state (no problems) and 5 indicates worst health state (confined to bed). ITT population. Number of subjects analyzed=participants with available data for this endpoint.
    End point type
    Secondary
    End point timeframe
    Week 25
    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 endpoint is applicable only for the reported arms; hence, other arms are not included.
    End point values
    		 Arm A (Episodic Treatment): Emicizumab Arm B (Episodic Treatment): No Emicizumab
    Number of subjects analysed
    30
    16
    Units: units on a scale
        arithmetic mean (standard deviation)
    0.83 ± 0.22
    0.60 ± 0.35
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Actual number of participants included for inferential statistics in Arm A is 29. Means adjusted for covariates: baseline score, treatment group and treatment by baseline interaction term.
    Comparison groups
    Arm A (Episodic Treatment): Emicizumab v Arm B (Episodic Treatment): No Emicizumab
    Number of subjects included in analysis
    46
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0014 [26]
    Method
    		 ANCOVA
    Parameter type
    		 Adjusted Mean Difference
    Point estimate
    -0.16
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.25
         upper limit
    		 -0.07
    Notes
    [26] - Statistical significance was controlled at a two-sided alpha level of 0.05.

    Secondary: Arm A and B: Hemophilia-Specific Quality of Life – Short Form (Haemo-Qol-SF) Questionnaire Total Score in Adolescents Participants (12-17 Years Old)

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    End point title
    		 Arm A and B: Hemophilia-Specific Quality of Life – Short Form (Haemo-Qol-SF) Questionnaire Total Score in Adolescents Participants (12-17 Years Old) [27]
    End point description
    The Haemo-QoL-SF contains 35 items, which cover nine domains considered relevant for the children’s health-related quality of life (physical health, feelings, view of yourself, family, friends, other people, sports and school, dealing with hemophilia and treatment). Items are rated with five respective response options: never, seldom, sometimes, often, and always. Haemo-QoL-SF total score range from 0 to 100, where lower scores reflect better health-related quality of life. Data for this outcome was to be analyzed only if >3 participant (in each arm) have available data. ITT population. Number of subjects analyzed=participants with available data for this endpoint. Here, '99999' represents data not analysed as the criterion for data analysis not met. Data was to be analyzed only if >3 participants have available data.
    End point type
    Secondary
    End point timeframe
    Week 25
    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 endpoint is applicable only for the reported arms; hence, other arms are not included.
    End point values
    		 Arm A (Episodic Treatment): Emicizumab Arm B (Episodic Treatment): No Emicizumab
    Number of subjects analysed
    3
    2
    Units: units on a scale
        arithmetic mean (standard deviation)
    99999 ± 99999
    99999 ± 99999
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Anti-Emicizumab Antibodies

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    End point title
    		 Percentage of Participants With Anti-Emicizumab Antibodies [28]
    End point description
    All emicizumab participants, referred to as all participants 2, included Arms A, C, and D and Arm B participants who switched to receive emicizumab (Arm Bemi). Number of subjects analyzed=participants with at least one post-baseline antibody assessment.
    End point type
    Secondary
    End point timeframe
    Baseline up to approximately 1 year
    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 endpoint is applicable only for the reported arms; hence, other arms are not included.
    End point values
    		 Arm A (Episodic Treatment): Emicizumab Arm C (Prophylactic Treatment): Emicizumab Arm D (Episodic or Prophylactic Treatment): Emicizumab Arm Bemi: Emicizumab after Week 24
    Number of subjects analysed
    33
    49
    6
    8
    Units: percentage of participants
        number (not applicable)
    0
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Plasma Trough Concentration of Emicizumab

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    End point title
    		 Plasma Trough Concentration of Emicizumab [29]
    End point description
    Plasma concentrations of emicizumab were analyzed using a validated Enzyme Linked Immunosorbent Assay (ELISA). The lower limit of quantification (LLOQ) was 100 nanograms per milliliter (ng/mL). Pharmacokinetic (PK) evaluable population included all participants who received at least one dose of emicizumab and had at least one post-dose emicizumab concentration result. Here, n=participants with available data for this endpoint at specified timepoints, each arm, respectively. Here, '99999' represents data not calculable due to single participant; '9999' represents data collection not planned for this arm at this time-point; and '999' represents no data available as the measurements were below LLOQ.
    End point type
    Secondary
    End point timeframe
    Arm A: Pre-dose (0 hour [hr]) on Weeks 1-5, 7, 9, 13, 17, 21, 25, 33, 41, 49; Arm B: Pre-dose (0 hr) on Weeks 25-29, 31, 33, 37, 41; Arm C: Pre-dose (0 hr) on Weeks 1-5, 7, 9, 13, 17, 21, 25, 33, 41; Arm D: Pre-dose (0 hr) on Weeks 1-5, 7, 9, 13
    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 endpoint is applicable only for the reported arms; hence, other arms are not included.
    End point values
    		 Arm A (Episodic Treatment): Emicizumab Arm C (Prophylactic Treatment): Emicizumab Arm D (Episodic or Prophylactic Treatment): Emicizumab Arm Bemi: Emicizumab after Week 24
    Number of subjects analysed
    34
    48
    7
    13
    Units: micrograms per milliliter (mcg/mL)
    arithmetic mean (standard deviation)
        Week 1 (n=33, 0, 48, 7)
    999 ± 999
    999 ± 999
    999 ± 999
    9999 ± 9999
        Week 2 (n=34, 0, 47, 6)
    16.2 ± 4.4
    15.7 ± 5.6
    19.8 ± 7.2
    9999 ± 9999
        Week 3 (n=34, 0, 48, 7)
    31.6 ± 7.3
    31.4 ± 8.5
    34.7 ± 15.3
    9999 ± 9999
        Week 4 (n=32, 0, 47, 7)
    43.8 ± 12.2
    44.4 ± 11.7
    53.0 ± 13.0
    9999 ± 9999
        Week 5 (n=33, 0, 46, 6)
    53.5 ± 15.1
    54.0 ± 13.2
    65.8 ± 13.1
    9999 ± 9999
        Week 7 (n=33, 0, 46, 4)
    52.8 ± 16.2
    53.6 ± 14.3
    58.2 ± 9.1
    9999 ± 9999
        Week 9 (n=32, 0, 40, 3)
    50.4 ± 12.4
    54.4 ± 15.6
    67.0 ± 10.2
    9999 ± 9999
        Week 13 (n=32, 0, 34, 1)
    49.3 ± 13.4
    53.8 ± 14.9
    63.6 ± 99999
    9999 ± 9999
        Week 17 (n=32, 0, 27, 0)
    50.7 ± 15.0
    51.9 ± 12.4
    9999 ± 9999
    9999 ± 9999
        Week 21 (n=32, 0, 22, 0)
    52.6 ± 17.4
    53.2 ± 14.5
    9999 ± 9999
    9999 ± 9999
        Week 25 (n=30, 13, 19, 0)
    54.9 ± 19.3
    47.3 ± 10.2
    9999 ± 9999
    999 ± 999
        Week 26 (n=0, 12, 0, 0)
    9999 ± 9999
    9999 ± 9999
    9999 ± 9999
    22.6 ± 12.5
        Week 27 (n=0, 13, 0, 0)
    9999 ± 9999
    9999 ± 9999
    9999 ± 9999
    32.2 ± 12.3
        Week 28 (n=0, 13, 0, 0)
    9999 ± 9999
    9999 ± 9999
    9999 ± 9999
    46.1 ± 21.6
        Week 29 (n=0, 13, 0, 0)
    9999 ± 9999
    9999 ± 9999
    9999 ± 9999
    54.1 ± 15.8
        Week 31 (n=0, 10, 0, 0)
    9999 ± 9999
    9999 ± 9999
    9999 ± 9999
    55.2 ± 22.7
        Week 33 (n=13, 7, 10, 0)
    52.7 ± 19.3
    54.0 ± 19.0
    9999 ± 9999
    54.6 ± 23.6
        Week 37 (n=0, 3, 0, 0)
    9999 ± 9999
    9999 ± 9999
    9999 ± 9999
    53.6 ± 19.0
        Week 41 (n=3, 1, 4, 0)
    44.2 ± 16.8
    51.9 ± 6.6
    9999 ± 9999
    46.0 ± 99999
        Week 49 (n=1, 0, 0, 0)
    32.5 ± 99999
    9999 ± 9999
    9999 ± 9999
    9999 ± 9999
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From Baseline up to clinical cut-off date (25 Oct 2016) (up to approximately 1 year)
    Adverse event reporting additional description
    Safety population 1 included for Arms A, C, and D, all participants who received at least one dose of emicizumab, and for Arm B, all participants who started the study period. Safety population 2 is exactly the same for Arms A, C, and D, but for Arm B it included only participants who received at least one dose of emicizumab (Arm Bemi).
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.1
    Reporting groups
    Reporting group title
    Arm A (Episodic Treatment): Emicizumab
    Reporting group description
    		 Participants, who received episodic treatment with bypassing agents prior to study entry, received prophylactic emicizumab. Emicizumab was administered at a loading dose of 3 mg/kg/week SC for the first 4 weeks followed by a maintenance dose of 1.5 mg/kg/week SC up to the end of study. Participants continued to receive episodic bypassing agent therapy to treat breakthrough bleeds, with rFVIIa and/or aPCC.

    Reporting group title
    Arm B (Episodic Treatment): No Emicizumab
    Reporting group description
    		 Participants, who received episodic treatment with bypassing agents prior to study entry, did not receive emicizumab prophylaxis. Participants in this arm could switch to emicizumab prophylaxis after completing at least 24 weeks on study. Participants continued to receive bypassing agent therapy to treat breakthrough bleeds, with rFVIIa and/or aPCC. Data reported for this arm represents data collected from all Arm B participants during 'no emicizumab' treatment; data from those participants who switched to emicizumab after at least 24 weeks is reported separately in Arm Bemi.

    Reporting group title
    Arm C (Prophylactic Treatment): Emicizumab
    Reporting group description
    		 Participants, who received prophylactic bypassing agents prior to study entry, received prophylactic emicizumab. Emicizumab was administered at a loading dose of 3 mg/kg/week SC for the first 4 weeks followed by a maintenance dose of 1.5 mg/kg/week SC up to the end of study. Participants continued to receive bypassing agent therapy to treat breakthrough bleeds, with rFVIIa and/or aPCC.

    Reporting group title
    Arm D (Episodic or Prophylactic Treatment): Emicizumab
    Reporting group description
    		 Participants, who received episodic bypassing agents prior to study entry, who participated in Study BH29768 but were unable to enroll in Arms A or B, were enrolled in this arm to receive prophylactic emicizumab. Emicizumab was administered at a loading dose of 3 mg/kg/week SC for the first 4 weeks followed by a maintenance dose of 1.5 mg/kg/week SC up to the end of study. Participants continued to receive bypassing agent therapy to treat breakthrough bleeds, with rFVIIa and/or aPCC.

    Reporting group title
    Arm Bemi: Emicizumab after Week 24
    Reporting group description
    		 This arm includes Arm B participants who switched to emicizumab prophylaxis after completing at least 24-week no prophylaxis. Emicizumab was administered at a loading dose of 3 mg/kg/week SC for the first 4 weeks (after at least 24 weeks) followed by a maintenance dose of 1.5 mg/kg/week SC up to the end of study. Data reported represents data collected during emicizumab treatment only.

    Serious adverse events
    		 Arm A (Episodic Treatment): Emicizumab Arm B (Episodic Treatment): No Emicizumab Arm C (Prophylactic Treatment): Emicizumab Arm D (Episodic or Prophylactic Treatment): Emicizumab Arm Bemi: Emicizumab after Week 24
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 34 (11.76%)
    4 / 18 (22.22%)
    4 / 49 (8.16%)
    0 / 7 (0.00%)
    1 / 13 (7.69%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    Injury, poisoning and procedural complications
    Subdural haemorrhage
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 18 (5.56%)
    0 / 49 (0.00%)
    0 / 7 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Thrombophlebitis superficial
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 18 (0.00%)
    0 / 49 (0.00%)
    0 / 7 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Headache
         subjects affected / exposed
    0 / 34 (0.00%)
    0 / 18 (0.00%)
    1 / 49 (2.04%)
    0 / 7 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Iron deficiency anaemia
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 18 (0.00%)
    0 / 49 (0.00%)
    0 / 7 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thrombotic microangiopathy
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 18 (0.00%)
    1 / 49 (2.04%)
    0 / 7 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastric ulcer haemorrhage
         subjects affected / exposed
    0 / 34 (0.00%)
    0 / 18 (0.00%)
    1 / 49 (2.04%)
    0 / 7 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 18 (5.56%)
    0 / 49 (0.00%)
    0 / 7 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Skin necrosis
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 18 (0.00%)
    0 / 49 (0.00%)
    0 / 7 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    0 / 34 (0.00%)
    0 / 18 (0.00%)
    1 / 49 (2.04%)
    0 / 7 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Haemarthrosis
         subjects affected / exposed
    0 / 34 (0.00%)
    2 / 18 (11.11%)
    0 / 49 (0.00%)
    0 / 7 (0.00%)
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Muscle haemorrhage
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 18 (0.00%)
    0 / 49 (0.00%)
    0 / 7 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Cavernous sinus thrombosis
         subjects affected / exposed
    0 / 34 (0.00%)
    0 / 18 (0.00%)
    1 / 49 (2.04%)
    0 / 7 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 18 (5.56%)
    0 / 49 (0.00%)
    0 / 7 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Device related sepsis
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 18 (5.56%)
    0 / 49 (0.00%)
    0 / 7 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 34 (0.00%)
    0 / 18 (0.00%)
    1 / 49 (2.04%)
    0 / 7 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 18 (5.56%)
    0 / 49 (0.00%)
    0 / 7 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Arm A (Episodic Treatment): Emicizumab Arm B (Episodic Treatment): No Emicizumab Arm C (Prophylactic Treatment): Emicizumab Arm D (Episodic or Prophylactic Treatment): Emicizumab Arm Bemi: Emicizumab after Week 24
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    22 / 34 (64.71%)
    8 / 18 (44.44%)
    15 / 49 (30.61%)
    2 / 7 (28.57%)
    4 / 13 (30.77%)
    Investigations
    Blood glucose increased
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 18 (5.56%)
    0 / 49 (0.00%)
    0 / 7 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Injury, poisoning and procedural complications
    Post procedural constipation
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 18 (5.56%)
    0 / 49 (0.00%)
    0 / 7 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Procedural hypotension
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 18 (5.56%)
    0 / 49 (0.00%)
    0 / 7 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Procedural nausea
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 18 (5.56%)
    0 / 49 (0.00%)
    0 / 7 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Procedural pain
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 18 (5.56%)
    0 / 49 (0.00%)
    0 / 7 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 18 (5.56%)
    0 / 49 (0.00%)
    0 / 7 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    3 / 34 (8.82%)
    0 / 18 (0.00%)
    5 / 49 (10.20%)
    2 / 7 (28.57%)
    1 / 13 (7.69%)
         occurrences all number
    3
    0
    6
    2
    1
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    1 / 34 (2.94%)
    1 / 18 (5.56%)
    0 / 49 (0.00%)
    0 / 7 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    Fatigue
         subjects affected / exposed
    3 / 34 (8.82%)
    0 / 18 (0.00%)
    2 / 49 (4.08%)
    0 / 7 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    3
    0
    2
    0
    1
    Injection site reaction
         subjects affected / exposed
    8 / 34 (23.53%)
    0 / 18 (0.00%)
    5 / 49 (10.20%)
    1 / 7 (14.29%)
    1 / 13 (7.69%)
         occurrences all number
    15
    0
    11
    1
    1
    Pyrexia
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 18 (5.56%)
    0 / 49 (0.00%)
    0 / 7 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Ear and labyrinth disorders
    Ear discomfort
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 18 (5.56%)
    0 / 49 (0.00%)
    0 / 7 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 18 (5.56%)
    0 / 49 (0.00%)
    0 / 7 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Enteritis
         subjects affected / exposed
    2 / 34 (5.88%)
    0 / 18 (0.00%)
    0 / 49 (0.00%)
    0 / 7 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    Large intestine polyp
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 18 (5.56%)
    0 / 49 (0.00%)
    0 / 7 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Toothache
         subjects affected / exposed
    2 / 34 (5.88%)
    0 / 18 (0.00%)
    0 / 49 (0.00%)
    0 / 7 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    2 / 34 (5.88%)
    0 / 18 (0.00%)
    0 / 49 (0.00%)
    0 / 7 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    3
    0
    0
    0
    0
    Oropharyngeal pain
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 18 (5.56%)
    0 / 49 (0.00%)
    0 / 7 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Skin and subcutaneous tissue disorders
    Hair growth abnormal
         subjects affected / exposed
    3 / 34 (8.82%)
    0 / 18 (0.00%)
    0 / 49 (0.00%)
    0 / 7 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    3
    0
    0
    0
    0
    Rash
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 18 (5.56%)
    0 / 49 (0.00%)
    0 / 7 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    2 / 34 (5.88%)
    0 / 18 (0.00%)
    3 / 49 (6.12%)
    0 / 7 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    3
    0
    6
    0
    1
    Myalgia
         subjects affected / exposed
    2 / 34 (5.88%)
    0 / 18 (0.00%)
    0 / 49 (0.00%)
    0 / 7 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    Infections and infestations
    Folliculitis
         subjects affected / exposed
    2 / 34 (5.88%)
    0 / 18 (0.00%)
    0 / 49 (0.00%)
    0 / 7 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    Nasopharyngitis
         subjects affected / exposed
    1 / 34 (2.94%)
    2 / 18 (11.11%)
    0 / 49 (0.00%)
    0 / 7 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    2
    0
    0
    0
    Upper respiratory tract infection
         subjects affected / exposed
    7 / 34 (20.59%)
    3 / 18 (16.67%)
    2 / 49 (4.08%)
    0 / 7 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    9
    3
    2
    0
    0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    1 / 34 (2.94%)
    1 / 18 (5.56%)
    0 / 49 (0.00%)
    0 / 7 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    Electrolyte imbalance
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 18 (5.56%)
    0 / 49 (0.00%)
    0 / 7 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    21 Apr 2016
    The main changes were as follows: - The planned number of participants to be enrolled in Arm C was increased from approximately 10-20 to 30-50, to enable the collection of additional safety and efficacy data from participants previously treated with prophylactic bypassing agents; - An additional emicizumab treatment arm (Arm D) was added, to enroll participants on episodic bypassing agents who had participated in NIS BH29768 but were unable to enroll in time to either Arm A or Arm B. This arm enabled the collection of additional efficacy, safety, pharmacokinetic, and pharmacodynamic data and plasma samples for the development and validation of in vitro diagnostic assay(s) suitable for participants receiving emicizumab treatment; - A secondary endpoint was added to compare all bleeds (i.e., treated with coagulation factors or not treated) as an additional assessment of efficacy given that some participants might have reported bleeds they did not treat; A planned interim analysis by the independent Data Monitoring Committee (iDMC), scheduled to occur during the execution of the primary efficacy period, was removed. This was due to the anticipated rapid completion of enrollment (i.e., approximately 7 months) and the very short time interval between the interim and primary analyses; - An option was provided for participants who were approved to up-titrate their dose to potentially combine emicizumab volumes from more than 1 vial into 1 syringe to reduce the number of subcutaneous injections they required.
    30 Nov 2016
    The main changes were as follows: - The permitted treatment for breakthrough bleeds was specified with guidance regarding the use of concomitant bypassing agents in participants being treated with emicizumab, as well as additional local and central laboratory assessments, in order to minimize the risk and monitor for thromboembolic and thrombotic microangiopathy events; - The use of short-term prophylaxis with aPCC concomitantly with emicizumab was prohibited, in order to minimize the risk of thromboembolic and thrombotic microangiopathy events; Microangiopathic hemolytic anemia/ thrombotic microangiopathy was newly classified as an adverse event of special interest (AESI), and an exclusion criterion to exclude participants at high risk to experience thrombotic microangiopathy was added; - A new efficacy objective to evaluate the clinical effect of emicizumab prophylaxis on the number of spontaneous bleeds over time (spontaneous bleed rate) was added, because this is a bleed category that is impacted by an effective treatment.

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    07 Oct 2016
    4 participants experienced serious adverse events (2 participants experienced thromboembolic events and 2 participants experienced thrombotic microangiopathy) that resulted in temporary enrollment halt until further evaluation of these safety events, implementation of adequate mitigation measures and discussion with iDMC.
    28 Nov 2016

    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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